Clinical trial NCT03519256
Conditions: Urinary Bladder Neoplasms
Keywords: Bladder Cancer BCG-unresponsive Nivolumab Intravesical BCG NMIBC Non-Muscle Invasive BMS-986205 CheckMate 9UT
Sponsor: Bristol-Myers Squibb
Start date: 2018-08-02; Completion date: 2022-08-24
Enrollment: 142 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the safety and tolerability of nivolumab or nivolumab Plus BMS-986205 with or without BCG in BCG-Unresponsive non-muscle invasive Bladder Cancer.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Nivolumab intervention 2: BCG intervention 3: BMS-986205
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 2, Randomized, Open-label Study of Nivolumab or Nivolumab/BMS-986205 Alone or 
Combined with Intravesical BCG in Participants with BCG-Unresponsive, High-Risk, 
Non-Muscle Invasive Bladder Cancer 
(CheckMate 9UT: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9UT) 
 
Protocol: CA209-9UT 
 
NCT Number: NCT03519256 
 
Document Date (Date in which document was last revised): 22-Sep-2021 


Page:
1
Protocol Number:
CA2099UT
IND Number:
136486
EUDRACT Number:
2017-003581-27
Date:
20-Dec-2017
Revised Date:
22-Sep-2021
Clinical Protocol CA2099UT
A Phase 2, Randomized, Open-label Study of Nivolumab or Nivolumab/BMS-986205 Alone or 
Combined with Intravesical BCG in Participants with BCG-Unresponsive, High-Risk, 
Non-Muscle Invasive Bladder Cancer
(CheckMate 9UT: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9UT)
Protocol Amendment Number: 04
Incorporates Administrative Letters 01 and 04
Clinical Trial Physician - Medical Monitor
Clinical Scientist
3401 Princeton Pike
Lawrenceville, NJ 08648
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 
Telephone (office): 
24-hr Emergency Telephone Number
USA:
International:
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1328, Japan
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
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Protocol Amendment No.: 04
Date: 22-Sep-2021
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confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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Protocol Amendment No.: 04
Date: 22-Sep-2021
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 
04
22-Sep-2021
•
Details of closure of the study, with provision for participants currently
on treatment to continue.
•
Removal of pharmacokinetic (except for immunogenicity), biomarker,
healthcare resource utilization, and patient-reported outcome (PRO)
assessments.
•
Removal of study-related efficacy assessment and Pathology Review
Committee. Sites should continue efficacy assessment as per the local
standard of care.
•
Updates were made to Appendices 1, 2, 4, 5, and 11
•
Administrative Letters 01 and 04 were incorporated.
Administrative 
Letter 04
16-Apr-2021
Updated study personnel information.
Administrative 
Letter 03
21-Oct-2020
Updated study personnel information.
Administrative 
Letter 02
17-Jun-2020
Updated study personnel information.
Administrative 
Letter 01
16-Dec-2019
To include GI Adverse Event Algorithm to Appendix 5, which had been 
inadvertently left out of the protocol.
Revised 
Protocol 03
01-Nov-2019
This revision incorporates the following:
•
Removed eligibility for non-CIS participants
•
Only 1 BCG-containing arm (Arm B) will be expanded after safety
lead-in instead of 2 (Arm B and Arm D)
•
Updated the randomization schema to address BCG strains and
availability
•
Updated sample size, CR estimates, and decision-making criteria
•
Updated appendices
•
Made minor typographical and grammar corrections
Revised 
Protocol 02
10-May-2019
 
 
 make random bladder biopsies at screening optional, allow 
for urine cytology to be tested on a voided specimen, and increase the 
window for repeat TURBT for participants with stage T1 disease from 4 to 8
weeks to be consistent with professional society guidelines. Yearly upper 
tract imaging is added to be consistent with NCCN guidelines, and histologic 
confirmation of tumor progression identified on imaging and/or clinical 
examination is added. Clarification is provided regarding the exclusion 
criterion for prior systemic chemotherapy and immunotherapy, which 
applies only if these therapies were administered for the treatment of 
urothelial carcinoma. A subsection was added to the protocol describing the 
adverse events of special interest of Hemophagocytic lymphohistiocytosis 
(HLH) and Drug reaction with eosinophilia and systemic symptoms 
(DRESS) syndrome. Language was added to clarify condom requirements 
for males who are sexually active with WOCBP. Secondary items 
incorporated into this revised protocol include clarifications regarding timing 
and need for some laboratory testing and some protocol-specific activities, 
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excluding participants who have received a live/attenuated vaccine within 30 
days of first treatment, prohibiting live/attenuated vaccines during treatment 
and until 100 days post last dose, and making minor clarifications and edits 
throughout the protocol to ensure consistency between sections.
Revised 
Protocol 01
23-Mar-2018
Revises language and stratification factors in alignment with final FDA 
guidance for BCG Unresponsive NMIBC
Adds language to provide plan for evaluation of suspicious urine cytology 
Allows randomization of participants with PD-L1 not evaluable tumor tissue
Clarifies exclusion criteria
Adds details regarding prohibited and restricted treatments and serotonin 
syndrome
Minor clarifications throughout document for consistency across sections
Original 
Protocol
20-Dec-2017
Not applicable
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OVERALL RATIONALE FOR THE PROTOCOL AMENDMENT 04
As of early April 2021, Study CA2099UT enrollment was significantly behind the projected target 
enrollment, at 28.1% (number of participants enrolled 135; target enrollment 480). Since the study 
would be unable to meet the scientific objectives within a projected timeline, a decision was made 
in May to close the study. Importantly, there is no change to the understanding of the safety profile 
of nivolumab or nivolumab/BMS-986205, with or without intravesical Bacillus Calmette-Guerin 
(BCG) in participants with BCG-unresponsive, high-risk, NMIBC.
Protocol Amendment 04 describes the modification to study procedures. All participants must be 
re-consented upon approval and implementation of Protocol Amendment 04. These changes affect 
all participants and should be implemented when Protocol Amendment 04 is implemented at the 
site.
Key changes in Protocol Amendment 04 include:
•
Details of closure of the study, with provision for participants currently on treatment to
continue
•
Removal of pharmacokinetic (except for immunogenicity), biomarker, healthcare resource
utilization, and patient-reported outcome (PRO) assessments
•
Removal of study-related efficacy assessment and Pathology Review Committee (PRC). Sites
should continue efficacy assessment as per local standard of care
Other clarifications and editorial updates were made throughout the protocol to improve clarity 
and readability and to keep consistency throughout the document.
Changes instituted in Protocol Amendment 04 should override any existing protocol requirements 
in the event of any apparent discrepancies.
This amendment incorporates the changes from the approved Administrative Letters 01 and 04, 
which are detailed in the Document History but not listed in the Summary of Key Changes below.
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Rationale
Added that no formal hypotheses or 
efficacy objectives would be done for this 
study. Only safety and immunogenicity 
assessments will be conducted.
Only safety and 
immunogenicity will be 
assessed.
Synopsis, Objectives and 
Endpoints
Only safety objectives and endpoints 
were retained in the table. 
Only safety and 
immunogenicity will be 
assessed.
Synopsis, Overall Design; Section 
5.1: Overall Design
Removed language pertaining to the first 
34 CIS participants, and the criteria to 
move to full enrollment.
The decision points are no 
longer planned due to the 
study closure.
Synopsis, Number of Participants; 
Section 5.2: Number of 
Participants
Text was deleted and number of 
participants enrolled was added.
As of 02-Jun-2021, 
enrollment for new 
participants was closed.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Study Schematic; 
Figure 5.1-1: Overall Design
Schema was updated to remove the 
decision points and follow-up.
The decision points and 
efficacy follow-up are no 
longer planned due to the 
study closure.
Synopsis, Treatment Arms and 
Duration
Removed language that the Data 
Monitoring Committee (DMC) will 
provide independent oversight over 
risk-benefit of study treatment.
DMC will review only safety 
and study conduct.
Synopsis, Duration; Section 5.3: 
End of Study Definition
Definition of study completion and full 
enrollment was removed.
The primary analysis and full 
enrollment are no longer 
planned.
Synopsis, Reference List
List was updated.
The efficacy follow-up is no 
longer planned due to the 
study closure.
Table 2-2: On-treatment 
Procedural Outline for Arms A 
and C (CA2099UT) and Table 2-
3: On-treatment Procedural 
Outline for Arms B and D 
(CA2099UT)
Added adverse event reporting 
requirements specified in Section 9.2.
Added to highlight 
requirements specified in 
Section 9.2.
Clarified that the pregnancy test requires 
serum or urine within 24 hours prior to 
first dose and then every 4 weeks 
(± 1 week) regardless of dosing schedule.
Updated to reflect the latest 
program level requirement.
Removed row for imaging assessments.
Efficacy assessments will be 
performed as per the local 
standard of care.
Deleted rows for individual efficacy tests 
and noted that efficacy assessments will 
be conducted per the local standard of 
care.
Efficacy assessments will be 
performed as per the local 
standard of care.
Deleted health outcomes and biomarker 
assessments.
Health outcomes and 
biomarker assessments are no 
longer collected.
Deleted PK (except immunogenicity) 
assessments.
PK (except immunogenicity) 
samples are no longer 
collected.
Footnote on handling of lab samples was 
deleted.
Samples are no longer 
submitted to PRC.
Table 2-4: Follow-up Procedural 
Outline (CA2099UT)
The column for efficacy follow-up was 
removed and all “Notes” associated with 
efficacy were removed. As a result, the 
associated footnote was also removed.
Efficacy assessment will be 
performed as per the local 
standard of care.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Added adverse event reporting 
requirements specified in Section 9.2.
Added to highlight 
requirements specified in 
Section 9.2.
Imaging and efficacy assessment rows 
were removed.
Efficacy assessment will be 
performed as per the local 
standard of care.
Deleted health outcome and PK (except 
immunogenicity) assessments.
Health outcome and PK 
(except immunogenicity) 
samples are no longer 
collected.
Section 3.1: Study Rationale
Deleted the paragraph regarding aim of 
the study.
No formal hypotheses or 
efficacy objectives are 
planned due to the study 
closure.
Section 3.1.1: Research 
Hypothesis
This section is no longer applicable as per 
this protocol amendment.
No formal research 
hypothesis due to the study 
closure.
Section 3.1.2: Changes Per 
Protocol Amendment 04
New section added to provide the changes 
that were made as per this protocol 
amendment.
This section is added to 
provide key changes and 
rationale.
Section 4: Objectives and 
Endpoints, Table 4-1 (Objectives 
and Endpoints)
The objectives and endpoints for efficacy, 
quality of life/patient-reported outcomes, 
pharmacokinetics, and healthcare 
resource utilization were removed.
These assessments are no 
longer being done as per this 
protocol amendment.
Section 5.1: Overall Design
Added language that efficacy follow-up 
along with other study procedures and 
risk-benefit assessment by DMC and PRC 
will not be done.
Efficacy follow-up and other 
procedures are no longer 
planned. 
Section 5.1.2: Randomization 
Phase
Removed Randomization Phase Part 3 
and Total Randomization.
Risk-benefit assessment by 
DMC and central efficacy 
review by PRC are no longer 
planned.
Section 5.1.3: Data Monitoring 
Committee and Other External 
Committees
Updated the text to remove risk-benefit 
assessment by DMC and independent 
review by PRC.
No risk-benefit assessment by 
DMC and independent review 
by PRC are planned.
Section 5.4.6: Rationale for 
Complete Response Rate in 
Participants with Carcinoma in 
Situ as a Primary Endpoint
Section was deleted as not applicable as 
per this protocol amendment.
Efficacy assessment will be 
conducted per the local 
standard of care.
Section 5.4.7: Rationale for 
Evaluation of Predictive 
Biomarkers
Section was deleted as not applicable as 
per this protocol amendment.
Biomarker samples will not 
be collected.
Section 6.1: Inclusion Criteria
Added text that enrollment to the study 
was closed and male participants should 
As of 02-Jun-2021, 
enrollment for new 
participants was closed. 
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
follow the updated contraceptive 
guidance.
Criteria 4)e) and 4)f) were updated.
Contraceptive language is 
updated to reflect the latest 
program level requirement.
Section 7.1: Treatments 
Administered
Removed requirements of when PK 
samples are obtained.
PK (except for 
immunogenicity) will not be 
collected.
Section 7.2: Method of Treatment 
Assignment
Clarified that there will be no centralized 
randomization.
Removed for clarification and 
consistency.
Section 7.3: Blinding
Clarified that this is a randomized open-
label study, so blinding procedures are 
not applicable and access to treatment 
assignment information is unrestricted.
Added to clarify expectation 
of the blinding procedures.
Section 7.4.4.1: Nivolumab
Added that in case of confirmed or 
suspected severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) 
infection, nivolumab administration 
should be delayed.
Included language to clarify 
expectations for delaying 
treatment in participants with 
suspected or confirmed 
SARS-CoV-2 infection.
Section 7.4.4.2: Nivolumab Plus 
BMS-986205
Added that in case of confirmed or 
suspected SARS-CoV-2 infection, 
nivolumab plus BMS-986205 
administration should be delayed.
Included language to clarify 
expectations for delaying 
treatment in participants with 
suspected or confirmed 
SARS-CoV-2 infection.
Section 7.4.5.1: Nivolumab; 
Section 7.4.5.2: Nivolumab Plus 
BMS-986205
Added the criteria to resume treatment in 
case of confirmed or suspected SARS-
CoV-2 infection.
Included language to clarify 
expectations for resuming 
treatment in participants with 
suspected or confirmed 
SARS-CoV-2 infection.
Section 7.7: Concomitant 
Therapy
Added that Coronavirus disease 2019 
(COVID-19) vaccines are allowed 
concomitant therapy.
Added clarification on 
COVID-19 vaccines, and risk 
benefit statement of non-live 
vaccines.
Section 7.7.1.1: Prohibited 
Treatments
Updates were made to the bullet points 
regarding herbal supplements and 
prophylactic antimicrobial therapy.
Updated to reflect the latest 
program level standard for 
complementary medication 
and added clarification on 
prophylactic antimicrobial 
therapy.
Section 7.7.1.2: Restricted 
Treatments
Removed the bullet point about 
participants avoiding proton pump 
inhibitors.
Results from Study 
CA017089 showed that 
coadministration with a 
proton pump inhibitor 
(omeprazole) did not 
meaningfully change the total 
exposure for BMS-986205 or 
total active moiety.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 8.1: Discontinuation from 
Study Treatment
In the bullet point for disease progression 
or recurrence, removed language 
pertaining to PRC confirmation of 
progression or recurrence.
Efficacy assessment is 
performed as per the local 
standard of care.
Section 8.1.4: Post Study 
Treatment Study Follow-up
Clarified that as per this protocol 
amendment, efficacy follow-up is not 
required, and participants will be 
followed for assessment of safety through 
100 days post last dose of study 
treatment.
Efficacy follow-up is no 
longer required.
Section 9: Study Assessments and 
Procedures (Follow-up Phase)
Clarified when the follow-up phase ends.
Added clarification as to 
when follow-up phase ends.
Section 9.1: Efficacy 
Assessments
Noted that efficacy assessments will be 
conducted as per local standard of care. 
Definitions of Complete Response, 
Recurrence, and Progression were 
updated accordingly.
Efficacy assessment will be 
conducted as per the local 
standard of care.
Section 9.1.1: Imaging 
Assessment for the Study; Section 
9.1.2: Cystoscopy; Section 9.1.3: 
Urine Cytology; Section 9.1.4: 
Bladder Biopsy
Noted that efficacy assessments will be 
conducted as per local standard of care.
Efficacy assessment will be 
conducted as per the local 
standard of care.
Section 9.2.1: Time Period and 
Frequency for Collecting AE and 
SAE Information
Added time period of collection of AEs 
(SAEs and non-serious AEs) associated 
with confirmed or suspected SARS-CoV-
2 infection.
To allow for the evaluation of 
the impact of SARS-CoV-2 
infection on participant 
safety.
Section 9.2.3: Follow-up of AEs 
and SAEs
Updated description of timing of AE/SAE 
collection to include the collection of 
SARS-CoV-2 infection-related 
AEs/SAEs.
To allow for the evaluation of 
the impact of SARS-CoV-2 
infection on participant 
safety.
Section 9.4.1: Clinical Safety 
Laboratory Assessments
In Table 9.4.1-1, added sensitivity for 
Pregnancy Tests.
Added to reflect the latest 
program level requirement.
Section 9.5.2: Pharmacokinetics 
and Immunogenicity Assessments
Removed “Pharmacokinetics” from 
Section heading and added that only 
immunogenicity assessments will be 
collected. As a result, the section and 
Table 9.5.2-1 was updated to remove PK 
assessments/timepoints.
PK (except for 
immunogenicity) will not be 
collected.
Section 9.6: Pharmacodynamics
Added that “Per Protocol Amendment 04,
pharmacodynamics will not be collected.”
Pharmacodynamics will not 
be collected.
Section 9.8: Biomarkers
Added that “Per Protocol Amendment 04,
biomarkers will not be collected.”
As a result, Table 9.8-1 was deleted.
Biomarkers will not be 
collected.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 9.9: Health Economics 
OR Medical Resource Utilization 
and Health Economics
Added that “Per Protocol Amendment 04, 
health economics/medical resource 
utilization and health economics 
parameters will not be evaluated.”
Health economics/medical 
resource utilization and health 
economics parameters will 
not be evaluated.
Section 9.10: Immunogenicity 
Assessments
Removed mention of efficacy and PK 
assessments.
Only the effect of 
immunogenicity on safety 
may be explored
Section 9.11.1: Patient-reported 
Outcomes
Added that “Per Protocol Amendment 04, 
patient-reported outcomes will not be 
evaluated.”
Patient-reported outcomes 
will not be evaluated.
Section 10: Statistical 
Considerations; Section 10.2: 
Populations for Analyses
Added that “Per Protocol Amendment 04, 
only safety and immunogenicity analyses 
will be conducted.”
Only safety and 
immunogenicity analyses will 
be conducted.
Section 10.1: Sample Size 
Determination
Added that “Per Protocol Amendment 04, 
sample size will be limited to the 
participants enrolled as of 02-Jun-2021.
As of 02-Jun-2021, 
enrollment for new 
participants was closed.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
The following sample size considerations 
refer to the original study design.”
Section 10.2: Populations for 
Analyses
Only Enrolled, Treated, and 
Immunogenicity populations were 
defined.
Only safety and 
immunogenicity analyses will 
be conducted.
Section 10.3: Statistical Analyses
Removed language regarding planned 
statistical analyses of primary and 
secondary endpoints.
Only safety and 
immunogenicity analyses will 
be conducted.
Section 10.3.1: Efficacy Analyses
Added that formal efficacy analyses will 
not be conducted, and descriptive 
summary statistics may be provided for 
internal dissemination only.
The tabular summary of the planned 
statistical analyses of primary and 
secondary endpoints was deleted.
Only safety and 
immunogenicity analyses will 
be conducted.
Section 10.3.2: Safety Analyses
Removed “secondary” and “exploratory”.
To align with other sections.
Section 10.3.3: Other Analyses 
Removed entire language and added 
language on immunogenicity analysis.
Only safety and 
immunogenicity analyses will 
be conducted.
Section 10.3.4: Initial Evaluation 
of Efficacy and Safety
This section was no longer applicable as 
per Protocol Amendment 04.
Only safety and 
immunogenicity analyses will 
be conducted. The decision 
points are no longer planned.
Section 11: References
List was updated.
Updated based on changes per 
Protocol Amendment 04.
Appendix 1: Abbreviations and 
Trademarks
List was updated.
Updated based on changes per 
Protocol Amendment 04.
Appendix 2: Study Governance 
Considerations
Monitoring section was updated.
Update allows for alternative 
monitoring in circumstances 
where on-site monitoring is 
not advised.
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception (Contraception 
Guidance for Male Participants 
with Partner(s) of Childbearing 
Potential)
Appendix was updated.
Specified that it is applied to Arms C and 
D of the study.
The definition of end of relevant systemic 
exposure was updated to 1 month 
(approximately 4 weeks).
Updated to reflect the latest 
program level requirement.
Appendix 5: Management 
Algorithms for Immuno-oncology 
Agents
Algorithms were updated.
Updated to reflect the latest 
program level requirement.
Appendix 11: Country Specific 
Requirements
Italy was removed from the list of 
countries where exclusion of HIV 
positive participants is locally mandated.
Updated as per the latest 
country level requirement.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
The numbering for exclusion criteria 
pertaining HIV test was corrected.
The numbering was corrected 
to align with exclusion 
criteria.
Protocol Amendment No.: 04
Date: 22-Sep-2021
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE PROTOCOL AMENDMENT 04 .................... 
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04 .................. 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.1.2 Changes Per Protocol Amendment 04 ..................................................... 
3.2 Background ....................................................................................................... 
3.2.1 Indication Background ............................................................................. 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
3.2.3 BMS-986205 Mechanism of Action ......................................................... 
3.2.4 BCG Mechanism of Action....................................................................... 
3.3 Benefit/Risk Assessment .................................................................................. 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Safety Lead-in Phase................................................................................ 
5.1.2 Randomization Phase............................................................................... 
5.1.3 Data Monitoring Committee and Other External Committees ................ 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Combination of Nivolumab with BMS-986205 in Non-
Muscle-Invasive Bladder Cancer ................................................................ 
5.4.2 Rationale for Combination of Nivolumab with BCG in Non-Muscle-
Invasive Bladder Cancer ............................................................................. 
5.4.3 Rationale for Combination of Nivolumab/BMS-986205 with BCG in Non-
Muscle-Invasive Bladder Cancer ................................................................ 
5.4.4 Rationale for Duration of Treatment ....................................................... 
5.4.5 Rationale for Open-Label Study Design .................................................. 
5.4.6 Rationale for Complete Response Rate in Participants with Carcinoma in 
Situ as a Primary Endpoint ......................................................................... 
5.4.7 Rationale for Evaluation of Predictive Biomarkers ................................. 
5.4.8 Rationale for PD-L1 Expression as a Candidate Biomarker of Immuno-
Oncology Therapy Efficacy......................................................................... 
5.4.9 Rationale for Modified Randomization .................................................... 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Justification for Nivolumab Dose ............................................................ 
5.5.2 Justification for BMS-986205 Dose ......................................................... 
5.5.3 Justification for Administration of BMS-986205 with Food.................... 
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Clinical Protocol
BMS-936558
CA2099UT
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2021
13
5.0
Approved
930120285
5.0
v
Approved
1.0
v


5.5.4 Justification for BCG Dose ...................................................................... 
5.5.5 Justification for Nivolumab 30-Minute Infusion ...................................... 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 Nivolumab Dosing ................................................................................... 
7.1.2 BMS-986205 Dosing ................................................................................ 
7.1.3 BCG Dosing ............................................................................................. 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modification ......................................................................................... 
7.4.1 Nivolumab Dose Modifications ................................................................ 
7.4.2 BMS-986205 Dose Modifications ............................................................ 
7.4.3 BCG Dose Modifications ......................................................................... 
7.4.4 Dose Delay Criteria ................................................................................. 
7.4.4.1 Nivolumab ....................................................................................... 
7.4.4.2 Nivolumab Plus BMS-986205 ......................................................... 
7.4.4.3 BCG................................................................................................. 
7.4.5 Criteria to Resume Dosing....................................................................... 
7.4.5.1 Nivolumab ....................................................................................... 
7.4.5.2 Nivolumab Plus BMS-986205 ......................................................... 
7.4.5.3 BCG................................................................................................. 
7.4.6 Management Algorithms .......................................................................... 
7.4.7 Detection of Methemoglobinemia ............................................................ 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.1.1 Prohibited Treatments .................................................................... 
7.7.1.2 Restricted Treatments ..................................................................... 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.2.1 Imaging Restrictions and Precautions ............................................ 
7.7.3 Permitted Therapy ................................................................................... 
7.7.4 Treatment of Methemoglobinemia ........................................................... 
7.7.5 Treatment of Infusion-related Reactions ................................................. 
7.8 Treatment After the End of the Study ............................................................... 
8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Discontinuation of Nivolumab ................................................................. 
8.1.2 Discontinuation of BMS-986205.............................................................. 
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Clinical Protocol
BMS-936558
CA2099UT
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2021
14
5.0
Approved
930120285
5.0
v
Approved
1.0
v


8.1.3 Discontinuation of BCG ........................................................................... 
8.1.4 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-up .............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.2 Cystoscopy ............................................................................................... 
9.1.3 Urine Cytology ......................................................................................... 
9.1.4 Bladder Biopsy ......................................................................................... 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.2.9 Adverse Events of Special Interest ........................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Clinical Safety Laboratory Assessments .................................................. 
9.4.2 Imaging Safety Assessment ...................................................................... 
9.5 Pharmacokinetics .............................................................................................. 
9.5.1 Background .............................................................................................. 
9.5.2 Immunogenicity Assessments ................................................................... 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
9.8 Biomarkers ........................................................................................................ 
 .......................................................................... 
 
 
 
 
 
 
 
 
 
 
9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
9.10 Immunogenicity Assessments ......................................................................... 
9.11 Other Assessments .......................................................................................... 
9.11.1 Patient-reported Outcomes .................................................................... 
10 STATISTICAL CONSIDERATIONS .................................................................... 
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Clinical Protocol
BMS-936558
CA2099UT
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2021
15
5.0
Approved
930120285
5.0
v
Approved
1.0
v


10.1 Sample Size Determination ............................................................................ 
10.2 Populations for Analyses ................................................................................ 
10.3 Statistical Analyses ......................................................................................... 
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.3 Other Analyses ....................................................................................... 
10.3.4 Initial Evaluation of Efficacy and Safety ............................................... 
11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0 ......................................................................................................... 
APPENDIX 6 ECOG PERFORMANCE STATUS SCALE ....................................... 
APPENDIX 7 CYP3A4, CYP1A2 AND CYP2B6 GUIDANCE ................................ 
APPENDIX 8 MEDICATIONS ASSOCIATED WITH QT PROLONGATION ....... 
APPENDIX 9 P-GP AND BCRP GUIDANCE ........................................................... 
APPENDIX 10 AGENTS KNOWN TO CAUSE METHEMOGLOBINEMIA .......... 
APPENDIX 11 COUNTRY SPECIFIC REQUIREMENTS ....................................... 
APPENDIX 12 DIAGNOSTIC CRITERIA FOR HLH AND DRESS SYNDROME  
APPENDIX 13 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY ...... 
 
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Clinical Protocol
BMS-936558
CA2099UT
nivolumab
Protocol Amendment No.: 04
Date: 22-Sep-2021
16
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title:
A Phase 2, Randomized, Open-label Study of Nivolumab or 
Nivolumab/BMS-986205 Alone or Combined with Intravesical BCG in Participants with 
BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer (CheckMate 9UT: 
CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9UT)
Study Phase: Phase 2b
Rationale:
Targeting the immunosuppressive properties of the cancer cells themselves, such as by inhibiting 
the immunosuppressive enzyme indoleamine-1,2-dioxygenase 1 (IDO1) and the immune 
checkpoint receptor programmed cell death protein-1 (PD-1), is a promising approach in cancer 
immunotherapy. Preliminary data in participants with advanced urothelial carcinoma (UC) 
evaluating an IDO1 inhibitor in combination with anti-PD-1 therapy have shown that this 
combination may improve the efficacy of anti-PD-1 therapy alone, with potentially similar
toxicity. BMS-986205 is an optimized IDO1 inhibitor characterized by once-daily dosing and 
deeper inhibition of IDO1 activity, as measured by peripheral blood kynurenine suppression, than 
other inhibitors. BMS-986205 has also demonstrated preliminary evidence of clinical activity in 
combination with immune checkpoint inhibitor nivolumab in multiple tumor types, including UC.
As of 02-Jun-2021, enrollment for new participants was closed. As a result of Protocol 
Amendment 04, there are no formal hypotheses or efficacy objectives for this study. Only safety 
and immunogenicity assessments will be conducted.
Study Population:
Adult participants (18 years of age and older, or age of majority) with pathologically proven 
carcinoma in situ (CIS)-containing bacillus Calmette-Guerin (BCG) unresponsive high-risk 
non-muscle-invasive bladder cancer (NMIBC).1,2,3 Patients must have CIS to participate. 
Participants should be considered medically unfit for radical cystectomy or should have refused 
radical cystectomy after consultation with their oncologist/urologist. Participants must not have 
evidence of UC in the upper urinary tracts (kidneys, renal pelves, ureters) or in the prostatic 
urethra. Previous or concurrent muscle invasive or disseminated bladder cancer is not permitted. 
Prior systemic treatment, radiation therapy, or surgery for bladder cancer other than transurethral 
bladder tumor resection (TURBT) or bladder biopsies is also not permitted.
Key Inclusion Criteria:
•
Pathologically demonstrated BCG-unresponsive*, CIS-containing high-risk NMIBC defined 
as CIS with or without papillary component diagnosis required within 10 weeks (70 days) 
prior to randomization and must be confirmed by the Pathology Review Committee (PRC).
* BCG-unresponsive disease is defined as being at least one of the following2,3: 
−Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary 
disease/tumor invades the subepithelial connective tissue) disease within 12 months 
of completion of adequate BCG therapy**
Protocol Amendment No.: 04
Date: 22-Sep-2021
17
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
−• Recurrent high-grade Ta/any T1 disease within 6 months of completion of adequate 
BCG therapy** [per revised protocol 03, participants must also have CIS to be 
eligible]
−• T1 high-grade disease at the first evaluation following an induction BCG course (at 
least 5 of 6 induction doses) [per revised protocol 03, participants must also have CIS 
to be eligible]
** Adequate BCG treatment is defined as at least 2 courses of BCG. This can include 2 
induction courses (at least five of six doses of an initial induction course plus at least two 
of six doses of a second induction course) or 1 induction course (at least 5 of 6 induction 
doses) and at least 2 of 3 doses of a maintenance cycle (“5+2”).
•
Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma
•
Must have undergone each of the following procedures within 10 weeks (70 days) of 
randomization (except 90 days for CT or MRI). If these procedures are performed as part of 
the participant’s routine care, they do not need to be repeated provided they were performed 
within the required time period:
−Complete excision of all papillary disease (T1/TaHG). For participants with T1 lesions, 
a re-staging TURBT must be performed within 8 weeks after the initial TURBT to 
ensure that the pathology specimen contains muscularis propria that is free of invasive 
tumor per PRC.
−Resection or fulguration of all detectable CIS, if feasible. Fluorescence-guided 
cystoscopy is encouraged but not mandated. It is understood that due to the nature of 
this disease, complete resection of CIS cannot be assured. 
−The presence of any suspicious lesions must be recorded and these lesions will be 
biopsied. Random sampling of bladder mucosa for detection of occult CIS during the 
screening period is optional, but should be performed at the time of screening 
transurethral resection/biopsy of bladder tumor and/or CIS within 10 weeks (70 days) 
of randomization, if possible. The bladder should be mapped by visual inspection and 
random biopsies taken from the trigone, right and left lateral walls, posterior wall, 
dome and prostatic urethra (in male participants).
−Urine cytology must be obtained from a voided specimen (except from the first 
morning urination) or by bladder wash. Recognizing the possibility of occult CIS, 
cytology at screening does not need to be negative for study participation.
−Computed tomography (CT) scan of the chest and CT or magnetic resonance imaging 
(MRI) of the abdomen and pelvis and all other areas of suspected disease to exclude 
locally advanced or metastatic bladder cancer or synchronous UC in the upper urinary 
tracts within 90 days prior to randomization
−Participants should either be deemed medically unfit for radical cystectomy, or should 
have refused radical cystectomy after consultation with their urologist or oncologist.
Key Exclusion Criteria:
•
Women who are pregnant or breastfeeding
Protocol Amendment No.: 04
Date: 22-Sep-2021
18
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
•
Participants with a personal or family (ie, in a first-degree relative) history of cytochrome b5 
reductase deficiency (previously called methemoglobin reductase deficiency) or other diseases 
that put them at risk of methemoglobinemia. All participants will be screened for 
methemoglobin levels prior to randomization.
•
Participants with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency or other 
congenital or autoimmune hemolytic disorders. All participants will be screened for G6PD 
deficiency prior to randomization.
•
Evidence of locally advanced or metastatic bladder cancer as seen in cross-sectional imaging
of the chest, abdomen, and pelvis 
•
UC in the upper genitourinary tract (kidneys, renal collecting systems, ureters) within 
24 months of enrollment
•
UC and/or CIS in the prostatic urethra within 12 months of enrollment
•
Locally advanced disease demonstrated by pelvic examination preferably performed under 
anesthesia
•
Previous or concurrent muscle invasive or disseminated/metastatic bladder cancer
•
Prior treatment with an anti-PD-1, anti-programmed death ligand 1 (PD-L1), anti-PD-L2, or 
anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody, or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
•
Prior treatment with BMS-986205 or any other IDO1 inhibitors
•
Prior systemic chemotherapy or immunotherapy for UC. Intravesical chemotherapy and/or 
interferon administered prior to the date of tumor sample submission is permitted.
•
Prior radiation therapy for bladder cancer
•
Prior surgery for bladder cancer other than TURBT and/or bladder biopsies
•
Participants who have received a live /attenuated vaccine within 30 days of first treatment
Objectives and Endpoints:
Only safety and immunogenicity assessments will be conducted. No analyses of efficacy, quality 
of life/patient-reported outcomes, pharmacokinetics, or healthcare resource utilization are planned. 
Previously collected biomarker samples may be analyzed, but no further collections are planned 
with this amended protocol.
Objectives
Endpoints
•
To describe the safety and tolerability of 
nivolumab and nivolumab + BMS-
986205, alone or in combination with 
intravesical BCG.
•
Overall safety and tolerability will be 
measured by the incidence of AEs, SAEs, 
AEs leading to discontinuation, immune-
mediated AEs, deaths, and laboratory 
abnormalities and changes from baseline.
Protocol Amendment No.: 04
Date: 22-Sep-2021
19
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Overall Design:
This is a Phase 2b, randomized, open-label study of nivolumab or nivolumab plus BMS-986205, 
with or without intravesical BCG, in adult (18 years of age and older, or age of majority) 
participants with BCG-unresponsive, high-risk NMIBC. 
•
After a safety-lead in the BCG-containing arms, participants will be randomized to one of 
4 parallel treatment arms as follows: Arm A (nivolumab monotherapy), Arm B (nivolumab 
and BCG), Arm C (nivolumab and BMS-986205), and Arm D (nivolumab and BMS-986205 
and BCG).
−
Per revised protocol 03, due to a global shortage of intravesical BCG, after the 
approximately 8 participants in Arm D complete the safety lead-in phase, further 
enrollment in Arm D will be paused. Enrollment in Arms A, B, and C will continue per 
protocol. 
•
Sufficient, recent tumor tissue obtained within 10 weeks (70 days) prior to randomization from 
the tumor obtained at TURBT must be submitted (1) for review by the PRC to confirm the 
diagnosis of high-risk NMIBC and exclude tumor invasion of the muscularis propria and (2) 
to the analytical testing laboratory for PD-L1 expression. If sufficient tissue is not available, 
either additional tissue will be requested from the site or a repeat TURBT will be required.
•
A 6-week safety lead-in will be conducted in participants randomized to receive BCG and 
nivolumab with or without BMS-986205 (Arms B and D) to determine safe dose levels to be 
administered during the treatment phase. Enrollment in the safety lead-in will be staggered so 
that the safety lead-in phase for Arm B is adequately assessed prior to the enrollment of Arm 
D.
•
Following the safety lead-in, participants with CIS, with or without papillary disease, will be 
randomized into study Arms A, B, and C. 
Number of Participants: 
As of 02-Jun-2021, enrollment for new participants was closed. Number of participants enrolled 
was 135, as of early April 2021.
Treatment Arms and Duration:
Study treatment: 
Study Drugs for CA2099UT
Medication 
Potency 
IP/Non-IP 
BMS-936558-01
(Nivolumab) Solution for Injection
10 mg/mL
IP
BMS-986205-04
100 mg
IP
BMS-986205-04
50 mg
IP
Protocol Amendment No.: 04
Date: 22-Sep-2021
20
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Study Drugs for CA2099UT
Medication
Potency
IP/Non-IP
BCG
Dose according to prescribing 
information for BCG strain and 
preparation administered
IP
Abbreviations: IP = investigational product
The study schematic is provided in Figure 1.
Protocol Amendment No.: 04
Date: 22-Sep-2021
21
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Figure 1:
Study Schematic
Protocol Amendment No.: 04
Date: 22-Sep-2021
22
5.0
Approved
930120285
5.0
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Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
During the treatment phase, participants will receive:
•
Arm A: Nivolumab 480 mg IV Q4W for up to 52 weeks (12 months)
•
Arm B: Nivolumab 480 mg IV Q4W for up to 52 weeks (12 months) and intravesical BCG
(induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks
at 3 months, 6 months and 12 months following the first intravesical dose. The dose used for
each weekly intravesical treatment will be based on current prescribing information for the
particular BCG strain and preparation administered. This may vary as BCG strain and/or
preparation administered may vary based on geographic region in which the participant is
receiving treatment. Every effort should be made to continue a participant on the same strain
of BCG for the duration of study participation.
•
Arm C: Nivolumab 480 mg IV Q4W and BMS-986205 100 mg PO QD for up to 52 weeks
(12 months)
•
Arm D: Nivolumab 480 mg IV Q4W and BMS-986205 100 mg PO QD for up to 52 weeks
(12 months), and intravesical BCG (induction) weekly for 6 weeks followed by maintenance
intravesical BCG weekly for 3 weeks at 3 months, 6 months, and 12 months following the first
intravesical dose. The dose used for each weekly intravesical treatment will be based on current
prescribing information for the particular BCG strain and preparation administered. This may
vary as BCG strain and/or preparation administered may vary based on geographic region in
which the participant is receiving treatment. Arm D enrollment will be paused after the safety
lead-in.
For each arm, 1 treatment cycle equals 4 weeks.
Dose reductions are not permitted for nivolumab or for BCG after the safe-dose level has been 
determined in the safety lead-in. One dose reduction is permitted for BMS-986205, from 100 mg 
QD to 50 mg QD. No re-escalation is permitted after dose reduction.
Doses of nivolumab, BMS-986205 and BCG should be delayed due to treatment-related AEs 
described in Section 7.4 of the protocol. Treatment-related AEs resulting in permanent 
discontinuation of study treatment are described in Section 8 of the protocol. Treatment may be
discontinued due to unacceptable toxicity, withdrawal of consent, disease recurrence or 
progression, or completion of treatment cycles and follow-up, whichever occurs first. An external
Data Monitoring Committee (DMC) will provide independent oversight of safety and study 
conduct.
Duration:
The start of the trial is defined as the first visit for the first participant screened. End of the trial 
and end of the study are defined as the final date when all participants have completed study 
procedures described in the protocol, including follow-up visits.
Protocol Amendment No.: 04
Date: 22-Sep-2021
23
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
1 Lerner SP, Dinney C, Kamat A, et al. Clarification of Bladder Cancer Disease States Following Treatment of
Patients with Intravesical BCG. Bladder Cancer 2015;1:29-30.
2 US Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research, Center for Biologics Evaluation and Research. BCG-Unresponsive 
Non-Muscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance 
for Industry. February 2018.
3 Steinberg RL, Thomas LJ, Mott SL, O’Donnell MA. Bacillus Calmette-Guerin (BCG) Treatment Failures with
Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease. Bladder Cancer
2016: 2: 215-224
Protocol Amendment No.: 04
Date: 22-Sep-2021
24
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Procedures to be performed during screening for all participants are listed in Table 2-1, during 
treatment for Arms A and C in Table 2-2, during treatment for Arms B and D in Table 2-3, and 
during follow-up for all participants in Table 2-4. Abbreviations are defined in Appendix 1.
Protocol Amendment No.: 04
Date: 22-Sep-2021
25
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099UT)
Procedurea
Screening
Visit
Notes
(All windows are based on calendar days)
Eligibility Assessments
Informed Consent
X
Register in Interactive Response Technology (IRT) system to obtain participant number. 
Informed consent must be obtained prior to any study procedure, except for those done as 
part of routine clinical practice including, but not limited to, cystoscopy, urine cytology, 
TURBT, or cross-sectional imaging.
Study allows for re-enrollment of a participant who has discontinued participation as a 
pretreatment failure. If re-enrolled the participant must be re-consented and assigned a new 
participant number from IRT.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization.
Medical History
X
All medical history relevant to the disease under study, which includes concomitant 
medications, prior cancer therapy, American Joint Committee on Cancer (AJCC) stage, 
glucose-6-phosphate dehydrogenase (G6PD) deficiency history, and personal and/or family 
(first-degree relative) history of cytochrome b5 reductase deficiency. Also include smoking 
history (including electronic cigarettes) and alcohol history.
Tumor Sample Submission (Bladder Biopsy)b
X
All participants must have tumor tissue available, obtained within 10 weeks (70 days) prior to 
randomization.
•
•
For diagnosis (Section 9.1.4): Tumor tissue samples (1-10 hematoxylin and eosin (H&E)
stained slides, with at least 1 slide /disease site) representing the diagnosis of high-risk
NMIBC (CIS, CIS with TaHG, or CIS with T1) and excluding tumor invasion into the 
muscularis propria will be collected and sent to independent Pathology Review 
Committee (PRC). At least one slide must contain muscularis propria, preferably taken 
from the most significant area of disease. If the diagnosis cannot be confirmed, then 
additional slides will be requested from the site.
For participants with T1 lesions, a re-staging TURBT must be performed within 
8 weeks after the initial TURBT to ensure that the pathology specimen contains 
muscularis propria that is free of invasive tumor and the H&E stained samples must 
be sent to PRC.
Protocol Amendment No.: 04
Date: 22-Sep-2021
26
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099UT)
Procedurea
Screening
Visit
Notes
(All windows are based on calendar days)
If tumor tissue was obtained > 70 days prior to randomization, participants must have a repeat 
cystoscopy ≤70 days prior to randomization. If the repeat cystoscopy shows papillary tumor, 
repeat TURBT is required (see Section 9.1.4).
Cystoscopy
X
See Section 9.1.2.
Urine Cytologyb
X
Sample will be reviewed by PRC prior to randomization. See Section 9.1.3.
Body Imaging
X
See Section 9.1.1. Must be performed within 90 days prior to randomization.
Safety Assessments
Full Physical Examination, Measurements, Vital 
Signs and Performance Status
X
Height, weight, ECOG Performance Status (Appendix 6), blood pressure, heart rate, and 
temperature must be collected within 14 days prior to randomization. 
Oxygen Saturation
X
Oxygen saturation by pulse oximetry or co-oximetry at rest within 14 days prior to 
randomization.
ECG
X
At rest.
Assessment of Signs and Symptoms
X
Must be collected within 14 days prior to randomization.
Concomitant Medication Use
X
Must be collected within 14 days prior to randomization.
Record vaccine use within 30 days prior to randomization.
Serious Adverse Event (SAE) Assessment
X
SAE collection from time of consent
Laboratory Tests
Complete Blood Count (CBC) with differential, 
Chemistry, Endocrine, Viral, methemoglobin 
levels, G6PD levels, C-reactive protein, 
Urinalysis
X
All testing, except viral, CRP, and G6PD below, must be performed within 14 days prior to 
randomization. 
Methemoglobin levels to be assessed on arterial or venous blood sample or by co-oximetry.
Viral testing, C-reactive protein, and G6PD must be within 28 days prior to randomization.
For HIV: testing at sites where locally mandated; see Appendix 11.
For full list of assessments, see Section 9.4.1.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) to 
be done at screening visit and within 24 hours of first dose of study therapy.
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a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
b Complete instructions on collecting, processing, handling and shipment of samples will be provided in a separate lab manual.
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BMS-936558
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Table 2-2:
On-treatment Procedural Outline for Arms A and C (CA2099UT) 
Procedurea
Arm A: Nivolumab 480 mg IV Q4W 
Arm C: Nivolumab 480 mg IV Q4W plus BMS-986205 100 mg PO QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2
(Day 1 ± 3 days)
Cycle 3-13
(Day 1 ± 3 days)
Notesb
Study Drug
Randomize
X
Dispense Study Drug
X
X
X
First dose to be administered within 3 calendar days 
following randomization.
Nivolumab will be administered at Day 1 of each
cycle.
For Arm C, BMS-986205 will be administered once a 
day during each cycle.
Dispense Pill Diary (Arm C 
only)
X
X
X
Review pill diary during each visit for compliance of 
daily administration of BMS-986205. Collect pill diary 
at the completion of each cycle.
Safety Assessments
Targeted Physical Examination, 
measurements, Vital Signs, 
Performance Status
X
also on C1D15 ± 3 
days for Arm C
X
X
For each cycle, weight, vital signs, and ECOG 
Performance Status within 3 calendar days prior to 
dosing.
For Cycle 1 Day 1 and beyond, targeted physical 
examination to be performed only as clinically 
indicated.
Oxygen Saturation (Arm C 
only)
X
also on C1D15 ± 3 
days
X
X
Oxygen saturation by pulse oximetry or co-oximetry at 
rest prior to dosing
ECG (12-lead)
X
also on C1D15 ± 3 
days for Arm C
See note
See note
At rest, pre-dose.
For C2 and beyond: Pre-dose, as clinically indicated, 
including if concomitant medications which may 
prolong the QTc interval are added (Appendix 8).
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Table 2-2:
On-treatment Procedural Outline for Arms A and C (CA2099UT) 
Procedurea
Arm A: Nivolumab 480 mg IV Q4W 
Arm C: Nivolumab 480 mg IV Q4W plus BMS-986205 100 mg PO QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2
(Day 1 ± 3 days)
Cycle 3-13
(Day 1 ± 3 days)
Notesb
Adverse Event (AE) 
Assessment (including SAEs)
Continuously 
Record at each visit.
All AEs and SAEs must be collected continuously 
during the treatment period and for a minimum of 100 
days following last dose.
Participants will be followed for all AEs and SAEs of 
special interest (as defined in Section 9.2.9), and all 
AEs and SAEs associated with confirmed or suspected 
SARS-CoV-2 infection until resolution, the condition 
stabilizes, the event is otherwise explained, the event is 
deemed irreversible, the participant is lost to follow-up 
(as defined in Section 8.3), or for suspected cases, until 
SARS-CoV-2 infection is ruled out.
See Section 9.2 for additional information on collection 
of AEs and SAEs.
Concomitant Medication Use
Continuously
Record at each visit.
Laboratory Tests
CBC with Differential, 
Chemistry Panel
Thyroid Testing
X
CBC with differential 
also on C1D15 ± 3 
days for Arm C
X
X
Must be performed within 72 hours prior to Nivolumab 
dosing
Refer to Section 9.4.1 for list of laboratory tests.
Thyroid testing to be performed every 8 weeks 
(2 cycles).
Methemoglobin must be assessed for Arm C on arterial 
or venous blood sample or by co-oximetry at every 
treatment visit or more frequently as clinically 
indicated based on symptoms (see Section 7.4.7).
Participants may continue BMS-986205 dosing until 
methemoglobin result is available unless clinical signs 
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BMS-936558
nivolumab
Table 2-2:
On-treatment Procedural Outline for Arms A and C (CA2099UT) 
Procedurea
Arm A: Nivolumab 480 mg IV Q4W 
Arm C: Nivolumab 480 mg IV Q4W plus BMS-986205 100 mg PO QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2
(Day 1 ± 3 days)
Cycle 3-13
(Day 1 ± 3 days)
Notesb
or symptoms of methemoglobinemia are present based 
on the clinical judgment of the investigator.
Methemoglobin testing can be stopped if BMS-986205 
is discontinued and the prior methemoglobin level is 
≤the ULN.
Pregnancy Test (WOCBP only)
X
X
X
Serum or urine within 24 hours prior to first dose and 
then every 4 weeks (± 1 week) regardless of dosing 
schedule.
Efficacy Assessments
See note
Efficacy assessments will be conducted per the local 
standard of care
Immunogenicity
Blood Samples for
Immunogenicity for Nivolumab
See note
Refer to Table 9.5.2-1.
a If a dose is delayed, the procedures scheduled for that same time point (except efficacy assessments) should also be delayed to coincide with when that time
point’s dosing actually occurs.
b Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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BMS-936558
nivolumab
Table 2-3:
On-treatment Procedural Outline for Arms B and D (CA2099UT) 
Procedurea
Arm B: Nivolumab 480 mg IV Q4W plus intravesical BCG 
Arm D: Nivolumab 480 mg IV Q4W plus intravesical BCG plus BMS-986205 100 mg QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2 - 13b
(Day 1 ± 3 days)
BCG only visitsb
(± 3 days)
Notesc
Study Drug
Randomize
X
Dispense Study Drug
X
X
X
First dose to be administered within 3 calendar 
days following randomization or 14 days 
following last TURBT/bladder biopsy, whichever 
is later.
Nivolumab will be administered at Day 1 of each 
cycle.
For Arm D, BMS-986205 will be administered 
once a day during each cycle.
BCG will be administered as described in 
footnote “b.”
Dispense Pill Diary (Arm D only)
X
X
Review pill diary during each visit for 
compliance of daily administration of BMS-
986205. Collect pill diary at the completion of 
each cycle.
Safety Assessments
Targeted Physical Examination, 
measurements, Vital Signs, 
Performance Status
X
Also on C1D15 ± 3 
days for Arm D
X
For each cycle, weight, blood pressure, heart rate, 
temperature, and ECOG Performance Status 
within 3 calendar days prior to dosing.
For Cycle 1 Day 1 and beyond, targeted physical 
examination to be performed only as clinically 
indicated.
Oxygen Saturation (Arm D only)
X
Also on C1D15 ± 3 
days
X
Oxygen saturation by pulse oximetry or co-
oximetry at rest prior to dosing
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Table 2-3:
On-treatment Procedural Outline for Arms B and D (CA2099UT) 
Procedurea
Arm B: Nivolumab 480 mg IV Q4W plus intravesical BCG 
Arm D: Nivolumab 480 mg IV Q4W plus intravesical BCG plus BMS-986205 100 mg QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2 - 13b
(Day 1 ± 3 days)
BCG only visitsb
(± 3 days)
Notesc
ECG
X
Also on C1D15 ± 3 
days for Arm D
See note
At rest, pre-dose. For cycle 2 and beyond, pre-
dose, as clinically indicated, including if 
concomitant medications which may prolong the 
QTc interval are added (Appendix 8).
Adverse Event (AE) Assessment 
(including SAEs)
Continuously 
Record at each visit.
All AEs and SAEs must be collected 
continuously during the treatment period and for 
a minimum of 100 days following last dose.
Participants will be followed for all AEs and 
SAEs of special interest (as defined in Section 
9.2.9), and all AEs and SAEs associated with 
confirmed or suspected SARS-CoV-2 infection 
until resolution, the condition stabilizes, the event 
is otherwise explained, the event is deemed 
irreversible, the participant is lost to follow-up (as 
defined in Section 8.3), or for suspected cases, 
until SARS-CoV-2 infection is ruled out.
See Section 9.2 for additional information on 
collection of AEs and SAEs.
Concomitant Medication Use
Continuously
Record at each visit.
Laboratory Tests
CBC with Differential, Chemistry 
Panel
X
CBC with differential 
also on C1D15 ± 3 
days for Arm D
X
Must be performed within 72 hours prior to 
Nivolumab dosing
Refer to Section 9.4.1 for list of laboratory tests.
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BMS-936558
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Table 2-3:
On-treatment Procedural Outline for Arms B and D (CA2099UT) 
Procedurea
Arm B: Nivolumab 480 mg IV Q4W plus intravesical BCG 
Arm D: Nivolumab 480 mg IV Q4W plus intravesical BCG plus BMS-986205 100 mg QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2 - 13b
(Day 1 ± 3 days)
BCG only visitsb
(± 3 days)
Notesc
Thyroid Testing
Thyroid testing to be performed every 8 weeks 
(2 cycles).
Methemoglobin must be assessed for Arm D on 
arterial or venous blood sample or by co-
oximetry at every treatment visit except BCG-
only visits or more frequently as clinically 
indicated based on symptoms (See Section 7.4.7).
Participants may continue BMS-986205 dosing 
until methemoglobin result is available unless 
clinical signs or symptoms of 
methemoglobinemia are present based on the 
clinical judgment of the investigator.
Methemoglobin testing can be stopped if BMS-
986205 is discontinued and the prior 
methemoglobin level is ≤the ULN.
Urinalysis
X
See note
X
Must be performed on the day of BCG dosing
Performed prior to dosing at visits BCG is
administered. Microscopic analysis required for 
abnormal dipstick urinalysis or clinical symptoms 
suggestive of urinary tract infection. A urine 
culture should be sent if there is suspicion of a 
urinary tract infection.
Pregnancy Test (WOCBP only)
X
X
Serum or urine within 24 hours prior to first dose 
and then every 4 weeks (± 1 week) regardless of 
dosing schedule.
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Table 2-3:
On-treatment Procedural Outline for Arms B and D (CA2099UT) 
Procedurea
Arm B: Nivolumab 480 mg IV Q4W plus intravesical BCG 
Arm D: Nivolumab 480 mg IV Q4W plus intravesical BCG plus BMS-986205 100 mg QD
Cycle 1 Day 1 
(C1D1)
(1 Cycle = 4 Weeks)
Cycle 2 - 13b
(Day 1 ± 3 days)
BCG only visitsb
(± 3 days)
Notesc
Efficacy Assessments
See note
Efficacy assessments will be conducted per the 
local standard of care
Immunogenicity
Blood Samples for Immunogenicity for 
Nivolumab 
See note
Refer to Table 9.5.2-1.
a If a dose is delayed, the procedures scheduled for that same time point (except efficacy assessments) should also be delayed to coincide with when that time
point’s dosing actually occurs.
b BCG will be administered at C1D1, C1D8, C1D15, C1D22, C2D1, C2D8, C4D1, C4D8, C4D15, C7D1, C7D8, C7D15, C13D1, C13D8, and C13D15. The first
BCG dose will be administered  at C1D1 (Nivolumab dosing) ± 3 days. Thereafter, BCG will be administered 7 days (± 3 days) from the last BCG dose, except 
for C4D1, C7D1 and C13D1. For C4D1, C7D1 and C13D1, BCG dose will be administered ± 3 days of nivolumab dosing, unless nivolumab dosing is delayed.
Also BCG treatment should not be given within 14 days after TURBT/bladder biopsy. Fourteen days is the minimum requirement; BCG can be delayed greater 
than 14 days after TURBT/bladder biopsy based on routine clinical practice.
c Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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Table 2-4:
Follow-up Procedural Outline (CA2099UT) 
Procedure
Follow-upa Visits 1 and 2
Notesb
Safety Assessments
Targeted Physical Examination, 
Measurements, Vital Signs, and 
Performance Status
See note
Weight, blood pressure, heart rate, temperature and ECOG Performance 
Status, to be performed only as clinically indicated.
Adverse Events Assessment 
(including Serious Adverse Events)
See note
Record at each visit.
SAEs should be approved in RAVE within 5 days from entry. All AEs and 
SAEs must be collected for a minimum of 100 days following the last dose of 
study treatment.
Participants will be followed for all SAEs, non-serious AEs of special interest 
(as defined in Section 9.2.9), and all AEs and SAEs associated with 
confirmed or suspected SARS-CoV-2 infection until resolution, the condition 
stabilizes, the event is otherwise explained, the event is deemed irreversible, 
the participant is lost to follow-up (as defined in Section 8.3), or for suspected 
cases, until SARS-CoV-2 infection is ruled out. 
See Section 9.2 for additional information on collection of AEs and SAEs.
Concomitant Medication Assessment
X
Record at each visit.
Subsequent Bladder Cancer 
Treatment
X
Laboratory Tests
CBC with Differential, Chemistry 
Panel, Thyroid Testing
Visit 1-yes
Visit 2 - only if toxicities are present
For full list of assessments, see Section 9.4.1.
Pregnancy (WOCBP only)
X
Serum or urine pregnancy testing.
Blood Samples for Immunogenicity
for Nivolumab 
See notes
Refer to Table 9.5.2-1.
a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit #1 should occur 30 days from the last dose (± 7 days) or
can be performed on the date of discontinuation if that date is greater than 30 days from the last dose. Follow-up visit #2 occurs approximately 100 days 
(± 7 days) from last dose of study treatment. Both follow-up visits should be conducted in person.
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b Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
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BMS-936558
nivolumab
3
INTRODUCTION
CA2099UT is an open-label, randomized Phase 2b trial of nivolumab or nivolumab combined with 
the indoleamine-1,2-dioxygenase 1 (IDO1) inhibitor BMS-986205 (linrodostat mesylate), either 
alone or in combination with intravesical bacillus Calmette-Guerin (BCG), in participants with 
BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). Nivolumab is an immuno-
oncologic checkpoint inhibitor that enhances T-cell migration to the tumor. BCG treatment results 
in tumor inflammation, with the potential result of improved response of the tumor to 
immunotherapy. BMS-986205 is an inhibitor of IDO1, an enzyme that participates in the 
immunosuppressive environment within tumors by converting tryptophan to kynurenine and other 
immunosuppressive metabolites. BMS-986205 is being developed for use in patients with multiple 
solid tumors, including bladder cancer. 
This is the first Phase 2 study evaluating nivolumab with or without BMS-986205 in participants 
with NMIBC. The study will assess the efficacy and safety of nivolumab alone (Arm A), 
nivolumab combined with BCG (Arm B), nivolumab combined with BMS-986205 (Arm C), and 
nivolumab combined with BMS-986205 and BCG (Arm D preliminary safety, as per revised 
protocol 03). Efficacy will be measured by the primary endpoint of complete response (CR) rate 
in the subgroup of participants with carcinoma in situ (CIS). This and other clinical endpoints will 
be evaluated in the treatment of pathologically proven high-risk, BCG-unresponsive NMIBC in 
participants who are either medically unfit for or have refused radical cystectomy.
3.1
Study Rationale
Individually targeting immune checkpoint receptors such as programmed cell death protein-1 
(PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) has demonstrated clinical 
activity across multiple tumor types including advanced urothelial carcinoma (UC), for which 
several studies to date have demonstrated activity of therapeutic compounds aimed at the PD-1 
receptor and its ligand, programmed cell death-ligand 1 (PD-L1).1,2,3
Targeting the 
immunosuppressive properties of the cancer cells themselves, such as by inhibiting IDO1, is a 
promising approach in cancer immunotherapy. Preliminary data in participants with advanced UC
evaluating an IDO1 inhibitor in combination with anti-PD-1 therapy have shown that this 
combination may improve the efficacy of anti-PD-1 therapy alone, with potentially similar 
toxicity.4 BMS-986205 is an optimized IDO1 inhibitor characterized by once-daily dosing and 
deeper inhibition of IDO1 activity than other inhibitors, as measured by peripheral blood 
kynurenine suppression. BMS-986205 has also demonstrated preliminary evidence of clinical 
activity in combination with nivolumab in multiple tumor types, including UC, in the first-in-
human Study CA017003.5,6
3.1.1
Research Hypothesis
This section is not applicable as per Protocol Amendment 04. 
3.1.2
Changes Per Protocol Amendment 04
As of early April 2021, Study CA2099UT enrollment was significantly behind the projected target 
enrollment, at 28.1% (number of subjects enrolled 135; target enrollment 480). Since the study 
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would be unable to meet the scientific objectives within a projected timeline, a decision was made 
in May 2021 to close the study. Importantly, there is no change to the understanding of the safety 
profile of nivolumab or nivolumab/BMS-986205, with or without intravesical BCG in participants 
with BCG-unresponsive, high-risk, NMIBC.
As of 02-Jun-2021, the following were put into effect:
•
Enrollment for new participants was closed effective immediately
•
Participants, who signed study consent prior to this notification and are undergoing screening,
can be permitted to be randomized to study treatment
•
Participants currently on treatment can be allowed to continue study treatment
•
For participants currently on efficacy follow-up, it is at the discretion of the investigator and
participant whether to continue the efficacy follow-up, until Protocol Amendment 04 is
approved by the relevant Health Authorities and Institutional Review Boards
(IRBs)/Independent Ethics Committees (IECs) at the site
Protocol Amendment 04 describes the modification to study procedures. All participants must be 
re-consented upon approval and implementation of Protocol Amendment 04. These changes affect 
all participants and should be implemented when Protocol Amendment 04 is implemented at the 
site.
Key changes in Protocol Amendment 04 will include:
•
Details of closure of the study, with provision for participants currently on treatment to
continue
•
Removal of pharmacokinetic (except for immunogenicity), biomarker, healthcare resource
utilization, and patient-reported outcome (PRO) assessments
•
Removal of study-related efficacy assessment and Pathology Review Committee (PRC). Sites
should continue efficacy assessment as per local standard of care
The changes instituted in Protocol Amendment 04 should override any existing protocol 
requirements in the event of any apparent discrepancies.
3.2
Background
3.2.1
Indication Background
Bladder cancer is the ninth most common cancer worldwide, with nearly 430,000 new cases 
diagnosed in 2012.7,8 Bladder cancer ranks as the fifth most commonly diagnosed non-cutaneous 
solid malignancy in the US, estimated to account for 79,000 new cases and almost 17,000 deaths 
in 2017.9 Bladder cancer is more common in men than in women, with a ratio of approximately 
3:1.9,10 The majority of cases are UCs, with mixed or variant histologies (such as squamous cell 
carcinoma, adenocarcinoma, micropapillary carcinoma, or neuroendocrine carcinoma) comprising 
a smaller subset.11
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Approximately 75% to 80% of all bladder cancers present as superficial, non-muscle-invasive 
disease, while the remaining 20% to 25% are muscle-invasive or metastatic at the time of 
presentation.12 NMIBCs are confined to either the mucosal lining or lamina propria of the bladder, 
not yet having penetrated into the muscular bladder wall.10 Initial treatment for patients with 
NMIBC includes transurethral resection of the bladder tumor (TURBT). This procedure is 
therapeutic in that the entire tumor is removed if feasible, and it is also prognostic in that it allows 
for accurate clinical staging and grading of the tumor. The need for subsequent therapy after 
TURBT is based on several well-described clinical and pathological risk factors for disease 
recurrence and progression that can be determined based on endoscopic examination of the bladder 
and pathologic evaluation of the tumor specimen. These risks factors include tumor grade, stage, 
size, multiplicity, recurrence rate, and the presence or absence of CIS.10 These risk factors have 
been used to create 3 clinical risk groupings (ie, low, intermediate, and high), which may assist 
clinicians and patients in determining prognosis and the need for additional therapy after TURBT. 
High-risk NMIBC includes any high-grade (HG) papillary Ta tumor (TaHG), any stage T1 tumor, 
and/or the presence of CIS.10,11
Soon following the initial report of its successful use in bladder cancer patients13, intravesical BCG 
became the standard of care (SOC) as adjuvant treatment for patients with high-risk NMIBC after 
TURBT. Multiple studies and meta-analyses have demonstrated that a 6-week induction course of 
intravesical BCG followed by 3 years of maintenance treatment significantly decreases the risk of 
bladder tumor recurrence and progression in patients with high-risk NMIBC when compared to no 
additional treatment or treatment with intravesical chemotherapy.10,14,15,16,17,18 Despite the 
recognized benefit of BCG treatment in this patient population, tumor recurrence and progression 
within 5 years following BCG induction and maintenance is not uncommon, occurring in 40% to 
80% (recurrence) and 25% to 45% (progression) of patients.19,20,21,22 While some patients will 
respond to a second induction course, treatment with BCG beyond 2 induction courses does not 
have any additional clinical benefit.23
Treatment for patients with high-risk NMIBC who do not respond to intravesical BCG treatment 
remains a challenge. A variety of single agents and treatment combinations, administered either 
intravesically or systemically, have been studied in the BCG-unresponsive population.24,25,26
Since the initial approval of BCG in 1990, no therapy to-date has proven sufficiently efficacious 
with a clinically meaningful durable response rate in BCG-unresponsive patients, resulting in only 
one treatment (valrubicin), with little long-term benefit, receiving approval by health authorities 
for the treatment of BCG-unresponsive NMIBC.25 As a result, the only remaining therapeutic 
option for patients with residual or recurrent high-risk NMIBC following unsuccessful BCG 
treatment is radical cystectomy.27 However, radical cystectomy is not performed in more than 50% 
of eligible patients due to reasons that include advanced age, comorbid conditions, or patient 
refusal.28 In those patients who undergo radical cystectomy, morbidity is significant, including a 
31% perioperative complication rate, a 21% readmission rate and a 1%-3% mortality rate 
following the procedure.29
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BMS-936558
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The lack of effective new treatments has led to an important unmet therapeutic need in patients 
with high-risk NMIBC who will no longer benefit from BCG therapy, and who are not candidates 
for or refuse radical cystectomy. This unmet therapeutic need has been recognized by 
organizations including the US Food and Drug Administration (FDA), the International Bladder 
Cancer Consensus Group, and the American Urological Association24,30, and it formed the basis 
for a recent FDA guidance titled “BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: 
Developing Drugs and Biologics for Treatment Guidance for Industry, February, 2018.”27 This 
communication provides guidance for the pharmaceutical industry with respect to the development 
of drugs and biologics for this patient population, and it is in alignment with recommendations 
from the International Bladder Cancer Group with respect to acceptable designs, durations, and 
endpoints for clinical studies. 
To facilitate trial design, disease states following treatment with BCG have been specified, and a 
consensus definition of “BCG unresponsive” NMIBC has been developed to specifically define 
the population of patients who will no longer benefit from further BCG treatment.26,31 Patients 
meeting this definition will have received adequate BCG treatment, defined as at least 2 courses 
of BCG (either 2 induction courses or 1 induction and 1 maintenance course) but have either not 
responded to treatment or have developed a high-risk recurrence within 6 months (for patients with 
papillary disease) or 12 months (for patients with CIS) of their last exposure to BCG.24,26,27,31
Endpoints for single-arm, registrational studies in the BCG-unresponsive NMIBC population have 
been clearly addressed in the FDA Guidance for developing drugs and biologics in this 
population.27 For BCG-unresponsive patients, the focus of registrational studies is placed on CIS. 
The FDA recognizes that the natural history of CIS is to persist despite surgical treatment, and that 
participants entering any study with a diagnosis of CIS will likely have residual CIS post-TURBT. 
For such patients, the CR rate can provide primary evidence of efficacy of a therapeutic
intervention, thereby supporting a regulatory submission. Some published literature suggests a 
50% CR rate at 6 months for CIS participants would be clinically meaningful;24 however, there 
are no regulatory guidelines specifying a minimum efficacy threshold, and durable CR rates (eg, 
30% at 12 months) would also be considered clinically meaningful.
3.2.2
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.32,33,34
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by mechanisms such as introducing cancer antigens by therapeutic 
vaccination or by modulating regulatory checkpoints of the immune system. T-cell stimulation is 
a complex process involving the integration of numerous positive as well as negative co-
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stimulatory signals in addition to antigen recognition by the T-cell receptor (TCR).35 Collectively, 
these signals govern the balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA.36 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of interleukin (IL)-2, IL-10, IL-13, interferon-gamma (IFN-γ) and Bcl-xL. PD-1 
expression has also been noted to inhibit T-cell activation, and expansion of previously activated 
cells. Evidence for a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, 
which develop a variety of autoimmune phenotypes.37 These results suggest that PD-1 blockade 
has the potential to activate anti-self T-cell responses, but these responses are variable and 
dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not 
accompanied by a universal loss of tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 = 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 = ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA 
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a 
cytomegalovirus (CMV) re-stimulation assay with human peripheral blood mononuclear cells 
(PBMC), the effect of nivolumab on antigen specific recall response indicates that nivolumab 
augmented IFN-γ secretion from CMV specific memory T-cells in a dose-dependent manner vs
isotype-matched control. In vivo blockade of PD-1 by a murine analog of nivolumab enhances the 
anti-tumor immune response and result in tumor rejection in several immunocompetent mouse 
tumor models (MC38, SA1/N, and PAN02).38
See also the Investigator Brochure (IB) for nivolumab Section 4.1 (nonclinical pharmacology 
studies) and Section 4.2 (nonclinical PK) for more information on the mechanism of action.
3.2.3
BMS-986205 Mechanism of Action
IDO1 catalyzes the degradation of tryptophan to N-formyl-kynurenine, which is the first and rate 
limiting step leading to the production of kynurenine and downstream metabolites. The activity of 
IDO1 causes immune tolerance by inhibiting T-cell function through local depletion of the 
essential amino acid tryptophan and through generation of inhibitory kynurenine pathway 
metabolites.39 In healthy humans, IDO1 is expressed in the placenta, the mucosa of the female 
genital tract, the lungs, and the lymphoid organs.40 IDO1 expression in the placenta is believed to 
play a role in maternal tolerance to allogeneic fetuses41. However, functional roles of IDO1 in the 
lungs and female genital tract are not as clear but may be involved in combating infections or play 
a role in immune tolerance. In the immune system, IDO1 is expressed in dendritic cells and 
macrophages. IDO1 is strongly induced by pro-inflammatory mediators such as IFN-γ and 
endotoxins during the late phase of inflammatory reactions, in which its immunosuppressive role 
contributes to the physiologic feedback control of the immune response.42
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IDO1 is highly expressed in several types of human malignancies. High levels or frequencies of 
IDO1 expression are detected in multiple tumor types.43,44 IDO1 expression in tumors is believed 
to induce immune tolerance as evident by a decrease in tumor infiltration of immune cells and an 
increase in the proportion of regulatory T-cells (Treg) in tumor infiltrating lymphocytic 
populations. Increased IDO1 is also correlated with diverse tumor progression parameters and 
shorter patient-survival times in many cancer indications. IDO1 has been shown to be significantly 
up-regulated together with the programmed death receptor ligand 1 (PD-L1).45 The enzyme is also 
reported to provide a critical resistance mechanism in anti-tumor T-cell immunotherapy targeting 
CTLA 4.46 Furthermore, tumor IDO1 transcript is increased in patients with advanced melanoma 
and metastatic renal cell carcinoma (RCC) after treatment with the anti-PD-1 antibody 
nivolumab.47,48
These findings suggest that IDO1 is an important regulator of the 
immunosuppressive mechanisms responsible for tumor escape from host immune surveillance. 
Inhibition of IDO1 using pharmaceutical agents such as BMS-986205 may alleviate the 
immunosuppressive properties of the tumor microenvironment and achieve more durable 
responses and greater patient survival benefits, particularly when used in combination with other 
cancer immunotherapy agents, such as nivolumab.
See also the Investigator Brochure (IB) for BMS-986205 Section 4.1 (nonclinical pharmacology 
studies) and Section 4.2 (nonclinical PK) for more information on the mechanism of action of 
BMS-986205.
3.2.4
BCG Mechanism of Action
Although the exact mechanism of action is unknown, the anti-tumor effects of BCG appear to be 
T-lymphocyte dependent. When administered intravesically to treat bladder cancer, BCG produces 
a local acute inflammatory reaction and a subacute granulomatous reaction that involves 
macrophage and lymphocyte infiltration in the mucosal bladder lining (urothelium) and lamina 
propria of the bladder. 
Evidence to date suggests that cells of the immune system, as well as bladder cancer cells 
themselves, have important roles in the anti-tumor effect of intravesical BCG.49 Requirements for 
effective BCG therapy include an intact immune system, live BCG, and close contact between 
cancer cells and BCG. BCG’s anti-tumor activity appears to be mediated through activation of the 
immune system and induction of an inflammatory response that includes an influx of immune cells 
into the bladder wall and release of a wide range of cytokines and chemokines that appear in the 
urine of BCG-treated patients. CD4+ cells predominate in the urine and bladder mucosa after BCG 
treatment. However, CD8+ cells are required for effective treatment and natural killer cells, 
granulocytes, and macrophages are also important constituents of the cellular response to BCG. 
BCG treatment results in a massive release of cytokines into the urine, including IL-1, IL-2, IL-5, 
IL-6, IL-8, IL-10, IL-12, IL-18, tumor necrosis factor (TNF), IFN-γ, granulocyte-macrophage 
colony-stimulating factor (GM-CSF) and TNF-related apoptosis-inducing ligand (TRAIL). 
Studies also support a role of BCG in the maturation of dendritic cells by signaling through 
Toll-like receptors and secretion of inflammatory cytokines such as IL-12, IFN-γ, and TNF-α.50
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Both bladder cancer cells and benign urothelial cells appear to play a role in the initial recognition 
and processing of BCG.49 Bladder cancer cell attachment to BCG is mediated through fibronectin, 
leading to BCG internalization and subsequent secretion of immune-activating effectors by cancer 
cells including IL-6, IL-8, GM-CSF and TNF. Bladder cancer cells also may function as antigen-
presenting cells for BCG, and BCG may have direct cytotoxic effects on bladder cancer cells. 
For additional information on the mechanism of action of live BCG (intravesical), see the current 
prescribing information (Summary of Product Characteristics [SmPC], US Prescribing 
Information [USPI], or country-specific label).
3.3
Benefit/Risk Assessment
There continues to be a significant unmet therapeutic need for patients with BCG-unresponsive, 
high-risk NMIBC that has been recognized by consensus groups, professional organizations, and 
health regulatory agencies.24,30 Radical cystectomy is the only treatment option for these patients, 
and for those who are either unable or unwilling to undergo this procedure, there is no remaining 
treatment option. Nivolumab, with or without BMS-986205, either alone or in combination with 
intravesical BCG, has the potential for clinically meaningful benefit in this BCG-unresponsive 
population. Nivolumab as monotherapy has received accelerated approval in the US for the 
treatment of patients with locally advanced or metastatic UC who have had disease progression 
during or following platinum-containing chemotherapy or who have had disease progression 
within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
It has received approval in the EU for the treatment of locally advanced unresectable or metastatic 
urothelial carcinoma in adults after failure of prior platinum-containing therapy. See the current 
prescribing information for nivolumab (Opdivo®) for more information.
Nivolumab has been shown to have an acceptable safety profile; this safety profile, based on 
extensive clinical experience, is described in detail in the current IB for nivolumab. Details 
concerning nonclinical toxicology and safety pharmacology of BMS-986205 are provided in the 
IB. Clinical experience regarding BMS-986205 is limited. The safety, tolerability, and efficacy of 
BMS-986205 administered alone and in combination with nivolumab is currently being assessed 
in Study CA017003, the first-in-human, Phase 1/2a dose escalation and cohort expansion study in 
advanced malignant tumors.6 Preliminary analysis of safety results from this study have revealed 
a favorable safety profile, with the most commonly reported drug-related adverse events (AEs) 
(occurring in > 5% of 286 participants as of 14-Sept-2017) being fatigue, nausea, decreased 
appetite, and aspartate transaminase/alanine transaminase (AST/ALT) elevations. Furthermore, 
the 100 mg once daily (QD) dose of BMS-986205 in combination with nivolumab appears to have 
a safety profile similar to that reported for nivolumab monotherapy, except for infrequent, 
manageable and reversible anemia and limited instances of clinically insignificant methemoglobin 
elevation, which may be related to p-chloroaniline production. Metabolism of BMS-986205 
produces a p-chloroaniline metabolite, which is associated with the formation of methemoglobin 
as well as with hemolytic anemia. In Study CA017003, as of 14-Sept-2017, 12% of participants 
(33 of 283 participants with reported values) had methemoglobin values above their institutional 
upper limit of normal (ULN). None of the participants with elevations in methemoglobin, nor any 
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other participants on study, had symptoms attributable to methemoglobin, nor were there any dose 
reductions, interruptions, or discontinuations due to elevations of methemoglobin. The highest 
methemoglobin level reported was 6%, below the commonly accepted thresholds for the 
development of cyanosis (10%) and the development of more severe symptoms (20%).51 Drug-
related Grade 3 anemia was reported in approximately 1.4% of participants. Based on these 
findings, entry criteria and monitoring parameters were developed in an attempt to reduce the risk 
of their occurrence and impact. Participants with cytochrome b5 reductase and glucose-6-
phosphate dehydrogenase (G6PD) deficiencies are excluded due to the increased risk of 
methemoglobinemia and hemolysis, respectively. Guidance for detection and management of 
methemoglobinemia as well as guidelines for dose interruptions, reductions, and discontinuation 
are provided in Section 7.4.7 (detection), Section 7.7.4 (management), Section 7.4.2 (dose 
modification), Section 7.4.4.2 (dose delay), and Section 8.1.2 (discontinuation). 
This study assesses investigational (BMS-986205) and marketed (nivolumab) drugs whose effects 
on pregnancy are not yet known or fully defined. Contraception is therefore required for 
participants who are women of child-bearing potential (WOCBP) or male, and for female partners 
of male participants who are WOCBP. Contraception guidelines presented in Appendix 4 were 
initially developed for the nivolumab development program and apply to all female participants 
and partners of male participants who could be exposed to the drug and who could become 
pregnant both during treatment and during a defined period after study treatment. In these 
nivolumab program contraceptive guidelines, hormone-based contraception (eg, pill or hormone-
releasing intrauterine device [IUD]) is considered to be a highly effective method for WOCBP 
who are participants in a nivolumab program study. However, in this study, hormone-based 
contraceptives are not considered highly effective methods of contraception for WOCBP 
participants in treatment Arms C and D or partners of male participants in Arms C and D, due to 
a lack of data regarding potential drug-drug interactions (DDI) between BMS-986205 and 
hormone-based contraception that could reduce the efficacy of these contraceptives. 
A pattern of immune-mediated adverse events (IMAEs) has been defined for treatment with 
nivolumab monotherapy and nivolumab in combination with other immune-targeting agents such 
as BMS-986205. Overall, the incidence, severity, and response to dose interruption and steroid 
treatment with BMS-986205 at 100 mg combined with nivolumab appears similar to that of 
nivolumab monotherapy. Management algorithms have been developed for these events and are 
provided in Appendix 5. Most high-grade events are manageable with the use of corticosteroids or 
hormone replacement therapy (for endocrinopathies) as instructed in these algorithms. 
Additional details on the safety profiles of BMS-986205 and nivolumab, including results from 
other clinical studies, are also available in the respective IBs.
The incidence and pattern of BCG-related adverse effects are well characterized and are presented 
in the current prescribing information. The safety and tolerability of nivolumab, with or without 
BMS-986205, in combination with intravesical BCG is currently unknown. A safety lead-in for 
the 2 BCG-containing treatment arms will be performed in order to determine any dose-limiting 
toxicity (DLT) as well as the safety profiles of these treatment combinations. See Section 5.1.1 for
details.
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To ensure an ongoing favorable risk/benefit assessment for participants enrolled into the present 
study, the following safety measures will be employed throughout the conduct of the study:
•
Institution of an external Data Monitoring Committee (DMC) to provide independent oversight
of safety, study conduct and benefit risk of BMS-986205 in combination with nivolumab, with
and without BCG
•
Rigorous safety monitoring by BMS to ensure participants’ safety including regular and
systematic review of safety data, close follow-up of reported adverse events, and intensive site
and study investigator training/education on the implementation of the BMS-986205,
nivolumab, and BCG toxicity management strategies.
Preliminary evidence of clinical activity of nivolumab in combination with BMS-986205 has been 
observed in the advanced bladder cancer cohort in Study CA017003, with 8 partial responses (PRs) 
out of 25 (32%; 95% CI: 15, 54) evaluable participants.6 ORR in participants with only one line 
of prior therapy has been 40% (95% CI 16, 68), and response has been associated with PD-L1 
expression with an ORR of 46% (95% CI 19, 75) in PD-L1 positive and 22% (95% CI 3, 60) in 
PD-L1 negative participants, respectively. These data are based on the first imaging assessment, 
and it is anticipated that responses for some participants will deepen with extended time on therapy 
as has been observed with immunotherapy treatments. Potential benefit of combining IDO1-
targeting therapies with anti-PD-1 therapies in patients with bladder cancer has also been reported 
for another IDO1 inhibitor that is currently in development.4
Evaluating the combination of nivolumab and BMS-986205, with or without intravesical BCG, 
will provide clinical data allowing clinicians to select the appropriate treatment for each patient 
based on the individual risk-benefit ratio. The promising clinical activity of BMS-986205 
combined with nivolumab in participants with advanced bladder cancer, together with the 
manageable safety profile and the ongoing need for recurrence-free and survival-prolonging agents 
for a large segment of the previously treated NMIBC population, supports further development of 
this combination and initiation of this Phase 2b study.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of nivolumab and BMS-986205 may be found in their respective IBs. The 
benefits/risks for live BCG can be determined by consulting the current Patient Information 
Leaflet, USPI, Development Safety Update Report or SmPC.
4
OBJECTIVES AND ENDPOINTS
Not applicable per Protocol Amendment 04. Only safety and immunogenicity assessments will be 
conducted. No analyses of efficacy, quality of life/patient-reported outcomes, pharmacokinetics, 
or healthcare resource utilization, are planned. Previously collected biomarker samples may be 
analyzed, but no further collections are planned with this amended protocol.
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
•
To describe the safety and tolerability of 
nivolumab and nivolumab + BMS-986205, 
alone or in combination with intravesical BCG.
•
Incidence of adverse events (AEs), serious AEs, deaths 
and laboratory abnormalities in all treated participants.
•
Overall safety and tolerability will be measured by the 
incidence 
of 
AEs, 
SAEs, 
AEs 
leading 
to 
discontinuation, immune-mediated AEs, deaths, and 
laboratory abnormalities and changes from baseline.
•
To 
characterize 
the 
immunogenicity 
of 
nivolumab.
•
Incidence of anti-nivolumab antibodies and their 
potential relationship with safety.
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2b, randomized, open-label study of nivolumab or nivolumab plus BMS-986205, 
with or without intravesical BCG, in adult (18 years of age and older, or age of majority) 
participants with pathologically proven BCG-unresponsive, high-risk NMIBC.27,31 UC must be 
the predominant histologic sub-type of the recurrent tumor. Participants should be considered 
medically unfit for radical cystectomy, or they should have refused radical cystectomy after 
consultation with their oncologist/urologist. Participants must not have evidence of UC in the 
upper urinary tracts (kidneys, renal pelvis, ureters) or in the prostatic urethra. Previous or 
concurrent muscle invasive or disseminated bladder cancer is not permitted. Prior systemic 
treatment, radiation therapy, or surgery for bladder cancer other than TURBT or bladder biopsies 
is also not permitted.
Representative diagnostic pathology slides, obtained at TURBT within 10 weeks (70 days) prior 
to randomization, which can be used to confirm the diagnosis of high-risk NMIBC and exclude 
the presence of tumor invasion into the muscularis propria, must be submitted to the PRC for 
confirmation of diagnosis. Sufficient, recent tumor tissue obtained within 10 weeks (70 days) prior 
to randomization from the bladder tumor tissue obtained at TURBT (formalin-fixed paraffin-
embedded block or 20 slides [minimum 15]) will be submitted to the analytical laboratory for 
determination of PD-L1 expression and for biomarker studies. If sufficient tissue is not available 
within 10 weeks (70 days) prior to randomization, then the site will be asked for additional tissue 
or a repeat TURBT will be required. The PRC and the analytical lab must provide IRT with 
confirmation of diagnosis and PD-L1 expression (≥1%, < 1%, indeterminate, not evaluable) prior 
to randomization. Participants should not have received any systemic or intravesical anticancer 
therapy after the date that the submitted tumor tissue was obtained.
The study design schematic is presented in Figure 5.1-1. 
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Figure 5.1-1:
CA2099UT Study Schematic
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During the treatment phase, participants will receive:
•
Arm A: Nivolumab 480 mg IV every 4 weeks (Q4W) for up to 52 weeks (12 months)
•
Arm B: Nivolumab 480 mg IV Q4W for up to 52 weeks (12 months) and intravesical BCG
(induction) weekly for 6 weeks followed by maintenance intravesical BCG weekly for 3 weeks
at 3 months, 6 months and 12 months following the first intravesical dose. The dose used for
each weekly intravesical treatment will be based on current prescribing information for the
particular BCG strain and preparation administered. This may vary as BCG strain and/or
preparation administered may vary based on geographic region in which the participant is
receiving treatment. Every effort should be made to continue a participant on the same strain
of BCG for the duration of study participation.
•
Arm C: Nivolumab 480 mg IV Q4W and BMS-986205 100 mg PO QD for up to 52 weeks
(12 months)
•
Arm D: Nivolumab 480 mg IV Q4W and BMS-986205 100 mg PO QD for up to 52 weeks
(12 months), and intravesical BCG (induction) weekly for 6 weeks followed by maintenance
intravesical BCG weekly for 3 weeks at 3 months, 6 months, and 12 months following the first
intravesical dose. The dose used for each weekly intravesical treatment will be based on current
prescribing information for the particular BCG strain and preparation administered. This may
vary as BCG strain and/or preparation administered may vary based on geographic region in
which the participant is receiving treatment. Arm D will be held to enrollment after the safety
lead-in.
For each arm, 1 treatment cycle equals 4 weeks.
Dose reductions will not be allowed for nivolumab or for BCG after the safe-dose level has been 
determined in the safety lead-in. One (1) dose reduction from 100 mg QD to 50 mg PO QD will 
be permitted for BMS-986205 (Section 7.4.2).
On-study cystoscopy and urinary cytology in all participants will begin 13 weeks following the 
first dose of nivolumab and will continue every 13 weeks thereafter. Bladder biopsies will be 
obtained at 26 weeks and 52 weeks after the first dose of nivolumab in CIS participants. Efficacy
assessments must occur until disease recurrence or progression per PRC, or until treatment 
discontinuation, whichever occurs later. Treatment beyond disease recurrence is not permitted
except in the case of a low-grade Ta UC recurrence only.
A safety lead-in will be conducted in participants randomized to receive BCG and nivolumab 
without or with BMS-986205 (Arms B and D, respectively) to determine safe-dose levels to be 
administered during the treatment phase. Enrollment in the safety lead-in will be staggered so that 
the safety lead-in phase for Arm B is adequately assessed prior to the enrollment of Arm D. After 
the safety lead-in (see Section 5.1.1), participants with CIS, with or without papillary disease, will 
be randomized in a 1:1:1 ratio into study Arms A through C.
Revised protocol 03 study design modifications include limiting enrollment only to participants 
with CIS and increasing the sample size for each arm, in order that this randomized study design 
will be able to demonstrate a CR rate and duration of response in CIS participants. A second key 
modification is that due to global shortages of BCG, only 1 BCG-containing arm (Arm B) will
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move forward with randomization instead of 2 (Arms B and D). Thus, after the safety lead-in to 
Arm D, enrollment will be paused. Modified randomization, based on the availability of BCG at 
the site, allows sites facing BCG shortage at the time of participant enrollment to enroll participants 
in the study (Section 5.4.9). Once 150 total participants have been randomized to Arm B, the BCG-
containing arm, Arm B will stop enrollment. At that point, new participants would be randomized 
via the “No BCG available” category to either Arm A or C, if open for enrollment 
(see Figure 5.1-1). Lastly, the number of non-TICE BCG treated participants was limited to 70 to 
ensure at least 80 participants are treated with TICE BCG in Arm B, the only strain approved in 
the US and many other countries.
As of 02-Jun-2021, enrollment into this study was closed. Protocol Amendment 04 removes the 
decision points and the efficacy follow-up along with other study procedures. As a result, 
randomization Phase Part 3, initial risk/benefit assessment by the Data Monitoring Committee, 
and Independent Pathology Review Committee (PRC) will be removed.
5.1.1
Safety Lead-in Phase
The safety lead-in will be conducted to evaluate the safe dose level of combination intravesical 
BCG and systemic IO therapy. Enrollment in the safety lead-in will be staggered so that the safety 
lead-in phase for Arm B is adequately assessed prior to the enrollment of Arm D. Approximately 
8 participants will be enrolled in Arm B, and these participants will receive BCG induction, 
consisting of 6 weekly treatments, plus nivolumab. The dose of nivolumab is 480 mg IV every 
4 weeks. BCG will be administered at full strength according to the prescribing information for 
the particular strain and preparation administered.
Safety data from these first 8 participants in Arm B who have been treated and followed for at least 
6 weeks on study (after completing BCG induction and nivolumab) will be evaluated, and a 
decision will be made as to whether or not to continue enrollment into Arm B with the starting 
dose or to de-escalate to a lower dose. The decision regarding de-escalation, including which study 
treatment to de-escalate, will be made based on the number and type of dose-limiting toxicities 
(DLTs). Particular attention will be given to the well-characterized, local bladder-related toxicity 
of intravesical BCG and whether the severity of these symptoms during treatment with full-dose 
BCG and systemic I-O therapy warrants dose modification or discontinuation in this patient 
population.
After the safety lead-in phase for Arm B is fully evaluated and a safe dose is established, 
enrollment in Arm D will begin. Approximately 8 participants will be enrolled in Arm D, and these 
participants will receive BCG induction, consisting of 6 weekly treatments, plus nivolumab and 
BMS-986205. The dose of nivolumab is 480 mg IV every 4 weeks and BMS-986205 is 100 mg 
administered orally daily. BCG will be administered at full strength according to the prescribing 
information for the particular strain and preparation administered. Safety data for these first 
8 participants in Arm D will be evaluated in a similar fashion to that described above for Arm B.
Per revised protocol 03, due to a global shortage of intravesical BCG, after the approximately 8 
participants in Arm D complete the safety lead-in phase, further enrollment in Arm D will be 
paused. Enrollment in Arms A, B, and C will continue per protocol.
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A safe dose will be established if ≤25% of the evaluable participants in a given treatment arm 
experience DLTs, at which point that treatment arm will be re-opened to randomization of CIS 
participants. If > 25% of the first 8 evaluable participants experience DLTs, and following DMC 
review and agreement, up to an additional 8 participants may be treated at the starting dose to 
better define safety and tolerability. Agreement will also be reached as to whether any additional 
treatment guidelines should be administered. If > 25% of DLT-evaluable participants in a given 
treatment arm exhibit DLTs after an additional 8 participants are treated and followed for at least 
6 weeks on study, the protocol may be amended to evaluate different dose levels of nivolumab, 
BMS-986205, and/or BCG, depending on the toxicities observed. 
Definition of DLTs in Safety Lead-in Phase (Arms B and D): Dose limiting toxicities are 
defined as any of the items listed below which occur during the first 6 weeks for which no 
alternative cause, other than study treatment, can be identified.
•
Any ≥Grade 2 uveitis or eye pain that does not respond to topical therapy and does not improve
to Grade 1 severity within the re-treatment period OR requires systemic treatment
•
Any ≥Grade 2 pneumonitis or interstitial lung disease that does not resolve with dose delay
and treatment with systemic steroids in 14 days (radiologic changes may take longer to
resolve). The management algorithm for pneumonitis or pulmonary toxicity can be found in
Appendix 5
•
Any ≥Grade 3 non-skin AE, with the exception of laboratory abnormalities, fatigue and
nausea, that cannot be attenuated (defined as returning to Grade 1, radiologic changes may take
longer to resolve) or controlled by appropriate care within 14 days (appropriate care being
defined as treatment outlined in AE management algorithms in Appendix 5).
•
Any ≥Grade 3 irritative bladder symptoms
•
Any ≥Grade 3 gross hematuria
•
Any fever >38.5°C that is attributed by the investigator to treatment with BCG
•
Any evidence of disseminated BCG infection including BCG sepsis, granulomatous prostatitis,
or granulomatous orchitis
•
Any Grade 4 AE including laboratory abnormalities except Grade 4 leukopenia or neutropenia
lasting < 14 days and asymptomatic amylase/lipase elevation
•
Any of the following hepatic function laboratory abnormalities:
−
AST or ALT > 5 to 8x ULN for > 2 weeks
−
AST or ALT >8x ULN
−
Total Bilirubin > 3 to 5x ULN for > 2 weeks
−
Total Bilirubin >5x ULN
−
Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN for which no alternative
cause, other than study treatment, can be identified
•
≥Grade 3 thrombocytopenia associated with bleeding
•
Methemoglobin levels ≥ 15 % (Arm D only)
•
Grade ≥ 3 hemolysis requiring transfusion or medical intervention such as steroids (Arm D
only)
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Safety lead-in participants should discontinue treatment if they experience any AE, laboratory 
abnormality or intercurrent illness (regardless of causality) which, in the opinion of the 
investigator, presents a substantial clinical risk to the participant with continued BCG, nivolumab 
and/or BMS-986205 dosing. Such discontinuation, however, will not be considered a DLT unless 
it meets at least one of the DLT criteria defined above. Treatment delay, modification and 
discontinuation criteria are to be followed for management of safety lead-in participants.
5.1.2
Randomization Phase
Participants are to have tumor tissue samples submitted for PD-L1 testing performed by the 
analytical laboratory during the screening period. PD-L1 testing together with tumor CIS and 
disease status per PRC (CIS alone vs CIS with Ta vs CIS with T1) will be used as stratification 
factors for randomization. Since this is an open-label study, randomization is for administrative 
purposes and balancing of treatment arms (see below).
Investigators will classify participants as BCG refractory or BCG early relapsing for the purpose 
of analysis and not for stratification. Per revised protocol 03, participants must have CIS to be 
eligible, but will be stratified based on the CIS as well as any Ta/T1 disease. BCG refractory will 
be defined as recurrent T1 or high-grade Ta disease within 6 months of completion of adequate 
BCG without a disease-free interval or persistent CIS (alone or with recurrent T1, high grade Ta) 
within 12 months of completion of adequate BCG without a disease-free interval. BCG refractory 
will also include high-grade T1 disease or any stage or grade progression (stage T1 after initial Ta 
or CIS, any-grade progression to high grade) at the first evaluation following BCG induction alone 
(at least 5 of 6 induction doses). BCG early relapsing will be defined as recurrent T1 or high grade 
Ta, after achieving a disease-free state, within 6 months of completion of adequate BCG therapy,
or recurrent CIS (alone or with recurrent T1, high grade Ta) after achieving a disease-free state 
within 12 months of adequate BCG therapy.
Safety Lead-In Phase: The Safety Lead-In phase will run from initiation of the study until 
approximately 16 participants are enrolled in the safety lead-in for Arms B and D.
•
The study will begin with enrollment of 8 CIS participants into Arm B. 
•
Enrollment will then be held until the safety lead-in for Arm B is adequately assessed and a 
safe dose is established. 
•
After the safety lead-in for Arm B is complete, approximately 8 CIS participants will be 
enrolled in Arm D. There will be a hold on enrollment into Arm D following completion of 
the safety lead-in.
•
If indicated, and upon DMC review, an additional 8 participants may subsequently be enrolled 
into Arm B and/or Arm D after evaluation of the initial 8 safety lead-in participants in that arm 
to better define safety and tolerability.
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Randomization: Randomization will be modified based on the availability of BCG and BCG 
strains (see Figure 5.1-1 and Section 5.4.9). 
•
Sites will be classified based on their BCG availability at the time of participant randomization:
1) “No BCG available” (6 induction and the first 3 maintenance doses not being available at
the time of consent)
2) “TICE BCG available” (for the purposes of randomization, any BCG strain that becomes
approved in the US during the conduct of the study [regardless of site geographic location]
will be included in the category of TICE BCG)
3) “Non-TICE BCG available”
•
The 3 arms (treatment details in Section 5.1) are:
1) Arm A with nivolumab, N = 100 participants
2) Arm B with nivolumab + intravesical BCG, N = 150 participants
a) Non-TICE participants capped at ≤ 70 to ensure at least 80 TICE participants; after
reaching the non-TICE cap, non-TICE participants will be randomized into either Arm
A or Arm C.
b) Once 150 total participants are randomized to Arm B, enrollment will be stopped. Arm
B is the only BCG-containing arm so once enrollment stops, future participants will be
randomized into either Arm A or C, if open for enrollment, via the “No BCG available”
category.
3) Arm C with nivolumab + BMS-986205, N = 100 participants
•
Based on BCG availability at the site, randomization will lead to participants’ enrollment in
the following arms:
−
No BCG available: Arm A and C (1:1)
−
TICE BCG available: Arm B; if Arm B is closed to enrollment, then Arm A or C (1:1)
−
Non-TICE BCG available: Arm A, B, and C (1:1:1) until Arm B is closed to non-TICE
participants, then Arm A or C (1:1)
•
If TICE BCG shortage resolves by assessment of the sponsor, randomization of TICE BCG
participants may switch to Arms A, B, or C in a 1:1:1 ratio at the sponsor’s discretion.
Randomization Phase Part 1: The Part 1 randomization will begin after treatment initiation of 
approximately 8 participants in the safety lead-in for Arm D, and it will run through the end of the 
Arm D safety lead-in.
•
After approximately 8 participants initiate treatment in the safety lead-in Arm D,
randomization of participants will begin into Arms A, B, and C.
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Randomization Phase Part 2: The Part 2 randomization will begin at the conclusion of the safety 
lead-in for Arm D and run until the 6-month decision point is reached for each treatment arm.
•
Randomization of CIS participants will continue in all treatment arms (A, B, C).
5.1.3
Data Monitoring Committee and Other External Committees
An independent, external Data Monitoring Committee (DMC) will be established to provide 
oversight of safety in this protocol and to provide advice to the Sponsor regarding actions the 
committee deems necessary for the continued protection of participants enrolled in the study. The 
DMC will act in an advisory capacity to Bristol-Myers Squibb (BMS) and will monitor participant 
safety for the study. Data and summaries will be made available to the DMC, and the committee 
will provide advice regarding toxicity during the safety lead-in period. The BMS Oncology 
Development Department has primary responsibility for design and conduct of the study. Details 
concerning governance are provided in Appendix 2.
Additional details concerning DMC oversight are provided in the DMC charter.
5.2
Number of Participants
As of 02-Jun-2021, enrollment into this study was closed. Number of participants enrolled was 
135, as of early April 2021.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of the trial 
and end of the study are defined as the final date when all participants completed study procedures 
described in Section 2 including follow-up visits.
5.4
Scientific Rationale for Study Design
Bladder cancer is an immunologic malignancy, and multiple studies have shown that bladder 
cancer specimens harbor tumor infiltrating lymphocytes.52,53 Immunohistochemical (IHC) 
staining for intratumoral CD8+ T-cells in tissue samples from 69 participants with bladder cancer 
(pT2, pT3, or pT4) demonstrated that participants with higher numbers of CD8+ tumor-infiltrating 
lymphocytes (TILs) within the tumor (8 or more) had better disease-free survival (p < 0.001) and 
overall survival (p = 0.018) than did participants with similar-staged bladder cancer and fewer 
intratumoral CD8+ TILs.53
Immunotherapy has played a major role in the treatment of superficial bladder cancer since the 
introduction of intravesical BCG.13 Randomized trials have repeatedly demonstrated that 
treatment with intravesical BCG results in significantly lower rates of tumor recurrence and 
progression.54 While the mechanism of action of BCG remains poorly defined, studies support an 
immunological mechanism including a role of BCG in the recruitment of CD4+ and CD8+ 
T-lymphocytes, the maturation of dendritic cells by signaling through Toll-like receptors, and in 
the secretion of inflammatory cytokines such as IL- 12, IFN-γ, and TNF-α.49,49
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Despite the immunogenicity of bladder cancer, patients with bladder cancer also exhibit tumor-
associated immunologic suppression, particularly evident as an impaired T-cell response, which
may worsen with advanced tumor stage.55,56,57 Bladder cancer specimens have been shown to be
infiltrated by regulatory T-cells, and to express high levels of inhibitory cytokines.56 In addition,
aberrant expression of T-cell coregulatory molecules, known to inhibit the immune response, have
been demonstrated on bladder cancer cells and TILs and have correlated with clinical outcomes.58
These findings suggest that the balance between CD8+ cytotoxic T-cells and negative immune
regulatory elements in the tumor microenvironment may be critical in determining the host’s 
overall immune response and ultimate clinical outcome.
High levels of PD-L1 expression have been noted in UC (eg, in a recent study, 46% of participants 
were reported with ≥1% PD-L1 expression and 30% of participants with ≥5% PD L1 
expression2), suggesting tumor-associated immune tolerance and escape from immune 
surveillance. PD-L1 expression has been reported in approximately 20% (5% cutoff) and 30% 
(1% cutoff) of tumor tissue samples.3,59,60
PD-1 and PD-L1 immune checkpoint inhibitors appear to show benefit in patients with bladder 
cancer progression on platinum-based therapy. Recently, atezolizumab (PD-L1 inhibitor) was 
approved in the US to treat metastatic UC in patients whose disease progressed during or after 
platinum-based chemotherapy, based on a 15% response rate in a single-arm study.3 Likewise, 
nivolumab has been approved in both the US and EU for the treatment of patients with locally 
advanced or metastatic UC who did not respond to platinum-based chemotherapy. In an open-
label, multicenter Phase 1/2 expansion cohort in participants with metastatic UC, nivolumab 
elicited a response rate of 24.4% with acceptable safety, regardless of tumor PD-L1 expression, in 
participants who had received one or more prior lines of chemotherapy (CheckMate 032
[CA209032]; NCT01928394).59
In a larger study in unresectable or metastatic UC, 
CheckMate 275 (CA209275), nivolumab had clinically meaningful efficacy and a manageable 
safety profile.2 In this study, at 7 months of median follow-up, 24.4% of participants remained on 
therapy. The confirmed objective response rate (ORR) was 19.6% (95% CI: 15.0–24.9), with 
Grade 3-4 treatment-related AEs occurring in 18% of participants (Grade 5, 1%), mainly fatigue 
and diarrhea (2% each). ORR was found to be associated with the level of tumor tissue PD-L1 
expression, being 28.4% with PD-L1 expression in ≥5% of tumor tissue, 23.8% with PD-L1 
expression in ≥1% of tumor tissue, and 16.1% with PD-L1 expression in < 1% of tumor tissue. 
PD-L1 expression has been examined in 280 participants with clinically localized bladder cancer, 
including 44 participants with NMIBC.61 PD-L1 expression in ≥1% of bladder tumor cells was 
associated with tumor stage in NMIBC, occurring in 7% of Ta, 16% of T1, and 45% of CIS tumors, 
respectively. All 44 NMIBC participants were treated with intravesical BCG, and 16 participants 
did not respond to treatment (36%). Eleven (11) of these 16 participants (69%) exhibited diffuse 
and intense PD-L1 expression that was present in > 90% of the cells. 
IDO gene expression has also been studied in NMIBC and may potentially possess an 
immunosuppressive role. IDO gene expression was examined in 74 participants undergoing 
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surgical treatment for NMIBC and was detected significantly more frequently, and to a higher 
extent, in cancer tissue as compared to normal bladder mucosa. 62 IDO expression was seen more 
frequently, and was higher in large, high-grade or T1 tumors when compared to small, low-grade 
or Ta tumors. Multivariate analysis suggested a trend towards longer overall survival in patients 
having tumors that did not express the IDO gene. 
Preliminary data suggest that oral IDO inhibitors in combination with nivolumab possess anti-
tumor activity in bladder cancer. Epacadostat and BMS-986205, both oral IDO inhibitors,
demonstrate a favorable safety profile and clinical activity in combination with nivolumab in 
multiple solid tumor types.5,63 In a study of 40 participants with advanced UC who had failure of 
prior systemic therapy, the oral IDO1 inhibitor epacadostat in combination with the anti-PD-1 
inhibitor pembrolizumab demonstrated an ORR of 35%, which was greater than that expected for 
pembrolizumab alone.4 BMS-986205 has also demonstrated preliminary evidence of clinical 
activity in combination with nivolumab in the first-in-humans CA017003 study in multiple tumor 
types, including UC. Preliminary data from CA017003 demonstrate an ORR of 32% 
(95% CI: 15, 54) in 25 participants with advanced bladder cancer who had received one or more 
prior systemic therapies. The ORR was 40% (95% CI: 16, 68) for participants with one prior 
therapy and 20% (95% CI: 3, 56) for participants with 2 or more prior therapies.6
5.4.1
Rationale for Combination of Nivolumab with BMS-986205 in Non-
Muscle-Invasive Bladder Cancer
PD-1 is a transmembrane protein primarily expressed on activated T-cells, B-cells, myeloid cells, 
and antigen presenting cells (APCs).64 Binding of PD-1 to PD-L1 and PD-L2 has been shown to 
down-regulate T-cell activation in both murine and human systems.36,65,66,67 PD-1/PD-L1 
interactions may also indirectly modulate the response to tumor antigens through T-cell/APC 
interactions. Therefore, PD-1 engagement may represent one means by which tumors evade 
immunosurveillance and clearance.68 Blockade of the PD-1 pathway by nivolumab has been 
studied in a variety of preclinical in vitro assays, and anti-tumor activity using a murine analog of 
nivolumab has been shown in a number of immunocompetent mouse cancer models. Nivolumab 
has been approved as treatment for melanoma, non-small cell lung carcinoma (NSCLC, both non-
squamous and squamous histologies), head and neck cancer, RCC, hepatocellular carcinoma, 
colorectal cancer, bladder cancer, and Hodgkin lymphoma in the US and other countries, and is 
being evaluated extensively across a wide range of other solid tumors and hematological 
malignancies.
PD-1-blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. 
IDO1 expression is also known to be strongly regulated by IFN-γ. In fact, in clinical trials of 
participants with advanced melanoma and metastatic RCC treated with nivolumab, IDO1 gene 
expression was increased in participants on treatment.47,48 These increases in the expression of 
IDO1 are indicative of potential adaptive mechanisms of resistance to counteract the increased 
anti-tumor immune cell activity potentiated by PD-1/PD-L1 blockade. 
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In conclusion, these data support the hypothesis that combination treatment involving PD-1/PD-L1 
blockade and IDO1 inhibition could result in enhanced anti-tumor activity by providing an 
additional mechanism of alleviating tumor-mediated immunosuppression. 
5.4.2
Rationale for Combination of Nivolumab with BCG in Non-Muscle-
Invasive Bladder Cancer
Immune checkpoint inhibitors such as nivolumab target pathways used by cancer cells to evade 
immune system attack.69 Such pathways may be important in BCG-unresponsive NMIBC as 
evidenced by the association between PD-L1 expression and higher bladder cancer stage, and by 
the high levels of PD-L1 expression in the BCG granulomata of those failing prior BCG 
treatment.61 Thus, elevated PD-L1 expression may be one possible mechanism by which bladder 
cancer cells evade treatment.
Previous studies in participants with advanced UC suggest that tumors with an immune-inflamed 
(associated with high CD8+ infiltration) or immune-suppressed phenotype may have better 
response to immunotherapies, including checkpoint inhibitors, than tumors with an immune-desert 
phenotype.69 BCG appears to have a role in the recruitment of CD4+ and CD8+ lymphocytes into 
the bladder wall,49 augmenting the inflamed phenotype of a particular bladder tumor and 
potentially making it more susceptible to treatment with a checkpoint inhibitor such as nivolumab.
These findings suggest that the balance between CD8+ cytotoxic T-cells and negative immune 
regulatory elements in the microenvironment of a bladder tumor may be critical in determining the 
host’s overall immune response and ultimate clinical outcome. An avid local immune response 
within the bladder that results from BCG treatment may improve response to anti-PD therapy, 
while 
anti-PD 
therapy 
with 
nivolumab 
may 
help 
to 
overcome 
tumor-associated 
immunosuppression that mitigates the effectiveness of BCG treatment in BCG-unresponsive 
tumors. This provides a strong rationale for combining nivolumab with BCG in patients with 
NMIBC.
5.4.3
Rationale for Combination of Nivolumab/BMS-986205 with BCG in Non-
Muscle-Invasive Bladder Cancer
The rationale for combining nivolumab individually with either BMS-986205 or with intravesical 
BCG is outlined in Section 5.4.1 and Section 5.4.2, respectively. Participants enrolled in this study 
are BCG unresponsive and therefore will not benefit any further from BCG treatment alone.31 In 
these BCG-unresponsive patients, it is possible that the balance between the immune stimulatory 
effects of BCG and the immune inhibitory effects in the tumor microenvironment is tipped towards 
inhibition of the anti-tumor effect of the BCG-induced local inflammatory response. In addition to 
PD-L1 expression, IDO gene expression also appears to be positively associated with tumor stage 
and grade in patients with bladder cancer.62 Higher IDO gene expression may be associated with 
poorer clinical outcome in patients treated for NMIBC. These findings may reflect a potential 
adaptive mechanism of resistance to counteract the increased anti-tumor immune cell activity 
potentiated by BCG treatment and PD-1/PD-L1 blockade, and they provide the rationale behind 
combining nivolumab, BMS-986205 and BCG in BCG-unresponsive high-risk NMIBC. 
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5.4.4
Rationale for Duration of Treatment
The optimal duration of immunotherapy is currently unknown. Because immunotherapy engages 
the immune system to control the tumor, continuous treatment as is required with targeted agents 
or cytotoxic therapy may not be necessary.
Accumulating evidence from several clinical trials in different tumor types with nivolumab or 
nivolumab combined with ipilimumab, including CheckMate 275 (CA209275) in bladder cancer, 
indicates that most of the responses are occurring early, with a median time to response of 2 to 
4 months.2,70,71,72,73,74 A recent analysis of 1 year of adjuvant treatment with nivolumab in 
participants with fully resected stages IIIB, IIIC or IV melanoma demonstrated a significantly 
longer recurrence-free survival, and significantly less toxicity, when compared to treatment with 
ipilimumab, which had been previously approved in the adjuvant melanoma setting.75 I-O 
treatment in the current study will be delivered as adjuvant therapy following TURBT, providing 
the rationale for 1 year (52 weeks) of I-O treatment.
In the current study, BCG is being utilized to augment the local immune response in the bladder 
of BCG-unresponsive patients. It is hypothesized that creating this inflamed phenotype will 
potentially improve the efficacy of I-O treatment. For this reason, duration of BCG treatment will 
be 12 months (52 weeks) to coincide with systemic I-O therapy. Induction and maintenance BCG 
will be administered according to the SWOG 8507 protocol.15
5.4.5
Rationale for Open-Label Study Design
This is an open label, Phase 2b study. There is no control arm or formal comparison between the 
treatment arms. Confirmation of CR and tumor recurrence will be made by central pathology 
review blinded to treatment arm, and not by the individual investigators. This obviates the need 
for treatment blinding and the administration of placebo, which would be unethical in the case of 
BCG treatment, which requires some participants to undergo multiple urethral catheterizations 
associated with no therapeutic benefit.
5.4.6
Rationale for Complete Response Rate in Participants with Carcinoma 
in Situ as a Primary Endpoint 
Not applicable per Protocol Amendment 04.
5.4.7
Rationale for Evaluation of Predictive Biomarkers
Not applicable per Protocol Amendment 04.
5.4.8
Rationale for PD-L1 Expression as a Candidate Biomarker of Immuno-
Oncology Therapy Efficacy
PD-L1 expression has previously been evaluated as a potential predictive marker for treatment 
outcome in patients receiving anti-PD-1 or anti-PD-L1 therapy for advanced UC. In a study of 
315 participants with advanced UC treated with atezolizumab whose disease had progressed after 
prior platinum-based chemotherapy, Rosenberg and colleagues reported an ORR of 15% in all 
participants, with higher response rates of 26% and 18% in participants with ≥5% and ≥1% 
immune cells positive for PD-L1 expression, respectively.3 A recent update from the 
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CheckMate 275 (CA209275) study demonstrated that the level of PD-L1 expression on tumor cells 
was associated with ORR in 270 participants with advanced UC receiving nivolumab monotherapy 
after failure of first-line platinum-based chemotherapy.60 ORR in all 270 participants was 19.6%, 
with a 25% ORR in 124 participants with ≥1% PD-L1 expression on tumor cells and a 15.8% ORR
in 146 participants with < 1% PD-L1 expression on tumor cells. Preliminary data suggest that PD-
L1 expression may also be a predictive marker of outcome for advanced bladder cancer patients 
receiving the anti-PD-1 agent pembrolizumab in combination with an oral IDO inhibitor. With 
only 19 evaluable participants, Smith and colleagues reported an ORR of 64% in 11 participants 
with ≥1% PD-L1 expression on a combination of tumor and immune cells, and an ORR of 13% 
in 8 participants with < 1% PD-L1 expression on a combination of tumor and immune cells.4
Inman and colleagues evaluated PD-L1 expression on tumor cells of 44 participants with NMIBC 
receiving intravesical BCG treatment.61 In addition to being associated with tumor stage and grade, 
PD-L1 expression was present and abundant in the BCG granulomata of 11/16 participants (69%) 
with disease recurrence. 
Taken together, the available data suggest that PD-L1 expression is a biomarker of clinical efficacy 
to I-O therapy. Therefore, PD-L1 will be utilized as a stratification factor in this clinical study and 
will be used to analyze for association with efficacy.
5.4.9
Rationale for Modified Randomization
The study design does not include formal statistical comparisons between the arms, but 
randomized assignment is used to ensure reasonable balance in baseline prognostic factors. Some 
study sites are facing intravesical BCG availability constraints due to a global BCG shortage. In 
light of this, randomization was modified based on BCG availability, so that sites with no BCG 
available continue to enroll participants. Additionally, different BCG strains are standard of care 
in varying regions, with some countries having more than one strain approved. There are no 
conclusive data showing a difference in efficacy or safety between available strains, although there 
is an ongoing non-inferiority trial comparing the TICE and Tokyo-172 strains in BCG-naive 
patients.76 As the TICE strain is the only strain approved in the US and many other countries, 
randomization was modified to include BCG strain (categorized as TICE BCG vs non-TICE
BCG). Having 3 BCG-based randomization categories (No BCG available, TICE BCG available, 
or Non-TICE BCG available) will maintain reasonable balance in baseline prognostic factors 
between the 3 treatment arms while addressing the BCG shortage (see Section 5.1.2 for
randomization details).
5.5
Justification for Dose
5.5.1
Justification for Nivolumab Dose
The nivolumab dose of 480 mg Q4W was selected based on clinical data and modeling and 
simulation approaches using PPK and exposure-response analyses examining relationships 
between nivolumab exposures and efficacy (eg, overall survival, ORR) and safety responses, using 
data from studies in multiple tumor types (melanoma, NSCLC, and RCC) with body weight-
normalized dosing (mg/kg). A flat dose is expected to reduce prescription dosing errors, shorten 
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pharmacy preparation time, and improve ease of administration. Extending the dosing interval to 
4 weeks provides numerous benefits to patients as they would have increased flexibility between 
clinical visits. The PPK analyses have shown that exposure to nivolumab increased dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks (Q2W), and no 
clinically meaningful differences in PK across ethnicities and tumor types were observed. 
Nivolumab clearance and volume of distribution were found to increase as body weight increases 
but less than proportionally with increasing weight, indicating that milligram-per-kilogram dosing 
represents an over-adjustment for the effect of body weight on nivolumab PK. 
Using the PPK and exposure-response models, nivolumab exposures and probabilities of efficacy 
responses and risks of AEs were predicted following nivolumab 480 mg Q4W and were 
comparable to those following nivolumab 3 mg/kg Q2W. The overall distributions of average 
nivolumab steady state exposures (Cavgss) were comparable following administration with either 
nivolumab 3 mg/kg Q2W or nivolumab 480 mg Q4W over a wide range of body weight ranges. 
Nivolumab 480 mg Q4W is predicted to result in approximately 43% greater steady state peak 
concentrations (Cmaxss) compared to nivolumab 3 mg/kg Q2W; however, these exposures are 
predicted to be lower than the exposure ranges observed at doses up to nivolumab 10 mg/kg Q2W 
used in the nivolumab clinical program. Although the Cmaxss of nivolumab is expected to be 
greater following nivolumab 480 mg Q4W compared to nivolumab 3 mg/kg Q2W, the predicted 
Cmaxss following nivolumab 480 mg Q4W is well below the median Cmaxss achieved following 
administration of nivolumab 10 mg/kg Q2W, a safe and tolerable dose level. 
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W, and the risks of discontinuations due to AEs or death, AE 
Grade 3+, and IMAEs Grade 2+, are predicted to be similar following nivolumab 480 mg Q4W 
relative to nivolumab 3 mg/kg Q2W across tumor types. Safety analyses using available data 
following nivolumab 3 mg/kg Q2W and 10 mg/kg Q2W administration indicated there were no 
differences in AE profiles across body weight groups. Finally, initial evidence demonstrates that, 
following administration of nivolumab 480 mg Q4W, nivolumab has been well tolerated.
Nivolumab 480 mg Q4W is predicted to have approximately 16% lower steady-state trough 
concentrations (Cminss) compared to nivolumab 3 mg/kg Q2W. While these exposures are 
predicted to be lower, they are on the flat part of the exposure-response curves and are not expected 
to affect efficacy, Exposure-efficacy analyses of multiple PK measures and efficacy endpoints 
indicated that, following administration of nivolumab 480 mg Q4W, efficacy is predicted to be 
similar to that following administration of nivolumab 3 mg/kg Q2W across multiple tumor types. 
Based on these data, nivolumab 480 mg Q4W is expected to have similar efficacy and safety 
profiles to nivolumab 240 mg Q2W or nivolumab 3 mg/kg Q2W.
5.5.2
Justification for BMS-986205 Dose
All participants will receive BMS-986205 100 mg PO QD in combination with nivolumab 480 mg 
Q4W. The selection of the dose and schedule for BMS-986205 is primarily based on available data 
from the ongoing Phase 1/2, first-in-human Study CA017003.
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In Study CA017003, doses of BMS-986205 from 25 mg to 400 mg QD in combination with 
nivolumab were studied in the dose escalation part and doses of BMS-986205 100 mg and 200 mg 
QD were evaluated in selected expansion cohorts. The maximum tolerated dose of BMS-986205 
established in this study was 200 mg QD.
At 100 mg, preliminary PK data indicated that average trough plasma levels of BMS-986205 
exceeded the in vitro human whole blood IC90. Significant and sustained inhibition of serum 
kynurenine levels was observed at all dose levels. PK-pharmacodynamic analysis of BMS-986205 
exposure and kynurenine inhibition further suggests the effects to plateau at doses starting at 
100 mg QD. Maximum inhibition of serum kynurenine levels were predicted to be similar at 
100 mg QD (61%) and 200 mg QD (64%). Marked but variable inhibition of intratumoral 
kynurenine levels was also observed at both dose levels. 
Preliminary safety data (as of 11-Oct-2017) from Study CA017003 indicate that BMS-986205 is 
safe and tolerable at both 100 mg QD and 200 mg QD. The data suggest a more favorable 
tolerability profile at 100 mg, with fewer participants experiencing treatment-related ≥Grade 3 
AEs (8.5% vs 21.4%) when compared to the 200 mg AE profile. 
Overall, preliminary safety data from 199 participants in Study CA017003 reveal an overall safety 
profile of 100 mg BMS-986205 combined with nivolumab consistent with that observed with 
nivolumab monotherapy, including IMAEs such as pneumonitis (2%), autoimmune hepatitis (1%), 
colitis (1%), and uveitis (1%). The safety profiles differ with respect to AEs potentially associated 
with p-chloroaniline production during metabolism of BMS-986205, including anemia and 
methemoglobinemia. These events were reported infrequently in participants receiving the 100 mg 
dose (treatment-related anemia of any grade in 3.5% of participants and Grade 3 in 1% of 
participants receiving 100 mg; Grade 1 methemoglobinemia in 0.5% of participants).
Available preliminary clinical activity data from Study CA017003 suggest that both doses of 
BMS-986205 are clinically active in participants with bladder cancer when administered in 
combination with nivolumab. An ORR of 32% (95% CI 15, 54) was observed in 25 previously 
treated bladder cancer participants.6 This includes an ORR of 40% (95% CI 16, 68) in 
15 participants with 1 prior line of therapy. ORR appeared to be associated with PD-L1 expression, 
being 46% (95% CI 19, 75) and 22% (95% CI 3, 60) in PD-L1 positive and PD-L1 negative 
participants, respectively. It is anticipated that responses for some subjects will deepen with 
extended time on therapy as has been observed with immunotherapy treatments.
In summary, BMS-986205 at 100 mg QD achieves trough plasma concentrations that exceed the 
human whole blood IC90, produces substantial serum kynurenine reductions similar to those 
observed at higher dose levels, demonstrates target engagement in the tumor microenvironment, 
appears (in combination with nivolumab) to have a more favorable tolerability profile compared 
to higher doses and similar to that of nivolumab monotherapy, and demonstrates clinical activity 
in combination with nivolumab. Based on this evidence, BMS-986205 100 mg QD will be 
administered in combination with nivolumab to participants in this study.
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5.5.3
Justification for Administration of BMS-986205 with Food
The effect of food on the PK of BMS-986205 was evaluated in healthy participants in Study 
CA017053. Following a single 100 mg dose, BMS̻986205 geometric mean Cmax and AUC(0-
168h) were 114% (90% CI 75.4% to 161.1%) and 52.8% (37.2% to 70.3%) higher, respectively, 
when dosed after a high-fat meal compared to under fasting condition. BMS-986205 Cmax and 
AUC(0-168h) were 96.5% (71.7% to 124.8%) and 42.6% (28.0% to 58.8%) higher respectively, 
when dosed after a light meal compared to under fasting condition. Tmax ranged from 2 hours to 
4 hours when dosing fasted and from 2 hours to 5 hours when dosed after a meal. PK variabilities 
were generally smaller when dosed after a meal. Similar results were also observed in cancer 
patients in a clinical pharmacology substudy in Study CA017003 (Data on File). Given that BMS-
986205 was administered with a light meal in CA017003 where its safety profiles were evaluated
and was deemed acceptable, based on these results, BMS-986205 will be administered after a meal 
in the current study without further restriction on the types of meal.
5.5.4
Justification for BCG Dose
The appropriate dose and dosing schedule of BCG in combination with systemic I-O agents in 
BCG-unresponsive patients is unknown. In the current study, BCG is being administered to 
augment the local immune response in the bladder and to work synergistically with nivolumab, 
with or without BMS-986205, in order to overcome potential immune inhibitory mechanisms used 
by bladder cancer cells to evade the local immune response induced by BCG. This rationale 
informs the duration of BCG therapy in this study, which will equal that of nivolumab and 
BMS-986205. 
BCG strains used in routine clinical practice vary by geographic location, with different strains 
currently being utilized in the United States, Europe and Japan.77 BCG will be sourced locally in 
some countries and will be provided by the sponsor in other countries, according to country-
specific guidelines related to the use and procurement of investigational medicinal products in 
clinical trials. The dose used for each weekly intravesical BCG treatment will be based on current 
prescribing information for the particular BCG strain and preparation provided to the site for 
administration.
The appropriate dosing schedule for intravesical BCG administration in BCG-unresponsive 
patients participating in clinical trials testing novel I-O therapy combinations is unknown. 
SWOG 8507 defined the current SOC for BCG induction and maintenance in patients with high-
risk NMIBC,15 and this treatment schedule will be followed for the 52 weeks that clinical trial 
participants in the two BCG-containing treatment arms receive this intravesical therapy
(Table 7.1-1).
5.5.5
Justification for Nivolumab 30-Minute Infusion
Long infusion times place a burden on participants and treatment centers. Using shorter infusion 
times of 30 minutes duration in participants will diminish the burden provided there is no change 
in safety profile. Previous clinical studies show that nivolumab has been administered safely over 
60 minutes at doses ranging up to 10 mg/kg over a long treatment duration. For example, in 
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Study CA209010 (a Phase 2, randomized, double-blinded, dose-ranging study of nivolumab in 
participants with advanced/metastatic, clear cell RCC, N=167), a dose association was observed 
for infusion site reactions and hypersensitivity reactions (5.1% at 0.3 mg/kg, 3.7% at 2 mg/kg and 
18.5% at 10 mg/kg).78 All the events were Grade 1/2 and were manageable. Establishing that 
nivolumab can be safely administered using a shorter infusion time (30 minutes) is under 
investigation. The safety of nivolumab 3 mg/kg administered as a 30-minute infusion was assessed 
in Study CA209153 in participants with previously treated advanced NSCLC. Overall, there were 
no clinically meaningful differences in the frequency of hypersensitivity/infusion-related reactions 
(of any cause or treatment-related) in participants administered nivolumab over a 30-minute 
infusion time compared with that reported for participants with the 60-min infusion time. An 
infusion duration of 30 minutes for nivolumab 480 mg (~ 60% of the dose provided at 10 mg/kg) 
is not expected to present any safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dose infused over a 60-minute duration. Key safety results from the interim safety 
population of Study CA209511 (Part 2) demonstrate that the safety profile of nivolumab 480 mg 
IV over 30 minutes Q4W (N=142) is consistent with the established safety profile of nivolumab 
(3 mg/kg Q2W administered IV over 60 minutes) across multiple indications with respect to Grade 
3-4 AEs, SAEs, AEs leading to discontinuation, and IMAEs including hypersensitivity/infusion 
reactions IMAEs. There were no new safety concerns identified. In addition, in Study CA017003, 
the Phase 1/2a trial of BMS-986205 combined with nivolumab, nivolumab was administered at 
doses of 240 mg Q2W and 480 mg Q4W, both over 30 minutes, in combination with BMS-986205 
given daily. There have been no signals of adverse tolerability with nivolumab given over 
30 minutes at a dose of 480 mg Q4W in that study.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
As of 02-Jun-2021, enrollment into this study was closed. Male participants continuing treatment 
should follow the updated contraceptive guidance below and in Appendix 4.
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol-related procedures that are not part of normal 
patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (see 
Appendix 6)
b) Life expectancy ≥ 6 months
3) Pathologically demonstrated BCG-unresponsive*, carcinoma in situ (CIS)-containing 
high-risk NMIBC defined as CIS with or without papillary component required within 
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10 weeks (70 days) prior to randomization and must be confirmed by the Pathology 
Review Committee (PRC).
* BCG-unresponsive disease is defined as being at least one of the following: 
•
Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary 
disease/tumor invades the subepithelial connective tissue) disease within 12 months 
of completion of adequate BCG therapy** 
•
Recurrent high-grade Ta/any T1 disease within 6 months of completion of adequate 
BCG therapy** [per revised protocol 03, participants must also have CIS to be 
eligible]
•
T1 high-grade disease at the first evaluation following an induction BCG course (at 
least 5 of 6 induction doses) [per revised protocol 03, participants must also have 
CIS to be eligible]
** Adequate BCG treatment is defined as at least 2 courses of BCG. This 
can include 2 induction courses (at least five of six doses of an initial 
induction course plus at least two of six doses of a second induction 
course) or 1 induction course (at least 5 of 6 induction doses) and at least
2 of 3 doses of a maintenance cycle (“5+2”).
a) Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma
b) Must have undergone each of the following procedures within 10 weeks (70 days) of 
randomization (except 90 days for CT or MRI). If these procedures are performed as part 
of the participant’s routine care, they do not need to be repeated provided that they were 
performed within the required time period:
i)
Complete excision of all papillary disease (T1/TaHG). For participants with T1 lesions, 
a re-staging TURBT must be performed within 8 weeks after the initial TURBT to 
ensure that the pathology specimen contains muscularis propria that is free of invasive 
tumor per PRC.
ii) Resection or fulguration of all detectable CIS, if feasible. Fluorescence-guided 
cystoscopy is encouraged but not mandated. It is understood that due to the nature of 
this disease, complete resection of CIS cannot be assured. 
iii) The presence of any suspicious lesions must be recorded and these lesions will be 
biopsied. Random sampling of bladder mucosa for detection of occult CIS during the 
screening period is optional, but should be performed at the time of screening 
transurethral resection/biopsy of bladder tumor and/or CIS within 10 weeks (70 days) 
of randomization, if possible. The bladder should be mapped by visual inspection and 
random biopsies taken from the trigone, right and left lateral walls, posterior wall, dome 
and prostatic urethra (in male participants). 
iv) Urine cytology must be obtained from a voided specimen (except from the first 
morning urination) or by bladder wash. Recognizing the possibility of occult CIS, 
cytology at screening does not need to be negative for study participation.
v) Computed tomography (CT) scan of the chest and CT or magnetic resonance imaging 
(MRI) of the abdomen, pelvis, and all other areas of suspected disease to exclude 
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locally advanced or metastatic bladder cancer or synchronous UC in the upper urinary 
tracts within 90 days prior to randomization.
vi) Participants should either be deemed medically unfit for radical cystectomy, or should
have refused radical cystectomy after consultation with their urologist or oncologist.
vii)If tumor tissue was obtained > 70 days prior to randomization, participants must have
a repeat cystoscopy ≤ 70 days prior to randomization (see Section 9.1.4).
c) Pelvic examination, preferably under anesthesia, should be performed within 10 weeks (70
days) of randomization to exclude locally advanced disease.
d) Availability of a suitable formulation and mode of administration of BMS-986205 for the
participant’s needs, as detailed in the IB and pharmacy manual at the time of enrollment.
Please contact the Medical Monitor with any queries.
4) Age and Reproductive Status
a) Males and Females, 18 years of age, or age of majority, and older
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception (see Appendix 4) for the duration of treatment with study
treatment plus 5 months after the last dose of study treatment (ie, 30 days [duration of
ovulatory cycle] plus the time required for nivolumab to undergo approximately 5 half-
lives).
e) Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception (see Appendix 4) for the duration of treatment with study
treatment plus 1 month (approximately 4 weeks) after the last dose of the study treatment.
In addition, male participants must be willing to refrain from sperm donation during this
time.
f)
Male participants will be required to always use a latex or other synthetic condom during
any sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the participants have
undergone a successful vasectomy or if their partner is already pregnant or breastfeeding.
Males should continue to use a condom while on study plus 1 month (approximately
4 weeks) after the last dose of the study treatment. This criterion applies to azoospermic
males as well.
g) WOCBP who are continuously not heterosexually active are exempt from contraceptive
requirements, and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception (Appendix 4), 
which have a failure rate of < 1% when used consistently and correctly. Hormonal contraceptives 
are not highly effective methods of contraception for participants in Arms C and D of this 
study who are WOCBP treated with BMS-986205, since drug interactions of BMS-986205 
with hormone-based contraceptives are not yet known.
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6.2
Exclusion Criteria
1) Medical Conditions
a) Women who are pregnant or breastfeeding
b) Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
c) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer 
with evidence of undetectable Prostate Specific Antigen (PSA), or carcinoma in situ of the 
cervix or breast
d) Participants with serious or uncontrolled medical disorders
e) Participants with a personal or family (ie, in a first-degree relative) history of cytochrome 
b5 reductase deficiency (previously called methemoglobin reductase deficiency) or other 
diseases that put them at risk of methemoglobinemia. All participants will be screened for 
methemoglobin levels prior to randomization.
f)
Participants with a history of G6PD deficiency or other congenital or autoimmune 
hemolytic disorders. All participants will be screened for G6PD deficiency prior to 
randomization.
g) Evidence of locally advanced disease or metastatic bladder cancer as seen in cross-
sectional images of the chest, abdomen, and pelvis 
h) Urothelial cancer (UC) in the upper genitourinary tract (kidneys, renal collecting systems, 
ureters) within 24 months of enrollment
i)
UC and/or CIS in the prostatic urethra within 12 months of enrollment
j)
Locally advanced disease demonstrated by pelvic examination preferably performed under 
anesthesia
k) Previous or concurrent muscle invasive or disseminated/metastatic bladder cancer
l)
Participants must have recovered from the effects of major surgery requiring general 
anesthetic or significant traumatic injury at least 14 days before treatment assignment.
m) Uncontrolled adrenal insufficiency
n) New York Heart Association (NYHA) functional Classification of Heart Failure: Class III 
or Class IV
o) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Participants with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as peripheral neuropathy after 
platinum based therapy, are permitted to enroll.
p) Dementia, altered mental status, or any psychiatric condition that would prohibit the 
understanding or rendering of informed consent or completing quality of life questionnaire.
q) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
unstable angina pectoris, or psychiatric illness/social situations that would limit 
compliance with study requirements.
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r)
Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity.
s) Participants with active interstitial lung disease / pneumonitis or with a history of interstitial 
lung disease/ pneumonitis requiring steroids
t)
Prior history of serotonin syndrome
2) Prior/Concomitant Therapy
a) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
b) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways
c) Prior treatment with BMS-986205 or any other IDO1 inhibitors
d) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization 
e) Prior systemic chemotherapy or immunotherapy for UC. Intravesical chemotherapy and/or 
interferon administered prior to the date of tumor sample submission is permitted.
f)
Prior radiation therapy for bladder cancer
g) Prior surgery for bladder cancer other than TURBT and/or bladder biopsies
h) Use of an investigational agent within 4 weeks of randomization.
i)
Participants who have received a live /attenuated vaccine within 30 days of first treatment.
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100* 103/μL
d) Hemoglobin < 9.0 g/dL (transfusion to achieve this level is not permitted within 2 weeks 
of this laboratory assessment)
e) Serum creatinine > 1.5x ULN, unless creatinine clearance (CLcr) ≥40 mL/min (measured 
or calculated using the Cockroft-Gault formula):
Female CLcr = (140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CLcr = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
f)
AST or ALT > 3.0x ULN
g) Total bilirubin > 1.5x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0x ULN)
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h) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C
antibody (anti-HCV) positive (except if HCV-RNA negative)
i)
Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). Note: Testing for HIV must be performed
at sites where mandated locally. See Appendix 11.
j)
Quantitative or qualitative G6PD assay results suggesting underlying G6PD deficiency
k) Blood methemoglobin > ULN, assessed in an arterial or venous blood sample or by
co-oximetry
l)
Positive pregnancy test at enrollment or prior to administration of study medication
4) Allergies and Adverse Drug Reaction
a) History or presence of hypersensitivity or idiosyncratic reaction to methylene blue
b) History of allergy or hypersensitivity to study drug components
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific
circumstances and only in countries where local regulations permit a person who has been
imprisoned may be included as a participant. Strict conditions apply and BMS approval is
required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, may be
randomized, but are not subsequently treated. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and to respond to queries 
from regulatory authorities. Minimal information includes date of consent, demography, screen 
failure details, eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been treated). If re-
enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single screening or lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
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The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
An investigational product (IP), also known as investigational medicinal product (IMP) in some 
regions, is defined as a pharmaceutical form of an active substance or placebo being tested or used 
as a reference in a clinical study, including products already with a marketing authorization but 
used or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Nivolumab, BMS-986205, and BCG are IPs/IMPs in this study (Table 7-1).
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as non-IPs.
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Table 7-1:
Study Treatments for CA2099UT
Product Description / 
Class and Dosage 
Form
Potency
IP/Non-IP
Blinded or Open 
Label
Packaging / 
Appearance
Storage Conditions
(per label)
BMS-936558-01
(Nivolumab) Solution 
for Injectiona
10 mg/mL
IP
Open Label
Vial
Refer to the label on 
container and/or 
pharmacy manual
BMS-986205-04
50 mg or 100 mg
IP
Open Label
Tablet
Refer to the label on 
container and/or 
pharmacy manual
BCGb
Dose according to 
prescribing information 
for BCG strain and 
preparation 
administered 
IP
Open Label
Vial
Refer to the label on 
container and/or 
pharmacy manual
a May be labeled as “Nivolumab” or “BMS-936558-01 Solution for Injection.”
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. These products
should be prepared/stored/administered in accordance with the package insert or summary of product characteristics (SmPC).
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7.1
Treatments Administered
The selection and timing of dose for each participant is presented in Table 7.1-1.
Study treatment will be dispensed at the study visits as listed in the Schedule of Activities 
(Section 2).
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Nivolumab
480 mg
Solution for injection/ 
every 4 weeks
IV
BMS-986205
100 mg
Tablet/once daily
PO
BMS-986205
50 mg
Tablet/once daily
PO
BCG
Dose according to 
prescribing information 
for BCG strain and 
preparation 
administered 
Once weekly for 6 
weeks, followed by 
once weekly for 3 
weeks at 3 months, 6 
months, and 12 months 
after first BCG dose
intravesical
7.1.1
Nivolumab Dosing
Participants should receive nivolumab at a dose of 480 mg as a 30-minute infusion on Day 1 of 
each treatment cycle (1 cycle = 4 weeks) until recurrence, progression, unacceptable toxicity, 
withdrawal of consent, or completion of 52 weeks of treatment, whichever occurs first. Participants 
randomized to Arms A or C should begin study treatment within 3 calendar days of randomization.
Participants randomized to Arms B or D should begin study treatment within 3 calendar days of 
randomization or after 14 days from last TURBT or bladder biopsy, whichever is later.
No dose escalations or reductions are allowed for nivolumab after the safe-dose level has been 
determined in the safety lead-in. For Q4W dosing cycles, participants may be dosed within a 
± 3 day window. Premedication is not recommended for the first dose of nivolumab.
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.7.5.
Doses of nivolumab may be interrupted (ie, infusion interruption), delayed, or discontinued 
depending on how well the participant tolerates the treatment. Dosing visits are not skipped, only 
delayed. BMS-986205 treatment should be continued if nivolumab dosing is interrupted or 
delayed. BMS-986205 treatment should be discontinued if nivolumab administration is 
discontinued.
7.1.2
BMS-986205 Dosing
A bottle of BMS-986205 should be dispensed to participants at each Day 1 visit within a cycle. 
Participants should be instructed that BMS-986205 should be administered once a day 
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(approximately 24 hours apart) following a meal, with approximately 240 mL (8 oz.) of water. 
Refer to Pharmacy Manual for additional details on dosing administration. Full details regarding 
BMS-986205 formulation and mode of administration at the time of enrollment are detailed in the 
IB and pharmacy manual, which may be updated throughout the study. Please contact the Medical 
Monitor with any queries.
Participants should be provided with pill diaries at each visit and instructed to record intake of 
BMS-986205 in the diary after each daily administration.
BMS-986205 will be administered on an out-patient basis. On days when nivolumab is 
administered, the dose of BMS-986205 should be given before the dose of nivolumab.
Participants should receive BMS-986205 until recurrence, progression, unacceptable toxicity, 
withdrawal of consent by the participant, or completion of 12 months (52 weeks) of treatment, 
whichever occurs first. Participants randomized to Arms A or C should begin study treatment 
within 3 calendar days of randomization. Participants randomized to Arms B or D should begin 
study treatment within 3 calendar days of randomization or after 14 days from the last TURBT or 
bladder biopsy, whichever is later. Doses of BMS-986205 may be modified, delayed, or 
discontinued depending on how well the participant tolerates the treatment (See Section 7.4.2
[modification], Section 7.4.4.2 [delay], and Section 8.1.2 [discontinuation]). If the dose of 
BMS-986205 is reduced, re-escalation will not be permitted. Skipped doses during dose delays
should not be administered within the same cycle.
If nivolumab dosing is delayed for reasons other than study drug toxicity (eg, administrative issues, 
holidays, etc), BMS-986205 dosing should continue uninterrupted.
For details on prepared drug storage, preparation, and administration, please refer to the BMS-
986205 IB and/or pharmacy binder. The selection and timing of dose for each participant is 
provided in Table 7.1-1.
7.1.3
BCG Dosing 
The first BCG treatment will begin a minimum of 14 days after the bladder biopsy and/or TURBT
performed prior to randomization. Participants should receive an intravesical instillation of BCG 
weekly for 6 weeks starting on Day 1 of treatment, and then weekly for 3 weeks at 3 months, 6 
months and 12 months after the first BCG dose. See Table 2-3 for the BCG dosing schedule. BCG 
should not be given within 14 days after any TURBT or bladder biopsy.
No dose escalations or reductions are allowed for BCG after the safe-dose level has been 
determined in the safety lead-in.
The BCG dose should be prepared and administered according to the package insert. BCG may 
be obtained by the investigational sites as local commercial product in certain countries if 
allowed by local regulations. These products should be prepared/stored/administered in 
accordance with the package insert or summary of product characteristics (SmPC).
A urethral catheter will be inserted into the bladder by a qualified medical professional under 
aseptic conditions. The bladder will then be drained, after which the BCG suspension will be 
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instilled slowly, under gravity. The catheter will then be withdrawn. BCG should not be given if 
the urethra is traumatized during catheter insertion or if there is gross hematuria.
The participant should retain the BCG suspension for as long as possible for up to 2 hours. The 
participant should lie prone during the first 15 minutes following instillation, after which the 
participant is allowed to be in the upright position. At the end of 2 hours, the participant should 
void in the seated position. The participant will be instructed to maintain adequate fluid intake in 
the hours following BCG treatment to flush the bladder.
Participants should receive BCG until recurrence, progression, unacceptable toxicity, withdrawal 
of consent by the participant, or completion of 52 weeks of treatment, whichever occurs first. 
Participants should begin study treatment within 3 calendar days of randomization or 14 days after 
the last bladder tumor resection or bladder biopsy, whichever occurs later. If BCG treatment is 
delayed for any reason, nivolumab with or without BMS-986205 treatment should continue as 
scheduled, unless the participant has study drug toxicity meeting nivolumab and/or BMS-986205 
dose delay criteria. If nivolumab and/or BMS-986205 treatment is delayed for any reason, BCG 
treatment should continue as scheduled, unless the participant has study drug toxicity meeting 
BCG dose delay criteria.
For details on prepared drug storage, preparation, and administration, please see the BCG package 
insert.
7.2
Method of Treatment Assignment
All participants will be randomized using an Interactive Response Technology (IRT). Before the 
study is initiated, each user will receive log-in information and directions on how to access the 
IRT. After the participant’s initial eligibility is established and informed consent has been 
obtained, the participant must be enrolled into the study by accessing an IRT to obtain the 
participant number. Every participant who signs the informed consent form must be assigned a 
participant number in IRT. The investigator or designee will register the participant for enrollment 
by following the enrollment procedures established by BMS. The following information is 
required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through the IRT. Disease status data will be transferred directly from the PRC. Tumor 
PD-L1 expression data will be transferred directly from analyzing lab. The following information 
is required for participant randomization:
•
Participant number 
•
Year of birth
•
Disease status based on PRC assessment (CIS alone vs CIS with Ta vs CIS with T1)
−
CIS participants with both Ta and T1 disease will be classified as CIS with T1
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Tumor PD-L1 status (expressing [≥1%] vs non-expressing [< 1%] or indeterminate/not 
evaluable)
The randomization procedure will dynamically minimize the imbalance between treatment groups 
within the levels of the 2 stratification factors above (disease status and tumor PD-LI status) (see 
Section 5.1.2).
•
Randomization will be based on the categories related to availability of BCG and BCG strains 
at the site at the time of participant randomization (No BCG available vs TICE BCG available 
vs Non-TICE BCG available)
−
For the purposes of randomization, any BCG strain that becomes approved in the US during 
the conduct of the study will be included in the category of TICE BCG
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
See Section 5.1.2 for a description of treatment assignment during the Randomization Phase of the 
study.
7.3
Blinding
This is a randomized, open-label study. It has been determined that blinding is not required to meet 
study objectives. Blinding procedures are not applicable and access to treatment assignment 
information is unrestricted. The specific treatment to be taken by a participant will be assigned 
using IRT. The site will contact the IRT prior to the start of study treatment administration for each 
participant. The site will record the treatment assignment on the applicable case report form, if 
required.
7.4
Dosage Modification
7.4.1
Nivolumab Dose Modifications
No dose modifications are permitted for nivolumab after a safe dose has been determined in the 
safety lead-in.
7.4.2
BMS-986205 Dose Modifications
A dose reduction of BMS-986205 is defined as a change from a 100 mg QD tablet to a 50 mg QD 
tablet. 
Only one dose reduction is permitted. The participant must discontinue study treatment if a 
subsequent dose reduction of BMS-986205 is required (see Section 8.1.2).
Re-escalation of BMS-986205 will not be permitted once the dose of BMS-986205 has been 
reduced for a participant.
Doses of BMS-986205 should be reduced for the following AEs attributable to study therapy that 
do not otherwise meet criteria for discontinuation:
•
Grade 3 fatigue, nausea, vomiting, or anemia related to study treatment
•
Methemoglobin ≥15%
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•
Clinically significant elevations in methemoglobin (generally 10%, with a normal hemoglobin
level) with any associated Grade 3 AE (hypoxia, dyspnea, confusion, etc.) attributable to
sustained elevations of methemoglobin and not attributable to another etiology
•
QTcF > 500 msec confirmed by at least 1 repeat ECG and at least 60 msec above baseline (See
Appendix 8)
Dose modification and delay of BMS-986205 may occur in the setting of lower grade AEs and/or 
be more conservative than indicated above based on the clinical judgment of the investigator and 
in consultation with the BMS Medical Monitor/designee. For an AE requiring dose modification, 
BMS-986205 should be delayed to allow improvement of the AE, even if the AE does not 
otherwise meet criteria for dose delay (Section 7.4.4.2).
7.4.3
BCG Dose Modifications
No dose modifications are permitted for BCG after the safe-dose level has been determined in the 
safety lead-in. In the event that BCG treatment must be discontinued due to an AE, the participant 
may be permitted to continue treatment with nivolumab or nivolumab plus BMS-986205 where 
applicable.
7.4.4
Dose Delay Criteria
7.4.4.1
Nivolumab
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related laboratory abnormality, with the following exceptions:
o
Grade 3 lymphopenia or asymptomatic amylase or lipase elevations does not require
dose delay
o
Grade ≥3 AST, ALT, or Total Bilirubin will require dose discontinuation (see
Section 8.1.1)
•
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, either confirmed
or suspected
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.
7.4.4.2
Nivolumab Plus BMS-986205
Nivolumab and BMS-986205 administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue, nausea, vomiting and anemia
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•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
Grade 3 drug-related fatigue, nausea, vomiting, and anemia
•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase elevations do not require dose 
delay
−
Grade ≥3 AST, ALT, or Total Bilirubin will require dose discontinuation (see Section 8.1)
•
SARS-CoV-2 infection, either confirmed or suspected
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication
If nivolumab dosing is delayed for reasons other than study drug toxicity (eg, administrative issues, 
holidays, etc.), BMS-986205 dosing should continue uninterrupted.
In addition, only BMS-986205 should be delayed for the following:
•
Methemoglobin ≥15%
•
Clinically significant elevations in methemoglobin (generally 10% with a normal hemoglobin 
level51) with any associated Grade 3 AE (hypoxia, dyspnea, confusion, etc.) attributable to 
sustained elevations of methemoglobin and not attributable to another etiology
•
QTcF > 500 msec confirmed by at least 1 repeat ECG and at least 60 msec above baseline (See 
Appendix 8)
Participants may continue to receive nivolumab during dose delays of BMS-986205 for elevations 
of methemoglobin and associated events, as well as QTcF prolongations.
For participants with methemoglobin elevations with associated Grade 3 AEs, if a contribution of 
nivolumab to the associated AE cannot be ruled out (eg, a participant with dyspnea in whom 
pneumonitis has not yet been ruled out), nivolumab dosing should be delayed as well. See 
Section 7.7.4 for management of methemoglobinemia.
If BMS-986205 dosing is delayed, dose reduction may be necessary. See Section 7.4.2.
If dosing is resumed after a delay, BMS-986205 may be resumed as soon as the criteria to resume 
treatment are met (see Section 7.4.5.2). Nivolumab should be resumed as soon as possible after 
criteria to resume treatment are met but may be resumed later than BMS-986205 given the 
differences in each drug’s administration.
Participants who require delay of any study treatment should be re-evaluated weekly or more 
frequently if clinically indicated and should resume dosing when re-treatment criteria are met.
Table 7.4.4.2-1 provides the conditions requiring dose delay or dose reduction for nivolumab and 
BMS-986205 in Arms C and D.
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Table 7.4.4.2-1:
Summary Table for Dose Delay and Reduction 
Situation
Nivolumab delay
BMS-986205 
delay
BMS-986205 
Reduction after 
Delay
Grade 2 non-skin, drug-related AE, except 
fatigue, nausea, vomiting and anemia
Yes
Yes
No
Grade 2 drug-related creatinine, AST, ALT 
and/or Total Bilirubin abnormalities
Yes
Yes
No
Grade 3 skin, drug-related AE
Yes
Yes
No
Grade 3 drug-related laboratory abnormality 
(exceptions apply)
Yes
Yes
No
Grade 3 drug-related fatigue, nausea, vomiting, 
and anemia
Yes
Yes
Yes
Methemoglobin ≥ 15% or any clinically 
significant elevation with associated Gr 3 AE not 
attributable to another etiology
No
Yes
Yes
QTcF > 500 msec (and > 60 msec above 
baseline)
No
Yes
Yes
Other lower grade AEs (in consultation with 
Medical Monitor/designee)
Possibly Yes
Possibly Yes
Possibly Yes
7.4.4.3
BCG
Administration of BCG should be delayed if the participant develops a concurrent febrile illness, 
a urinary tract infection (UTI), or gross hematuria during the treatment period. Administration of 
nivolumab or nivolumab plus BMS-986205 should not be delayed if BCG treatment is delayed.
7.4.5
Criteria to Resume Dosing
7.4.5.1
Nivolumab
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor (or designee).
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Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume 
treatment if they meet all of the following:
−
At least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive test result (eg, reverse transcription-polymerase chain reaction [RT-
PCR] or viral antigen)
−
Resolution of acute symptoms (including at least 24 hours has passed since last fever 
without fever reducing medications)
−
Evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment
−
Consultation with the Medical Monitor or designee. For suspected cases, treatment may 
also resume if SARS-CoV-2 infection is ruled out and other criteria to resume treatment 
are met
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor (or 
designee). Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement.
7.4.5.2
Nivolumab Plus BMS-986205
Participants may resume treatment with study treatments when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue.
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity.
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete.
•
Participants with combined AST/ALT AND total bilirubin values meeting discontinuation 
parameters (Section 8.1.1) should have treatment permanently discontinued. 
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor/designee.
•
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume
treatment if they meet all of the following:
−
At least 10 days (20 days for severe/critical illness) have passed since symptoms first 
appeared or positive test result (eg, RT-PCR or viral antigen)
−
Resolution of acute symptoms (including at least 24 hours has passed since last fever 
without fever reducing medications)
−
Evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment
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−
Consultation with the Medical Monitor or designee. For suspected cases, treatment may
also resume if SARS-CoV-2 infection is ruled out and other criteria to resume treatment
are met
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor/designee. Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.
For participants who have BMS-986205 held for elevations of methemoglobin, dosing may resume 
when the methemoglobin levels have decreased to below the institutional ULN and any associated 
AEs have resolved to Grade ≤1 or baseline value. Dose modification of BMS-986205 should be 
considered when resuming after a delay (see Section 7.4.2).
7.4.5.3
BCG
BCG administration can resume when the concurrent febrile illness, UTI, or gross hematuria 
resolve and antibiotic treatment has ended.
7.4.6
Management Algorithms 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and BMS-986205 are considered as 
immuno-oncology agents in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary (For participants with dyspnea, CBC and methemoglobin should be measured)
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological (For participants with confusion, methemoglobin should be measured)
•
Myocarditis
The above algorithms are found in the Appendix 5 of this protocol.
7.4.7
Detection of Methemoglobinemia
BMS-986205 may produce a p-chloroaniline metabolite. P-chloroaniline has been associated with 
the production of methemoglobin. Symptoms of methemoglobinemia are related to the lack of 
oxygen delivery to tissues and are proportional to the fraction of methemoglobin, as described 
below for participants with normal hemoglobin levels. 
Symptoms associated with elevations of methemoglobin are as follows:
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0% to 10% - Usually asymptomatic
•
10% to 20% - Cyanosis without other symptoms
•
20% to 50% - Headache, dyspnea, lightheadedness (possibly syncope), weakness, confusion, 
palpitations, chest pain
•
50% to 70% - Coma, seizures, arrhythmias; acidosis
¾ 70% - Usually death
Note that participants with anemia may experience symptoms at lower methemoglobin percentages 
than listed above, depending on the degree of anemia. 
Increasing levels of methemoglobin may confound the results of standard pulse oximeters, with 
values of around 85% reported consistently as methemoglobin levels increase, regardless of the 
true oxygen saturation.
When methemoglobinemia is suspected, part of the diagnostic work-up includes evaluation for 
other disorders that can present with a similar clinical picture, including cardiac and pulmonary 
disease. A fresh peripheral blood sample (either venous or arterial) should be sent for evaluation 
of methemoglobin levels; methemoglobin levels may vary with storage of blood.
For management of methemoglobinemia, see Section 7.7.4. Testing is performed at screening, and 
as clinically indicated for all participants, and at every cycle for participants in Arms C and D.
7.5
Preparation/Handling/Storage/Accountability
For nivolumab, refer to the current version of the IB and/or Pharmacy Manual for complete 
storage, handling, dispensing, and infusion information.
Similarly, for BMS-986205, refer to the current version of the IB and/or Pharmacy Manual for 
complete storage, handling, and dispensing information.
For BCG, refer to the current prescribing information for complete storage, handling, and 
dispensing information.
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
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documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
7.5.1
Retained Samples for Bioavailability / Bioequivalence
Not applicable.
7.6
Treatment Compliance
Treatment compliance of nivolumab and BCG will be monitored by drug accountability as well as 
the participant’s medical record and electronic case report form (eCRF). 
Treatment compliance of BMS-986205 will be monitored by drug accountability, as well as by 
recording BMS-986205 administration in the participant pill diary (as applicable), medical record, 
and eCRF. Participants should bring all drug containers to each study visit for drug reconciliation. 
The pill diary should be reviewed at each clinic visit and submitted at the end of each cycle, as 
applicable.
7.7
Concomitant Therapy
Concomitant medications are recorded at baseline and throughout the treatment phase of the study 
in the appropriate section of the eCRF. All medications (prescriptions or over-the-counter 
medications) continued at the start of the study or started during the study and different from the 
study treatment must be documented in the concomitant therapy section of the eCRF.
Coronavirus disease 2019 (COVID-19) vaccines that are NOT live are allowed and should be 
handled in the same manner as other vaccines. Administration may occur during the study, 
including during the administration of the BMS study treatment and after the last administration 
of the BMS study treatment. Non-live COVID-19 vaccination is considered a simple concomitant 
medication within the study. However, the efficacy and safety of non-live vaccines (including non-
live COVID-19 vaccines) in participants receiving nivolumab or nivolumab plus BMS-986205, 
with or without intravesical BCG is unknown.
7.7.1
Prohibited and/or Restricted Treatments
Prohibited and/or restricted medications taken prior to and during study treatment administration 
in the study are described below. Medications taken within 14 weeks prior to study treatment 
administration must be recorded on the CRF. Vaccine use 30 days prior to randomization should 
be documented. 
7.7.1.1
Prohibited Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):
•
Concomitant use of strong inhibitors of CYP3A4 and/or CYP1A2 or strong inducers of 
CYP3A4 and/or CYP1A2 (see Appendix 7) (Treatment Arm C and D only)
•
Immunosuppressive agents
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Immunosuppressive doses of systemic corticosteroids (except as stated in Sections 7.7.2 and 
7.7.3)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of malignancy)
•
Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as
supportive care. Please see Section 7.7.1.2 for additional restricted medications. BMS Medical 
Monitor (or designee) approval is required prior to concurrent use with BMS-986205
•
Prophylactic antimicrobial therapy except for those administered prior to TURBT as per the 
institutional guidelines
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.
7.7.1.2
Restricted Treatments
Restricted therapies are not prohibited but are not recommended. Investigators should consider 
possible benefit risk implications of enrolling and treating participants in whom the following are 
clearly medically indicated:
•
Grapefruit and Seville oranges and their juices can inhibit CYP3A4 (see Appendix 7) and 
should not be consumed while on treatment.
•
Concurrent use of moderate inhibitors or inducers of CYP3A4 and/or CYP1A2 may affect the 
systemic exposure of BMS-986205. See Appendix 7 for a list of CYP3A4 and/or CYP1A2 
modulators.
•
Concurrent smoking (tobacco, marijuana, etc.) may induce CYP1A2 and decrease the systemic 
exposure of BMS-986205. 
•
Caution is warranted when consuming marijuana by means other than smoking as it may lead 
to increased exposure of BMS-986205 through interaction with metabolic enzymes.
•
Caution is warranted when administering BMS-986205 to participants taking drugs that are 
highly dependent on CYP3A4 or CYP2B6 for metabolism. See Appendix 7 for a list of 
sensitive CYP3A4 and CYP2B6 substrates.
•
Caution is warranted when administering BMS-986205 to participants taking drugs that may 
be associated with QT prolongation. See Appendix 8 for a list of common medications 
associated with QT prolongation.
•
Caution is warranted when administering BMS-986205 to participants taking drugs that are 
subject to extensive intestinal efflux by P-gp/BCRP. See Appendix 9 for a list of common 
P-gp/BCRP substrates.
•
Caution is warranted when using other agents known to cause methemoglobinemia (see 
Appendix 10). Dapsone, topical anesthetics, and antimalarial drugs are the most likely agents, 
and thus these medications should only be used after discussion with the Medical 
Monitor/designee.
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Antibacterial agents are permitted for treatment of UTIs but necessitate delay of BCG dosing
until treatment with antibacterial agent(s) has ended.
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses >10 
mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
The development of serotonin syndrome has been associated with exposure to another 
investigational agent that inhibits the IDO1 enzyme. No case of serotonin syndrome has been 
observed with administration of BMS-986205. Given the possibility of a class effect, there is a 
theoretical risk that BMS-986205 could cause an increase in serotonin levels in the brain that might 
trigger serotonin syndrome when administered in combination with serotonergic agents or 
tryptophan supplements. Use caution and monitor for symptoms of serotonin syndrome in 
participants receiving concurrent serotonergic psychiatric medications and/or tryptophan 
supplements.
7.7.2.1
Imaging Restrictions and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this participant population. In addition, participants may be excluded from MRI if 
they have tattoos, metallic implants, pacemakers, etc.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator and the standards set by the local Ethics Committee.
7.7.3
Permitted Therapy
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-
type hypersensitivity reaction caused by a contact allergen) is permitted.
7.7.4
Treatment of Methemoglobinemia
The following management recommendations are intended as guidelines for the investigator and 
may be modified based on institutional practices or local SOC, as appropriate. See Section 7.4.7
for guidance on detection of methemoglobinemia.
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Initial care includes supportive measures and the administration of supplemental oxygen. In mild 
cases, recovery often occurs simply by delaying the administration of the offending medication. 
Concomitant medication lists should be reviewed for medications besides study treatment which 
can cause methemoglobinemia (see Appendix 10).
Further treatment is generally indicated when the methemoglobin level is above 20% or is 
associated with symptoms.
Intravenous methylene blue is the first-line antidotal agent and works by restoring the oxygen 
carrying capacity of hemoglobin by reduction of methemoglobin from its oxidized state. It is given 
as a 1% solution at a dose of 1 to 2 mg/kg. Most participants require only 1 dose, and symptoms 
should resolve within 1 hour. Methylene blue may confound the interpretation of methemoglobin 
levels detected by co-oximetry; alternative methods should be used after treatment with methylene 
blue if methemoglobin level monitoring is required. Methylene blue should be used with caution 
in participants with concurrent use of serotonergic psychiatric medications, as this could increase 
the risk of serotonin syndrome. 
Exchange transfusion and hyperbaric oxygen treatment are second-line options for participants 
with severe methemoglobinemia whose condition does not respond to methylene blue or who 
cannot be treated with methylene blue. Participant transfer should occur when life-threatening 
methemoglobinemia that is refractory to treatment occurs in a facility that cannot provide the 
appropriate critical care.
7.7.5
Treatment of Infusion-related Reactions
If an infusion-related reaction should occur, it might manifest with fever, chills, rigors, headache, 
rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions. All Grade 3 or 4 infusion reactions should be reported within 24 hours to the study 
Medical Monitor/designee and reported as an SAE if it meets the criteria. Infusion reactions should 
be graded according to NCI CTCAE (Version 4.03) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
≤24 hours):
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•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant 
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant 
closely. If symptoms recur, then no further study treatment will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab infusion. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, 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):
•
Immediately discontinue infusion of study treatment. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.8
Treatment After the End of the Study
Not applicable.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
•
Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
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consent for any further contact with him/her or persons previously authorized by participant to 
provide this information.
•
Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the
investigator, indicates that continued participation in the study is not in the best interest of the
participant
•
Termination of the study by BMS
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under
specific circumstances and only in countries where local regulations permit, a participant who
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and
BMS approval is required.)
•
Additional protocol-specified reasons for discontinuation (Section 8.1.1)
•
Disease progression or recurrence
Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study treatment will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for participant safety). Please 
call the BMS Medical Monitor within 24 hours of awareness of the pregnancy. If the investigator 
determines a possible favorable benefit/risk ratio that warrants continuation of study treatment, a 
discussion between the investigator and the BMS Medical Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate CRF page.
8.1.1
Discontinuation of Nivolumab
Nivolumab treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical
therapy and does not improve to Grade 1 severity within the time frame permitted for dose
delays OR requires systemic treatment
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•
Any Grade 3 non-skin, drug-related AE lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic
toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation.
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT or total bilirubin requires discontinuation*
♦Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN
*In most cases of Grade 3 AST or ALT elevation, study treatment(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study treatment(s), a discussion between the investigator and the 
BMS Medical Monitor/designee must occur.
•
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not require 
discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
3 calendar days of their onset
−
Grade 4 drug-related endocrinopathy AEs, such as, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor/designee. 
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the participant with continued nivolumab 
dosing
•
Any event requiring 10 mg per day or greater prednisone or equivalent for more than 12 weeks
•
Any event that leads to delay in dosing lasting > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. (Note: Protocol AE management algorithms provide guidance to initiate steroid 
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taper when AE has resolved to < Grade 1.  Therefore, persistent Grade > 2 AEs 
necessitating delay for > 10 weeks would require discontinuation).
−
Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-related
reasons may be allowed if approved by the BMS Medical Monitor/designee.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the BMS 
Medical Monitor/designee must be consulted. Efficacy assessments must continue as per protocol 
even if dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 4 weeks or more frequently if clinically indicated during such dosing delays.
8.1.2
Discontinuation of BMS-986205 
BMS-986205 treatment should be permanently discontinued for the following:
•
Any event requiring discontinuation of nivolumab as in Section 8.1.1
•
Any event requiring more than 1 dose reduction of BMS-986205 (see Section 7.4.2)
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the
investigator, presents a substantial clinical risk to the participant with continued BMS-986205
dosing
•
For participants who delay BMS-986205 but continue nivolumab with or without BCG, any
dose delay of BMS-986205 lasting >
10 weeks will result in the discontinuation of
BMS-986205 only and participants may continue treatment with nivolumab with or without
BCG.
•
Any occurrence of serotonin syndrome
8.1.3
Discontinuation of BCG
BCG treatment should be permanently discontinued for the following:
•
Any event requiring discontinuation of nivolumab as in Section 8.1.1
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the
investigator, presents a substantial clinical risk to the participant with continued BCG dosing
•
Systemic BCG reaction (see current BCG prescribing information for description)*
•
BCG infection (see current BCG prescribing information for description)*
* Participant may continue nivolumab treatment with or without BMS-986205 if intolerance to
BCG develops.
8.1.4
Post Study Treatment Study Follow-up
Per Protocol Amendment 04, efficacy follow-up is not required. Participants, on efficacy follow-up 
at the time of Protocol Amendment 04 implementation at each site, will conclude study 
participation.
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Participants will be followed for assessment of safety through 100 days post last dose of study 
treatment.
BMS may request that data be collected on all treated participants outside of the protocol defined 
window (Section 2). At the time of this request, each participant will be contacted to determine 
their disease status unless the participant has withdrawn consent for all contacts or is lost to follow-
up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the
investigator, as to whether the withdrawal is from further treatment with study treatment only
or also from study procedures and/or post treatment study follow-up, and entered on the
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured,
publicly available information should be used to determine vital status only as appropriately
directed in accordance with local law.
•
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.
8.3
Lost to Follow-up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study
has been included in the participant’s informed consent, then the investigator may use a
Sponsor retained third-party representative to assist site staff with obtaining participant’s
contact information or other public vital status data necessary to complete the follow-up
portion of the study.
•
The site staff and representative will consult publicly available sources, such as public health
registries and databases, in order to obtain updated contact information.
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If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2). 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
labs until all study drug-related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary AEs, the participant should be immediately evaluated 
to rule out pulmonary toxicity, according to the suspected pulmonary toxicity management 
algorithm in the BMS-936558 (nivolumab) Investigator Brochure (see also Appendix 5). In 
addition, blood methemoglobin levels should be evaluated to rule out methemoglobinemia (see 
Section 7.4.7) and CBC measured to rule out anemia in participants with dyspnea.
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
This study will consist of three phases: screening, treatment, and follow-up.
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Screening Phase:
•
Begins by establishing the participant’s initial eligibility and signing of the informed consent
form (ICF).
Treatment Phase:
•
Begins with the randomization request to the IRT. Based on categories related to the
availability of BCG and/or strain at the time of participant randomization, the participant is
assigned to one of the 3 following arms: nivolumab (Arm A), nivolumab + BCG (Arm B), or
nivolumab + BMS-986205 (Arm C) (see Figure 5.1-1); nivolumab + BMS-986205 + BCG
(Arm D) will be paused after the safety lead-in.
•
Ends when the participant is discontinued from study therapy or completes 52 weeks of study
therapy. For a complete list of reasons for treatment discontinuation, see Section 8.
Follow-up Phase
•
Begins when the decision to discontinue a participant from study therapy is made (no further
treatment with study therapy) or when 12 months (52 weeks) of study therapy has been
completed, and ends when safety follow-up is completed by participant.
9.1
Efficacy Assessments
Per Protocol Amendment 04, efficacy assessments will be conducted per the local standard of care.
Complete Response (CR) Definition
CR will be determined throughout the duration of the study by the investigator. Determination of 
CR will be based on the local standard of care. 
Recurrence Definition
Recurrence will be determined in all participants throughout the duration of the study by the 
investigator according to the local standard of care. 
Progression Definition
Progression will be determined in all participants throughout the duration of the study by the 
investigator according to the local standard of care.
9.1.1
Imaging Assessment for the Study
Per Protocol Amendment 04, efficacy assessments will be conducted per the local standard of care.
9.1.2
Cystoscopy
Per Protocol Amendment 04, efficacy assessments will be conducted per the local standard of care.
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9.1.3
Urine Cytology
Per Protocol Amendment 04, efficacy assessments will be conducted per the local standard of care.
9.1.4
Bladder Biopsy
Per Protocol Amendment 04, efficacy assessments will be conducted per the local standard of care.
Complete resection of all papillary disease (Ta/T1) is required for all participants within 10 weeks 
(70 days) of randomization. For participants with clinical stage T1 disease, a repeat TURBT is 
required within 8 weeks after the initial TURBT to confirm complete resection of disease and to 
ensure that no tumor has invaded the muscularis propria of the bladder. The location, number, and 
size of each bladder tumor should be documented in the screening CRF.
Any areas of abnormality consistent with possible CIS (such as erythema) must be biopsied and/or 
resected prior to randomization. The location of the abnormality should be documented in the CRF. 
Random sampling of the bladder mucosa for the detection of occult CIS should also be performed 
prior to randomization if possible. Biopsies should be obtained from the bladder dome, right and 
left lateral walls, posterior wall, trigone, and prostatic urethra (in male participants). 
If the tumor tissue was obtained > 70 days prior to the anticipated randomization date, a repeat 
cystoscopy is required to ensure the participant does not have recurrent papillary disease. The 
repeat cystoscopy must be completed ≤ 70 days prior to randomization. If there is evidence of
papillary NMIBC on the repeat cystoscopy, TURBT is required and the participant’s eligibility 
needs to be reassessed and the baseline disease stage will be updated to take account of all TURBT 
findings. Tumor tissue samples collected during the repeat biopsy (1-10 hematoxylin and eosin 
[H&E] stained slides, with at least 1 slide/disease site) confirming the diagnosis of high-risk 
NMIBC must be submitted to the independent PRC prior to randomization. At least one slide 
containing muscularis propria will be submitted. For participants with clinical stage T1 disease, a 
repeat TURBT is required within 8 weeks after the initial TURBT to confirm complete resection 
of disease and to ensure that no tumor has invaded the muscularis propria of the bladder.
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
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exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s CRF.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of non-serious AE information should begin at the initiation of study treatment and 
at the time points specified in the Schedule of Activities (Section 2). All non-serious adverse events 
(not only those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 100 days following discontinuation of study treatment. 
Non-serious AE information should also be collected from the start of a placebo lead-in period or 
other observational period intended to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the IBs for nivolumab and BMS-986205 represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized and never treated with study drug, SAEs 
should be collected for 30 days from the date of randomization.
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a 
follow-up cystoscopy). The investigator must report any SAE that occurs after these time periods 
and that is believed to be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed
consent will be recorded on the appropriate section of the CRF section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated
in Appendix 3.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of this being
available.
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection must be collected from the date of the participant’s written consent until 100 days 
following last dose.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the Sponsor.
The method of evaluating and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
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9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in 
the context of known adverse events, when appropriate for the program or protocol.
9.2.3
Follow-up of AEs and SAEs
•
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they
become serious (see Appendix 3).
•
Follow-up is also required for non-serious AEs that cause interruption or discontinuation of
study treatment and for those present at the end of study treatment as appropriate.
•
All identified non-serious AEs must be recorded and described on the non-serious AE page of
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2), and AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, until the event is deemed irreversible, or until the participant is lost 
to follow-up (as defined in Section 8.3), or for suspected cases, until SARS-CoV-2 infection is 
ruled out.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of a
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the BMS 
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Medical Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form 
to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor within 
24 hours of awareness of the pregnancy.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as: 
1) ALT or AST elevation > 3 times ULN
AND
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND
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3) No other immediately apparent possible causes of aminotransferase elevation and
hyperbilirubinemia, including, but not limited to, viral hepatitis, preexisting chronic or acute
liver disease, or the administration of other drug(s) known to be hepatotoxic
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should
also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.
9.2.9
Adverse Events of Special Interest
Adverse events of special interest (AEOSI) have been defined for this protocol. BMS requires 
expedited reporting by the investigator of these AEOSI to BMS. These are:
•
Hemophagocytic lymphohistiocytosis (HLH; also known as histiocytosis haematophagic)
•
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome
These AEOSI, whether related or not related to study drug, must be reported to BMS or designee
within 24 hours of awareness of the event. These AEOSI are medically important events. The 
reporting system for SAEs should be used (see Section 9.2.4 and Appendix 3). HLH and DRESS 
syndrome may both pose diagnostic challenges due to varying clinical manifestations and signs 
and symptoms that may overlap with other clinical events. To assist investigators in identifying 
constellations of clinical symptoms that may be consistent with one of these diagnoses, 
standardized scoring criteria are provided in Appendix 12. Formal evaluation and documentation 
of diagnostic scores based on these systems is not required; investigators should use their best 
clinical judgment as informed by these provided criteria to determine if a participant has 
experienced one of these AEOSI.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important.
Overdoses that meet the regulatory definition of SAE will be reported as an SAE (see Appendix 
3).
In the event of an overdose the investigator/treating physician should:
1) Contact the Medical Monitor/designee immediately
2) Closely monitor the participant for AEs/SAEs and laboratory abnormalities
3) Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2). 
Safety assessments include AEs, physical examinations, vital signs, performance status, oxygen 
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saturation, ECGs, assessment of signs and symptoms, laboratory tests, and pregnancy tests as 
outlined in the Schedule of Activities.
9.4.1
Clinical Safety Laboratory Assessments
•
Investigators must document their review of each laboratory safety report.
•
All clinical safety laboratory assessments will be performed locally per the Schedule of 
Activities. These laboratory assessments are identified in Table 9.4.1-1.
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Table 9.4.1-1:
Clinical Laboratory Assessments
Hematology
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Methemoglobin - screening, every cycle for participants in Arms C and D, and as clinically indicated
G6PD levels - screening only
Serum Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Gamma-glutamyl transferase (only when alkaline phosphatase is 
≥Grade 2)
Direct bilirubin
Albumin
Lactate dehydrogenase (LDH)
Uric acid
TSH (reflex to free T3 and T4 if abnormal)
Sodium
Potassium
Chloride
Calcium
Phosphate
Magnesium
Creatinine
Creatinine clearance (CLcr) - screening only
Blood Urea Nitrogen (BUN) or Serum Urea 
Level
Glucose 
Urinalysis (at screening)
Protein
Glucose
Blood
Leukocyte esterase and/or WBC
Specific gravity
pH
Urinalysis (at visits BCG is administered)
Protein
Glucose
Blood
Leukocyte esterase and/or WBC
Specific gravity
pH
Microscopic analysis required for abnormal dipstick urinalysis or clinical symptoms suggestive of urinary 
tract infection.
Presence of WBCs, RBCs, or bacteria
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Table 9.4.1-1:
Clinical Laboratory Assessments
Serology (at screening)
Serum for hepatitis C antibody (if Hepatitis C antibody is positive reflex to hepatitis C RNA) or hepatitis C RNA, 
hepatitis B surface antigen, HIV-1 and HIV-2 antibodies. (Testing for HIV-1 and HIV-2 must be performed at 
sites where mandated by local requirements [Appendix 11])
C-reactive protein
Other Analyses
Pregnancy test (women of child-bearing potential [WOCBP] only: minimum sensitivity 25 IU/L or equivalent 
units of human chorionic gonadotropin [HCG]), Section 2).
Follicle stimulating hormone (FSH) screening -only required to confirm menopause in women < age 55 (if 
needed to document postmenopausal status as defined in Appendix 4)
9.4.2
Imaging Safety Assessment
Not applicable.
9.5
Pharmacokinetics
9.5.1
Background
Pharmacokinetics of BMS-986205 
Preliminary
PK data are available from participants who received BMS-986205 in 
Study CA017003 at doses of 25 to 400 mg during monotherapy. Following BMS-986205 
administration with a light meal, the median Tmax was 3 to 4 hours (ranging from 1 to 8 hours). 
Geometric mean apparent clearance (CL/F) values on Day 14 ranged from 12.5 to 20.8 L/h. 
Accumulation based on AUC(0-24h) between Days 1 and 14 ranged from 2.1- to 3.6-fold, 
supportive of once daily dosing of BMS-986205. Based on the observed accumulation index of 
AUC, an effective half-life in the range of 26 hours to 51 hours can be estimated. Following a 
single dose administration of 100 mg BMS-986205, the mean terminal half-life of BMS-986205 
was determined to be 98 hours. Full details on the clinical pharmacology aspects of BMS-986205 
can be found in the BMS-986205 IB. 
Pharmacokinetics of Nivolumab
The PK of nivolumab were studied in participants over a dose range of 0.1 to 10 mg/kg 
administered as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric 
mean (% CV%) CL was 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state 
(Vss) was 8.0 L (30.4%), and geometric mean elimination half-life was 26.7 days (101%). Steady-
state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg Q2W, 
and systemic accumulation was approximately 3 fold. The exposure to nivolumab increased dose 
proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The clearance 
of nivolumab increased with increasing body weight. The PPK analysis suggested that the 
following factors had no clinically important effect on the CL of nivolumab: age (29 to 87 years), 
gender, race, baseline LDH, PD-L1. A PPK analysis suggested no difference in CL of nivolumab 
based on age, gender, race, tumor type, baseline tumor size, and hepatic impairment.
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Although ECOG status, baseline glomerular filtration rate (GFR), albumin and body weight had 
an effect on nivolumab CL, the effect was not clinically meaningful. 
Full details on the clinical pharmacology aspects of nivolumab can be found in the nivolumab IB.
9.5.2
Immunogenicity Assessments
Per Protocol Amendment 04, ONLY immunogenicity assessments will be collected. Samples for 
anti-drug antibody (ADA) assessments will be collected from all participants receiving study 
treatment. Immunogenicity samples will be analyzed for anti-nivolumab antibody. Given that 
BMS-986205 is a small molecule, the immunogenicity of BMS-986205 will not be evaluated.
Table 9.5.2-1 lists a detailed sampling schedule to be followed for the assessment of 
immunogenicity for all study treatments, where applicable. Treatment assignments will be released 
to the bioanalytical laboratory in order to minimize unnecessary analysis of samples. All on-
treatment immunogenicity sample collections are intended to align with days on which nivolumab 
and BMS-986205 are co-administered. If it is known that a dose is going to be delayed, then the 
predose sample should be collected just prior to the delayed dose. However, if a predose sample 
is collected but the dose is subsequently delayed, an additional predose sample should not be 
collected. 
Separate detailed instructions for the collection, processing, handling, labeling, storage, and 
shipment of immunogenicity samples will be provided in the laboratory procedures manual.
Table 9.5.2-1:
Anti-drug Antibody Sampling Schedule for Nivolumab 
Study Day of Sample Collection
(1 cycle = 4 weeks)
Event
Time Relative to Dosinga
Hour:Minutes
ADA Blood Sampleb
Nivolumab
(Serum)
Cycle 1, Day 1
Predosec
00:00
X
Cycle 3, Day 1
Predosec
00:00
X
Cycle 6, Day 1
Predosec
00:00
X
Cycle 10, Day 1
Predosec
00:00
X
First 2 Follow-up Visitsd
FU1
X
FU2
X
Abbreviations: FU = follow-up; ADA=anti-drug antibody
a
For nivolumab samples, the time of collection is relative to the start of nivolumab infusion.
b ADA samples will be collected for nivolumab only. No ADA sample collection is required for BMS-986205.
c Predose samples should be collected just prior to administration of nivolumab (preferably within 30 minutes). If it
is known that a dose is going to be delayed, then the predose sample should be collected just prior to the delayed 
dose. However, if a predose sample is collected but the dose is subsequently delayed, an additional predose sample 
should not be collected.
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d If a participant permanently discontinues study drug treatment during the sampling period, then they will move to
sampling at follow-up visits.
9.6
Pharmacodynamics
Per Protocol Amendment 04, pharmacodynamics will not be collected.
9.7
Pharmacogenomics
See Section 9.8.
9.8
Biomarkers
Per Protocol Amendment 04, biomarkers will not be collected.
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Per Protocol Amendment 04, health economics/medical resource utilization and health economics 
parameters will not be evaluated.
9.10
Immunogenicity Assessments
See Table 9.5.2-1 for timing of blood sampling for immunogenicity assessments.
Nivolumab immunogenicity will be reported for ADA positive status (such as persistent positive, 
other positive, only last sample positive, or baseline positive) and ADA negative status, relative to 
baseline. In addition, presence of neutralizing antibody may be reported, if applicable. The effect 
of immunogenicity on safety may be explored.
9.11
Other Assessments
9.11.1
Patient-reported Outcomes
Per Protocol Amendment 04, patient-reported outcomes will not be evaluated.
10
STATISTICAL CONSIDERATIONS
Per Protocol Amendment 04, only safety and immunogenicity analyses will be conducted.
10.1
Sample Size Determination 
Per Protocol Amendment 04, sample size will be limited to the participants enrolled as of 
02-Jun-2021. The following sample size considerations refer to the original study design.
The sample size of this study is calculated in order to estimate the CR rate in treated participants 
with CIS randomized to receive either nivolumab monotherapy, nivolumab combined with 
intravesical BCG, or nivolumab combined with BMS-986205.
Using modified randomization based on BCG availability and BCG strain, as described in Section 
7.2, it is expected that approximately 100 CIS participants will be treated each in Arm A and C 
and 150 CIS participants in Arm B. It is expected that approximately 8 CIS participants will be 
treated in Arm D during the safety lead-in. Table 10.1-1 summarizes the different boundaries of 
the exact 95% CI (based on Clopper-Pearson method) for different observed CR rates in 100 and 
150 CIS treated participants. For example, if at least 40 participants with CR in a treatment group 
are observed among the 100 CIS treated participants (ie, CR rate ≥ 40%), then the lower bound of 
the 95% CI is above 30%.
Table 10.1-1:
Observed Complete Response Rate and Exact 95% Confidence 
Interval in the CIS Population
Observed CR 
(CR rate [%])
(N=100)
95% Exact CI
Observed CR (CR rate [%])
(N=150)
95% Exact CI
25 (25%)
(16.9% - 34.7%)
37 (24.7%)
(18.0% - 32.4%)
30 (30%)
(21.2% - 40.0%)
45 (30.0%)
(22.8% - 38.0%)
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Table 10.1-1:
Observed Complete Response Rate and Exact 95% Confidence 
Interval in the CIS Population
Observed CR 
(CR rate [%])
(N=100)
95% Exact CI
Observed CR (CR rate [%])
(N=150)
95% Exact CI
35 (35%)
(25.7% - 45.2%)
53 (35.3%)
(27.7% - 43.6%)
40 (40%)
(30.3% - 50.3%)
60 (40.0%)
(32.1% - 48.3%)
45 (45%)
(35.0% - 55.3%)
68 (45.3%)
(37.2% - 53.7%)
50 (50%)
(39.8% - 60.2%)
75 (50.0%)
(41.7% - 58.3%)
55 (55%)
(44.7% - 65.0%)
82 (54.7%)
(46.3% - 62.8%)
60 (60%)
(49.7% - 69.7%)
90 (60%)
(51.7% - 67.9%)
An initial evaluation of efficacy and safety will be performed for each treatment group when 
34 CIS participants in each treatment group have been treated and followed up to 6 months. If 
≤9 (26%) participants achieve CR at 6 months, the treatment group may not be considered
promising and accrual in this treatment group may then be stopped based on the recommendation
of the DMC and decision of the Sponsor. If ≥10 (29%) participants achieve CR at 6 months, the
treatment group will be considered promising and accrual in this treatment group could then
continue to full enrollment. If the true CR rate at 6 months for a treatment group is 20%, there is a
probability of 87% of observing ≤9 CR among 34 first CIS participants. If the true CR rate at 6
months for a treatment group is 40%, there is only a probability of 7% of observing ≤9 CR among
34 first CIS participants. These probabilities were considered appropriate in light of recent efficacy
results of another anti-PD1 monotherapy regimen in the same indication showing an encouraging
CR rate of 40.2% [95% CI: 30.6-50.4].79
CIS participants will be randomized in a 1:1:1 ratio (dependent on BCG availability) after safety 
lead-in completion. Enrollment in the safety lead-in will be staggered so that the safety lead-in 
phase for Arm B is adequately assessed prior to the enrollment of Arm D. Once the number of 
participants for the safety lead-in is reached in Arm D, accrual will only continue in the 3 other 
arms. Once 34 CIS treated participants in a given treatment group have been followed for at least 
6 months, an initial evaluation of efficacy and safety for that treatment group will be conducted. 
Accrual will not be stopped prior to this initial evaluation.
The primary analysis of the primary endpoint CR rate will be performed when all CIS treated 
participants with CR in each treatment group have had at least 12 months of follow up from the 
time of initial CR.
10.2
Populations for Analyses
Per Protocol Amendment 04, only safety and immunogenicity assessments will be conducted.
For purposes of analysis, the following populations are defined:
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Population
Description
Enrolled Participants
All participants who sign informed consent and are registered into 
IRT
Treated 
All randomized participants who received at least one dose of any 
study medication.
Immunogenicity
All treated participants with available ADA data.
10.3
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. 
A description of the participant population will be included in the statistical output and reported, 
including subgroup of age, gender, and race.
10.3.1
Efficacy Analyses
Per Protocol Amendment 04, formal efficacy analyses will not be conducted. Descriptive summary 
statistics may be provided for internal dissemination only.
10.3.2
Safety Analyses
All safety analyses will be performed on the Treated Population.
Safety analyses will be performed in all treated participants and for each treatment group. 
Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 by treatment group. All on-study 
AEs, treatment-related AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade 
per NCI CTCAE v 4.03 criteria by system organ class and preferred term. On-study lab parameters 
including hematology, chemistry, liver function, and renal function will be summarized using 
worst grade NCI CTCAE v 4.03 criteria.
Additional safety analyses will be described in the SAP finalized before database lock.
10.3.3
Other Analyses 
Immunogenicity analyses will be described in the SAP finalized before database lock.
10.3.4
Initial Evaluation of Efficacy and Safety
Not applicable per Protocol Amendment 04.
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26 Steinberg RL, Thomas LJ, Mott SL, et al. Bacillus Calmette-Guerin (BCG) Treatment Failures 
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31 Lerner SP, Dinney C, Kamat A, et al. Clarification of Bladder Cancer Disease States Following 
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32 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol 
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33 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
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34 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
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35 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
36 Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
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37 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
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38 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
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39 Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin 
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40 Theate I, van Baren N, Pilotte L, et al. Extensive profiling of the expression of the indoleamine 
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41 Munn DH, Zhou M, Attwood J, et al. Prevention of allogeneic fetal rejection by tryptophan 
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42 Heitger A. Regulation of expression and function of IDO in human dendritic cells. Curr Med 
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43 van Baren N, Van den Eynde BJ. Tryptophan-degrading enzymes in tumoral immune 
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44 Godin-Ethier J, Hanafi L-A, Piccirillo CA, et al. Indoleamine 2,3-dioxygenase expression in 
human cancers: clinical and immunologic perspectives. Clin Cancer Res 2011;17:6985-91.
45 Spranger S, Spaapen RM, Zha Y, et al. Up-regulaton of PD-1, IDO, and Tregs in the melanoma 
tumor microenvironment is driven by CD8+ T-cells. Sci Transl Med 2013; 5:200ra116.
46 Holmgaard RB, Zamarin D, Munn D, et al. Indoleamine 2,3-dioxygenase is a critical resistance 
mechanism in antitumor T-cell immunotherapy targeting CTLA-4. J Exp Med 2013;210:1389-
402.
47 Urba WJ, Martin-Algarra S, Callahan M, et al. Immunomodulatory activity of nivolumab 
monotherapy in patients with advanced melanoma. American Association for Cancer Research 
2015 Annual Meeting; 2015 Apr 18-22; Philadelphia, PA. Abstract 2855.
48 Choueiri TK, Fishman MN, Escudier B, et al. Biomarker results from a clinical trial of 
nivolumab in patients (pts) with metastatic renal cell carcinoma (mRCC) (Study CA209009): 
gene 
expression, 
serum 
profiling 
for 
immune 
markers, 
and 
multiplex 
tissue 
immunohistochemistry (IHC). American Association for Cancer Research 2015 Annual 
Meeting; 2015 Apr 18-22; Philadelphia, PA. Abstract 1306.
49 Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for 
bladder cancer -- a current perspective. Nat Rev Urol 2014;11:153-62.
50 Tsuji S, Matsumoto M, Takeuchi O, et al. Maturation of human dendritic cells by cell wall 
skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of toll-like receptors. 
Infect Immun 2000;68:6883-90.
51 Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for 
management. J Cardiothorac Vasc Anesth 2014;28:1043-7.
52 Hilmy M, Campbell R, Bartlett JM, et al. The relationship between the systemic inflammatory 
response, tumor proliferative activity, T-lymphocytic infiltration and COX-2 expression and 
survival in patients with transitional cell carcinoma of the urinary bladder. British Journal of 
Cancer 2006;95:1234-8.
53 Sharma P, Shen Y, Wen S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival 
in muscle-invasive urothelial carcinoma. Proceedings of the National Academy of Sciences of 
the United States of America 2007;104:3967-72. 
54 Alexandroff AB, Jackson AM, O'Donnell MA, et al. BCG immunotherapy of bladder cancer: 
20 years on. Lancet 1999;353:1689-94.
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55 Herr HW, Bean MA, Whitmore WF, Jr. Decreased ability of blood leukocytes from patients 
with tumors of the urinary bladder to act as stimulator cells in mixed leukocyte culture. Cancer 
Research 1976;36:2754-60.
56 Loskog A, Ninalga C, Paul-Wetterberg G, et al. Human bladder carcinoma is dominated by T-
regulatory cells and Th1 inhibitory cytokines. J Urol 2007;177:353-8.
57 Mukamel E, Shohat B, Servadio C. Immunological profile of patients with transitional cell 
carcinoma of the bladder. Br J Urol 1982;54:11-5.
58 Boorjian SA, Sheinin Y, Crispen PL, et al. T-cell coregulatory molecule expression in 
urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin 
Cancer Res 2008;14:4800-8.
59 Sharma P, Bono P, Kim JW, et al. Efficacy and safety of nivolumab monotherapy in metastatic 
urothelial cancer (mUC): Results from the Phase 1/2 CheckMate 032 study [abstract]. J Clin 
Oncol 2016;34 suppl; abs 4501, oral presentation.
60 Galsky M, Retz M, Siefker-Radtke A, et al. Efficacy and safety of nivolumab monotherapy in 
patients with metastatic urothelial cancer (mUC) who have received prior treatment: Results 
from the Phase 2 CheckMate 275 study. Presented at: 2016 ESMO Congress; October 7-11, 
2016; Copenhagen, Denmark. Abstract LBA31.
61 Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of 
the bladder and BCG-induced granulomata: associations with localized stage progression. 
Cancer 2007;109:1499-1505.
62 Hudolin T, Menqus C, Coulot J, et al. Expression of Indoleamine 2,3-Dioxygenase Gene is a 
Feature of Poorly Differentiated Non-muscle-invasive Urothelial Cell Bladder Carcinomas. 
Anticancer Res 2017;37:1375-80.
63 Perez RP, Riese MJ, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced 
solid tumors; Preliminary phase I/II results of ECHO-204. American Society of Cancer 
Research Annual Meeting 2017. Abstract 3003.
64 Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Ann 
Rev Immunol 2008;26:677-704.
65 Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T-
cell activation. Nat Immunol 2001;2:261-8.
66 Carter LL, Fouser LA, Jussif J, et al. PD-1: PD-L1 inhibitory pathway affects both CD4+ and 
CD8+ T-cells and is overcome by IL-1. Eur J Immunol 2002;32:634-43.
67 Barber DL, Wherry EJ, Masopust D et al. Restoring function in exhausted CD8 T-cells during 
chronic viral infection. Nature 2006;439:682-7.
68 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
2012;12:252-64.
69 Farina MS, Lundgren KT, Bellmunt J. Immunotherapy in Urothelial Cancer: Recent Results 
and Future Perspectives. Drugs 2017;77:1077-89.
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70 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-
Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(2):123-35.
71 Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373 (17):1627-39.
72 Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line 
treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, 
phase 1, multicohort study. Lancet Oncol 2017;18(1):31-41.
73 Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in 
untreated melanoma. N Engl J Med 2015;373(13):1270-1.
74 Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-
cell carcinoma. N Engl J Med 2015 Nov 5;373(19):1803-13. 
75 Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in 
Resected Stage III or IV Melanoma. N Engl. J Med 2017 Sep 10. doi: 
10.1056/NEJMoa17009030 (Epub ahead of print).
76 Svatek RS, Tangen C, Delacroix S, et al. Background and Update for S1602 “A Phase III 
Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming 
with Intradermal BCG Before Intravesical Therapy for BCG-naïve High-grade Non-muscle-
invasive Bladder Cancer. Eur Urol Focus 4(2018):522-524.
77 Witjes JA, Dalbagni G, Karnes RJ, et al. The efficacy of BCG TICE and BCG Connaught in a 
cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer. Urol Oncol 
2016;34:484.
78 Study CA209010, A Randomized, Blinded, Phase 2 Dose-Ranging Study of Nivolumab 
(MDX-1106, BMS-936558) in Subjects with Progressive Advanced/Metastatic Clear-Cell 
Renal Cell Carcinoma (RCC) Who Have Received Prior Anti-Angiogenic Therapy. 2013.
Document Control No. 930074316.
79 Ronald De Wit et al. Pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–
muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): 
Updated follow-up from KEYNOTE-057. Journal of Clinical Oncology 2019 37:15_suppl, 
4530-4530.
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APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ADA
anti-drug antibody
AE
adverse event
AEOSI
adverse events of special interest
AIDS
acquired immunodeficiency syndrome
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APC
antigen-presenting cell
AST
aspartate aminotransferase
AUA
American Urological Association
AUC
area under the concentration-time curve
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
BCG 
Bacillus Calumette-Guerin
BCRP
breast cancer resistance protein
β-HCG
beta-human chorionic gonadotrophin
BMS
Bristol-Myers Squibb
BUN
blood urea nitrogen
C
Celsius
Cavgss
average concentration at steady state
CBC
complete blood count
CFR
Code of Federal Regulations 
CI
confidence interval
CIS
carcinoma in situ
CL
clearance
CLcr
creatinine clearance
Cmax
maximum observed concentration
Cmaxss
maximum observed concentration at steady state
Cminss
minimum observed concentration at steady state
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Term
Definition
CMV
cytomegalovirus
CONSORT
Consolidated Standards of Reporting Trials
COVID 19
coronavirus disease 2019
CR
complete response
CRF
case report form, paper or electronic
CT
computed tomography
CTAg
clinical trial agreement
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
CYP
cytochrome p-450
DC
dendritic cell
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DRESS
drug reaction with eosinophilia and systemic symptoms
EC50
half maximal effective concentration
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EFS
event-free survival
eg
exempli gratia (for example)
EOI
end of infusion
EU
European Union
EAU
European Association of Urology
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
FU, F/U
follow-up
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Term
Definition
G6PD
glucose 6-phosphate dehydrogenase
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GM-CSF
granulocyte macrophage-colony stimulating factor
h
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gondotropin
HCV
hepatitis C virus
HG
high grade
HIPAA
Health Insurance Portability and Accountability Act (US)
HIV
human Immunodeficiency Virus
HLH
hemophagocytic lymphohistiocytosis; also known as histiocytosis 
haematophagic
IB
Investigator Brochure
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation 
IDO
indoleamine-1,2-dioxygenase 1
ie
id est (that is)
IEC
Independent Ethics Committee
IFN
interferon
IHC
imunohistochemistry
IL
interleukin
IMAE
immune mediated adverse event
IMP
investigational medicinal products
I-O
immuno-oncology(ic)
IP
investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology
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Term
Definition
IU
International Unit
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
kg
kilogram
L
liter
LAM
lactation amenorrhea method
LDH
lactate dehydrogenase
mg
milligram
MIBC
Muscle-invasive bladder cancer
min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
μg
microgram
N
number of subjects or observations
N/A
not applicable
NCI
National Cancer Institute
NMIBC
non-muscle-invasive bladder cancer
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
ORR
objective response rate
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD-1
programmed cell death protein 1
PD-L1
programmed cell death-ligand 1
P-gp
permeability glycoprotein
PK
pharmacokinetics
PO
per os (by mouth route of administration)
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Term
Definition
PPK
population pharmacokinetics
PR
partial response
PRC
Pathology Review Committee
PRO
patient-reported outcome
PS
Performance Status
PSA
prostate-specific antigen
Q2W
every 2 weeks
Q4W
every 4 weeks
QD
quaque die, once daily
QLQ-NMIBC24
Quality of Life Questionnaire - Non-Muscle Invasive Bladder Cancer 24
QoL
quality of life
R&D
Research and Development
RBC
red blood cell
RCC
renal cell carcinoma
RNA
ribonucleic acid
RT-PCR
reverse transcription-polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SmPC
Summary of Product Characteristics
SOC
standard of care
SUSAR
suspected unexpected serious adverse reaction
TaHG
high-grade Ta tumor
TCR
tumor cell receptor
TIL
tumor-infiltrating lymphocyte
Tmax
time of maximum observed concentration
TNF
tumor necrosis factor
TRAIL
TNF-related apoptosis-inducing ligand
Treg
regulatory T-cell
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Term
Definition
TSH
thyroid stimulating hormone
TTR
time to response
TURBT
transurethral resection of the bladder tumor
UC
urothelial cancer, urothelial carcinoma
UK
United Kingdom
ULN
Upper limit of normal
US
United States
USPI
United States Prescribing Information
UTI
urinary tract infection
VAS
visual analog scale
Vss
volume at steady state
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS)
International Ethical Guidelines Good Clinical Practice (GCP),
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects/
participants currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given by subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
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When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage area
•
amount currently in storage area
•
label identification number or batch number
•
amount dispensed to and returned by each 
participant, including unique participant
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (eg, lost, wasted) 
•
amount destroyed at study site, if applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence/biocomparability, 
if applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the Delegation 
of Authority Form.
Sourced by site, and not supplied by 
BMS or its vendors (examples include IP 
sourced 
from 
the 
sites 
stock or 
commercial supply, or a specialty 
pharmacy)
The investigator or designee accepts responsibility 
for documenting traceability and study treatment
integrity in accordance with requirements applicable 
under law and the SOPs/standards of the sourcing 
pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
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or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. The investigator must retain a copy of the CRFs including records of the changes and 
corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
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RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
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•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report. 
For each CSR related to this protocol, the following criteria will be used to select the signatory 
investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.  
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Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE:
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via 
email or confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Note: For WOCBP participants treated with BMS-986205 in this study, hormone-based 
contraceptives are not considered highly effective methods of contraception since potential 
interactions of BMS-986205 with hormonal contraceptives are not known at this time. This 
constraint applies to Arms C and D in this study.
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya
•
Not acceptable in WOCBP participants treated with BMS-986205 in this study (Arms 
C and D): Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation/or implantation (These methods of contraception 
cannot be used by WOCBP participants in studies where hormonal contraception is 
prohibited)b
−
oral (birth control pills)
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−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
transdermal 
•
Not acceptable in WOCBP participants treated with BMS-986205 in this study (Arms 
C and D): Progestogen-only hormonal contraception associated with inhibition of ovulationb
−
oral 
−
injectable 
•
Not acceptable in WOCBP participants treated with BMS-986205 in this study (Arms 
C and D): Hormonal methods of contraception including oral contraceptive pills containing 
a combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)b,c
−
Highly Effective Methods That Are User Independent
•
Not acceptable in WOCBP participants treated with BMS-986205 in this study (Arms 
C and D): Implantable progestogen-only hormonal contraception associated with inhibition 
of ovulation b
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
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 drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that the 
IMP and other study medications will not alter hormonal exposures such that contraception would be ineffective 
or result in increased exposures that could be potentially hazardous.  In this case, alternative methods of 
contraception should be utilized.  
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c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness. The absence of such interactions is not known for BMS-986205 when administered 
with nivolumab. Therefore, for participants of child-bearing potential who receive these 2 medications, 
intrauterine hormone-releasing systems are not acceptable methods of contraception.
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. This 
constraint applies to Arms C and D in this study.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a synthetic or latex condom during any sexual activity 
with WOCBP for study duration and until end of relevant systemic exposure defined as 1
month (approximately 4 weeks) after the end of study treatment. This applies even if the 
participant has undergone a successful vasectomy. 
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 1 month (approximately 
4 weeks) after the end of treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male latex or synthetic condom during each episode of 
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penile penetration during the treatment and until 1 month (approximately 4 weeks) after the 
end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 1 month 
(approximately 4 weeks) after the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 4.0
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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孵孻孰宖宨害孰孵孳孵孳
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APPENDIX 6
ECOG PERFORMANCE STATUS SCALE
ECOG PERFORMANCE STATUSa
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead
a Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655.
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APPENDIX 7
CYP3A4, CYP1A2 AND CYP2B6 GUIDANCE
The lists below are not meant to be all inclusive. Please consult individual drug labels for further 
information. Additional information is also available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm
Table 1:
Classification of In Vivo Inhibitors of CYP Enzymes
CYP Enzymes
Strong Inhibitorsa
≥5-fold Increase in AUC
or > 80% Decrease in CL
Moderate Inhibitorsb
≥2 but < 5-fold Increase in 
AUC or 50-80% Decrease 
in CL
Weak Inhibitorsc
≥1.25 but < 2-fold Increase 
in AUC or 20-50% 
Decrease in CL
CYP3A
Boceprevir, clarithromycin, 
conivaptan, grapefruit juice,d
indinavir, itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil,e nefazodone, 
nelfinavir, posaconazole, 
ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, 
diltiazem, erythromycin, 
fluconazole, fosamprenavir, 
grapefruit juice,d imatinib, 
verapamil
Alprazolam, amiodarone, 
amlodipine, atorvastatin, 
bicalutamide, cilostazol, 
cimetidine, cyclosporine, 
fluoxetine, fluvoxamine, 
ginkgo,f goldenseal,f
isoniazid, nilotinib, oral 
contraceptives, ranitidine, 
ranolazine, 
tipranavir/ritonavir, zileuton
CYP1A2
ciprofloxacin, enoxacin,
fluvoxamineg, zafirlukast
methoxsalen, mexiletine, 
oral contraceptives
acyclovir, allopurinol, 
cimetidine, peginterferon 
alpha-2a, piperine, zileuton
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450.
Please note that this is not an exhaustive list.
a A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a substrate for that CYP 
by equal or more than 5-fold.
b A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold.
c A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by less than 2-fold but equal to or more than 1.25-fold.
d The effect of grapefruit juice varies widely among brands and is concentration, dose, and preparation dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used 
(eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low 
dose, single strength).
e Withdrawn from the United States market because of safety reasons.
f Herbal product.
g Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A
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Table 2:
Classification of In Vivo Inducers of CYP Enzymes
CYP Enzymes
Strong Inducers
≥80% Decrease in AUC
Moderate Inducers
50-80% Decrease in AUC
Weak Inducers
20-50% Decrease in AUC
CYP3A
Avasimibe,a carbamazepine, 
phenytoin, rifampin, St. 
John’s wortb
Bosentan, efavirenz, 
etravirine, modafinil, 
nafcillin
Amprenavir, aprepitant, 
armodafinil, echinacea,c
pioglitazone, prednisone, 
rufinamide
CYP1A2
Phenytoind, rifampine, 
ritonavirf, smoking, 
teriflunomide
Please note that this is not an exhaustive list.
a Not a marketed drug.
b The effect of St. John’s wort varies widely and is preparation dependent.
c Herbal product.
d Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19.
e Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9.
f Strong inducer of CYP2C19 and moderate inducer of CYP1A2, CYP2B6, CYP2C9.
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450.
Table 3:
Examples of Sensitive In Vivo CYP Substrates and CYP Substrates 
with Narrow Therapeutic Range
CYP Enzymes
Sensitive Substratesa
Substrates with Narrow 
Therapeutic Rangeb
CYP3A
Alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, 
triazolam, vardenafil
Alfentanil, astemizole,c cisapride,c
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus,
terfenadinec
CYP2B6
Bupropion, efavirenz
Abbreviations: AUC = area under the concentration-time curve; CYP = cytochrome P450.
Please note that this is not an exhaustive list.
a Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when co-administered with a known CYP inhibitor.
b CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that 
small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de Pointes).
c Withdrawn from the United States market because of safety reasons.
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APPENDIX 8
MEDICATIONS ASSOCIATED WITH QT PROLONGATION
The list below is not meant to be all inclusive. Please consult individual drug labels for further 
information.
quinidine, procainamide, disopyramide,
amiodarone, sotalol, ibutilide, dofetilide,
erythromycins, clarithromycin,
chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide,
cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
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APPENDIX 9
P-GP AND BCRP GUIDANCE
The list below is not meant to be all inclusive. Please consult individual drug labels for further 
information. Additional information is also available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm
Table 1:
Examples of In Vivo Substrates for Selected Transporters
Transporter
Gene
Substrate
P-gp
ABCB1
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxin, everolimus, fexofenadine, imatinib, lapatinib, 
maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, tolvaptan, topotecan
BCRP
ABCG2
Methotrexate, mitoxantrone, imatinib, irrinotecan, lapatinib, 
rosuvastatin, sulfasalazine, topotecan
Please note that this is not an exhaustive list.
Abbreviations: BCRP = breast cancer resistance protein; P-gp = P-glycoprotein.
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APPENDIX 10
AGENTS KNOWN TO CAUSE METHEMOGLOBINEMIA
Acetanilid
p-Amino salicylic acid
Aniline, aniline dyes
Benzene derivatives
Clofazimine
Chlorates
Chloroquine
Dapsone
Local anesthetic agents 
Benzocaine 
Lidocaine 
Prilocaine 
Menadione
Metoclopramide
Methylene blue*
Naphthoquinone
Naphthalene
Nitrites 
Amyl nitrite 
Farryl nitrite 
Sodium nitrite 
Nitroglycerin 
Nitric oxide 
Nitrobenzene
Paraquat
Phenacetin
Phenazopyridine
Primaquine
Rasburicase
Resorcinol
Sulfonamides
* While methylene blue is a recognized treatment for methemoglobinemia, it is an agent with oxidant potential (and 
may worsen the clinical situation) since in individuals with glucose-6-phosphate dehydrogenase deficiency, it induces 
acute hemolysis that can further decrease oxygen delivery to the tissues. Paradoxically, in high doses, methylene blue 
can also increase methemoglobinemia.
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APPENDIX 11
COUNTRY SPECIFIC REQUIREMENTS
Argentina, Czech Republic, France, Germany, Spain, and Any Other Countries Where 
Exclusion of HIV Positive Participants Is Locally Mandated
Country-specific language
Section 2 Schedule of Activities, 
Table 2-1: 
Screening Procedural Outline -
Laboratory Tests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 3) i)
“Known history of testing positive for human immunodeficiency virus (HIV)
or known acquired immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
Section 9.4 SafetyAssessments
(baseline laboratoryassessments)
Add “HIV” test to Baseline local laboratory assessments to be done within 14
days prior to first dose.
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APPENDIX 12
DIAGNOSTIC CRITERIA FOR HLH AND DRESS SYNDROME
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Table 2
Scoring system for classifying HSS/DRESS cases as definite, probable, 
possible, or no case 
Kardaun SH, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does 
a DRESS syndrome really exist? SHBr J Dermatol. 2007 Mar;156(3):609-11.
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APPENDIX 13
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for the Revised Protocol 03, 01-Nov-2019
In the context of its natural history, carcinoma in situ (CIS) in intravesical bacillus Calmette-
Guerin (BCG)-unresponsive patients persists despite surgical treatment, and participants entering 
a study with a CIS diagnosis will likely have residual CIS post-TURBT. For BCG-unresponsive 
disease, complete response (CR) rate and duration of response in patients with CIS in a single 
treatment arm can be attributed to treatment. Therefore, the focus of study CA2099UT has been 
limited to participants with CIS, and the sample size for each arm has been increased in order to 
enable a statistically robust analysis of CR rate and duration of response. These study endpoints 
for single-arm, registrational studies in the BCG-unresponsive non-muscle-invasive bladder 
cancer (NMIBC) population are in accordance with the the FDA Guidance in this population.1
Due to global shortages of intravesical BCG, only 1 BCG-containing arm (Arm B) will be 
expanded, after safety lead-in, instead of 2 (Arm B and Arm D). Accordingly, after completion of 
the safety lead-in to Arm D, enrollment in that arm will be paused. 
In addition, randomization was modified to include both BCG availability and strain based on the 
following reasons: 
•
different BCG strains are standard of care in varying regions, 
•
some countries have more than one strain approved, and 
•
the TICE strain is the only strain approved in the US and is approved for use in many 
other countries. 
Three BCG-based randomization categories (No BCG available, TICE BCG available, non-TICE 
BCG available) will ensure reasonable balance between the 3 treatment arms. The number of non-
TICE BCG-treated participants will be limited to ≤ 70 to ensure at least 80 TICE BCG-treated 
participants in Arm B.
Based on these key changes, subsequent revisions were made to sample size, 6 month decision 
point CR estimates, etc., throughout the protocol. Several appendices were updated as well. 
Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
1 Synopsis
3 Introduction
3.1 Study Rationale
5.1 Overall Design
5.1-1 Study Diagram
5.1.1 Safety Lead-in Phase
5.1.2 Randomization Phase
5.4.9 Rationale for Modified 
Randomization
Revised study design to pause 
enrollment into Arm D once the safety
lead-in is completed.
Introduced modified randomization to 
account for BCG availability.
In the context of a global 
shortage of intravesical BCG, 
only 1 BCG-containing arm 
(Arm B) will be expanded 
after safety lead-in instead of 
2 (Arms B, D). 
Availability of BCG is 
incorporated into 
randomization in order to 
allow sites without BCG 
available to enroll 
participants.
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Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
7.2 Method of Treatment 
Assignment
9.0 Study Assessment and 
Procedures, Treatment Phase
10.1 Sample Size Determination 
The modified randomization 
will allow efficacy data from 
all arms to be mature around 
the same time.
1 Synopsis
3 Introduction
3.1.1 Research Hypothesis
3.2.1 Indication Background
Table 4-1 Objectives and 
Endpoints
5.1 Overall Design
5.1.2 Randomization Phase 
[through-out]
5.2 Number of Participants
5.3 End of Study Definition
6.1 Inclusion Criteria (3)
7.2 Method of Treatment 
Assignment
8.1.4 Post Study Treatment Study 
Follow-up
9.0 Study Assessment and 
Procedures, Follow-up Phase
9.1 Efficacy Assessments
9.8.3 Urine Markers
10.2 Populations for Analyses
Removed eligibility for non-CIS 
participants.
Deleted the endpoint of event free 
survival (EFS) in non-CIS participants 
In 6.1, removed Ta or T1 alone from 
eligibility.
In the context of a global 
shortage of intravesical BCG 
and the FDA guidance on 
registrational studies in BCG-
unresponsive NMIBC, 
patients with CIS are being 
prioritized. Non-CIS
participants will not be 
eligible, and the associated 
EFS endpoint was removed.
1 Synopsis
Table 2-2 On-treatment Procedural 
Outline for Arms A and C 
(CA2099UT)
Table 2-3 On-treatment Procedural 
Outline for Arms B and D 
(CA2099UT)
Table 2-4 Follow-up Procedural 
Outline (CA2099UT)
5.1 Overall Design
Revised language from Methemoglobin 
“should” to “must” be assessed.
Revised language from a negative 
pregnancy test “should” be to “must” be 
documented within 24 hours prior to 
start of each dose of nivolumab.
Revised language from “should” to 
“efficacy assessments must occur” until 
disease recurrence or progression, per 
PRC, based on a positive urinary 
cytology or bladder biopsy.
Imaging changed from “should” to 
“must” be performed per instructions.
The assessments are not 
optional so more explicit 
language was used.
1 Synopsis
5.1 Overall Design
5.1-1 Study Diagram
5.1.2 Randomization Phase, Part 2
5.1.2 Randomization Phase, Part 3
Increased N in Arms A, B, and C.
Revised 6-month decision point CR 
numbers for CIS participants.
Only CIS participants will be 
enrolled and the number of 
participants per arm will be 
increased to enable more 
robust evaluation of CR rate 
on each arm, with subsequent 
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Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
5.1.3 Data Monitoring Committee 
and Other External Committees
5.2 Number of Participants
10.3.4 Initial Evaluation of 
Efficacy and Safety
revisions to the decision point 
numbers.
1 Synopsis
Table 7-1 Study Treatments for 
CA2099UT
From Potency column, deleted 100 mg 
and 40 mg.
This administrative update 
clarifies that potency is 
expressed as 10mg/mL, not 
mg.
1 Synopsis
5.1 Overall Design
Added that participants should remain 
on their same BCG strain throughout the 
study whenever possible.
To enable the clearest 
interpretation of safety and 
efficacy data, it is preferred 
that participants remain on 
one BCG strain.
1 Synopsis
5.3 End of Study Definition
Revised end of study for the primary 
completion definition for the CR rate of 
CIS participants to 12 months after the 
initial CR for all participants. 
Reworded definitions for study 
completion and added end of trial and 
end of study definition.
Changed time period to achieve full 
enrollment from 22 to 37 months.
The end of study changed due 
to the drop of EFS endpoint.
Revised Study Completion 
and added End of Trial for 
consistency with US NIH 
Clinical Trial Registry and 
The EU Clinical Trial 
Registry, respectively; added 
end of study for consistency 
with internal BMS guidance.
Revised timing based on 
current projection.
Table 2-1 Screening Procedural 
Outline (CA2099UT)
9.1.4 Bladder Biopsy
Specified that tumor tissue samples for 
diagnosis are 1-10 hematoxylin and 
eosin (H&E) stained slides, with at least 
1 slide/disease site, representing the 
diagnosis of high-risk NMIBC (CIS, CIS 
with TaHG, or CIS with T1).
Provided clarity on the slides 
needed for diagnosis.
Table 2-1 Screening Procedural 
Outline (CA2099UT)
6.1 Inclusion Criteria
9.1.4 Bladder Biopsy
Specified that if tumor tissue was 
obtained > 70 days prior to 
randomization, participants must have a 
repeat cystoscopy ≤ 70 days prior to 
randomization. Disease stage will be 
updated to take account of all TURBT 
findings.
Revised language that if 
tissue collection timelines 
exceed 70 days, additional 
time is allowed for 
completion of repeat 
cystoscopy to confirm 
participant eligibility. 
Table 2-2 On-treatment Procedural 
Outline for Arms A and C 
(CA2099UT)
Table 2-3 On-treatment Procedural 
Outline for Arms B and D 
(CA2099UT)
Table 2-4 Follow-up Procedural 
Outline (CA2099UT)
Added that PK samples of BMS-986205 
will be analyzed for select metabolites.
 
Select metabolite analysis 
was added to support future 
exposure-response analysis.
For ease of understanding.
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Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
Table 4-1 Objectives and 
Endpoints 
9.5.2 Pharmacokinetics and 
Immunogenicity Assessments
Table 9.5.2-1 Pharmacokinetic and 
Anti-drug Antibody Sampling 
Schedule for Nivolumab and PK 
Sampling Schedule for BMS-
986205 and Select Metabolites
Table 2-2 On-treatment Procedural 
Outline for Arms A and C 
(CA2099UT)
Table 2-3 On-treatment Procedural 
Outline for Arms B and D 
(CA2099UT)
9.11.1 Patient-reported Outcomes
Changed timing of health outcomes 
questionnaires assessments from every 4 
weeks following randomization to D1 of 
every cycle.
To clarify the timing.
3 Introduction
Added the new generic name 
“linrodostat mesylate” to BMS-986205 
To remain current and 
transparent.
5.1 Overall Design
5.1.2 Randomization Phase, Part 2
5.2 Number of Participants
Removed text on 2 arms continuing to 
full enrollment.
For consistency with changes 
made throughout protocol.
5.1.2 Randomization Phase, Part 1
Corrected text to indicate that the 
randomization phase begins after the 
safety lead-in participants begin 
treatment rather than after safety lead-in 
enrollment.
Added statement that if BCG shortage 
resolves, randomization will switch to 
Arms A, B, or C in a 1:1:1 ratio.
Corrected misstatement.
Allows for adjustments if 
BCG shortage resolves.
5.4.6 Rationale for Complete 
Response Rate in Participants with 
Carcinoma in Situ as a Primary 
Endpoint 
5.4.7 Rationale for EFS in All 
Non-CIS Participants as a Co-
primary Endpoint
Revised Section 5.4.6 Heading to change 
“Co-Primary” to “Primary.”
Deleted Section 5.4.7 to remove EFS 
endpoint.
Enrollment limited only to 
CIS participants so EFS of 
non-CIS participants removed 
as co-primary endpoint.
5.5.3 Justification for 
Administration of BMS-986205 
with Food
Updated text based on a definitive food 
effect assessment in normal healthy 
volunteers.
Provide most recent data.
7.2 Method of Treatment 
Assignment
9 Study Assessment and 
Procedures, Treatment Phase
10.3.1 Efficacy Analyses
Revised randomization to be based on 
BCG availability (No BCG available vs 
TICE BCG available vs Non-TICE BCG
available).
Specified that for the purposes of 
randomization, any BCG strain that 
becomes approved in the US during the 
Modified randomization to 
utilize available BCG in the 
context of a global shortage 
of intravesical BCG.
Added analyses for Arm B to 
assess the primary and 
secondary endpoints on the 
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Summary of key changes of Revised Protocol 03
Section Number & Title
Description of Change
Brief Rationale
conduct of the study will be included in 
the category of TICE BCG available.
subgroup of participants 
receiving BCG TICE strain.
7.4.6 Management Algorithms
Added algorithm on myocarditis to 
Appendix 6.
Provide new algorithm per 
recent Nivolumab 
Investigator Brochure.
9.3 Overdose
Clarified that only overdose occurrences 
that meet regulatory SAE definitions are 
to be reported as SAE.
Made consistent with 
Appendix 3.
10.1 Sample Size Determination 
10.1-1 Observed Complete 
Response Rate and Exact 95% 
Confidence Interval in the CIS 
Population
Removed Arm D and revised sample 
size to enable most robust assessment of 
CR rate in each arm.
Increased number of participants at the 
early decision point (from 27 to 34).
Revised the decision-marking CR 
criteria from ≥ 11 to ≥ 10 participants.
Removed text related to Arm D 
enrollment.
 
. 
The protocol is being revised 
to address the BCG shortage 
and improve the ability of the 
study to demonstrate efficacy.
Given the recent KEYNOTE-
057 report of ~40% overall 
CR rate and ~30% 6 month 
CR rate, 30% CR rate at 6 
months may be clinically 
meaningful in terms of 
improving upon existing 
SOC.
Appendix 4 WOCBP Definitions 
and Methods of Contraception
Moved hormonal methods of 
contraception from User Independent to 
User Dependent. Added additional 
detail.
Meets current standards.
Appendix 5 Management 
Algorithms for Immuno-Oncology 
Agents 
Added algorithm on myocarditis and 
replaced all algorithms with updated 
versions.
Meets current standards.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not 
been summarized.
Overall Rationale for the Revised Protocol 02, 10-May-2019
The purpose of this revised protocol is to increase the window for screening procedures, 
 
, make random bladder biopsies 
at screening optional, allow for urine cytology to be tested on a voided specimen, and increase the 
window for repeat TURBT for participants with stage T1 disease from 4 to 8 weeks to be consistent 
with professional society guidelines. Yearly upper tract imaging is added to be consistent with 
NCCN guidelines, and histologic confirmation of tumor progression identified on imaging and/or 
clinical examination is added. Clarification is provided regarding the exclusion criterion for prior 
systemic chemotherapy and immunotherapy, which applies only if these therapies were 
administered for the treatment of urothelial carcinoma. A subsection was added to the protocol 
describing the adverse events of special interest of Hemophagocytic lymphohistiocytosis (HLH) 
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Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Language was 
added to clarify condom requirements for males who are sexually active with WOCBP to prevent 
seminal transmission of investigational agents. Secondary items incorporated into this revised 
protocol include clarifications regarding timing and need for some laboratory testing and some 
protocol-specific activities, excluding participants who have received a live/attenuated vaccine 
within 30 days of first treatment, prohibiting live/attenuated vaccines during treatment and until 
100 days post last dose, and making minor clarifications and edits throughout the protocol to ensure 
consistency between sections.
This revised protocol applies in all countries, at all sites, to all future participants enrolled in the 
study, and where applicable, to all participants currently enrolled in the study. 
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis, Key Inclusion 
Criteria
Section 2, Schedule of 
Activities, Table 2-1
Screening Procedural 
Outline
5.1 Overall design
6.1 Inclusion Criteria (3, 
3b, 3c)
9.1.2 Cystoscopy
9.1.3 Urine Cytology
9.1.4 Bladder Biopsy
 
Increased window for diagnostic 
pathology slides from 8 weeks/56 
days to 10 weeks/70 days
Increased window for screening 
cystoscopy and urine cytology 
from 8 weeks/56 days to 10 
weeks/70 days
Increased window for complete 
resection from 8 weeks/56 days to 
10 weeks/70 days
Increased window to allow additional time 
for completion of all screening activities 
including collection and evaluation of 
diagnostic biopsy slides and determination 
of  PD-L1 status
Synopsis, Key Inclusion 
Criteria
5.1 Study Design
6.1 Inclusion Criteria (3)
9.1.4 Bladder Biopsy
Changed diagnostic pathology 
slides timing to prior to 
randomization
Provides consistent language throughout 
protocol
Synopsis, Key Inclusion 
Criteria 
6.1 Inclusion Criteria (3b 
[i])
Extended time for repeat TURBT 
after the initial TURBT to 8 
weeks
Aligns with global practice patterns
Synopsis, Key Inclusion 
Criteria
6.1 Inclusion Criteria (3b 
[iii])
9.1.4 Bladder Biopsy
Random sampling of bladder 
mucosa during screening changed 
from required to optional with 
added details about timing
In 9.1.4, added text on random 
bladder biopsies in CIS 
participants at 26 weeks
Based on extensive feedback from study 
investigators, random bladder biopsies are 
no longer performed as part of routine care 
in this patient population. The first four 
randomized participants in this study 
required a separate, additional surgical 
procedure to obtain random bladder biopsies 
prior to randomization, thereby placing them 
at increased risk and increasing the burden 
Protocol Amendment No.: 04
Date: 22-Sep-2021
159
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
on participants and investigators. As a result, 
random bladder biopsies at screening have 
been changed from required to optional. For 
CIS participants not undergoing random 
bladder biopsy at screening, requirement 
was added for inclusion of random biopsies 
during the mandatory 26 week bladder 
biopsy to fully stage the participant’s 
response to therapy. Because these biopsies 
will be performed in conjunction with an 
already required procedure, no additional 
burden will be placed on the participant or 
investigator.
Synopsis, Key Inclusion 
Criteria
6.1 Inclusion Criteria (3b 
[iv])
9.1.3 Urine Cytology
Added voided specimen (except 
for first morning urination) as an 
option for obtaining urine 
cytology
Requirement for bladder wash cytology 
placed additional burden on investigator and 
participant as in some cases, a separate, 
additional catheterization procedure was 
necessary to obtain the cytology specimen. 
Allowing for either a voided specimen or 
bladder wash specimen removes the need for 
catheterization in circumstances where the 
participant is not being catheterized for 
another reason.
Synopsis, Key Inclusion 
Criteria
6.2 Exclusion Criteria (2e)
Specified prior systemic 
chemotherapy or immunotherapy 
for UC
Provides clarification that prior systemic 
chemotherapy or immunotherapy is only an 
exclusion if it was administered to treat UC
Synopsis, Key Exclusion 
Criteria
6.2 Exclusion Criteria (2
[i])
Added exclusion for participants 
who had received a 
live/attenuated vaccine within 30 
days of first treatment
Reflects new required content
Synopsis, Overall Design
Section 2, Schedule of 
Activities, Table 2-3 On-
treatment Procedural 
Outline for Arms B and D
Extends cystoscopy and bladder 
biopsy for CIS participants (± 5 
weeks) at week 26 and 52
In Table 2.3 Footnote b, added 
clarification on the timing of 
BCG administration after 
TURBT/bladder biopsy
Allows for greater flexibility in scheduling 
week 26 and week 52 cystoscopy and 
bladder biopsy in CIS participants receiving 
BCG
Synopsis, Study Treatment
6.1 Inclusion Criteria (3d)
7.1.2 BMS-986205 Dosing
Deleted text about BMS-986205 
only in tablet formulation
Allow treatment with alternative modes of 
administration (eg, crushed tablets) as 
detailed in IB and pharmacy manual
Section 2, Schedule of 
Activities, Table 2-1
Screening Procedural 
Outline
 
 
 
Allows for participants with limited 
remaining tumor tissue to be enrolled into 
the study
Protocol Amendment No.: 04
Date: 22-Sep-2021
160
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2 On-treatment
Procedural Outline for 
Arms A and C
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
Table 2-4 Follow-up 
Procedural Outline
 
Section 2, Schedule of 
Activities, Table 2-1
Screening Procedural 
Outline
All testing, except viral, CRP, and 
G6DP, within 14 days prior to 
randomization
Provides clarification for timing of 
laboratory studies
Section 2, Schedule of 
Activities, Table 2-1
Screening Procedural 
Outline
G6PD testing to be done within 
28 days prior to randomization
Aligns with global capabilities for G6PD 
testing
Section 2, Schedule of 
Activities, Table 2-2 On-
treatment Procedural 
Outline for Arms A and C
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
Physical examination revised to
only as clinically indicated
starting from Cycle 1 Day 1
Full physical examination is required at 
screening; performing as clinically indicated 
at time points after screening decreases 
burden on participants and investigators
Section 2, Schedule of 
Activities, Table 2-2 On-
treatment Procedural 
Outline for Arms A and C
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
Specified that CBC with 
differential, chemistry panel, and 
thyroid testing must be done
within 72 hours prior to 
nivolumab dosing
Provides clarification for timing of 
laboratory studies
Section 2, Schedule of 
Activities, Table 2-2 On-
treatment Procedural 
Outline for Arms A and C
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
Added that participants may 
continue BMS-986205 dosing 
until methemoglobin result is 
available unless clinical signs or 
symptoms of methemoglobinemia 
are present
Provides clarification for BMS-986205 
dosing while methemoglobin results are 
pending
Section 2, Schedule of 
Activities, Table 2-2 On-
treatment Procedural 
Outline for Arms A and C
Methemoglobin testing can be 
stopped if BMS-986205 is 
discontinued and prior 
methemoglobin level is ≤to ULN
Methemoglobinemia is no longer a risk if 
participant discontinued BMS-986205
Protocol Amendment No.: 04
Date: 22-Sep-2021
161
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
Section 2, Schedule of 
Activities, Table 2-2 On-
treatment Procedural 
Outline for Arms A and C
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
Table 2-4 Follow-up 
Procedural Outline
9.1.1 Imaging Assessment 
for the Study
Specified upper tract imaging 
every 52 weeks (± 3 weeks); 
added new row to 2-4
Consistent with NCCN guidelines on 
follow-up of high-risk NMIBC patients
Section 2, Schedule of 
Activities, Table 2-2 On-
treatment Procedural 
Outline for Arms A and C
Table 2-3 On-treatment
Procedural Outline for 
Arms B and D
9.1.4 Bladder Biopsy
Added that any abnormality 
suspicious for recurrent papillary 
tumor or CIS must be biopsied 
and evaluated
Random biopsy changed to
mandatory in CIS participants at 
26 weeks if not performed prior 
to randomization and details of 
the biopsy were provided 
Provides clarification
Section 2, Schedule of 
Activities, Table 2-3 On-
treatment Procedural 
Outline for Arms B and D
Specifies timing of urinalysis 
relative to BCG dosing
Consistent with routine clinical practice
Section 2, Schedule of 
Activities, Table 2-3 On-
treatment Procedural 
Outline for Arms B and D
Footnote b: added timing of first 
BCG dose at CID1 (± 3 days) and 
± 3 day window for subsequent 
BCG dosingAdded that BCG 
treatment should not be given 
within 14 days after 
TURBT/bladder biopsy
Provides window for BCG dosing
Section 2, Schedule of 
Activities, Table 2-4 
Follow-up Procedural 
Outline
Clarified that pregnancy testing is 
only required at FU1 and FU2 
visits, unless increased frequency 
and/or duration is required per 
local regulations
Language allows for compliance with 
guidelines that may differ between countries 
with respect to frequency and duration of 
pregnancy testing
Section 2, Schedule of 
Activities, Table 2-4 
Follow-up Procedural 
Outline
9.11.1 Patient-reported 
Outcomes
In 2-4, specified administration of 
PRO assessments prior to any 
procedures
Added EQ-5D-3L through 
Efficacy Follow-up
9.11.1 only: added minimum 
important differences (MIDs
Added PRO to Efficacy Follow-up as 
currently QoL only being collected through 
Follow-up 2.
MIDs included in the protocol for 
informational purposes
Protocol Amendment No.: 04
Date: 22-Sep-2021
162
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
6.1 Inclusion Criteria (3b
[i])
9.1.4 Bladder Biopsy
For T1 lesions, increased re-
staging TURBT window from 
within “4” to “8” weeks
Changed to be consistent with AUA and 
EAU guidelines
6.1 Inclusion Criteria (4f)
For male participants, specified 
type of condom and expanded 
their use with any sexual activity
Clarified condom requirements and type of 
sexual activity for males who are sexually 
active with WOCBP to prevent seminal 
transmission. Revised Appendix 4 to make 
consistent
6.1 Inclusion Criteria
Deleted text on female partners of 
male participants treated with 
BMS-986205 
For consistency with Appendix 4 Women of 
Childbearing Potential Definitions; drug 
interactions with BMS-986205 not a concern 
in partners
6.2 Exclusion Criteria (2h)
Changed use of investigational 
agent to within 4 weeks of 
randomization
Provides consistent language throughout 
protocol
6.2 Exclusion Criteria (5a)
8.1 Discontinuation from 
Study Treatment
Added “only in countries where 
local regulations permit”
Provides clarification
Table 7-1 Study 
Treatments for CA2099UT
7.1.3 BCG Dosing
Inserted Footnote b in table and 
text in 7.1.3
Provides clarification as BCG to be obtained 
as local commercial product in countries 
where local regulations permit
7.1.3 BCG Dosing
Revised text related to study drug 
treatment delay and continuation 
of other study drugs
Provides consistent approach to dose delays
7.7.1.1 Prohibited 
Treatments
Added “Treatment Arm C and D 
only” to first bullet because it 
only applies to BMS-986205
Concomitant use of strong inhibitors or 
inducers of CYP3A4 and/or CYP1A2 are 
only prohibited for participants taking BMS-
986205
7.7.1.1 Prohibited 
Treatments
Added prohibitions against 
live/attenuated vaccines during 
treatment and until 100 days post 
last dose and included vaccine 
examples
Reflects new requirement for BMS 
nivolumab studies
9.1 Efficacy Assessments, 
Complete Response
Removed “for cause” describing 
imaging for CR; specified 
indeterminate “for response”
Clarification
9.1 Efficacy Assessments 
(Progression Definition)
9.1.1 Imaging Assessment 
for the Study
Added histological confirmation 
of progression detected by 
imaging and/or clinical 
examination, if feasible
Note: 9.1.1 specifies confirmation 
by PRC
Histologic confirmation (or exclusion) of 
progression detected on imaging/clinical 
examination will allow for more accurate 
determination of progression when 
imaging/examination suggestive but not 
conclusive
Protocol Amendment No.: 04
Date: 22-Sep-2021
163
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
9.1.1 Imaging Assessment 
for the Study
Specified CT and post-contrast 
CT/MRI that must be done during 
screening and through-out the 
study
Deleted 2 paragraphs on 
contraindications
Clarification
Consistent with NCCN guidelines on 
follow-up of high-risk NMIBC patients
9.2.9 Adverse Events of 
Special Interest
Appendix 12 Diagnostic 
Criteria for HLH and 
DRESS Syndrome
Added AE subsection containing 
Hemophagocytic
lymphohistiocytosis (HLH) and 
drug reaction with eosinophilia 
and systemic symptoms (DRESS) 
syndrome
HLH and DRESS have been reported (in 1 
participant each) with BMS-986205 and 
nivolumab. These AEs have been 
determined to be AEOSI requiring expedited 
reporting. Diagnostic criteria have been 
added to aid investigators in identifying 
these adverse events of special interest.
Added new Appendix 12 to provide 
diagnostic criteria
Table 9.4.1-1 Clinical 
Laboratory Assessments
Added “and/or WBC” to 
leukocyte esterase in two places
Addresses minor differences in reporting of 
urinalysis results in different regions
Table 9.5.2-1 PK and ADA 
Sampling Schedule
Added statement to Footnote c 
Provides clarification since only participants 
in Arm C and Arm D receive BMS-986205
Appendix 2 Study 
Governance Consideration
Slightly modified definition of 
“serious breach”; provided 
additional criteria for the CSR 
Signatory Investigator; added 
publication policy
Meets current standards
Appendix 3 AEs and SAEs
Updated definitions and 
procedures for recording, 
evaluating, follow-up, and 
reporting AEs and SAEs
Meets current standards
Appendix 4 Women of 
Childbearing Potential 
Definitions
Moved hormonal methods of 
contraception from User 
Independent to User Dependent
For male participants, specified 
synthetic or latex condom during 
any sexual activity
Clarified condom requirements and type of 
sexual activity for males who are sexually 
active with WOCBP to prevent seminal 
transmission. Revised Section 6.1 Inclusion 
Criteria (4f) to be consistent.
Appendix 5 I-O Treatment 
Algorithms
Updated treatment algorithms
Note: Footnotes in Hepatic AE 
Management Algorithm are 
consistent with prior 2016 version
Meets current standards
ALL
Minor edits made throughout 
document to align sections for 
consistency
Minor, therefore have not been summarized
Overall Rationale for the Revised Protocol 01, 23-Mar-2018
Protocol Amendment No.: 04
Date: 22-Sep-2021
164
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
The purpose of this revised protocol is to align language with the FDA Final guidance for BCG 
Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) dated February 2018 
 
Secondary items incorporated into this revised 
protocol include plan for evaluating suspicious urine cytology, allowing randomization of 
participants with PD-L1 not evaluable tumor tissue, clarification of exclusion criteria, adding 
CYP1A2 inhibitors and inducers to prohibited and restricted treatments and details added 
regarding serotonin syndrome, and minor clarifications made throughout document for 
consistency across sections.
This revised protocol applies in all countries, at all sites, to all future participants enrolled in the 
study, and where applicable, to all participants currently enrolled in the study.
Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis, Key Inclusion 
Criteria
Section 6.1, Inclusion 
Criteria
Updated language defining BCG -
unresponsive disease
Revised language in alignment with 
FDA final guidance for BCG 
Unresponsive NMIBC
Synopsis, Figure 1 Study 
Schematic
Section 5.1, Figure 5.1-1 
Study Schematic
Revised schematic to update stratification 
factors and add stagger to safety lead-in 
phase
Revised stratification factors in 
alignment with FDA final guidance 
for BCG Unresponsive NMIBC. 
Stagger of safety lead-in phase 
allows for adequate assessment of 
Arm B prior to the enrollment of 
Arm D.
Synopsis, Study Treatment
Section 6.1, Inclusion 
Criteria
Section 7.1.2, BMS-
986205 Dosing
Updated language for BMS-986205 
formulation and added reference to IB and
Pharmacy manual
Ongoing clinical pharmacology 
studies may expand options 
available for administration of 
BMS-986205 (eg crushing tablet). 
New language refers to IB and 
Pharmacy manual for updates.
Section 2, Schedule of 
Activities Table 2-1
ECG and smoking and alcohol history 
added as part of screening procedure 
Language added since ECG is 
performed at screening and 
smoking and alcohol history is 
collected with medical history
Section 2, Schedule of 
Activities Table 2-4
Revised notes section for subsequent 
bladder cancer treatment
Revised language to further specify 
the collection of subsequent 
Protocol Amendment No.: 04
Date: 22-Sep-2021
165
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
bladder cancer treatment in 
alignment with FDA final guidance 
for BCG Unresponsive NMIBC
Section 2, Schedule of 
Activities Table 2-1, 
Section 5.1, Schema 
Overall Design
Language revised to allow participants 
with tumor tissue that is not evaluable for 
PD-Ll expression to be randomized
Allows for participants with PD-L1 
not evaluable status to be 
randomized and enter study. 
Provides expanded opportunity for 
screened patients to participate in 
study thereby increasing the 
eligible study population and 
potentially providing more 
generalizable results. 
Section 2, Schedule of 
Activities Table 2-2 and 
Table 2-3
Section 9.8, Biomarkers 
Table 9.8-1
Increased windows for cystoscopy, urine 
cytology and bladder biopsy from ±孵
weeks to ± 3 weeks
Window during which to perform
efficacy assessments increased to 
+/- 3 weeks to allow Investigators 
greater flexibility in scheduling 
evaluations
Section 5.1.2, 
Randomization Phase
Added language detailing classifications 
and definitions of BCG refractory and 
BCG early relapsing
Language added since BCG 
refractory vs Early Relapsing are 
no longer stratification factors but 
will still be recorded by 
investigators for the purpose of 
analysis
Section 6.1, Inclusion 
Criteria
Added language to criteria 4f detailing 
requirements specific to condom use 
during penile vaginal intercourse 
Clarified condom requirements for 
males who are sexually active with 
WOCBP. Language made 
consistent with Appendix 4
Section 5.1, Overall 
Design
Section 5.5.4, Justification 
for BCG Dose, 
Section 7.1, Treatments 
Administered
Language revised to indicate BCG dosing 
according to prescribing information for 
BCG strain and preparation administered 
BCG will be locally sourced in 
some countries and provided by 
sponsor in other countries. As a 
result, dose will not be based on 
local SOC but rather will be based 
on prescribing information for 
BCG strain/preparation 
administered.
Section 7.2, Method of 
Treatment Assignment
Updated language for disease status that 
will be used to stratify participants at time 
of randomization
Revised language in alignment with 
FDA final guidance for BCG 
Unresponsive NMIBC
Protocol Amendment No.: 04
Date: 22-Sep-2021
166
5.0
Approved
930120285
5.0
v
Approved
1.0
v


Clinical Protocol
CA2099UT
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.7.1.1, Prohibited 
Treatments
Section 7.7.1.2, Restricted 
Treatments
Updated language to add CYP1A2 
inhibitors and inducers and add details 
regarding marijuana and concurrent 
smoking
Clinical pharmacology studies have 
further clarified the metabolic 
pathway of BMS-986205 as it 
relates to CYP1A2
Section 6.2, Exclusion 
Criteria 
Section 7.7.2, Other 
Restrictions and 
Precautions
Section 8.1.2,
Discontinuation of BMS-
986205
Added language regarding theoretical risk 
of serotonin syndrome and updated 
exclusion criteria and discontinuation 
criteria for serotonin syndrome
There is a theoretical chance that 
BMS-986205 could cause an 
increase in serotonin levels in the 
brain that may contribute to 
occurrence of serotonin syndrome.
Section 9.1, Efficacy 
Assessments
Added language providing detailed plan 
for evaluating suspicious urine cytology 
and clarified definitions for complete 
response and recurrence for participants 
with suspicious cytology undergoing 
subsequent evaluation 
Revised language in alignment with 
FDA final guidance for BCG 
Unresponsive NMIBC
Section 2, Schedule of 
Activities Table 2-2 & 2-3
Section 9.8, Biomarkers 
Table 9.8-1
 
 
 
ALL
Minor edits made throughout document to 
align sections for consistency
Minor, therefore have not been 
summarized
Protocol Amendment No.: 04
Date: 22-Sep-2021
167
5.0
Approved
930120285
5.0
v
Approved
1.0
v