A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus Bempegaldesleukin (NKTR-214), Versus Nivolumab Alone Versus Standard of Care in Participants With Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible
Phase: PHASE3
Conditions: Bladder Cancer, Bladder Tumor, Muscle-Invasive Bladder Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus 
Bempegaldesleukin (NKTR-214), Versus Nivolumab Alone Versus Standard of Care in 
Participants with Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible 
 
NCT Number: NCT04209114 
Document Date (Date in which document was last revised): June 10, 2022 

Page:
1
Protocol Number:
CA045009/18-214-13
IND Number:
141262
EUDRACT Number:
2018-002676-40
NCT:
NCT04209114
UTN:
U1111-1216-7529
Date:
05-Oct-2018
Revised Date:
10-Jun-2022
CLINICAL PROTOCOL CA045009/18-214-13
A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus 
Bempegaldesleukin (NKTR-214), Versus Nivolumab Alone Versus Standard of Care in 
Participants with Muscle-Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible
Protocol Amendment 04
Incorporates Administrative Letter 04
Medical Monitor
Bristol-Myers Squibb Company
Bristol-Myers Squibb Company
3401 Princeton Pike
3401 Princeton Pike
Lawrenceville, NJ 08648
Lawrenceville, NJ 08648
Telephone (office): 
Telephone (office): 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
Route 206 & Province Line Road
Lawrenceville, NJ 08543
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
Date: 10-Jun-2022
2
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 
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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Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
Date: 10-Jun-2022
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 04
10-Jun-2022
Participants who are currently receiving bempegaldesleukin plus
nivolumab are required to discontinue bempegaldesleukin and may
continue nivolumab monotherapy on protocol for the remainder of
their treatment duration. New enrollment in this study has been
stopped.
Imaging will be performed per local standard of care; blinded
independent central review is discontinued. All study treatment
decisions including progression and recurrence will be based on the
investigator’s assessment of tumor images.
The efficacy endpoints of pathologic complete response, event-free
survival, and overall survival, as well as safety and tolerability for
each treatment arm, will be summarized descriptively in all
randomized participants. Secondary 
 objectives
except for safety 
 parameters will not be required. No
further efficacy data will be collected/analyzed.
For each randomized participant, the maximum duration of the
study is 62 weeks plus 100 days of safety follow-up.
Participants currently in survival follow-up will discontinue from
the study following one recurrence update and survival status
update.
Administrative 
Letter 04
06-Apr-2022
The purpose of this letter is to clarify and align the Schedule of 
Activities for collection and submission of tumor tissue samples for 
participants assigned to Arm C in the CA045009 trial following 
radical cystectomy with the protocol text, Section 5.1.2.2 Surgery 
(Radical Cystectomy). To clarify, tissue samples for all participants, 
irrespective of study assignment, must be submitted to central lab for 
pathologic confirmation after radical cystectomy.
Protocol 
Amendment 03
26-Aug-2021

Revised to include participants with high-risk urothelial
carcinoma (UC) of the bladder with N1 disease and muscle-
invasive bladder cancer (MIBC), addition of nivolumab +
bempegaldesleukin 
vs 
nivolumab 
secondary 
endpoint
comparisons, and the updated alpha allocation for the pathologic
complete response (pCR) and event free survival (EFS) primary
endpoints

Modifications made to align with Bempegaldesleukin and
Nivolumab program standards

Align with changes to safety assessments including safety
management algorithms, guidance for severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) status, and coronavirus
disease 2019 (COVID-19) vaccine
Administrative 
Letter 03
06-Jun-2020
This letter is to correct inconsistency in the protocol:

The note referring to AE biopsy was inadvertently not removed
in treatment section 7.4.1 of the protocol. 
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Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
Date: 10-Jun-2022
4
Document
Date of Issue
Summary of Change
Revised Protocol 02
05-Mar-2020

Revised to align with most recent language for BMS program 
updates

Modifications made to align with NKTR-214 program and IB 
updates

Appendix 2 updated (Study Governance Considerations)

Appendix 6 updated (Management Algorithms)

Appendix 7 added (CVA Management Algorithm)
Revised Protocol 01
21-Jan-2019

Modifications made to align with BMS policy updates

Added nivolumab and NKTR-214 program updates

Correction to Section 5.1.4: added missing paragraph regarding 
adjudicated events

Appendix 3 updated (Adverse Events)

Appendix 4 updated (WOCBP)

Appendix 9 added (Country Specific Requirements)
Original Protocol
05-Oct-2018
Not applicable
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04
Three recent studies from the bempegaldesleukin and nivolumab development program, Study 
CA045-001/17-214-08, a Phase 3 study in metastatic melanoma, Study 17-214-09/PIVOT-09, a 
Phase 3 study in metastatic renal cell carcinoma, and Study 18-214-10/PIVOT-10, a Phase 2 study 
in cisplatin ineligible metastatic urothelial carcinoma have demonstrated that there was no 
additional benefit of combining bempegaldesleukin with nivolumab. On 14-Apr-2022, Nektar 
Therapeutics and Bristol-Myers Squibb (BMS) announced a joint decision to end the clinical 
development program for bempegaldesleukin in combination with nivolumab. Per Protocol 
Amendment 04, participants who are currently receiving bempegaldesleukin plus nivolumab in 
Arm A of CA045009 are required to discontinue bempegaldesleukin and may continue to receive 
nivolumab monotherapy. The purpose of this amendment is to allow participants who are deriving 
benefit to continue on study treatment while minimizing participant burden. 
All new enrollment to CA045009 has been stopped, and study procedures that no longer apply due 
to the discontinuation of bempegaldesleukin are indicated throughout the protocol and are 
specified below.
Minor formatting and typographical corrections have been made; therefore, they have not been 
summarized.
This protocol amendment applies to all participants.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Updated synopsis to align with 
protocol revisions.
To align the Synopsis with 
updates made to the full 
protocol.
Title page
The 
 for 
this study has changed..
Updated to reflect current 
study personnel.
Table 2-1 Screening Procedural 
Outline (CA045009) 
Note added to the table title 
indicating that all new 
enrollment has been stopped. 
Enrollment has been stopped 
per the joint decision of 
Nektar Therapeutics and 
BMS to end the clinical 
development program of 
bempegaldesleukin in 
combination with nivolumab. 
Table 2-2: Pre-surgery 
(Neoadjuvant) Procedures and 
Assessments (Arm A + Arm B)
Table 2-3: Post-surgery (Adjuvant) 
Procedures and Assessments (Arm 
A + Arm B)
Note to the table titles to specify 
text related to 
bempegaldesleukin is not 
applicable, but criteria for 
nivolumab remain unchanged.
Bempegaldesleukin will no
longer be administered.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: Pre-surgery 
(Neoadjuvant) Procedures and 
Assessments (Arm A + Arm B)
Update of Administer Study 
Drug: Arm A: 
Bempegaldesleukin (0.006 
mg/kg) and Nivolumab (360 mg) 
(Arm A): Text added to indicate 
that bempegaldesleukin dose is 
not applicable. Note has also 
been updated. 
Bempegaldesleukin will no
longer be administered.
Table 2-2: Pre-surgery 
(Neoadjuvant) Procedures and 
Assessments (Arm A + Arm B)
Table 2-3: Post-surgery (Adjuvant) 
Procedures and Assessments (Arm 
A + Arm B)
Added text to indicate that the 
procedures listed below and 
corresponding notes are not 
applicable per Protocol 
Amendment 04: 

Administer Intravenous (IV) 
Fluids, (Arm A ONLY) 

Review Hydration 
Guidelines with Participants
(Arm A ONLY)

Oral Hydration Follow-up 
(Arm A ONLY)
 

Submission of Tissue for 
 Analysis (Table 
2-3)

Submission of Tissue for 
pCR (Table 2-3)  

Severe Acute Respiratory 
Syndrome Coronavirus 2; 
(SARS-CoV-2) Serology
(Table 2-2)
 
 
 
 
 
 
 
 
Bempegaldesleukin will no 
longer be administered.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Table 2-2: Pre-surgery 
(Neoadjuvant) Procedures and 
Assessments (Arm A + Arm B)
Table 2-3: Post-surgery (Adjuvant) 
Procedures and Assessments (Arm 
A + Arm B)
Laboratory Tests, Clinical -
Laboratory Testing - Deletion of 
bempegaldesleukin from 
instruction for pre-dose testing 
of renal function. 
No longer applicable as 
bempegaldesleukin will no 
longer be administered.
Table 2-2: Pre-surgery 
(Neoadjuvant) Procedures and 
Assessments (Arm A + Arm B)
Table 2-3: Post-surgery (Adjuvant) 
Procedures and Assessments (Arm 
A + Arm B)
Efficacy: Body Imaging: Text 
added to indicate that per 
Protocol Amendment 04, 
imaging will be performed per 
local standard of care (SOC) and 
images will no longer be 
submitted for blinded 
independent central review 
(BICR)
Since further efficacy will not 
be assessed, imaging will be 
performed per local SOC and 
tumor assessments will be 
evaluated by investigator 
assessment. 
Table 2-3: Post-surgery (Adjuvant) 
Procedures and Assessments (Arm 
A + Arm B)
Cystoscopy - Text added within 
Table 2-3 and to Footnote c to 
indicate that per Protocol 
Amendment 04, cystoscopy will 
be performed per local SOC. 
No further efficacy
assessments. 
Table 2-4: Long-term Follow-up 
Assessments (Arm A and Arm B)
Text has been added to indicate 
that participants will have a final 
follow-up for recurrence status 
and overall survival and then 
will discontinue from the study. 
Added text to indicate that the 
sections listed below as well as 
corresponding notes are not 
applicable per Protocol 
Amendment 04:
 
 
Subsequent Anti-cancer 
Therapy
Survival Status 
Footnote c.
Per Protocol Amendment 04, 
survival follow-up every 3 
months is no longer 
applicable. 
Indicated assessments are no 
longer applicable; the. 
program is being 
discontinued.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Efficacy: Body Imaging: Text 
added to indicate that per 
Protocol Amendment 04, 
imaging will be performed per 
local SOC and images will no 
longer be submitted for BICR.
Aligned with change to 
investigator assessment of 
imaging. 
Cystoscopy - Text added to 
indicate that per Protocol 
Amendment 04, cystoscopy will 
be performed per local SOC.
No further efficacy 
assessments.
Table 2-5: Study Assessment -
Arm C
Text has been added to indicate 
that participants will have a final 
follow-up for recurrence status 
and overall survival and then 
will discontinue from the study. 
Per Protocol Amendment 04, 
survival follow-up every 3 
months is no longer 
applicable.
Subsequent Anti-cancer 
Therapy: note added to indicate 
that per Protocol Amendment 04, 
the details of subsequent anti-cancer 
therapy will no longer be collected 
after 100 days of safety follow-up.
Efficacy: Body Imaging: Text 
added to indicate that per 
Protocol Amendment 04, 
imaging will be performed per 
local SOC, and images will no 
longer be submitted for BICR.
Aligned with change to 
investigator assessment of 
imaging.
Cystoscopy - Text added to
indicate that per Protocol 
Amendment 04, cystoscopy will 
be performed per SOC.
No further efficacy 
assessments.
Added text to indicate that the 
sections listed below as well as 
corresponding notes are not 
applicable per Protocol 
Amendment 04:
 
 
 
Indicated assessments are no 
longer applicable; the. 
program is being 
discontinued.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
 

Subsequent Anti-cancer 
Therapy

Submission of Tissue for 
Pathologic Complete Response

Footnote b
Section 3: Introduction
Section 3.1.1 Research Hypothesis
Section 3.2.1:
Epidemiology/Indication
Added text that sections are not 
applicable per Protocol 
Amendment 04 and if required 
by the content of the specific 
section, that participants 
receiving bempegaldesleukin 
plus nivolumab are required to 
discontinue bempegaldesleukin 
and may continue to receive 
nivolumab monotherapy.
No longer applicable as 
bempegaldesleukin is no 
longer administered in the 
study. .
Section 3.2.4.2: Study 16-214-02 
(PIVOT-02; Bempegaldesleukin 
and Nivolumab Combination 
Therapy)
Section 9.2.1: Time Period and 
Frequency for Collecting AE and 
SAE Information
Section 9.2.7: Adverse Events of 
Special Interest (AEOSI)
Text added to indicate that the 
Cerebrovascular Accident 
Adverse Event Management 
Algorithm ([(CVA-AE] 
Appendix 7) is no longer 
applicable per Protocol 
Amendment 04.
Bempegaldesleukin will no 
longer be administered. 
Section 3.2.4.3: Study 18-214-10 
(PIVOT-10); Bempegaldesleukin 
and Nivolumab Combination 
Therapy
New section added that 
summarizes the results of Study 
18-214-10 (PIVOT-10).
Addition of summary 
background that supported 
the joint decision of Nektar 
Therapeutics and BMS to
discontinue clinical 
development.
Section 3.3 3: Bempegaldesleukin 
and Nivolumab Benefit and Risk 
Assessment
Added statement on the joint
decision by Nektar Therapeutics 
and BMS to stop the global 
clinical development of the 
bempegaldesleukin and 
nivolumab combination 
program.
Benefit/Risk section adjusted 
per changes of Protocol 
Amendment 04. 
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 4: Objectives and 
Endpoints 

Added that secondary 
 
 endpoints except 
for safety 
 
 are not 
applicable per Protocol 
Amendment 04.

Efficacy endpoints of 
pathologic complete 
response (pCR), event free 
survival (EFS) and overall 
survival (OS), as well as 
safety and tolerability, will 
be summarized descriptively 
in all randomized 
participants.
Additional data for secondary 
 objectives, 
 
will not be captured.
Section 5.1: Overall Design 

The updates in this section 
describe the end of the global 
clinical program and indicate 
text that is not applicable per 
Protocol Amendment 04 and 
that participants receiving 
bempegaldesleukin plus 
nivolumab are required to 
discontinue 
bempegaldesleukin and may 
continue to receive 
nivolumab monotherapy.

In addition, the disposition of 
participants who are 
receiving treatment on the 
study or in safety follow-up 
or long term follow-up is 
specified.
Section is now aligned with 
changes of Protocol 
Amendment 04 and includes 
instructions for disposition of
participants who remain on 
the study. 
Section 5.1.1: Screening Period
Section 5.1.2.1: Neoadjuvant 
(Pre-surgical Treatment)
Randomized Participants 
Section 5.1.2.3: Adjuvant (Post-
surgical Treatment) 
Section 5.1.4: Data monitoring 
Committee and Other External 
Committees 
Added that these sections are not 
applicable per Protocol 
Amendment 04 and, if required 
by the content of the specific 
section, that participants 
receiving bempegaldesleukin 
plus nivolumab are required to 
discontinue bempegaldesleukin 
and may continue to receive 
nivolumab monotherapy.
No longer applicable as 
bempegaldesleukin will no 
longer be administered. 
Protocol Amendment No.: 04
Date: 10-Jun-2022
10
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930131308
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.2.2: Surgery (Radical 
Cystectomy)
Per Protocol Amendment 04, 
radical cystectomy will be 
performed per local SOC.
In addition, text referring to 
pathology slides are designated 
as no longer applicable per 
Protocol Amendment 04 as is 
text with procedures for 
participants who do not undergo
radical cystectomy (RC).
No further efficacy 
assessments.
Section 5.1.3: Long-term Follow-
up
Per Protocol Amendment 04, 
participants will have a final 
follow-up for recurrence status 
and overall survival and then 
will discontinue from the study.
For each randomized participant, 
the total maximum duration of 
the study is up to 62 weeks + 
100 days of safety follow up.
Per Protocol Amendment 04, 
survival follow-up every 3 
months is no longer 
applicable.
Descriptive analyses will now 
be performed in the study, the 
maximum duration of the 
study for each participant was
shortened to the study
treatment period plus 100 
days safety follow-up.
Section 5.1.4.1: Blinded Pathology 
and Radiology Review 
Text added to indicate that this 
section is no longer applicable 
but descriptive analysis of 
pathologic complete response 
(pCR) will be conducted on 
samples collected prior to 
Protocol Amendment 04.
Radiology Review is no longer 
applicable per Protocol 
Amendment 04.
The program is being 
discontinued and no further 
efficacy data is being 
collected. Descriptive 
analyses on pathology
samples collected prior to 
Protocol Amendment 04 will
be conducted. 
Section 5.2: Number of 
Participants 
Updated to specify that all new 
enrollment in CA045009 has 
stopped. 
Aligned with the Nektar
Therapeutics and BMS joint
decision to stop clinical 
development of 
bempegaldesleukin and 
nivolumab combination.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 5.3: End of Study 
Definition
Paragraph that previously 
defined end of the study in terms 
of accrual events is no longer 
applicable per Protocol 
Amendment 04.
No longer applicable as study 
will stop once last participant 
completes the treatment 
period plus safety follow-up
or earlier on the Sponsor’s 
decision. 
Section 5.4.4: Rationale for Open-
label Design 
Section 5.5.1: Justification for 
Dose of Bempegaldesleukin
Added that sections are not 
applicable per Protocol 
Amendment 04.
No longer applicable as 
bempegaldesleukin will no 
longer be administered.
Section 5.5.3: Rationale for 
Bempegaldesleukin/Nivolumab 
Combination Dose
Table 5.5.3-1: Patient Exposure 
Supporting Combination Dose 
Added text to the section and to 
the table title to specify not 
applicable per Protocol 
Amendment 04.
Section 6: Study Population
Section 6.1: Inclusion Criteria
Section 6.2: Exclusion Criteria
Text added to indicate no longer 
applicable per Protocol 
Amendment 04 as enrollment 
has stopped. 
New enrollment in the study 
has stopped. 
Section 6.3: Lifestyle Restrictions 
Added that section is not 
applicable per Protocol 
Amendment 04.
No longer applicable as 
bempegaldesleukin will no 
longer be administered.
Section 7: Treatment
Table 7-1: Study Treatment for 
CA045009/18-214-13
Section 7.1: Treatments 
Administered 
Table 7.1-1: Selection and Timing 
of Dose 
Section 7.1.1: Bempegaldesleukin 
Dosing
Added to the section text and 
in the study tables text to 
specify that 
bempegaldesleukin is not 
applicable per Protocol 
Amendment 04. 
Updated text states that
participants receiving 
bempegaldesleukin plus 
nivolumab are required to 
discontinue 
bempegaldesleukin and may 
continue to receive nivolumab 
monotherapy 360 mg IV 
Q3W for the remainder of the 
study treatment period.
Section 7.1.1.1: Hydration 
Guidelines 
Added that section is not 
applicable per Protocol 
Amendment 04.
Bempegaldesleukin will no 
longer be administered.
Protocol Amendment No.: 04
Date: 10-Jun-2022
12
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 7.4: Dosage Modification
Section 7.4.1: Nivolumab and 
Bempegaldesleukin Dose Delay, 
Resume, and Discontinuation 
Criteria
Added text that section is not 
applicable per Protocol 
Amendment 04, but criteria 
remain unchanged for 
nivolumab.
Bempegaldesleukin will no 
longer be administered, and 
participants may receive 
nivolumab monotherapy. 
Table 7.4.1-1:
Adverse Event 
Criteria for Delay, Resumption, 
and Discontinuation of Nivolumab 
and Bempegaldesleukin (if One is 
Delayed, Both Delayed)
Added to the table title that 
text related to 
bempegaldesleukin is not 
applicable per Protocol 
Amendment 04 but criteria 
remain unchanged for 
nivolumab.
Note added to table title that 
participants must discontinue 
bempegaldesleukin.
Bempegaldesleukin will no 
longer be administered, and 
the participants may receive 
nivolumab monotherapy.
Table 7.4.1-2: Bempegaldesleukin-
specific Adverse Event Criteria for 
Delay, Resumption, and 
Discontinuation of Nivolumab and 
Bempegaldesleukin (if one is 
delayed, both are delayed)
Added to the table title that 
text related to 
bempegaldesleukin is not 
applicable per Protocol 
Amendment 04 but criteria 
remain unchanged for 
nivolumab.
Note added after the table to 
specify that 
bempegaldesleukin must be 
discontinued for participants 
receiving bempegaldesleukin 
plus nivolumab and that 
participants may continue on 
nivolumab monotherapy.

In addition, note states 
participants with CVA must 
be managed by Advanced 
Cardiac Life Support (ACLS)
and institutional guidelines 
and Appendix 7 no longer 
applies for the management of 
participants with CVA/TIA. 
Bempegaldesleukin will no 
longer be administered, and 
the participants may continue 
to receive nivolumab 
monotherapy.
Protocol Amendment No.: 04
Date: 10-Jun-2022
13
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930131308
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 7.4.1.1: Dose Modification 
Criteria for Bempegaldesleukin 
and Nivolumab for Cycle 1 
AST/ALT Elevations
Section 7.4.2: Monitoring and 
Management of Elevated Hepatic 
Transaminases  
Section 7.4.3: Monitoring and 
Management of 
Bempegaldesleukin-induced 
Eosinophilia
Added that sections are not 
applicable per Protocol 
Amendment 04. 
No longer applicable as 
bempegaldesleukin will no 
longer be administered.
Section 7.4.5: Management 
Algorithms for Immuno-oncology 
Agents 
Added that text related to 
bempegaldesleukin is not 
applicable per Protocol 
Amendment 04 but criteria 
remain unchanged for 
nivolumab.
Advanced Cardiac Life Support 
(ACLS) and institutional 
guidelines should be followed 
for all CVA cases.
Text added to indicate that the 
Cerebrovascular Accident 
Adverse Event  Management 
Algorithm ([(CVA-AE] 
Appendix 7) is no longer 
applicable per Protocol
Amendment 04.
Bempegaldesleukin will no 
longer be administered, and 
the participants may continue 
to receive nivolumab 
monotherapy.
Section 7.4.5.1: Management 
Algorithm for Cytokine-release 
Syndrome 
Added that the algorithm for the 
management of Cytokine -
Release Syndrome (CRS),
provided in Appendix 8, is not 
applicable per Protocol 
Amendment 04.
No longer applicable as 
bempegaldesleukin will no 
longer be administered.
Section 7.4.6: Treatment of 
Bempegaldesleukin-related or 
Nivolumab-related Infusion 
Reactions
Added that text related to 
bempegaldesleukin is not 
applicable per Protocol 
Amendment 04, but criteria 
remain unchanged for 
nivolumab.
Bempegaldesleukin will no 
longer be administered, and 
the participants may receive 
nivolumab monotherapy.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 7.7: Concomitant Therapy
Added text to indicate that Per 
Protocol Amendment 04, 
bempegaldesleukin will no 
longer be administered.
Bempegaldesleukin will no 
longer be administered.
Section 7.6: Treatment 
Compliance
Section 7.7.1.1: Effect of 
Bempegaldesleukin on PK of 
Concomitant Medications 
Section 7.7.2.3: Blood Pressure 
Precautions
Added that section is not 
applicable per Protocol 
Amendment 04.
Bempegaldesleukin will no 
longer be administered, and 
the participants may receive 
nivolumab monotherapy.
Section 7.7.2.1: Restricted 
Treatments
Added first paragraph on 
ischemic cerebrovascular events 
and anticoagulation therapy no 
longer being mandated for the 
study.
Participants are required to 
discontinue 
bempegaldesleukin.
Section 7.7.3: Permitted Therapy 
Added that text related to 
bempegaldesleukin is not 
applicable per Protocol 
Amendment 04, but criteria 
remain unchanged for 
nivolumab.
Bempegaldesleukin will no 
longer be administered, and 
the participants may continue 
to receive nivolumab 
monotherapy.
Section 7.8: Treatment After the 
End of the Study
Text added to specify how 
treatment will be available to 
participants if the study is 
terminated. 
The Sponsor will determine 
access to care if the study is 
terminated.
Section 8.1.1: Nivolumab and 
Bempegaldesleukin 
Discontinuation Criteria
Text added to specify that Per 
Protocol Amendment 04 
participants receiving 
bempegaldesleukin plus 
nivolumab are required to 
discontinue bempegaldesleukin 
and may continue to receive 
nivolumab monotherapy and that 
per Protocol Amendment 04 
bempegaldesleukin is not 
applicable but criteria remain 
unchanged for nivolumab.
Bempegaldesleukin will no 
longer be administered, and 
participants may continue to 
receive nivolumab 
monotherapy.
Section 8.1.2: Post-study 
Treatment Study Follow-up
For each randomized participant, 
the maximum total duration of 
For each randomized 
participant, the maximum 
duration of the study was
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
the study is 62 weeks plus 100 
days of safety follow-up.
No longer applicable per 
Protocol Amendment 04 is the 
collection of subsequent cancer 
therapy details.
shortened to the study 
treatment period plus 100 
days for safety follow-up.
Section 8.2: Discontinuation from 
the Study
Updated to specify that 
participants who wish to 
discontinue study treatment will 
remain in the study and will be 
followed for up to 100 days of 
safety follow-up and will be 
documented for last overall 
survival. 
Recommended duration of 
safety follow-up for 
nivolumab.
Section 9.1: Efficacy Assessments
Section 9.1.2 Imaging Assessment 
for the Study
Section 9.1.2.2: BICR 
Confirmation of Progression or 
Recurrence
Section 9.1.2.3: Confirmation and 
Date of Progression or Recurrence
Per Protocol Amendment 04, 
tumor assessments will be 
determined by investigator. 
Updated to reflect that per 
Protocol Amendment 04, 
images will no longer be 
submitted for central review.
Per Protocol Amendment 04, 
BICR will be discontinued,
and all study treatment 
decisions will be based on 
the investigator’s assessment 
of tumor images. 
As there are no further 
efficacy assessments, BICR
will not be conducted, and 
images will be assessed by 
the investigator.
Section 9.2.6, Immune-mediated 
Adverse Events
Per Protocol Amendment 04, 
text related to collection of 
additional information on select 
AEs related to 
bempegaldesleukin is not 
applicable. 
No longer applicable as 
bempegaldesleukin will no 
longer be administered.
Section 9.4.7 Clinical Safety 
Laboratory Assessments
Per Protocol Amendment 04, all 
clinical safety laboratory 
Submission to the central 
laboratory is no longer 
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
assessments will be performed 
locally. 
required; the program is being 
discontinued. 
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 10.1: Sample Size 
Determination 
Table 10.1-1: Sample Size 
Calculations per Comparison for 
Primary Endpoints
Updated to indicate that section 
is not applicable per Protocol 
Amendment 04. 
The underlying assumptions 
for efficacy comparisons 
between Arm A and Arm C in 
sample size determinization 
are no longer applicable.
Section 10.3: Statistical Analyses
Text added in alignment with the 
termination of the global 
development of 
bempegaldesleukin, the study 
will be unblinded and there will 
be no hypothesis testing. The 
efficacy endpoints of pCR, EFS,
and OS will be summarized 
descriptively. 
No hypothesis testing for any 
efficacy endpoints will be 
performed between the 
treatment arms. 
Table 10.3-1: Efficacy Analyses
Figure 10.3-1: Graphical 
Representation of the Statistical 
Testing Approach
Text added to indicate Not 
Applicable per Protocol 
Amendment 04. 
Text below study table not 
applicable per Protocol 
Amendment 04. 
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 10.3.3: Interim Analyses 
Table 10.3.3-1: Interim Analyses
Schedule
Section 10.3.4: Interim Analyses 
for EFS
Section 10.3.5: Interim Analyses 
for OS 
Text added to indicate Not 
Applicable per Protocol 
Amendment 04. 
No hypothesis testing for any 
efficacy endpoints will be 
performed between the 
treatment arms.
Section 11: References
Reference to joint decision of 
Nektar Therapeutics and BMS
on the decision to discontinue 
development program of the 
combination of 
bempegaldesleukin and 
nivolumab has been added.
Support of new text in 
Section, 3.2.4.3, Study 18-
214-10 (PIVOT-10); 
Bempegaldesleukin and 
Nivolumab Combination 
Therapy
Appendix 7: Cerebrovascular 
Accident Adverse Event 
Management Algorithm 
Added that Appendix 7 is not 
applicable per Protocol 
Amendment 04.
Participants are required to 
discontinue 
bempegaldesleukin.
Appendix 8: Cytokine Release 
Syndrome (CRS) Management 
Algorithm
Added that Appendix 8 is not 
applicable per Protocol 
Amendment 04.
Participants are required to 
discontinue 
bempegaldesleukin.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 04 ............................. 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 04 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Epidemiology/Indication .......................................................................... 
 
3.2.2 Nivolumab ................................................................................................ 
 
3.2.2.1 Mechanism of Action....................................................................... 
 
3.2.2.2 Clinical Experience with Nivolumab .............................................. 
 
3.2.3 Bempegaldesleukin .................................................................................. 
 
3.2.3.1 Mechanism of Action....................................................................... 
 
3.2.4 Clinical Experience with Bempegaldesleukin .......................................... 
 
3.2.4.1 Study 15-214-01 (EXCEL; Bempegaldesleukin Monotherapy) ...... 
 
3.2.4.2 Study 16-214-02 (PIVOT-02; Bempegaldesleukin and Nivolumab 
Combination Therapy) .......................................................................... 
 
3.2.4.3 Study 18-214-10 (PIVOT-10); Bempegaldesleukin and Nivolumab 
Combination Therapy ........................................................................... 
 
3.2.4.4 Pooled Safety Analysis of Participants with Bempegaldesleukin and 
Nivolumab Exposure ............................................................................. 
 
3.2.4.5 Observed Events of Cerebrovascular Accident .............................. 
 
3.3 Benefit-risk Assessment .................................................................................... 
 
3.3.1 Bempegaldesleukin Safety Profile ............................................................ 
 
3.3.2 Nivolumab Safety Profile ......................................................................... 
 
3.3.3 Bempegaldesleukin and Nivolumab Benefit and Risk Assessment .......... 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Screening Period ...................................................................................... 
 
5.1.2 Treatment Period ..................................................................................... 
 
5.1.2.1 Neoadjuvant (Pre-surgical Treatment) Randomized Participants . 
 
5.1.2.2 Surgery (Radical Cystectomy) ........................................................ 
 
5.1.2.3 Adjuvant (Post-surgical Treatment) ............................................... 
 
5.1.3 Long-term Follow-up ............................................................................... 
 
5.1.4 Data Monitoring Committee and Other External Committees ................ 
 
5.1.4.1 Blinded Pathology and Radiology Review ...................................... 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
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CA045009/18-214-13
bempegaldesleukin (NKTR-214)
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5.4.1 Rationale for the Combination of Bempegaldesleukin and Immune 
Checkpoint Inhibitors.................................................................................. 
 
5.4.2 Rationale for Study Comparator and Study Population .......................... 
 
5.4.2.1 Rationale for Including Participants with Clinical Stage T2 Bladder 
Cancer ................................................................................................... 
 
5.4.2.2 Rationale for Including Participants with N1 in Bladder Cancer .. 
 
5.4.3 Rationale for Choice of Endpoints ........................................................... 
 
5.4.3.1 Rationale for pCR as One of the Primary Endpoints ..................... 
 
5.4.3.2 Rationale for Event-free Survival as One of the Primary Endpoints
............................................................................................................... 
 
5.4.4 Rationale for Open-label Design ............................................................. 
 
5.4.5 Rationale for Stratification by Disease State and PD-L1 ........................ 
 
5.4.6 Duration of Treatment with Nivolumab/Bempegaldesleukin ................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Justification for Dose of Bempegaldesleukin ........................................... 
 
5.5.2 Justification for Dose of Nivolumab ........................................................ 
 
5.5.3 Rationale for Bempegaldesleukin/Nivolumab Combination Dose .......... 
 
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 Period ......................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Bempegaldesleukin Dosing ...................................................................... 
 
7.1.1.1 Hydration Guidelines ...................................................................... 
 
7.1.2 Nivolumab Dosing ................................................................................... 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Nivolumab and Bempegaldesleukin Dose Delay, Resume, and 
Discontinuation Criteria ............................................................................. 
 
7.4.1.1 Dose Modification Criteria for Bempegaldesleukin and Nivolumab 
for Cycle 1 AST/ALT Elevations ........................................................... 
 
7.4.2 Monitoring and Management of Elevated Hepatic Transaminases ........ 
 
7.4.3 Monitoring and Management of Bempegaldesleukin-induced 
Eosinophilia ................................................................................................ 
 
7.4.4 Monitoring and Management of Adrenal Insufficiency and Hypophysitis
..................................................................................................................... 
 
7.4.5 Management Algorithms for Immuno-oncology Agents .......................... 
 
7.4.5.1 Management Algorithm for Cytokine-release Syndrome ................ 
 
7.4.6 Treatment of Bempegaldesleukin-related or Nivolumab-related Infusion 
Reactions ..................................................................................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability/Bioequivalence/Biocomparability 
 
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CA045009/18-214-13
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
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7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.1.1 Effect of Bempegaldesleukin on PK of Concomitant Medications . 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Restricted Treatments ..................................................................... 
 
7.7.2.2 Imaging Restriction and Precautions ............................................. 
 
7.7.2.3 Blood Pressure Precautions ........................................................... 
 
7.7.3 Permitted Therapy ................................................................................... 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Nivolumab and Bempegaldesleukin Discontinuation Criteria ................ 
 
8.1.2 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 Definition of Events in EFS ...................................................................... 
 
9.1.1.1 Definition of Disease Recurrence ................................................... 
 
9.1.1.2 Definition of Disease Progression .................................................. 
 
9.1.1.3 Definition of pCR ............................................................................ 
 
9.1.2 Imaging Assessment for the Study............................................................ 
 
9.1.2.1 Methods of Measurement ................................................................ 
 
9.1.2.2 BICR Confirmation of Progression or Recurrence ........................ 
 
9.1.2.3 Confirmation and Date of Progression or Recurrence................... 
 
 
 
 
 
 
 
 
 
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 Immune-mediated Adverse Events ........................................................... 
 
9.2.7 Adverse Events of Special Interest (AEOSI) ............................................ 
 
9.2.8 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.9 Potential Drug-induced Liver Injury (DILI) ............................................ 
 
9.2.10 Other Safety Considerations .................................................................. 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Vital Signs and Oxygen Saturation .......................................................... 
 
9.4.2 Physical Examinations ............................................................................. 
 
9.4.3 Electrocardiograms ................................................................................. 
 
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Clinical Protocol
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CA045009/18-214-13
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
Date: 10-Jun-2022
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9.4.4 Echocardiogram ...................................................................................... 
 
9.4.5 Pregnancy Tests ....................................................................................... 
 
9.4.6 Imaging Safety Assessment ...................................................................... 
 
9.4.7 Clinical Safety Laboratory Assessments .................................................. 
 
 
 
 
 
 
 
9.7 Pharmacogenomics ........................................................................................... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Safety Analyses....................................................................................... 
 
 
 
 
 
 
 
10.3.3 Interim Analyses ..................................................................................... 
 
10.3.4 Interim Analyses for EFS ....................................................................... 
 
10.3.5 Interim Analyses for OS ......................................................................... 
 
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 ECOG (ADULT) PERFORMANCE STATUS SCALES .................... 
 
APPENDIX 6 MANAGEMENT ALGORITHMS ....................................................... 
 
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BMS-986321
CA045009/18-214-13
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
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APPENDIX 7 CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM *PER PROTOCOL AMENDMENT 04 NO 
LONGER APPLICABLE. ...................................................................................... 
 
APPENDIX 8 CYTOKINE RELEASE SYNDROME (CRS) MANAGEMENT 
ALGORITHM *PER PROTOCOL AMENDMENT 04 NO LONGER 
APPLICABLE. ....................................................................................................... 
 
APPENDIX 9 DEFINITIONS OF AJCC TNM ........................................................... 
 
APPENDIX 10 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
 
APPENDIX 11 COUNTRY SPECIFIC REQUIREMENTS ....................................... 
 
APPENDIX 12 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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BMS-986321
CA045009/18-214-13
bempegaldesleukin (NKTR-214)
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
1
SYNOPSIS
A Phase 3, Randomized, Study of Neoadjuvant and Adjuvant Nivolumab Plus Bempegaldesleukin 
(NKTR-214), Versus Nivolumab Alone Versus Standard of Care in Participants with Muscle-
Invasive Bladder Cancer (MIBC) Who Are Cisplatin Ineligible
Study Phase: Phase 3
Rationale:
On 14-April-2022, Nektar Therapeutics and BMS jointly decided to end the global clinical 
development program for bempegaldesleukin in combination with nivolumab. All new 
enrollment to CA045009 has been stopped. Per Protocol Amendment 04, participants who 
are currently receiving bempegaldesleukin plus nivolumab are required to discontinue 
bempegaldesleukin and may continue to receive nivolumab monotherapy.
The study of neoadjuvant nivolumab and bempegaldesleukin followed by continued adjuvant 
nivolumab and bempegaldesleukin after radical cystectomy (RC), aims to demonstrate that 
perisurgical treatment with nivolumab combined with bempegaldesleukin will significantly 
increase the rate of pathologic complete response (pCR) and prolong event-free survival (EFS) in 
cisplatin-ineligible participants with high-risk urothelial carcinoma (UC) of the bladder, including 
MIBC who undergo RC.
Study Population:
Male or female participants, aged 18 years or local age of majority, inclusive, with previously 
untreated high-risk UC, including MIBC, who are candidates for RC and cisplatin-ineligible.
Key Eligibility Criteria: *No longer applicable as all new enrollment has stopped.
Inclusion

Participants with UC of the bladder clinical stage T2-T4a, N0 (< 15 mm in short axis on CT or 
MRI), M0 or T1-T4aN1 (≥ 15 mm in short axis on computed tomography [CT] or magnetic 
resonance imaging [MRI]), M0, diagnosed at transurethral resection of bladder tumor (TURBT)
within 12 weeks of randomization. Variant histology is acceptable if there is a predominant 
urothelial component.
Note: Stained slides from the initial TURBT used to make the UC of the bladder/MIBC 
diagnosis and associated pathology report must be submitted to the vendor for confirmation of 
UC of the bladder/MIBC prior to randomization.

Participant must be deemed eligible for RC by his/her urologist, and must agree to undergo 
RC. For arms A and B, participants must agree to undergo RC after completion of neoadjuvant 
therapy.

Documentation of programmed cell death ligand-1 (PD-L1) status by immunohistochemistry 
(IHC) performed by the central laboratory during the screening period; the tumor should be 
classified as PD-L1 1% or PD-L1 < 1% as determined by a central laboratory during the 
screening period and the results must be submitted to interactive response technology (IRT)
Protocol Amendment No.: 04
Date: 10-Jun-2022
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
prior to randomization. Indeterminate participants are allowed in the study. Either a formalin-
fixed paraffin-embedded (FFPE) tissue block or 20 unstained tumor tissue sections with an 
associated pathology report, must be submitted for 
 evaluation prior to 
randomization. The bladder tumor sample submitted should be from the initial TURBT 
(obtained within 12 weeks of randomization) in which the UC of the bladder/MIBC diagnosis 
was made. Submitted tissue sample must not be previously irradiated and systemic therapy 
must not be given after samples are obtained prior to enrollment.
Note: If despite best efforts, a minimum of 20 unstained slides is not obtainable, submission 
of fewer slides may be acceptable in some circumstances following discussion with the 
Medical Monitor.

A documented left ventricular ejection fraction (LVEF) > 45% within 60 days prior to 
randomization, using standard echocardiogram or multigated acquisition (MUGA) scan test

Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Cisplatin-ineligible participants will be defined by any one of the following criteria:

Impaired renal function (glomerular filtration rate [GFR] 30 but < 60 mL/min)

GFR should be assessed by direct measurement (ie, creatinine clearance) or, if not 
available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)

Common Terminology Criteria for Adverse Events (CTCAE) version 5, Grade 2 hearing 
loss (assessed per local standard of care[SOC])

CTCAE version 5, Grade 2 peripheral neuropathy
Exclusion

Clinical evidence of ≥ N2 or metastatic bladder cancer

Prior systemic therapy, radiation therapy, or surgery for bladder cancer other than TURBT or 
biopsies is not permitted. Prior Bacillus Calmette-Guerin (BCG) or other intravesicular
treatment of non-muscle invasive bladder cancer (NMIBC) is permitted if completed at least 
6 weeks prior to initiating study treatment

Evidence of UC in upper urinary tracts (ureters or renal pelvis) or history of previous MIBC
Objectives and Endpoints:
Per Protocol Amendment 04, the secondary 
 objectives except for safety 
 parameters are no longer applicable. 
 
 
Per Protocol Amendment 04, Nektar Therapeutics and Bristol Myers Squibb (BMS) are 
terminating the development of bempegaldesleukin in combination with nivolumab. The efficacy 
endpoints of pCR, EFS by investigator assessment and overall survival (OS), as well as safety and 
tolerability for each treatment arm, will be summarized descriptively in all randomized 
participants. Details will be included in the Statistical Analysis Plan (SAP). 
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Table 1-1:
Objectives and Endpoints
Objective
Endpoint
Primary
To compare the pCR rate of neoadjuvant nivolumab + 
bempegaldesleukin to Standard of Care (SOC, no 
neoadjuvant therapy) in all randomized participants 
pCR rate, defined by the proportion of randomized 
participants with absence of any cancer (T0, N0) in 
pathology specimens after RC, based on blinded 
independent pathology review
To compare the EFS of neoadjuvant nivolumab + 
bempegaldesleukin followed by adjuvant nivolumab 
+ bempegaldesleukin after radical cystectomy (RC) 
versus SOC (no neoadjuvant or adjuvant therapy) in 
all randomized participants
EFS, defined as the time from randomization to any of 
the following events: progression of disease that 
precludes surgery, local or distant recurrence based on 
BICR assessments, or death due to any cause
Secondary
To compare the pCR rate of neoadjuvant nivolumab 
monotherapy to SOC (no neoadjuvant therapy) in all 
randomized participants
pCR rate, defined by the proportion of randomized 
participants with absence of any cancer (T0, N0) in 
pathology specimens after RC, based on blinded 
independent pathology review
To compare the EFS of neoadjuvant nivolumab 
followed by adjuvant nivolumab versus SOC in all 
randomized participants
EFS, defined as the time from randomization to any of 
the following events: progression of disease that 
precludes surgery, local or distant recurrence based on 
BICR assessments, or death due to any cause
To compare the overall survival (OS) of each 
experimental arm versus SOC in all randomized 
participants
OS, defined as the time between the date of 
randomization and the date of death from any cause. OS 
will be censored on the last date a participant was known 
to be alive
To assess safety and tolerability for each treatment 
arm in all treated participants
Worst grade AEs, SAEs, AEs leading to discontinuation, 
immune-mediation AEs and worst grade clinical 
laboratory values
To evaluate (descriptively) the pCR rate of 
neoadjuvant nivolumab + bempegaldesleukin to 
neoadjuvant nivolumab monotherapy in all 
randomized participants
pCR rate, defined by the proportion of randomized 
participants with absence of any cancer (T0, N0) in 
pathology specimens after RC, based on blinded 
independent pathology review
To evaluate (descriptively) the EFS of neoadjuvant 
nivolumab + bempegaldesleukin followed by 
adjuvant nivolumab + bempegaldesleukin after 
radical cystectomy (RC) versus neoadjuvant 
nivolumab followed by adjuvant nivolumab after RC 
in all randomized participants
EFS, defined as the time from randomization to any of 
the following events: progression of disease that 
precludes surgery, local or distant recurrence based on 
BICR assessments, or death due to any cause
Overall Design:
Per Protocol Amendment 04, this section is no longer applicable. 
This is a multicenter, randomized, Phase 3, study of neoadjuvant and adjuvant nivolumab plus 
bempegaldesleukin, versus nivolumab alone versus standard of care in participants with high-risk 
UC of the bladder, including MIBC, who are candidates for RC and cisplatin-ineligible. 
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Participants must have pathologically proven UC of the bladder, clinical stage T2-T4aN0M0
or T1-T4aN1M0, that has not been previously treated (except for TURBT or prior intravesicular
treatment of NMIBC). Participants must be deemed potentially curable, medically fit for RC, and 
be willing to undergo RC as part of the study treatment.
The study is divided into screening period, treatment period and long-term follow-up period.
Randomization will be stratified by the following:

Clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1)

PD-L1 status (1% vs < 1%/indeterminate)
Number of Participants:
All new enrollment to CA045009 has been stopped.
It is anticipated that approximately 720 participants will be screened for approximately 
540 participants to be randomized overall to the 3 arms in a 1:1:1 ratio, assuming a screen failure 
rate of approximately 25%.
Treatment Arms and Duration:
Participants were randomized (1:1:1) to one of the following 3 treatment arms:
Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin 
plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue 
to receive nivolumab monotherapy.

Arm A: Bempegaldesleukin 0.006 mg/kg Q3W + nivolumab 360 mg Q3W x 3 cycles as 
neoadjuvant therapy, followed by RC, followed by bempegaldesleukin 0.006 mg/kg Q3W + 
nivolumab 360 mg Q3W up to an additional 12 cycles (approximately 9 months of adjuvant 
therapy).

Arm B: Nivolumab 360 mg Q3W x 3 cycles as neoadjuvant therapy, followed by RC, followed
by nivolumab 360 mg Q3W up to an additional 12 cycles (approximately 9 months of adjuvant 
therapy).

Arm C: SOC (cystectomy alone, without neoadjuvant or adjuvant therapy)
Per Protocol Amendment 04:

Participants in Arm A are required to discontinue bempegaldesleukin and may continue 
nivolumab monotherapy. 

Participants on adjuvant nivolumab monotherapy can receive up to a maximum of 12 cycles. 

All participants in Arm A and Arm B who have completed therapy or are currently within the 
100 days safety follow-up should discontinue from the study once they complete the safety 
follow-up 100 days, if AE reporting requirements have been fulfilled as per Section 9.2.3. 
Documentation of recurrence status and last overall survival should occur upon 
discontinuation.
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
All participants in Arm C who have completed radical cystectomy or are currently within the 
100 days safety follow-up after radical cystectomy, should discontinue from the study once 
they complete the safety follow-up 100 days, if AE reporting requirements have been fulfilled 
as per Section 9.2.3. Documentation of recurrence status and last overall survival should occur 
upon discontinuation.

Participants who have completed therapy, including 100 days safety follow-up, and are 
currently in survival follow-up should discontinue from the study if AE reporting requirements 
have been fulfilled as per Section 9.2.3. Documentation of last overall survival should occur 
upon discontinuation.
For each randomized participant, the total maximum duration of the study is up to 62 weeks + 100 
days of safety follow-up. 
Study Design Schematic
Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin 
plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue 
to receive nivolumab monotherapy.
Abbreviations: Bempeg, bempegaldesleukin; CT, computed tomography; EFS, event-free survival; Nivo, nivolumab; 
pCR, pathologic complete response; PD-L1, programmed death ligand 1; PS, performance score; Q3W, every 3 weeks; 
SOC, standard of care.
Screening
Pre-surgical Treatment
Post-surgical Treatment
Follow-up
High-risk urothelial carcinoma (UC) 
/ muscle-invasive/resectable 
bladder cancer (MIBC)
Clinical stage T2-T4aN0 (< 15 mm 
on CT scan) M0 OR clinical stage 
T1-T4aN1 (≥15 mm on CT scan) 
M0
Cisplatin-ineligible
PS 0-1
N = 540 
Stratification factors:
Clinical Stage (T2N0 vs 
T3-T4aN0 vs T1-T4aN1)
PD-L1 status (≥ 1% vs
< 1%/indeterminate)
Randomization 1:1:1
Arm A
Nivo 360 mg +
Bempeg 0.006 mg/kg Q3W x 3 cycles
Arm B
Nivo 360 mg Q3W x 3 cycles
Arm C
SOC 
No induction or adjuvant treatment
Radical Cystectomy
Nivo 360 mg +
Bempeg 0.006 mg/kg Q3W x 12 cycles 
(9 months)
Nivo 360 mg Q3W x 12 cycles 
(9 months)
1 Cycle = 3 Weeks
Follow-up visits, 
monitor for recurrence 
and survival, Follow-up 
until death
pCR and EFS 
A vs C primary endpoints
(B vs C secondary)
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Study Treatment:
Study Drug for CA045009
Medication 
Potency 
IP/Non-IP 
*Not applicable per Protocol Amendment 
04 Bempegaldesleukin (NKTR-214) Powder 
for Solution for Injection
0.3 mg, 0.5 mg, or 1 mg of
rhIL-2 per viala
IP
Nivolumab Solution for Injectionb
100 mg (10 mg/mL)
IP
a *Not applicable per Protocol Amendment 04 Note: For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer 
to the same molecule.
b May be labeled as either “BMS-936558-01” or “nivolumab.”
Data Monitoring Committee: Yes. Per Protocol Amendment 04, this section is no longer 
applicable.
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2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA045009)
*All new enrollment to CA045009 has been stopped.
Procedurea
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Must be obtained prior to performing any screening procedures. Register in the Interactive 
Response Technology (IRT) to obtain participant number.
Study allows for re-enrollment of a participant that has discontinued the study as a pre-
treatment 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, including the following: any serious 
organ system dysfunction; prior cancer therapy; Tumor; Node and Metastasis (TNM) stage 
(T1, T2/T3 or T4a, N0, N1, or M0); smoking history (including electronic cigarettes); and 
alcohol history.
Urothelial Carcinoma (UC) of the 
Bladder/Muscle-invasive Bladder 
Cancer (MIBC) Confirmation
X
Diagnostic hematoxylin and eosin (H&E) and, if applicable, immunohistochemistry (IHC) 
stained slides from the initial transurethral resection of bladder tumor (TURBT) (conducted 
within 12 weeks of randomization) in which the UC of the bladder/MIBC diagnosis was 
made, along with associated pathology report must be submitted to the vendor for 
confirmation of UC of the bladder/MIBC prior to randomization. Submitted tissue must not 
be previously irradiated and systemic therapy must not be given after samples are obtained 
prior to enrollment.
Vendor must provide IRT with UC of the bladder/MIBC confirmation prior to 
randomization. See Section 5.1.4.1 for further details.
Tumor Sample Submission
X
All participants must have bladder tumor tissue submitted for 
 analysis prior to 
randomization.
To be randomized, a participant must have quantifiable programmed death ligand 1 (PD-
L1) expression (1% [positive] or < 1% [negative] tumor cell membrane staining) or be 
classified as PD-L1 indeterminate.
PD-L1 non-evaluable participants are not eligible for randomization.
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CA045009/18-214-13
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bempegaldesleukin (NKTR-214)
Table 2-1:
Screening Procedural Outline (CA045009)
*All new enrollment to CA045009 has been stopped.
Procedurea
Screening
Visit
Notes
Pre-randomization bladder tumor tissue submitted must be from the initial TURBT (ie, 
obtained within 12 weeks of randomization) in which the UC of the bladder/MIBC 
diagnosis was made. One (1) formalin-fixed paraffin-embedded (FFPE) tumor tissue block 
or 20 unstained tumor tissue sections with an associated pathology report are acceptable.
Submitted tissue must not be previously irradiated and systemic therapy must not be given 
after samples are obtained prior to enrollment.
1)
Note: If despite best efforts, a minimum of 20 unstained slides is not obtainable, 
submission of fewer slides may be acceptable in some circumstances following 
discussion with the Medical Monitor.
See 
 the Study Laboratory Manual for additional information.
PD-L1 Analysis
X
The analytical laboratory must provide IRT with confirmation of the PD-L1 results prior to 
randomization.
Safety Assessments
Prior and Concomitant Medication 
Review/Use
X
Within 14 days prior to randomization.
Document vaccine use within 30 days prior to first study treatment.
Physical Examination, 
Measurements, Vital Signs, and 
Performance Status
X
Must be collected within 14 days prior to randomization
Vital signs including the following: Blood Pressure (BP), Heart Rate, Temperature
Height, Weight
Pulse oximetry
ECOG performance status (Appendix 5)
Serious Adverse Events (SAEs) 
Assessment
X
SAEs collected and reported from time of consent.
All adverse events (AEs [SAEs or non-serious AEs]) associated with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection collected from time of 
consent.
Clinical Complaints/Signs and 
Symptoms
X
Collected within 14 days from randomization.
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Table 2-1:
Screening Procedural Outline (CA045009)
*All new enrollment to CA045009 has been stopped.
Procedurea
Screening
Visit
Notes
ECG 
X
Within 14 days of randomization. See Section 9.4.3.
Echocardiogram (ECHO) or 
MUGA
X
Left Ventricular Ejection fraction > 45% within 60 days is required prior to randomization.
The investigator should further evaluate participants with other significant abnormalities 
on echocardiogram / MUGA. Decision regarding treatment should be based on 
investigator’s best clinical judgement.
See Section 9.4.4.
Laboratory Tests
Clinical Laboratory Testing
X
All laboratory assessments to be performed within 14 days prior to randomization, except 
for viral testing, which is to be completed within 28 days prior to randomization.
See Table 9.4.7-1 for a list of laboratory tests to conduct.
Pregnancy Test
X
WOCBP only: Serum or urine test (minimum sensitivity 25 IU/L or equivalent units of 
HCG) to be done at screening visit and repeated within 24 hours prior to first dose of study 
therapy in women of childbearing potential (WOCBP).
Tumor Assessments
Body Imaging
X
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis (including excretory 
imaging), and all other known and/or suspected sites of disease to be completed within 
35 days prior to randomization.
See Section 9.1.2 for further details.
Other Imaging for Staging
See notea
As clinically indicated per local standards.
See Section 9.1.2.3.
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bempegaldesleukin (NKTR-214)
a NOTE: Some of the assessments referred to in this table 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 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
Study Treatment
Randomize
X
First dose must occur within 3 calendar 
days of randomization.
Administer Study Drug
*The text below 
related to 
bempegaldesleukin 
is not applicable. 
Bempegaldesleukin 
(0.006 mg/kg) and 
Nivolumab (360 mg) 
(ARM A)
X
X
Not applicable per Protocol Amendment 
04.
See Section 7.1 for complete details.
Nivolumab (360 mg) 
(ARM B)
X
X
See Section 7.1 for complete details.
*Not applicable per 
Protocol 
Amendment 04. 
Administer 
Intravenous (IV) 
Fluids
(Arm A ONLY)
X
X
Not applicable per Protocol Amendment 
04. May be withheld if deemed in the best 
interest of the participant by the 
investigator.
See Section 7.1.1.1 for additional 
information.
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Table 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
*Not applicable per 
Protocol 
Amendment 04. 
Review Hydration 
Guidelines with 
Participant
(Arm A ONLY)
X
X
Not applicable per Protocol Amendment 
04. Applicable only to Study Arm A treated 
with bempegaldesleukin.
See Section 7.1.1.1.
*Not applicable per 
Protocol 
Amendment 04. 
Oral Hydration 
Follow-up
(Arm A ONLY)
X
(Day 3-5)
X
Not applicable per Protocol Amendment 
04. 
For the first two doses of 
bempegaldesleukin, between Days 3 and 5, 
following infusion (inclusive), site 
personnel must contact the participant (by 
telephone or clinic visit) at least once to 
remind the participant of the oral hydration 
guidelines, to assess for any 
symptomatology and compliance with the 
guidelines, and document the results of the 
discussion. For subsequent administrations 
of bempegaldesleukin, the oral hydration 
follow-up should be conducted as clinically 
indicated for participants receiving 
bempegaldesleukin.
See Section 7.1.1.1for details.
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bempegaldesleukin (NKTR-214)
Table 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
Safety Assessments
Targeted Physical 
Examination, 
Measurements, Vital 
Signs, and 
Performance Status
X
X
Vital 
Signs only
X
Vital Signs: BP, Heart Rate, and 
Temperature Weight
ECOG performance status (Appendix 5).
Monitor and record vital signs at predose 
and within 30 minutes after administration 
of nivolumab in Arms A and B.
Adverse Event and 
Serious Adverse 
Event Assessments
Continuously
All AEs (SAEs or non-serious AEs), 
including those associated with SARS-
CoV-2 infection, must be collected 
continuously during the treatment period. 
Concomitant 
Medication Use
Continuously
Record at each visit.
Laboratory Tests
Clinical Laboratory 
Testing
X
X
X
Hematology and chemistry assessments 
scheduled for the day of study drug(s) 
dosing must be available and assessed 
before dosing. Hematology and chemistry 
assessments can be drawn within 72 hours 
prior to treatment, including renal function 
(ie, serum creatinine) must be assessed 
within 24 hours prior to dosing or as soon as 
locally feasible. For the first treatment visit, 
labs, except pregnancy test, may not need to 
be repeated if they were performed within 
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bempegaldesleukin (NKTR-214)
Table 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
72 hours and the results are available and 
have been reviewed for eligibility. Refer to 
Section 9.4.7 Clinical Safety Laboratory 
Assessments for list of laboratory tests to be 
conducted.
Pregnancy Test
X
X
Serum or urine pregnancy test (minimum 
sensitivity equivalent units 25 IU/L or 
equivalent units of HCG) is required within 
24 hours prior to treatment in WOCBP.
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CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
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CA045009/18-214-13
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bempegaldesleukin (NKTR-214)
Table 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
Efficacy Assessment
Body Imaging
Per Protocol Amendment 04, imaging will be performed per local SOC, and images will no longer be submitted for blinded 
independent central review (BICR). 
FIRST post-baseline tumor assessment should be performed after completion of last dose of neoadjuvant therapy (3 cycles or fewer).
Participants who undergo RC, should have the first post-baseline tumor assessment within 4 weeks prior to RC.
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis (including excretory imaging), and all other known and/or 
suspected sites of disease. 
See Section 9.1.2.1 for details.
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CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-2:
Pre-surgery (Neoadjuvant) Procedures and Assessments (Arm A + Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Procedurea
Cycle 1 Onlyb
1 cycle = 3 weeks
Cycle 2 and 3b
1 cycle = 3 weeks
Pre-surgery 
(Within 
14 Days Before 
Surgery)
Notes
Day 1
Day 5 
(± 1 day)
Day 8
(-1 day)
Day 1 
(3 days)
Day 3-5
a Some assessments referred to in this section may not be captured as data in the eCRF. These assessments 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 If a dose is delayed, the procedures scheduled for that same time point, except body/brain imaging and pregnancy testing, should also be delayed to coincide 
with when the time point’s dosing actually occurs.
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6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
Administer Study Drug
*Not applicable per 
Protocol Amendment 
04. 
Bempegaldesleukin
(0.006 mg/kg) and 
nivolumab (360 mg) 
(Arm A)
X
X
Nivolumab (360 mg) 
(Arm B)
X
X
*Not applicable per 
Protocol Amendment 
04. 
Administer IV Fluids
(Arm A only)
X
X
Not applicable per Protocol Amendment 04.
Applicable only to Arm A with bempegaldesleukin
May be withheld if deemed in the best interest of the 
participant by the investigator.
See Section 7.1.1.1 for additional information.
*Not applicable per 
Protocol Amendment 
04. 
Review Hydration 
Guidelines with 
Participants 
(Arm A only)
X
X
Not applicable per Protocol Amendment 04.
Applicable only to Arm A with bempegaldesleukin.
See Section 7.1.1.1.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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5.0
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Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
*Not applicable per 
Protocol Amendment 
04. 
Oral Hydration 
Follow-up
(Arm A only)
X
(Day 3-5)
X
(Day 3-5)
Not applicable per Protocol Amendment 04.
For the first two doses of bempegaldesleukin, between 
Days 3 and 5, inclusive, following infusion, site 
personnel must contact the participant (by telephone or 
clinic visit) at least once to remind the participant of the 
oral hydration guidelines, to assess for any 
symptomatology and compliance with the guidelines, and 
document the results of the discussion. For subsequent 
administrations of bempegaldesleukin, the oral hydration 
follow-up should be conducted as clinically indicated for 
participants receiving bempegaldesleukin.
See Section 7.1.1.1 for details.
Safety Assessments
Adverse Event and 
Serious Adverse Event 
Assessments
Continuously 
All AEs (SAEs or non-serious AEs), including those 
associated with SARS-CoV-2 infection, must be 
collected continuously during the treatment period. 
Concomitant
Medication Use
Continuously. Record at each visit.
Protocol Amendment No.: 04
Date: 10-Jun-2022
43
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Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
ECG
X
ECHO/MUGA
Pre- dose, only if clinically indicated
Cystoscopy
Per Protocol Amendment 04, cystoscopy will be performed per local 
SOC. 
Participants who do not undergo RC, for reasons other than progression, 
will be monitored for disease recurrence/progression by cystoscopy, 
every 12 weeks (± 7 days) for the next 2 years, and then every 24 weeks 
(± 14 days) for 3 additional years. For these participants maximal 
TURBT of all visible tumor should be performed at the time of the first 
cystoscopic examination.
For participants who do not undergo RC at the time of the 
decision made, a cystoscopy with maximum TURBT for 
visible tumor should be performed instead. Monitoring 
will begin from the first cystoscopic examination.
Targeted Physical 
Examination, 
Measurements, Vital 
Signs, and 
Performance Status
X
X
X
Vital Signs: BP, Heart Rate, and Temperature
Weight
ECOG performance status (Appendix 5).
Monitor and record vital signs at predose and within 
30 minutes after administration of nivolumab.
Protocol Amendment No.: 04
Date: 10-Jun-2022
44
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
Laboratory Tests
Clinical Laboratory 
Testing
X
X
X
Hematology and chemistry assessments scheduled for the 
day of study drug(s) dosing must be available and 
assessed before dosing.
Hematology and chemistry assessments can be drawn 
within 72 hours prior to treatment, including renal 
function (ie, serum creatinine) must be assessed within 24 
hours prior to dosing or as soon as locally feasible. Refer 
to Section 9.4.7 Clinical Safety Laboratory Assessments 
for list of laboratory tests to be conducted.
Pregnancy Test 
X
X
Serum or urine pregnancy test (minimum sensitivity 
equivalent units 25 IU/L or equivalent units of HCG) is 
required within 24 hours prior to treatment in WOCBP.
Protocol Amendment No.: 04
Date: 10-Jun-2022
45
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
Efficacy Assessments
*Not applicable per 
Protocol 
Amendment 04.
Submission of 
Tissue for 
Pathologic Complete 
Response (pCR)
Not applicable per Protocol Amendment 04.
Please review details for specimen collection and submission in the Laboratory Manual.
Protocol Amendment No.: 04
Date: 10-Jun-2022
46
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
Body Imaging
Per Protocol Amendment 04, for any participant remaining on 
study treatment, imaging will be performed per schedule of local 
SOC and images will no longer be submitted for BICR. 
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis 
(including excretory imaging), and all other known and/or suspected sites 
of disease.
Participants having RC should undergo tumor assessments 60 to 90 days 
after RC and within 2 weeks prior to beginning adjuvant therapy.
Tumor assessments should continue to be performed every 12 weeks 
(1 week) for up to 2 years from randomization date. Then every 
24 weeks (2 weeks) up to a maximum of 5 years from the date of 
randomization, or until investigator-assessed disease progression that 
precludes surgery, until blinded independent central review (BICR) 
confirmed disease progression or recurrence (whichever occurs later).
Participants who do not undergo RC (for reasons other than disease 
progression) should be aligned with continuing tumor assessments 
schedule including cystoscopy assessments.
See Section 9.1.2.1 for details on methodology.
All study treatment decisions will be based on the 
investigator’s assessment of tumor images.
See Section 9.1.2.2.
Protocol Amendment No.: 04
Date: 10-Jun-2022
47
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
Protocol Amendment No.: 04
Date: 10-Jun-2022
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5.0
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Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-3:
Post-surgery (Adjuvant) Procedures and Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable: however, the criteria remain 
unchanged for nivolumab, unless specifically designated.
Participants who have not completed radical cystectomy, may continue onto cycles 1-12 once consent has been obtained and follow the post-surgery 
on study assessmentsa
Procedure
Post-surgery 
Visitb,d
Cycle 1c,d
(started within 60 to 120 
days)
1 cycle = 3 weeks
C2-C12c,d
Day 1 (3 days) 
1 cycle = 3 weeks
Notes
60 to 90 Days
Post-surgeryd,e
a Some assessments referred to in this section may not be captured as data in the eCRF. These assessments are intended to be used as safety monitor by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
b All participants are required to have a visit at 60-90 days after RC or cystoscopy to collect data related to RC/cystoscopy and imaging is required at this visit. 
Participants who do not undergo RC for reasons other than disease progression, must have cystoscopy prior to their planned post-surgical treatment following 
the first post-baseline tumor assessment (see Section 5.1.2.2 for further details).
c Per Protocol Amendment 04, cystoscopy will be performed per local SOC. Participants who do not have RC, but continue on study, will require cystoscopy 
every 12 weeks (± 7 days) for the next 2 years, and then every 24 weeks (± 14 days) for 3 additional years, then once per year for subsequent years.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
d If a dose is delayed, the procedures scheduled for that same time point, except body/brain imaging and pregnancy testing, should also be delayed to coincide 
with when the time point’s dosing actually occurs.
e If participant does not have RC, participant needs to have post-surgery procedures before starting adjuvant therapy (eg, cystoscopy with tumor removal and 
imaging).
Protocol Amendment No.: 04
Date: 10-Jun-2022
50
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-4:
Long-term Follow-up Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
*Not applicable per 
Protocol Amendment 
04.
Survival Follow-up
Every 3 Months
(14 Days)c,b
Notes
Safety Assessments
Targeted Physical 
Examination, Measurements, 
Vital Signs, and Performance 
Status
X
X
Vital Signs: BP, Heart Rate, and Temperature
Weight
ECOG Performance Status
Adverse Events Assessment
(Including SAEs)
X
X
See Notes
SAEs to be collected after the 100-day safety visit if the SAE 
is deemed to be related or residual toxicities are persisting.
All SAEs and non-serious AEs should be collected 
continuously during the treatment period and for a minimum 
of 100 days following discontinuation of study treatment for 
adjuvant therapy and 100 days following RC in participants 
who do not have adjuvant therapy. 
Participants will be followed for all SAEs, non-serious AEs of 
special interest (as defined in Section 9.8), and all AEs (SAEs 
and non-serious AEs) 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.
Review of 
Concomitant/Subsequent
Medications
X
X
Record at each visit.
Protocol Amendment No.: 04
Date: 10-Jun-2022
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1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-4:
Long-term Follow-up Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
*Not applicable per 
Protocol Amendment 
04.
Survival Follow-up
Every 3 Months
(14 Days)c,b
Notes
Subsequent Anti-cancer 
Therapy
X
X
X
Per Protocol Amendment 04, the following will no longer 
be collected after 100 days of follow- up:  Collect every 3 
months at Survival Visits until death,
lost to follow-up, withdrawal of study consent, or up to 
5 years. May be performed by phone contact or office visit.
Include documentation of additional subsequent cancer
therapy details such as regimen, setting of the regimen, line of 
therapy, start date and end date of each regimen, and best 
response to the regimen and date of progression to subsequent 
anti-cancer therapies will be collected.
Laboratory Tests
Clinical Laboratory Testing
X
Follow-up Visit 2
(if toxicities are 
present)
Hematology and Chemistry:
See Table 9.4.7-1.
Pregnancy Test 
X
X
WOCBP only. Serum or urine pregnancy test (minimum 
sensitivity equivalent units 25 IU/L or equivalent units of 
HCG) is required.
Protocol Amendment No.: 04
Date: 10-Jun-2022
52
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-4:
Long-term Follow-up Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
*Not applicable per 
Protocol Amendment 
04.
Survival Follow-up
Every 3 Months
(14 Days)c,b
Notes
Efficacy Assessments
Survival Status
Per Protocol Amendment 04, during follow-up: after 100 days from last dose, participants will be discontinued.  
For participants already in survival follow-up, recurrence and overall survival should be documented and participant 
will then come off study.  
During Safety Follow-up (Follow-up Visits 1 and 2) and every 3 months (clinic visit or by telephone) during Survival 
Follow-up. Include documentation of subsequent cancer therapy (ie, systemic therapy, tumor-directed surgery, or radiation 
therapy).
Body Imaging
Per Protocol Amendment 04, imaging will be performed per local SOC and images will no longer be submitted for 
BICR. 
Only for participants without BICR-confirmed progression or recurrence and without investigator-assessed progression 
precluding surgery.
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis (including excretory imaging), and all other known 
and/or suspected sites of disease.
See Section 9.1.2.1 for details on methodology.
Every 12 weeks (1 week) for up to 2 years from the date of randomization. Then every 24 weeks (2 weeks) up to a 
maximum of 5 years from the date of randomization, or until investigator-assessed disease progression that precludes 
surgery, until BICR confirmed disease progression or recurrence, whichever occurs later.
Protocol Amendment No.: 04
Date: 10-Jun-2022
53
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-4:
Long-term Follow-up Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
*Not applicable per 
Protocol Amendment 
04.
Survival Follow-up
Every 3 Months
(14 Days)c,b
Notes
Participants who do not have RC (for reasons other than disease progression) should be aligned with continuing tumor 
assessments schedule including cystoscopy assessments.
Cystoscopy
Per Protocol Amendment 04, cystoscopy will be 
performed per local SOC. 
Participants who do not undergo RC for reasons other than 
progression, will be monitored for disease 
recurrence/progression by cystoscopy, every 12 weeks 
(± 7 days) for the next 2 years, and then every 24 weeks (± 
14 days) for 3 additional years, then once per year for 
subsequent years.
For these participants, maximal TURBT of all visible tumor 
should be performed at the time of the first cystoscopic 
examination.
Monitoring will begin from the first cystoscopic 
examination.
Protocol Amendment No.: 04
Date: 10-Jun-2022
54
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-4:
Long-term Follow-up Assessments (Arm A and Arm B)
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Follow-up 
Visit 1a,b
Follow-up 
Visit 2a,b
*Not applicable per 
Protocol Amendment 
04.
Survival Follow-up
Every 3 Months
(14 Days)c,b
Notes
a Participants must be followed for at least 100 days after the 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 42 days from the last dose. Follow-up Visit 2 occurs approximately 100 days 
(7 days) from the last dose of study treatment. Both follow-up visits should be conducted in person. 
b Some assessments referred to in this section may not be captured as data in the eCRF. These assessments are intended to be used as safety monitor by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
c *Not Applicable per Protocol Amendment 04. Survival follow-up visits to occur every 3 months (14 days) from Follow-up Visit 2. Survival visits may be 
conducted in person or by telephone. Bristol-Myers Squibb may request that survival data be collected on all treated participants outside of the 3-month specified 
window. At the time of this request, each participant will be contacted to determine his or her survival status unless the participant has withdrawn consent for 
all contact.
Protocol Amendment No.: 04
Date: 10-Jun-2022
55
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Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-5:
Study Assessments - Arm C
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Pre-surgery
Pre-surgery
Post-surgery 
Follow-upa
Notes
Within 
14 Days Before 
Surgery
60-90 Days 
Post- surgery
Follow-up
Visits 1 and 2
*Not applicable 
per Protocol 
Amendment 04. 
Survival
Follow-up
Visitsb
Study Treatmentc
Randomize
X
Radical Cystectomy must occur 
within 6 weeks from randomization.
Safety Assessments
Targeted Physical 
Examination, 
Measurements, Vital 
Signs, and Performance 
Status
X
X
X
Vital Signs: BP, Heart Rate, and 
Temperature 
Weight
ECOG Performance Status
Concomitant Medication
Use
Continuously
Record at each visit.
Subsequent Anti-cancer 
Therapyd
X
X
Per protocol amendment 04, the 
following will no longer be 
collected after 100 days of follow-
up: Collect every 3 months at
Survival Visits until death, lost to 
follow-up, withdrawal of study 
consent, or up to 5 years. May be 
performed by phone contact or office 
visit.
Include documentation of additional 
subsequent cancer therapy details 
Protocol Amendment No.: 04
Date: 10-Jun-2022
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v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-5:
Study Assessments - Arm C
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Pre-surgery
Pre-surgery
Post-surgery 
Follow-upa
Notes
Within 
14 Days Before 
Surgery
60-90 Days 
Post- surgery
Follow-up
Visits 1 and 2
*Not applicable 
per Protocol 
Amendment 04. 
Survival
Follow-up
Visitsb
such as regimen, setting of the 
regimen, line of therapy, start date 
and end date of each regimen, and 
date of progression to subsequent 
anti-cancer therapies will be 
collected.
SAE/AE Assessment
Continuously until 100 days from RC. Participants will be followed for all SAEs, non-serious AEs of special interest (as defined in 
Section 9.8), and all AEs (SAEs and non-serious AEs) 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.
Efficacy Assessments
*Not applicable per 
Protocol Amendment 
04. 
Submission of Tissue for 
Pathologic Complete 
Response (pCR)
*Not applicable per Protocol Amendment 04.
Please review details for specimen collection and submission in the Laboratory Manual.
Body Imaging
Per Protocol Amendment 04, Imaging will be performed per SOC and images will no longer be submitted for BICR. 
Contrast enhanced CT of the chest, CT/MRI of the abdomen, pelvis (including excretory imaging), and all other known and/or 
suspected sites of disease.

Participants that have RC should undergo tumor assessments 60-90 days after RC
Protocol Amendment No.: 04
Date: 10-Jun-2022
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v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-5:
Study Assessments - Arm C
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Pre-surgery
Pre-surgery
Post-surgery 
Follow-upa
Notes
Within 
14 Days Before 
Surgery
60-90 Days 
Post- surgery
Follow-up
Visits 1 and 2
*Not applicable 
per Protocol 
Amendment 04. 
Survival
Follow-up
Visitsb

Tumor assessment should continue to be performed every 12 weeks (1 week) for up to 2 years from randomization date,
then every 24 weeks (2 weeks) up to a maximum of 5 years from the date of randomization until investigator-assessed 
disease progression that precludes surgery, or until BICR confirmed disease progression or recurrence, whichever occurs later.

Participants who do not have RC (for reasons other than disease progression) should be aligned with continuing tumor 
assessments schedule including cystoscopy assessments

See Section 9.1.2.1 for details on methodology.
Cystoscopy 
Per Protocol Amendment 04, cystoscopy will be performed per local SOC. 
Participants who do not undergo RC for reasons other than progression, will be monitored 
for disease recurrence/progression by cystoscopy, every 12 weeks (± 7 days) for the next 
2 years and then every 24 weeks (± 14 days) for 3 additional years, then once per year for 
subsequent years.
For these participants, maximal TURBT of all visible tumor should be performed at the 
time of the first cystoscopic examination.
Monitoring will begin from the first 
cystoscopic examination.
Protocol Amendment No.: 04
Date: 10-Jun-2022
58
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Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321
bempegaldesleukin (NKTR-214)
Table 2-5:
Study Assessments - Arm C
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Pre-surgery
Pre-surgery
Post-surgery 
Follow-upa
Notes
Within 
14 Days Before 
Surgery
60-90 Days 
Post- surgery
Follow-up
Visits 1 and 2
*Not applicable 
per Protocol 
Amendment 04. 
Survival
Follow-up
Visitsb
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Table 2-5:
Study Assessments - Arm C
*Per Protocol Amendment 04, participants will discontinue from the study following one recurrence update and survival 
status update.
Procedure
Pre-surgery
Pre-surgery
Post-surgery 
Follow-upa
Notes
Within 
14 Days Before 
Surgery
60-90 Days 
Post- surgery
Follow-up
Visits 1 and 2
*Not applicable 
per Protocol 
Amendment 04. 
Survival
Follow-up
Visitsb
a Follow-up Visit 1 should occur 30 days from post-surgery visit (± 7 days). Follow-up Visit 2 should occur approximately 100 days (± 7 days) from post-surgery
visit. Both follow up visits should be conducted in person.
b Not applicable per Protocol Amendment 04. Survival visits: every 3 months from Follow-up Visit 2 (14 days). Survival visit may be conducted in person 
or by telephone. Bristol-Myers Squibb (BMS) may request that survival data be collected on all treated participants outside of the 3-month specified window. 
At the time of this request, each participant will be contacted to determine his or her survival status unless the participant has withdrawn consent for all contact.
c Some assessments referred to in this section may not be captured as data in the eCRF. These assessments are intended to be used as safety monitor by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations.
d Including details on subsequent therapy such as start and stop dates, best response, date of progression.
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3
INTRODUCTION
CA045009 is a Phase 3, randomized study of neoadjuvant nivolumab plus NKTR-214 
(bempegaldesleukin) or nivolumab alone followed by radical cystectomy (RC) and further post-
surgery immuno-oncology (IO) therapy, versus standard of care (SOC) treatment with RC alone
in participants with previously untreated high-risk urothelial carcinoma (UC) of the bladder, 
including muscle-invasive bladder cancer (MIBC) who are candidates for RC and are cisplatin-
ineligible.
About 20%-25% of patients diagnosed with UC of the bladder present with MIBC, defined as 
stage T2-T4a, N0, M0, or prognostic stage II or IIIA per the American Joint Committee on Cancer 
(AJCC) staging manual.1 Primary tumor assessment includes multiple factors and examinations to 
properly stage a patient’s cancer. The tumor, node, and metastasis (TNM) categories are assigned 
by using the information and with that, the prognostic stage groups are assigned for these cancers. 
For UC, regional lymph node staging is of significant prognostic importance given the negative 
impact on recurrence after treatment and long-term survival. Clinical staging of regional lymph 
node involvement by imaging often is inaccurate and does not necessarily provide information on 
the extent of disease within the nodes.
The 8th edition of the AJCC staging manual, included changes to the staging of urinary bladder 
carcinoma, including the AJCC prognostic stage groups, stages III and IV disease (stage III into 
stage IIIA and stage IIIB; stage IV into stage IVA and stage IVB).1 Notably, the new staging 
system groups T1-T4aN1M0 within stage IIIA and similar prognostic category as the T3-
T4aN0M0. And based on the new staging, the National Comprehensive Cancer Network (NCCN)
guidelines includes the T1-T4aN1M0 within the same treatment as the T3-T4aN0M0 in the same 
prognostic category.2
For patients who are ineligible to receive cisplatin-based chemotherapy, the primary treatment for 
these patients is RC, without any neoadjuvant therapy. Although this can be curative for some, up 
to 50% of patients ultimately develop recurrent, metastatic disease.
This Phase 3 study in the neoadjuvant and adjuvant treatment of participants with clinical stage 
T2-T4aN0M0 or T1-T4aN1M0 UC of the bladder ineligible for cisplatin will allow for direct 
comparison of nivolumab plus bempegaldesleukin versus SOC treatment with RC alone. The study 
is designed with an analysis of the rate of pathologic complete response (pCR) and will continue 
follow-up for an analysis of event free survival (EFS).
Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin 
plus nivolumab are required to discontinue bempegaldesleukin and may continue to receive 
nivolumab monotherapy.  
3.1
Study Rationale
The study of neoadjuvant nivolumab and bempegaldesleukin followed by continued adjuvant 
nivolumab and bempegaldesleukin after RC, aims to demonstrate that perisurgical treatment with 
nivolumab combined with bempegaldesleukin will significantly increase the rate of pCR and 
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prolong EFS in cisplatin-ineligible participants with high-risk UC of the bladder, including MIBC
who undergo RC.
3.1.1
Research Hypothesis
This section is not applicable per Protocol Amendment 04. 
The combination of nivolumab and bempegaldesleukin as neoadjuvant and adjuvant therapy will
significantly increase the pCR and prolong EFS following RC in participants with high-risk UC, 
including MIBC who are ineligible for cisplatin therapy.
3.2
Background
3.2.1
Epidemiology/Indication
Urothelial cancer of the bladder is the ninth most common cancer in the world3 and the fifth most
common malignancy in the United States.4 In 2020, an estimated 81,400 patients were newly 
diagnosed with bladder cancer in the United States and approximately 17,980 patients will 
succumb to the disease.5 Bladder cancer is more common in men with nearly a 3:1 incidence.
Nonmuscle-invasive tumors account for 75%–85% of bladder neoplasms, whereas the remaining 
15% to 25% are muscle-invasive or metastatic tumors at the time of initial presentation.6 Once 
invasive into the muscularis propria, urothelial cancer of the bladder is an aggressive disease that 
requires multimodal treatment with surgery or radiation therapy with or without chemotherapy. 
Despite multimodality treatment, more than 50% of patients will develop metastatic disease. 
Median survival of patients with metastatic urothelial cancer of the bladder is 12 to 14 months.7
Management of UC of the Bladder, Including MIBC
Patients with UC of the bladder, including clinical stage T2-T4aN0M0, and clinical stage T1-
T4aN1M0, are at a high risk for developing metastatic disease, even after receiving SOC treatment 
RC.8,9,10 For patients with MIBC who are eligible to receive cisplatin-based chemotherapy, level 
1 evidence demonstrates a significant increase in overall survival (OS) with the use of neoadjuvant 
chemotherapy. The SWOG 8710 Phase 3 study, which compared neoadjuvant MVAC 
(methotrexate, vinblastine, doxorubicin, cisplatin) plus RC to RC alone, showed a 66% increased 
risk of death from bladder cancer (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.22-
2.45) and a 33% increased risk of death from all causes (HR = 1.33; 95% CI = 1.00-1.76) in patients 
who received RC alone compared to combination treatment.11 A meta-analysis of 3005 patients 
found a 5% absolute improvement in OS at 5 years (HR = 0.86, 95% CI 0.77-0.95, P = 0.003) and 
a 9% absolute disease free survival (DFS) improvement at 5 years (HR = 0.78 95% CI 0.71-0.86, 
P < 0.0001) in the chemotherapy group.12 The combination of gemcitabine and cisplatin (GC) is
considered an acceptable community standard as neoadjuvant therapy based on large retrospective 
analyses demonstrating similar pCR rates compared to MVAC.13,14
The OS benefit from neoadjuvant chemotherapy is closely associated with achieving a 
pCR.11,15,16,17,18 The pCR rate associated with 3 to 4 cycles of approved chemotherapy regimens 
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(GC or MVAC) is 25 to 30%.17,18 Patients who attain a pCR after neoadjuvant chemotherapy have 
5-year EFS and OS rates of greater than 80%.11,19
However in clinical practice, cisplatin-ineligible patients account for 40% to 50% of the total 
population with MIBC. Patients with MIBC who are ineligible for cisplatin-based chemotherapy 
due to poor renal function (usually defined as a creatinine clearance of < 60 mL/minute), advanced 
age, hearing loss, peripheral neuropathy, or poor performance status represent a population with a 
high unmet medical need because there is currently no recommended neoadjuvant therapy (or 
adjuvant therapy) for this group. SOC therapy is to proceed directly to RC, which is associated 
with a 50% recurrence rate at 2 years. The majority of patients will die from metastatic UC within 
1 year.8
Equally, there are no definitive randomized trials that demonstrate unequivocal support for the use 
of adjuvant chemotherapy for MIBC in patients who are cisplatin-ineligible. However, meta-
analyses and retrospective studies for patients that were able to receive cisplatin chemotherapy 
suggest there may be a benefit from adjuvant chemotherapy after cystectomy in select 
patients.10,20,21 A meta-analysis of available studies published in 2005 showed a HR for survival 
of 0.75 for adjuvant chemotherapy (95% CI = 0.60–0.96); however, this meta-analysis included 
only 491 patients from 6 trials and was thus underpowered.21,22 Since then, several larger 
randomized trials have been performed, but results of individual studies have been conflicting. An 
updated meta-analysis in 2014 found a similar benefit of adjuvant chemotherapy (HR = 0.77, 95% 
CI = 0.59-0.99) in pooled data from 9 clinical trials.22,23 The majority of these trials included 
patients with high-risk disease defined as extravesical extension and/or positive lymph nodes.
A Spanish Oncology Genitourinary Group (SOGUG) 99/01 study enrolled high-risk patients with 
MIBC after cystectomy and randomized them to 4 cycles of paclitaxel, gemcitabine, and cisplatin 
(PGC) or observation. This study suffered from poor recruitment, and 142 patients were enrolled. 
However, those who received adjuvant chemotherapy had a significantly improved 5-year survival 
compared to those who did not (60% vs 31%, P < 0.0009).22,24
The adjuvant Phase 3 trial of EORTC 30994, recruited 284 of a planned 660 patients, once again 
limited in power due to under accrual. Patients with high-risk MIBC (pT3-pT4 or node positive) 
were randomized to 4 cycles of adjuvant chemotherapy (GC or MVAC or high-dose MVAC [HD-
MVAC]) or deferred chemotherapy at relapse. Adjuvant therapy improved progression-free 
survival (PFS) compared to deferred treatment with a median PFS of 3.11 years (95% CI = 1.84-
7.77) in the immediate treatment group compared with 0.99 years (95% CI = 0.63-1.49) in the 
deferred treatment group (HR = 0.54, 95% CI = 0.4-0.73, P < 0.0001) with no statistically 
significant improvement in OS (HR = 0.78, 95% CI = 0.56-1.08).10,22
Galsky et al. presented an abstract of the comparative effectiveness of adjuvant chemotherapy 
using the National Cancer Data Base (NCDB).22,25 This study compared those who received 
adjuvant chemotherapy with a propensity-score matched control group that received cystectomy 
alone. Adjuvant chemotherapy was associated with improved survival with an adjusted HR of 
0.72 (95% CI = 0.71-0.86) compared to observation.
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Recently at the American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers 
Symposium 2021, data from the largest adjuvant trial to date was presented for CheckMate-274
(NCT02632409), a Phase 3, randomized, double-blind study, comparing nivolumab and placebo 
in a 1:1 randomized fashion among participants with high-risk muscle-invasive UC (with primary 
tumor sites including bladder, ureter, or renal pelvis) after radical surgery. 
In total, 709 participants were randomized to the following:

353 participants to nivolumab 240 mg every 2 weeks 

356 participants to placebo
All participants had to have underwent radical surgery (cystectomy or nephroureterectomy) within 
120 days of randomization and received adjuvant therapy for up to 1 year. The primary endpoints 
of the trial were DFS in all randomized participants (ie, the intention-to-treat [ITT] population) 
and in the subset of participants whose tumors express PD-L1 ≥ 1%. Key secondary endpoints 
included OS, non-urothelial tract recurrence-free survival, and disease-specific survival.
Over a median follow-up of approximately 20 months, median DFS was significantly longer for 
participants receiving nivolumab (21 months) compared to placebo (11 months; HR = 0.70, 95% 
CI = 0.54-0.89). The improvement in DFS was generally consistent across subgroups. 
Additionally, non-urothelial tract recurrence-free survival and distant metastasis-free survival 
were improved with the administration of nivolumab in both the ITT and PD-L1 ≥1% populations. 
The safety profile of nivolumab was consistent with previously reported studies in participants 
with solid tumors. Treatment-related adverse events (TRAEs) occurred in 77.5% of participants 
who received nivolumab vs 55.5% of participants who received placebo, while Grade 3 or 4 
TRAEs were observed in 17.9% vs 7.2% of participants, respectively.26
Since there is currently no neoadjuvant or adjuvant SOC for patients who are eligible for RC, but
not eligible for cisplatin-based chemotherapy, defining an unmet medical need, novel therapies are 
needed to increase the number of patients who qualify to receive neoadjuvant and adjuvant therapy 
and subsequently achieve a pCR and improved EFS. Data from 2 ongoing clinical studies 
demonstrate the safety and potential activity of programmed cell death protein-1 (PD-1) inhibitors 
as neoadjuvant therapy for MIBC.27,28 A Phase 2 Study investigating the safety and efficacy of 
neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS) enrolled cisplatin-
ineligible patients with operable bladder cancer. After receiving only 2 cycles of neoadjuvant 
atezolizumab, pCR occurred in 31% (95% CI = 21%-41%) (37% [95% CI = 21%-55%] of 
programmed death ligand 1 [PD-L1]–positive patients and 24% [95% CI = 13%-39%] of PD-L1–
negative patients).27 TRAEs were relatively infrequent and study medication was well tolerated. 
In an ongoing Phase 2, open-label study of neoadjuvant pembrolizumab before RC for MIBC, 
regardless of cisplatin eligibility, neoadjuvant treatment with a PD-L1 agent was also well 
tolerated and was associated with pCR in about 37% of patients (95% CI: 28%-46%).28
*Per Protocol Amendment 04, this paragraph is not applicable. This current Phase 3 study 
examining the neoadjuvant and adjuvant treatment of high-risk UC including MIBC participants,
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ineligible for cisplatin, will allow for direct comparison of nivolumab plus bempegaldesleukin
versus SOC treatment with RC alone. The study is designed with an analysis of the rate of pCR 
and will continue follow-up for an analysis of EFS.
3.2.2
Nivolumab
3.2.2.1
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.29,30,31
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either 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 and negative co-stimulatory signals in addition to 
antigen recognition by the T-cell receptor (TCR).32 Collectively, these signals govern the balance 
between T-cell activation and tolerance. 
PD-1 is a member of the CD-28 family of T-cell co-stimulatory receptors that also includes CD-28, 
CTLA4, ICOS, and B and T lymphocyte associated (BTLA).33 PD-1 signaling has been shown to 
inhibit CD-28-mediated upregulation of IL-2, IL-10, IL-13, IFN-γ, and Bcl-xL. PD-1 expression 
also been noted to inhibit T-cell activation, and the 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.34 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 = ± 1nM). 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 cell
(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 
versus 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/NPAN02).35
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3.2.2.2
Clinical Experience with Nivolumab
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), 
classical Hodgkin’s lymphoma (cHL), SCLC, gastric cancer, squamous cell carcinoma of the head 
and neck (SCCHN), urothelial cancer, hepatocellular carcinoma (HCC), and colorectal cancer 
(CRC). Please refer to the Investigator's Brochure (IB) for additional details.36
Nivolumab monotherapy has demonstrated clinical benefit in participants with UC who have 
progressed during or following platinum-containing chemotherapy or progressed within 12 months 
of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, and has been 
approved for use in the United States and European Union.
The safety and efficacy of nivolumab 3 mg/kg as a single agent for the treatment of patients with 
locally advanced or metastatic UC was evaluated in a Phase 2, multicenter, open-label, single-arm 
study (CA209275).37 The study included patients (18 years or older) who had disease progression 
during or following platinum-containing chemotherapy for advanced or metastatic disease or had 
disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy. Patients had an Eastern Cooperative Oncology Group (ECOG)
performance status score of 0 or 1 and were enrolled regardless of their tumor PD-L1 status. 
Patients with active brain metastases or leptomeningeal metastases, active autoimmune disease, or 
medical conditions requiring systemic immunosuppression were excluded from the study. Patients
who received more than 2 prior lines of chemotherapy with liver metastases were excluded. A 
total of 270 patients who received nivolumab 3 mg/kg administered intravenously over 60 minutes 
every 2 weeks with a minimum follow-up of 8.3 months were evaluable for efficacy. Treatment 
was continued as long as clinical benefit was observed or until treatment was no longer tolerated.
The primary efficacy outcome measure was objective response rate (ORR) as determined by 
blinded independent central review (BICR). Additional efficacy measures included duration of 
response (DOR), PFS, and OS. Median age was 66 years (range: 38 to 90 years) with 55% of 
patients aged 65 years and 14% aged 75 years. The majority of patients were White (86%) and 
male (78%). Baseline ECOG performance score was 0 (54%) or 1 (46%). Median time to response 
was 1.9 months (range: 1.6-7.2 months). In 77 patients who received prior systemic therapy only 
in the neoadjuvant or adjuvant setting, the ORR was 23.4% (95% CI = 14.5%-34.4%).
Median treatment duration was 3.3 months (range: 0 to 13.4+ months). Forty-six percent of 
patients had a drug delay for an adverse reaction. Fourteen (5.2%) patients died from causes other 
than disease progression. This includes 4 (1.5%) patients who died from pneumonitis or 
cardiovascular failure that was attributed to treatment with nivolumab. Nivolumab was 
discontinued for adverse reactions in 17% of patients. Serious adverse reactions occurred in 54% 
of patients. The most frequent serious adverse reactions reported in at least 2% of patients were 
urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health 
deterioration. The most common adverse reactions (reported in at least 20% of patients) were 
fatigue, musculoskeletal pain, nausea, and decreased appetite.
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3.2.3
Bempegaldesleukin
3.2.3.1
Mechanism of Action
Bempegaldesleukin is a prodrug of a conjugated cancer immunotherapy cytokine that exerts its 
biological activity by binding to the interleukin-2 (IL-2) receptor and subsequent activation of 
effector T cells. As a PEGylated human recombinant IL-2 molecule of aldesleukin with an average 
of 6 releasable polyethylene glycol (PEG) chains, bempegaldesleukin can be administered 
conveniently in the outpatient setting using an antibody-like dosing regimen. The polymer 
conjugation renders the cytokine initially inactive. Upon intravenous (IV) administration, the PEG 
chains slowly release to generate the active cytokine species (mainly 2-PEG-IL-2 and 1-PEG-IL-
2) that have a peak plasma concentration of 24 to 48 hours after infusion. The slow generation of 
the 2-PEG-IL-2 and 1-PEG-IL-2 significantly mitigates the rapid-onset, systemic cytokine-related 
toxicities associated with high-dose IL-2. 
The polymer conjugation of bempegaldesleukin promotes biased signaling through the IL-2 
receptor beta gamma (IL-2Rβγ). Specifically, the location of the bempegaldesleukin PEG chains 
interferes with the binding to the IL-2 alpha receptor subunit responsible for the undesirable effect 
of activating Tregs in the tumor while continuing to permit binding to the IL-2Rβγ (CD122) 
receptor. Upon infusion, bempegaldesleukin preferentially increases the proliferation, activation 
and effector function of tumor antigen-specific CD8+ T cells and natural killer (NK) cells within 
the tumor microenvironment (TME) over expansion of unwanted intra-tumoral regulatory T cells 
(Tregs) that are activated through the IL-2 receptor alpha beta gamma (IL-2Rαβγ).38,39 Consistent 
with this mechanism of action, recent nonclinical studies demonstrate strong synergy of 
bempegaldesleukin with adoptive T cell therapy (ACT), with PD-1 checkpoint blockade, and with 
tumor antigen-specific vaccination, in a variety of mouse models.40,41 This synergy was mediated 
by expansion of tumor-specific CD8+ T cells in the periphery and tumor, without strong expansion 
of Tregs in the tumor tissue. Bempegaldesleukin also correspondingly promotes expression of PD-
1 on the surface of CD8+ T cells and induction of a Type II interferon gene signature in the TME, 
driving cell surface expression of programmed cell death ligand 1 (PD-L1) on tumor cells.42
The immunological properties of bempegaldesleukin with the induction of tumor infiltrating 
lymphocytes and upregulation of the PD-1/PD-L1 axis makes bempegaldesleukin a potentially 
promising combination therapy for use with checkpoint inhibitors that target and inhibit the PD-
1/PD-L1 pathway. Moreover, the safety profile of bempegaldesleukin generally does not overlap 
with that of checkpoint inhibitors, further supporting the use of bempegaldesleukin as a potentially 
complimentary combination partner with checkpoint inhibitors.
3.2.4
Clinical Experience with Bempegaldesleukin
3.2.4.1
Study 15-214-01 (EXCEL; Bempegaldesleukin Monotherapy)
The bempegaldesleukin clinical development program started with the monotherapy study EXCEL 
(Study 15-214-01; A Phase 1/2, Open-label, Multicenter, Dose-Escalation and Dose Expansion 
Study of bempegaldesleukin in Subjects with Locally Advanced or Metastatic Solid Tumor 
Malignancies). The first part of the study was a dose escalation phase, designed to evaluate the 
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safety and tolerability, and define the maximum tolerated dose (MTD) or recommended Phase 2 
dose (RP2D) of bempegaldesleukin. 
The second part of the study was an expansion phase following identification of the RP2D, 
designed to evaluate the safety and tolerability, as well as the efficacy of bempegaldesleukin in 
specific tumor types. Bempegaldesleukin at a dose of 0.009 mg/kg administered once every
3 weeks (q3w) was deemed the MTD by pre-defined dose-limiting toxicity (DLT) criteria. The 
RP2D was determined to be 0.006 mg/kg q3w. Enrollment was closed after 28 patients were 
exposed to bempegaldesleukin in the dose-escalation phase and the dose expansion phase was not 
initiated. 
The safety of single-agent bempegaldesleukin has been assessed in 28 patients across 5 dose 
cohorts administered bempegaldesleukin q3w at doses ranging from 0.003 mg/kg to 0.012 mg/kg 
and a dosing frequency of every 2 weeks (q2w) was explored at 0.006 mg/kg. For the q3w dosing 
frequency, doses up to 0.009 mg/kg were well tolerated. One patient dosed at 0.012 mg/kg 
experienced cytokine release syndrome and the DLTs of hypotension and syncope; this patient 
received 2 additional cycles of bempegaldesleukin at a lower dose of 0.006 mg/kg and tolerated 
treatment well. The bempegaldesleukin dose of 0.009 mg/kg was determined to be the MTD.
As of the data cutoff date of 29-Mar-2018, 593 treatment-emergent adverse events (TRAEs) were 
reported among the 28 patients who received single-agent bempegaldesleukin. Overall, the most 
common TRAEs fatigue (82.1%), flu-like symptoms (consisting of influenza-like illness, 
influenza, pyrexia, and chills, 71.4%), pruritus (67.9%), hypotension (64.3%), rash (also consisting 
of erythema, rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, rash 
pustular, rash vesicular, rash generalized, and rash macular, 53.6%), decreased appetite (53.6%), 
and arthralgia or cough (42.9% each).43
The most common AEs considered by the investigator to be related to bempegaldesleukin were 
fatigue (71.4%), flu-like symptoms(67.9%), pruritus (64.3%), hypotension (57.1%), rash(50.0%), 
decreased appetite (46.4%), and arthralgia or cough (32.1% each). Such TRAEs as flu-like 
symptoms, rash and pruritus were generally mild or moderate in severity, predictable, manageable, 
and short-lived. These cytokine-related AEs generally occurred 3 to 4 days after dosing and 
corresponded to the time of peak plasma concentration of the active cytokines. The flu-like 
symptoms were managed with acetaminophen and non-steroidal anti-inflammatory drugs 
(NSAIDs) and the cases of rash/pruritus were either self-limiting or treated with anti-histamines 
(steroids were administered for occasional patients who had severe rash/pruritus).
Six of 28 patients reported Grade 3 TRAEs, which included hypotension, abdominal pain, 
infusion-related reaction, headache, and syncope. The cases of Grade 3 hypotension were rapidly 
reversed with intravenous fluids, and a hydration management guideline was implemented during 
the study which mitigated the hypotension severity. One patient, who had a prior history of an 
infusion reaction to a previously administered immunotherapy, discontinued treatment due to an 
infusion-related reaction following the first dose of bempegaldesleukin 0.009 mg/kg. With the 
exception of one event of hypothyroidism, no other immune mediated AEs consistent with 
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checkpoint inhibitors were reported. No patient experienced capillary leak syndrome and no 
Grade 4 TRAEs or treatment-related deaths were reported on the study.
Fifteen patients (53.6%) reported 31 SAEs in monotherapy Study 15-214-01. Eleven SAEs 
reported among 7 (25.0%) patients were considered related to treatment. The only 
treatment-related SAE reported for more than 1 patient was hypotension (5 patients, 17.9%, 4 of 
5 were Grade 3 in severity). 
In the 28 patients evaluable for efficacy in Study 15-214-01, best overall response included stable 
disease (SD) in 14 patients (50%), progressive disease (PD) in 12 patients (42.9%), and not 
evaluable (NE) for 2 patients (7.1%). While no objective responses were observed in Study 15-
214-01, 9 patients experienced tumor shrinkage between 1% and 30% and two patients, after 
progressing on multiple prior therapies, had durable stable disease over 1 year. One patient with 
metastatic melanoma, who was previously treated with ipilimumab and a BRAF inhibitor, received 
25 cycles of bempegaldesleukin and had durable stable disease for 18 months. A second patient
with metastatic renal cell carcinoma (RCC), who had progressed on high-dose IL-2 and was 
refractory to single-agent OX40 (ie, an antibody targeting the tumor necrosis factor receptor 
superfamily member 4) and nivolumab, was treated with 19 cycles of bempegaldesleukin and had 
durable stable disease for 14 months. Given the biological properties of bempegaldesleukin and 
nivolumab these observations further supported the rationale for combining these two agents.
In Study 15-214-01, hypotension was identified as a principal toxicity. Hypotension is a known 
AE associated with both IL-2 and engineered cytokines. Instances of hypotension most commonly 
appeared 2-4 days following the infusion of bempegaldesleukin. Participants for whom 
intravenous (IV) fluid administration was clinically indicated responded rapidly (in less than 
24 hours) to IV hydration. To mitigate the risk of hypotension, management guidelines were 
implemented during the conduct of the study.
3.2.4.2
Study 16-214-02 (PIVOT-02; Bempegaldesleukin and Nivolumab 
Combination Therapy)
The PIVOT-02 trial (NCT02983045) is an ongoing Phase 1/2 open-label, multicenter, dose 
escalation, and dose expansion study of bempegaldesleukin in combination with nivolumab and 
other anti-cancer therapies in patients with locally advanced or metastatic solid tumors. Part 1 of 
the study was a dose escalation phase to evaluate the safety and tolerability, and define the MTD 
or RP2D of bempegaldesleukin in combination with nivolumab. Following determination of the 
RP2D (0.006 mg/kg bempegaldesleukin q3w plus 360 mg nivolumab q3w), Part 2 of the study is 
evaluating the safety and tolerability as well as the efficacy of the combination by assessing the 
objective response rate (ORR) at the RP2D. The indications studied in Part 2 include melanoma, 
RCC, non-small cell lung cancer (NSCLC), UC, breast cancer, gastric cancer, colorectal carcinoma 
(CRC), and small cell lung cancer (SCLC). Parts 3 and 4 are schedule-finding and dose expansion 
for the triplet, studying the safety and tolerability of bempegaldesleukin in combination with 
nivolumab and ipilimumab in patients with metastatic RCC, UC, melanoma, or NSCLC who are 
treatment-naïve.
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The bempegaldesleukin + nivolumab dose escalation portion of PIVOT-02 has been completed, 
with the safety results of bempegaldesleukin at 0.006 mg/kg in combination with nivolumab 
360 mg every 3 weeks indicating no DLTs and no Grade ≥ 3 TRAEs at the time of completion. 
Bempegaldesleukin 0.006 mg/kg in combination with nivolumab 360 mg every 3 weeks was the 
recommended dose regimen to be taken forward into expansion cohorts in Part 2.
As of 28-Oct-2020, a total of 557 patients had been treated with bempegaldesleukin in combination 
with nivolumab (503 patients with doublet [bempegaldesleukin and nivolumab]; 43 patients with 
triplet [bempegaldesleukin, nivolumab, and ipilimumab]; and 11 patients with doublet 
[bempegaldesleukin and nivolumab] plus other anti-cancer study drug). Of the 557 patients, most 
have NSCLC (184 patients [33%]), RCC (139 [25%]), or melanoma (102 [18%]), followed by UC
(61 [11%]), breast cancer (47 [8%]), and CRC (22 [4%]), and gastric cancer (2 [< 1%]). The 
median duration of exposure was 106.0 days (doublet, 101.0; triplet, 179.0; doublet plus other anti-
cancer drug, 113.0) (range: 1 to 817 days). 
As of 28-Oct-2020, among the 503 patients who received the doublet:

94.6% (476 of 503) of patients reported TRAEs; the most frequent were fatigue (47.1%), 
pyrexia (44.7%), pruritus (36.0%), nausea (31.4%), influenza-like illness (26.8%), decreased 
appetite (26.6%), rash (26.0%), and chills (25.8%).

24.9% (125 of 503) of patients reported treatment-related, Grade ≥ 3 AEs; the most frequent 
(> 2%) were syncope (2.8%), hypotension (2.6%), and lipase increased (2.2%).

16.3% (82 of 503) of patients reported treatment-related SAEs; the most frequent were pyrexia 
(3.0%), hypotension (2.0%), and pneumonitis (1.0%).
Therefore, 
the 
generally 
non-overlapping 
toxicities 
observed 
with 
nivolumab 
and 
bempegaldesleukin are expected to result in a reasonably well-tolerated IO combination therapy.
Serious events of cerebrovascular accident (CVA) have been observed in patients who have 
received bempegaldesleukin in the triplet combination with nivolumab and ipilimumab and in the 
doublet combination with nivolumab. A total of 3 of 43 patients (7.0%) who received 
bempegaldesleukin, nivolumab, and ipilimumab (triplet immunotherapy) and 8 of 478 patients 
(1.7%) who received bempegaldesleukin and nivolumab (doublet immunotherapy) in Study 
16-214-02 were determined to have CVA events that were confirmed by the independent 
neurology consultants. No confirmed CVA events occurred in any patients in any other studies of 
bempegaldesleukin. The incidence of CVA, combining all clinical trials in which the doublet of 
bempegaldesleukin plus nivolumab was administered was 8 out of 593 patients (1.3% or 3.52 per 
100 person-years [P-Y]). By comparison, incidence rates of ischemic CVA among patients treated 
with nivolumab monotherapy was 1.4 per 100 (P-Y). Rates of CVA in metastatic cancer patients, 
based on Pharmetrics and MarketScan data, are 4.17 and 5.35 per 100 P-Y, respectively. The 
incidence rate in the patients receiving doublet immunotherapy is likely within the incidence rate 
of CVA in patients with advanced malignancies. The relationship of these events to the triplet and 
doublet combinations is unclear. As more information is needed to better understand and 
characterize these events, CVA events will be monitored as adverse events of special interest, 
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which will involve additional monitoring and expedited reporting for any new events. The CVA 
AE Management Algorithm, which was added to the protocol as Appendix 7, is no longer 
applicable per Protocol Amendment 04.
Tumor response data are available for 37 of the dose escalation patients, including 11 with 
metastatic melanoma, 21 with RCC, and 5 with NSCLC. Of these 37 response-evaluable patients, 
25 were treated at 0.006 mg/kg bempegaldesleukin combined with nivolumab 360 mg flat dose 
every 3 weeks. As of 18-Jan-2019, 22 of 37 response evaluable patients (59.5%) achieved an 
investigator-assessed response (complete or partial response) by RECIST v1.1.44
For select tumors, additional efficacy data have been presented. PIVOT-02 has a 2-stage design 
and data for either the Stage 1 (N1) population alone or in combination with the Stage 2 (N2; 
expansion) population were presented depending on data maturity. Data presented for the efficacy 
evaluable population (defined as having received one dose of study treatment and having 
undergone at least one scan) were as follows:

In first-line RCC patients, a 46% (12 of 26 patients) ORR was observed (N = 48 enrolled; 
N = 26 in the N1 + N2 population; 29-May-2018 cutoff).45

In first-line melanoma patients, a 53% (20 of 38 patients) ORR via blinded independent central 
review (BICR) was observed (N = 41 enrolled; N = 38 included in the N1 + N2 population; 
01-Sep-2020 data cutoff).46

In first-line metastatic UC patients, a 48% (13 of 27 patients) ORR was observed (N = 41 
enrolled; N = 27 in the efficacy evaluable population; 03-Dec-2018 data cutoff).47

In metastatic triple-negative breast cancer (TNBC) patients, a 13% (5 of 38 patients) ORR was 
observed (N = 43 enrolled; N = 38 in the efficacy evaluable population; 01-Jul-2019 data 
cutoff).48
Additional details on the clinical experience with bempegaldesleukin are provided in the 
bempegaldesleukin Investigator’s Brochure.
3.2.4.3
Study 18-214-10 (PIVOT-10); Bempegaldesleukin and Nivolumab 
Combination Therapy
On 14-Apr-2022, Nektar Therapeutics and Bristol Myers Squibb (BMS) announced updates on 
results from a late-stage clinical study of bempegaldesleukin in combination with nivolumab in 
bladder cancer (PIVOT-10).49
PIVOT-10 is a global Phase 2 single-arm study evaluating bempegaldesleukin combined with 
nivolumab in patients deemed ineligible for cisplatin therapy including those whose baseline tumor 
cells express low levels of PD-L1. A total of 192 patients were enrolled and patients were treated 
until disease recurrence, unacceptable toxicity or withdrawal of consent for up to 24 months. A 
final ORR analysis assessed by BICR showed that bempegaldesleukin in combination with 
nivolumab did not reach an efficacy threshold to support continuing the program in urothelial 
carcinoma.
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Additional details on the clinical experience with bempegaldesleukin are provided in the 
bempegaldesleukin Investigator’s Brochure.
3.2.4.4
Pooled Safety Analysis of Participants with Bempegaldesleukin and 
Nivolumab Exposure
A pooled safety analysis (28-Oct-2020 data cutoff) is available of participants who received the 
bempegaldesleukin and nivolumab doublet from the ongoing combination Phase 1/2 studies 
(16214-02 and 16-214-05), the ongoing combination Phase 2 study (18-214-10), and the 
completed Phase 1 study in Japan (CA045010). Of the 696 participants who received the 
bempegaldesleukin and nivolumab doublet:

93.0% (647 of 696) of participants reported TRAEs; the most frequent were pyrexia (42.1%), 
fatigue (39.9%), pruritis (37.6%), nausea (27.9%), rash (24.6%), decrease appetite (23.7%), 
influenza-like illness (22.4%), and chills (22.1%). 

24.6% (171 of 696) of participants reported treatment-related, Grade ≥3 AEs; the most 
frequent were hypotension (2.6%), fatigue (2.0%), arthralgia (1.1%), diarrhea (0.9%), and 
pyrexia (1.1%).

15.8% (110 of 696) of participants reported treatment-related SAEs; the most frequent were 
pyrexia (2.6%), hypotension (1.7%), dehydration (0.9%), pneumonitis (0.7%), acute kidney 
injury, atrial fibrillation, myocarditis (0.6% each).
3.2.4.5
Observed Events of Cerebrovascular Accident
3.2.4.5.1
Initial Analysis of Cerebrovascular Accident Events in PIVOT-02 (16-214-02) Study
Serious events of CVA, including one fatal event, have been observed in participants who have 
received bempegaldesleukin in the triplet combination with nivolumab and ipilimumab, and in the 
combination of bempegaldesleukin, nivolumab, and other anti-cancer therapy. As of 28-Oct-2019, 
3 of 43 participants (7.0%) who received triplet therapy in Study 16-214-02 (PIVOT-02) were 
reported to have CVA events, including one fatal event, all of which were considered by the 
investigator to be related to treatment with bempegaldesleukin, nivolumab, and ipilimumab. 
Additionally, 9 of 488 participants (1.8%) who received doublet therapy (bempegaldesleukin and 
nivolumab) had 10 CVA events, which were considered by the investigator to be related to at least 
one of the study treatments in 4 participants (3 related to the doublet therapy and 1 related to 
nivolumab only); and one of 10 (10.0%) participants who received combined bempegaldesleukin,
nivolumab, and other anti-cancer therapy (platinum-based chemotherapy) had a CVA event, which 
was considered by the Investigator to be unrelated to study treatment. 
Updated Analysis of CVA Events Observed with Bempegaldesleukin
A cumulative search of the bempegaldesleukin global safety database was conducted on 28-Oct-
2020, which included 1,345 participants who received bempegaldesleukin in triplet combinations 
with nivolumab plus ipilimumab or with nivolumab plus NKTR-262 (a toll-like receptor agonist 
7/8); in doublet combinations with checkpoint inhibitors; in a doublet combination with nivolumab 
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plus chemotherapy, and in combination with NKTR-262 from the following Studies: 15-214-01, 
16-214-02, 16-214-05, 17-214-09, 18-214-10, 20-214-29, CA045001 (17-214-08), CA045009 
(18-214-13), CA045010 (18-214-14), SP-IND, and 17-262-01.
Overall, 1.9% (26 of 1,345) of participants exposed to bempegaldesleukin reported CVA events. 
Of the 26 participants, 13 participants experienced Grade 3 or 4 events and 4 participants had a 
fatal outcome. The mean time to first CVA event was 218.7 days (range 4 to 727 days; median 
158 days). Twenty of the 26 participants with CVA events received a doublet combination with a 
checkpoint inhibitor, which included 1.7% (19 of 1,116) of participants who received nivolumab, 
1.3% (1 of 76) who received pembrolizumab, and 0% (0 of 23) who received atezolizumab.
Based on these events, CVA was escalated to an AEOSI and mitigations were put in place to 
reduce the risk of CVA. These mitigations include implementation of a CVA adverse event 
management algorithm (Appendix 7) and updates to the exclusion criteria, renal function and 
hydration assessment, hydration guidelines, concomitant and prohibited medications, dose 
modification guidelines, and discontinuation criteria. Additional information on the clinical safety 
and risk of CVA is found in the bempegaldesleukin Investigator’s Brochure.
3.3
Benefit-risk Assessment
3.3.1
Bempegaldesleukin Safety Profile
Bempegaldesleukin was designed to mitigate the severe toxicities associated with rapid systemic 
immune activation seen with administration of aldesleukin. The identified risks of 
bempegaldesleukin include hypotension, cytokine-related toxicities (eg, flu-like symptoms, rash, 
pruritus, fatigue, hepatic transaminase elevations, and serum creatinine elevations), infusion-related 
reactions/hypersensitivity reactions, thyroid dysfunction, eosinophilic disorder (including cases of 
hypereosinophilic syndrome), and arthralgia. The majority of these AEs are mild to moderate in 
severity and can be monitored and managed in the clinical setting. The goal of engineering a 
PEGylated form of IL-2 that reduces the treatment-limiting toxicities of aldesleukin, that is, those 
necessitating in-hospital administration, appears to have been realized with bempegaldesleukin at 
the doses tested. 
Additional details on the clinical experience with bempegaldesleukin are provided in the 
bempegaldesleukin Investigator’s Brochure.
3.3.2
Nivolumab Safety Profile
Extensive details on the safety profile of nivolumab are available in the IB and will not be repeated 
herein.
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials with no MTD reached at any dose tested up to 
10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively few related high-grade 
(Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or causality of AEs with 
respect to nivolumab dose level.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 6. Most high-grade events were manageable with the 
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use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms.
Additional details on the safety profile of nivolumab, including results from other clinical studies,
are also available in the nivolumab IB.
3.3.3
Bempegaldesleukin and Nivolumab Benefit and Risk Assessment
Bempegaldesleukin has been generally well-tolerated in the clinical studies to date, both as 
monotherapy as well as in combination with nivolumab, with promising evidence of clinical 
efficacy and a potentially favorable benefit-risk profile. Bempegaldesleukin has been safely 
administered in an outpatient setting supported by appropriate clinical monitoring.
Hypotension has been identified as a clinically significant adverse effect of bempegaldesleukin, 
and can be effectively mitigated by prophylaxis and hydration guidelines. Other risks associated 
with bempegaldesleukin include cytokine-related toxicities (eg, flu-like symptoms, rash, pruritus, 
fatigue, hepatic transaminase elevations and serum creatinine elevation), infusion related reactions, 
thyroid dysfunction, eosinophilic disorder, and arthralgia; these AEs are generally mild or 
moderate in severity, and can be monitored and managed in clinical setting. Cases of thyroid 
dysfunction (hypothyroidism, hyperthyroidism, thyroiditis), dermatitis, pneumonitis, hepatitis, 
myocarditis, myositis/myasthenia gravis and vitiligo/hypopigmentation consistent with immune-
mediated mechanism have been observed in patients receiving bempegaldesleukin plus 
nivolumab; however, there is no evidence that bempegaldesleukin increases the frequency or 
severity of immune-mediated AEs associated with nivolumab with the limitation of small sample 
size and relatively shorter treatment duration for bempegaldesleukin-treated patients. 
The continued development of bempegaldesleukin in combination with nivolumab for the 
treatment of various cancers is warranted based on a positive benefit-risk profile. In addition, the 
early efficacy data along with the correlative biomarker showing conversion of PD-L1 negative 
patients to PD-L1 positive patients suggests that the addition of bempegaldesleukin to a checkpoint 
inhibitor (nivolumab) may change the tumor microenvironment in PD-L1 negative patients such 
that the combination may contribute to anti-tumor activity with an acceptable safety profile.
In conclusion, the currently available safety data demonstrates that bempegaldesleukin and 
nivolumab is a well-tolerated immuno-oncology combination therapy. Given the encouraging 
clinical activity and manageable and generally non-overlapping toxicity profile, the potential for 
direct benefit in patients warrants continued evaluation of the combination bempegaldesleukin and 
nivolumab in the clinical setting and supports further development of combination of 
bempegaldesleukin and nivolumab regimens in patients with cancer.
If a participant had coronavirus disease 2019 (COVID-19) during the trial, then the benefit and 
risk considerations remain the responsibility of the investigator. Non-live COVID-19 vaccination 
is considered a standard concomitant medication within the study. However, the efficacy and 
safety of non-live vaccines (including non-live COVID-19 vaccines) in participants receiving 
nivolumab and bempegaldesleukin is not fully known.
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Given there was no additional clinical benefit with the addition of bempegaldesleukin to 
nivolumab in  the PIVOT-10 study, Nektar Therapeutics and BMS have jointly decided to end the 
clinical development program for bempegaldesleukin in combination with nivolumab and new 
enrollment to all studies has been discontinued.
4
OBJECTIVES AND ENDPOINTS
The secondary 
 objectives except safety 
 parameters are no longer 
applicable. 
 
Per Protocol Amendment 04, Nektar Therapeutics and BMS are terminating the development of 
bempegaldesleukin in combination with nivolumab. The efficacy endpoints of pCR, EFS, and OS, 
as well as safety and tolerability for each treatment arm will be summarized descriptively in all 
randomized participants. Details will be included in SAP. 
Table 4-1:
Objectives and Endpoints
Objective
Endpoint
Primary
To compare the pCR rate of neoadjuvant 
nivolumab + bempegaldesleukin to Standard of Care 
(SOC, no neoadjuvant therapy) in all randomized 
participants 
pCR rate, defined by the proportion of randomized 
participants with absence of any cancer (T0, N0) in 
pathology specimens after RC, based on blinded 
independent pathology review
To compare the EFS of neoadjuvant nivolumab +
bempegaldesleukin followed by adjuvant nivolumab + 
bempegaldesleukin after radical cystectomy (RC) versus 
SOC (no neoadjuvant or adjuvant therapy) in all 
randomized participants
EFS, defined as the time from randomization to any 
of the following events: progression of disease that 
precludes surgery, local or distant recurrence based 
on BICR assessments, or death due to any cause
Secondary
To compare the pCR rate of neoadjuvant nivolumab 
monotherapy to SOC (no neoadjuvant therapy) in all 
randomized participants
pCR rate, defined by the proportion of randomized 
participants with absence of any cancer (T0, N0) in
pathology specimens after RC, based on blinded 
independent pathology review
To compare the EFS of neoadjuvant nivolumab followed 
by adjuvant nivolumab versus SOC in all randomized 
participants
EFS, defined as the time from randomization to any 
of the following events: progression of disease that 
precludes surgery, local or distant recurrence based 
on BICR assessments, or death due to any cause
To compare the overall survival (OS) of each 
experimental arm versus SOC in all randomized 
participants
OS, defined as the time between the date of 
randomization and the date of death from any cause. 
OS will be censored on the last date a participant was 
known to be alive
To assess safety and tolerability for each treatment arm in 
all treated participants
Worst grade AEs, SAEs, AEs leading to 
discontinuation, immune-mediation AEs and worst 
grade clinical laboratory values
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
To evaluate (descriptively) the pCR rate of neoadjuvant 
nivolumab + bempegaldesleukin to neoadjuvant 
nivolumab monotherapy in all randomized participants
pCR rate, defined by the proportion of randomized 
participants with absence of any cancer (T0, N0) in 
pathology specimens after RC, based on blinded 
independent pathology review
To evaluate (descriptively) the EFS of neoadjuvant 
nivolumab + bempegaldesleukin followed by adjuvant 
nivolumab + bempegaldesleukin after RC versus 
neoadjuvant nivolumab followed by adjuvant nivolumab
after RC in all randomized participants
EFS, defined as the time from randomization to any 
of the following events: progression of disease that 
precludes surgery, local or distant recurrence based 
on BICR assessments, or death due to any cause
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Table 4-1:
Objectives and Endpoints
Objective
Endpoint
5
STUDY DESIGN
5.1
Overall Design
Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin 
plus nivolumab in Arm A of CA045009 are required to discontinue bempegaldesleukin and 
may continue to receive nivolumab monotherapy.
Three
recent studies
from the 
bempegaldesleukin and nivolumab development program, Study CA045-001/17-214-08, a Phase 
3 study in metastatic melanoma, Study 17-214-09/PIVOT-09, a Phase 3 study in metastatic renal 
cell carcinoma, and Study 18-214-10/PIVOT-10, a Phase 2 Study in cisplatin-ineligible metastatic 
urothelial carcinoma have demonstrated that there was no additional benefit of combining 
bempegaldesleukin with nivolumab. On 14-Apr-2022, Nektar Therapeutics and BMS announced 
a joint decision to end the clinical development program for bempegaldesleukin in combination 
with nivolumab. All new enrollment to CA045009 has been stopped.
CA045009 is a multicenter, randomized, Phase 3, study of neoadjuvant and adjuvant nivolumab 
plus bempegaldesleukin, versus nivolumab alone versus SOC in participants with high-risk UC of 
the bladder, including MIBC, who are candidates for RC and cisplatin-ineligible. Participants must
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have pathologically proven UC of the bladder, clinical stage T2-T4aN0M0 or T1-T4aN1M0,
that has not been previously treated (except for Transurethral Resection of Bladder Tumor 
[TURBT] or prior intravesicular treatment of non-muscle invasive bladder cancer [NMIBC]).
Participants must be deemed potentially curable, medically fit for RC, and be willing to undergo
RC as part of the study treatment.
The study is divided into screening period, treatment period and long-term follow-up period.
Participants were randomized (1:1:1) to one of the following 3 treatment arms: Per Protocol 
Amendment 04, participants who are currently receiving bempegaldesleukin plus nivolumab 
in Arm A are required to discontinue bempegaldesleukin and may continue to receive 
nivolumab monotherapy.

Arm A: Bempegaldesleukin 0.006 mg/kg Q3W + nivolumab 360 mg Q3W x 3 cycles as 
neoadjuvant therapy, followed by RC, followed by bempegaldesleukin 0.006 mg/kg Q3W + 
nivolumab 360 mg Q3W up to an additional 12 cycles (approximately 9 months of adjuvant 
therapy)

Arm B: Nivolumab 360 mg Q3W x 3 cycles as neoadjuvant therapy, followed by RC, followed 
nivolumab 360 mg Q3W up to an additional 12 cycles (approximately 9 months of adjuvant 
therapy)

Arm C: SOC (cystectomy alone, without neoadjuvant or adjuvant therapy)
Randomization will be stratified by the following:

Clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1)

PD-L1 status (1% vs < 1%/indeterminate)
Per Protocol Amendment 04:

Participants in Arm A are required to discontinue bempegaldesleukin and may continue 
nivolumab monotherapy. 

Participants on adjuvant nivolumab monotherapy can receive up to a maximum of 12 cycles. 

All participants, in Arm A and Arm B, who have completed therapy or are currently within the 
100 days safety follow-up should discontinue from the study once they complete the safety 
follow-up 100 days, if AE reporting requirements have been fulfilled as per Section 9.2.3.  
Documentation of recurrence status and
last overall survival should occur upon 
discontinuation.

All participants, in Arm C, who have completed radical cystectomy or are currently within the 
100 days safety follow-up after radical cystectomy, should discontinue from the study once 
they complete the safety follow-up 100 days, if AE reporting requirements have been fulfilled 
as per Section 9.2.3. Documentation of recurrence status and last overall survival should occur 
upon discontinuation.
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
Participants who have completed therapy, including 100 days safety follow-up, and are 
currently in survival follow-up should discontinue from the study if AE reporting requirements 
have been fullfilled as per Section 9.2.3. Documentation of last overall survival should occur 
upon discontinuation. 
The study design schematic is presented in Figure 5.1-1.
Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin 
plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue 
to receive nivolumab monotherapy.
Figure 5.1-1:
Study Design Schematic
Abbreviations: Bempeg, bempegaldesleukin; CT, computed tomography; EFS, event-free survival; Nivo, nivolumab; 
pCR, pathologic complete response; PD-L1, programmed death ligand 1; PS, performance score; Q3W, every 3 weeks; 
SOC, standard of care.
5.1.1
Screening Period
Not applicable per Protocol Amendment 04 as all new enrollment to CA045009 has been 
stopped.
Participants will provide written informed consent to participate in the study before completing 
any protocol-specified procedures or evaluations not considered to be part of the participants’ 
standard care. After signing the informed consent form (ICF), participants will be evaluated for 
entry criteria during the Screening period before randomization. Rescreening after screen failure 
will be allowed.
Screening
Pre-surgical Treatment
Post-surgical Treatment
Follow-up
High-risk urothelial carcinoma (UC) 
/ muscle-invasive/resectable 
bladder cancer (MIBC)
Clinical stage T2-T4aN0 (< 15 mm 
on CT scan) M0 OR clinical stage 
T1-T4aN1 (≥15 mm on CT scan) 
M0
Cisplatin-ineligible
PS 0-1
N = 540 
Stratification factors:
Clinical Stage (T2N0 vs 
T3-T4aN0 vs T1-T4aN1)
PD-L1 status (≥ 1% vs
< 1%/indeterminate)
Randomization 1:1:1
Arm A
Nivo 360 mg +
Bempeg 0.006 mg/kg Q3W x 3 cycles
Arm B
Nivo 360 mg Q3W x 3 cycles
Arm C
SOC 
No induction or adjuvant treatment
Radical Cystectomy
Nivo 360 mg +
Bempeg 0.006 mg/kg Q3W x 12 cycles 
(9 months)
Nivo 360 mg Q3W x 12 cycles 
(9 months)
1 Cycle = 3 Weeks
Follow-up visits, 
monitor for recurrence 
and survival, Follow-up 
until death
pCR and EFS 
A vs C primary endpoints
(B vs C secondary)
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Diagnostic hematoxylin and eosin (H&E) and, if applicable, immunohistochemistry (IHC) stained 
slides from the initial TURBT (conducted within 12 weeks of randomization) confirming UC of 
the bladder/MIBC diagnosis along with pathology report must be submitted to the vendor for 
confirmation of UC of the bladder/MIBC prior to randomization. 
The central laboratory must provide IRT with UC of the bladder/MIBC confirmation prior to 
randomization (refer to the Laboratory Manual for detailed instructions on required sample 
submission of UC of the bladder diagnosis and MIBC confirmation).
Sufficient (ie, one [1] formalin-fixed paraffin-embedded [FFPE] block or 20 unstained slides), 
recent bladder tumor tissue obtained within 12 weeks prior to randomization from the initial 
TURBT confirming UC of the bladder/MIBC diagnosis will be submitted to the central laboratory. 
Submitted tissue must not be previously irradiated and systemic therapy must not be given after 
samples are obtained prior to enrollment. PD-L1 results must be determined by central testing prior 
to study randomization.
The central laboratory must provide IRT with PD-L1 results from tumor tissue sample prior to 
randomization (Section 5.1.4.1). All research sites will be blinded to the results of 
 
PD-L1  testing.
Screening images should be performed and submitted to the central imaging vendor per study 
inclusion criteria (Section 6.1). Any relevant historical scans should be submitted as well. At the 
discretion of the Sponsor, additional historical scans may be requested.
5.1.2
Treatment Period
5.1.2.1
Neoadjuvant (Pre-surgical Treatment) Randomized Participants
Per Protocol Amendment 04, participants who are currently receiving bempegaldesleukin 
plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue 
to receive nivolumab monotherapy.

Arm A: Bempegaldesleukin 0.006 mg/kg Q3W + nivolumab 360 mg Q3W up to 3 cycles

Arm B: Nivolumab 360 mg Q3W up to 3 cycles

Arm C: SOC (no therapy), participants will go to RC within 6 weeks after randomization
Dose reduction will not be allowed for nivolumab. Some participants may not receive all 3 cycles
of planned pre-surgical therapy (eg, toxicity, refusal to receive further therapy). However,
participants should receive as much of the planned pre-surgical therapy as possible, with a 
minimum of at least one cycle. If one of the components of the treatment is not tolerated after the 
first cycle(s) of therapy, then the other component may be continued to complete 3 cycles. Thus,
a participant may receive all 3 cycles of bempegaldesleukin even though nivolumab was
discontinued sooner, or may complete all 3 cycles of nivolumab even though bempegaldesleukin 
was previously discontinued. Such treatment decisions will be at the discretion of the Investigator
and participant (in case it is being proposed to continue treatment as monotherapy and permanently 
discontinue one of the agents).
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5.1.2.2
Surgery (Radical Cystectomy)
Per Protocol Amendment 04, radical cystectomy will be performed per local SOC. 
Participants should receive RC within 6 weeks of the last neoadjuvant treatment administration
(Arm A and Arm B), after recovery from any immunotherapy-related toxicities or within 6 weeks 
of randomization (Arm C).
In specific cases, when RC does not occur within 6 weeks of the last neoadjuvant treatment 
administration, RC may be permitted at a later date after consultation with Medical Monitor.
Analysis of data from the SWOG-8710 Phase 3, randomized, neoadjuvant study for patients 
undergoing RC showed that negative surgical margins (P = 0.0007) and removal of > 10 lymph
nodes (LN) (P = 0.0001) were associated with longer survival and decreased local recurrence.50
Positive surgical margins are associated with a poor prognosis, and in experienced hands, the
positive soft-tissue margin rate should be 5%.51 Lymph node numbers vary among patients, 
making it difficult to judge the quality of the pelvic lymph node dissection (PLND) by LN numbers
alone. Rather the PLND surgical template
is the key, and if followed, should yield adequate
numbers of pelvic LN from critical sites that drain the bladder.52,53 For RC, the following is
recommended as the surgical SOC:

When performing RC, the surgeon should remove the bladder, prostate and seminal vesicles
in males, and the bladder, uterus, fallopian tubes, ovaries and anterior vaginal wall in females. 
All efforts should be made to obtain grossly negative surgical margins.54

Bilateral pelvic lymphadenectomy, should include at a minimum the region below the
bifurcation of the common iliac artery, which involves removal of the external and internal
iliac and obturator LNs (standard lymphadenectomy). Dissection along the common iliac
artery to at least the crossing of the ureter, but most commonly the aortic bifurcation, and
sometimes the inferior mesenteric artery is recommended when the surgeon is experienced in
performing this extent of surgery termed an extended lymph node dissection.55
If this template is followed, > 10 LN should be obtained in most cases.
Pathologists must examine the RC specimen according to SOC practices. To the extent feasible, 
all excised lymph nodes should be identified, processed, and examined microscopically for the 
presence or absence of metastatic bladder cancer.
Not applicable per Protocol Amendment 04.  Pathology slides, which includes all H&E from 
every specimen sampled from the entire RC specimen (involved and uninvolved tissue), and if 
applicable, any diagnostically relevant IHC that was used in addition to H&E (comprehensive 
guidelines for bladder specimen handling and identification of the tumor bed are described in the
Laboratory Manual) from the RC specimen should be submitted to pathology review to confirm 
whether a pCR 
was achieved.
Not applicable per Protocol Amendment 04.  Participants must agree to submit all diagnostic 
stained slides including H&E and, if applicable, all diagnostically relevant IHCs from the RC
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specimen for pCR assessment, as well as unstained tissue from the RC specimen for use in
studies. Stained slides from the RC specimen will be used for 
pathology review and an additional 2 FFPE tumor blocks or a minimum of 25 unstained slides
obtained from a single block that meet acceptable criteria, as defined in the Laboratory Manual,
will be used for 
 analysis.
It is planned that all participants will undergo RC following recovery from pre-surgical therapy.
Participants with PD that precludes RC will be discontinued from treatment. Participants in Arm
A or B who have completed pre-surgical treatment, but are no longer considered medically fit for
RC (due to treatment-related toxicity or other medical issues) or refuse, will be eligible to receive
follow-up
immunotherapy (see Section 5.1.2.3), provided that the participant’s physician
considers the treatment to be safe and appropriate and that the participant has not experienced 
PD.
Prior to surgery, participants with disease progression that precludes surgery (as judged by the
investigator, see Section 9.1.1.2) must be discontinued from study treatment and tumor 
assessments. Participants who do not undergo RC for reasons other than disease progression that
precludes surgery may continue on protocol-defined treatment once consent has been obtained.
Not applicable per Protocol Amendment 04. Participants who do not undergo RC but continue 
on study (eg, do not have disease progression) will be surveyed for disease recurrence/progression 
by cystoscopy every 12 weeks (± 7 days) for the next 2 years, then every 24 weeks (± 14 days) for 
3 additional years, and then once per year for subsequent years. Monitoring will begin from the 
first cystoscopic examination. For these participants, maximal TURBT of all visible tumor should 
be performed at the time of the first cystoscopic examination.
5.1.2.3
Adjuvant (Post-surgical Treatment)
Per Protocol Amendment 04 , participants who are currently receiving bempegaldesleukin 
plus nivolumab in Arm A are required to discontinue bempegaldesleukin and may continue 
to receive nivolumab monotherapy.

Arm A: Bempegaldesleukin 0.006 mg/kg Q3W + nivolumab 360 mg Q3W for 12 cycles 
(approximately 9 months)

Arm B: Nivolumab 360 mg Q3W for 12 cycles (approximately 9 months)

Arm C: SOC (no therapy) observation
For participants in Arms A and B, post-surgical treatment must begin within 60 to 120 days from 
the date of RC. All participants must have restaging imaging at the post-surgery visit after RC and 
prior to beginning post-surgical immunotherapy to rule-out recurrence of UC. See Section 2 for
details.
Some participants in Arm A or B who have completed neoadjuvant therapy (3 or fewer cycles),
may develop medical conditions either due to neoadjuvant therapy, refusal, or other causes that,
in the opinion of the participant’s physician, precludes them from safely undergoing RC. The 
reasons for not proceeding with RC should be clearly documented in the medical record and the 
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CRF. Despite
not
having undergone this protocol-specified surgery, these participants
(Arms A and B only) will be eligible to receive the planned post-surgery immunotherapy once 
consent has been obtained (see Section 5.1.2.2). This therapy (bempegaldesleukin + nivolumab or 
nivolumab alone), can begin no sooner than 3 weeks after completion of the last dose of
neoadjuvant therapy. An imaging assessment must be done prior to continuation of this therapy, 
when all significant toxicities associated with neoadjuvant therapy have recovered.
Participants will complete 12 cycles of adjuvant therapy except in the event of disease progression, 
death, unacceptable toxicity, symptomatic deterioration, investigator’s decision to discontinue 
treatment, the participant’s decision to discontinue treatment or withdraw consent, the participant 
being lost to follow-up, or BMS and Nektar Therapeutics’ decision to terminate the study.
5.1.3
Long-term Follow-up
Per Protocol Amendment 04, participants will be followed one final time for recurrence status and 
overall survival and will be discontinued from study.  
Long-term follow-up should continue until withdrawal of consent, death, or study termination by 
the Sponsor. For each randomized participant, the total maximum duration of the study is up to 62 
weeks + 100 days of safety follow-up.
Timing for long-term follow-up will be as follows:

Assessments should continue as described in Table 2-4

Participants in Arms A and B must be followed for safety for at least 100 days after the 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 42 days from the 
last dose. Follow-up Visit 2 occurs approximately 100 days (7days) from the last dose of 
study treatment. Both follow-up visits should be conducted in person

Participants in Arm C will be followed as described in Table 2-5

Per Protocol Amendment 04 this is not applicable: All participants will be contacted for 
survival every 3 months (14 days). BMS may request that survival data be collected on all 
treated participants outside of the 3-month specified window

In cases where clinically significant AEs deemed related to the study drug present at any time
during the follow-up phase, the participant will be followed for safety until resolution or 
permanent sequelae of all toxicities attributable to study drugs (bempegaldesleukin and/or 
nivolumab). If the participant discontinues study drug for a clinically significant AE, the 
participant will be followed until resolution of the AE or the event is considered to be stable 
and/or chronic
5.1.4
Data Monitoring Committee and Other External Committees
Per Protocol Amendment 04, this section will not be applicable. 
A Data Monitoring Committee will be established to provide oversight of safety and efficacy 
considerations 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 be 
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charged with assessing such actions in light of an acceptable benefit-risk profile for 
bempegaldesleukin and nivolumab. The DMC will act in an advisory capacity to BMS and will 
monitor participant safety and evaluate the available efficacy data for the study. The oncology 
therapeutic area of BMS has primary responsibility for design and conduct of the study.
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation.
Additional details concerning DMC oversight are provided in the DMC charter.
5.1.4.1
Blinded Pathology and Radiology Review
Per Protocol Amendment 04, this section is not applicable. However, descriptive analysis of 
pCR by central review will be conducted based on samples collected before Protocol 
Amendment 04 and reviewed by the independent pathology review committee. 
Independent radiology review will be performed by BICR and will assess for the confirmation of 
endpoints. Images and pathology sample acquisition guidelines and submission process will be 
outlined in the study Imaging/Laboratory Manuals to be provided by the vendors.
Pathology Review
UC of the bladder/MIBC will be clinically diagnosed by pathological examination of stained slides 
from tumor tissue obtained at initial TURBT establishing diagnosis of UC of the bladder/MIBC 
(obtained within 12 weeks of randomization); central pathology review and confirmation are 
required prior to randomization (refer to the Laboratory Manual for detailed instructions on 
required sample submission). Details of the above process will be specified in the pathology review 
charter. 
For RC surgical specimens, the Laboratory Manual will provide detailed instructions for the 
collection and handling of specimens. 
Blinded central review by an independent pathology review committee with extensive prior 
experience interpreting post-neoadjuvant bladder specimens will be performed on all RC 
specimens to determine the pathology stage and whether the participant achieved pCR 
. All 
pathologists will be blinded to participant treatment arm.
The pCR is defined as pT0N0
Radiology Review
Per Protocol Amendment 04, this section will not be applicable.   Radiologic tumor assessments 
outlined in Section 2 should be submitted to the third-party central imaging vendor. The site should
submit screening tumor assessments as well as any relevant historical scans. In addition, the site 
will also inform the central imaging vendor when the investigator assessment indicates either (i)
unequivocal disease progression per RECIST v 1.1 (for participants without RC), or (ii) 
unequivocal evidence of disease recurrence (see Section 9.1.1.2 for further details). Details of the 
BICR responsibilities and procedures will be specified in the BICR charter with the vendor.
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5.2
Number of Participants
Not applicable per Protocol Amendment 04 as all new enrollment to CA045009 has been 
stopped.
It is anticipated that approximately 720 participants will be screened for approximately 
540 participants to be randomized overall to the 3 arms in a 1:1:1 ratio, assuming a screen failure 
rate of approximately 25%. See Section 10.1 for sample size determination.
5.3
End of Study Definition
The start of the trial is defined as the first visit for the first participant screened. End of trial is 
defined as the last participant’s last visit in the Schedule of Activities (Section 2). Study completion 
is defined as a maximum of 12 cycles of adjuvant therapy + 100 days safety follow-up (Arm A 
and Arm B) or 100 days safety follow-up from radical cystectomy (Arm C) from last participant 
randomized or earlier on sponsor decision.
This paragraph is not applicable per Protocol Amendment 04. The total duration of the study 
for the primary endpoints will be determined by accrual events. Final analysis for the primary 
endpoint examining pCR rate will occur approximately 47 months after the date of the first 
participant randomized (approximately 4 months after the end of last participant randomized). 
Final analysis for the primary endpoint EFS will occur approximately 65 months after the date of 
the first participant to be randomized and is also determined by accrual of events (Section 10.3).
Additional follow-up for OS may be conducted up to approximately 5 years after the 
randomization of the last participant.
5.4
Scientific Rationale for Study Design
About 20-25% of patients diagnosed with bladder cancer present with MIBC, defined as stage T2-
T4a, N0-N1, M0. The primary treatment for these patients is RC, which can be curative for some
but up to 50% ultimately develop recurrent, metastatic disease. Neoadjuvant chemotherapy has 
been shown in randomized trials to prolong OS in cisplatin-eligible patients and is the current SOC 
for this patient population. However, in clinical practice, cisplatin-ineligible patients account for 
40% to 50% of the total population with MIBC. Standard of care for these patients is to proceed 
directly to RC, which is associated with a 50% recurrence rate at 2 years, with most of these 
patients who recur, dying from metastatic urothelial cancer within 1 year.8
Data presented at ASCO 2018 demonstrate the safety and potential activity of PD-1 inhibitors as 
neoadjuvant therapy for MIBC. Since there is currently no neoadjuvant SOC for patients who are 
not eligible to receive cisplatin-based chemotherapy, defining an unmet medical need, novel 
therapies are needed to increase the number of patients who qualify to receive neoadjuvant therapy 
and subsequently achieve a pCR and improved EFS. See Section 3.2.1 for additional details on 
study design rationale.
5.4.1
Rationale for the Combination of Bempegaldesleukin and Immune 
Checkpoint Inhibitors
The ongoing PIVOT-02 study of nivolumab and bempegaldesleukin includes an expansion cohort 
in patients with previously untreated, advanced or metastatic UC. Updated data from that cohort 
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with a cutoff date of 03-Dec-2018 were presented at the ASCO GU Symposium 2019. The cohort 
included 41 patients who were cisplatin-eligible (n=25) or ineligible (n=16). PD-L1 status, as 
determined using tumor staining with the DAKO PD-L1 IHC 28-8 pharmDx assay, was ≥1% 
(positive) in 32%, <1% (negative) in 32%, and unknown or not evaluable in 37%. Twenty-seven 
patients were efficacy evaluable, defined as having at least one post-treatment scan to evaluate 
response; one patient was not evaluable (no target lesions), 3 patients discontinued prior to the first 
scan, and 10 patients were still pending a first scan. Among the efficacy evaluable population, the 
ORR was 44.4%, including 5 (18.5%) CRs and 7 (25.9%) PRs. The response rate was similar in 
PD-L1 positive (5/11, 45.5%) and PD-L1 negative (6/12, 50%) subgroups. The safety profile was 
consistent with previously published bempegaldesleukin + nivolumab data, with the most common 
TRAEs being flu-like symptoms and fatigue.
5.4.2
Rationale for Study Comparator and Study Population
Patients with high-risk UC of the bladder (T1-T4a, N1M0), including MIBC (stage T2-T4a, N0, 
M0), are at high-risk for the development of metastatic disease, even after receiving SOC treatment 
RC. Currently, there are no neoadjuvant or adjuvant approved therapies for this patient population 
with cisplatin-ineligible MIBC.56 Study comparators are not available.
5.4.2.1
Rationale for Including Participants with Clinical Stage T2 Bladder 
Cancer
For participants with MIBC confined to the bladder (clinical stage T2N0), it has been suggested
that outcomes with RC are good, and further neoadjuvant therapy is not needed.57 However, data
from SWOG 8710 demonstrate that MVAC neoadjuvant chemotherapy increased median survival
in patients with clinical stage T2 (cT2) disease by 2.5 years.58 One of the reasons for this is
that many patients diagnosed with cT2 bladder cancer are upstaged at RC; clinical staging of
early stage bladder cancer is notoriously inaccurate. Data from MD Anderson Cancer Center
showed that 43% of 174 patients with low-risk disease who underwent RC without neoadjuvant 
chemotherapy (NAC) were upstaged to more advanced disease.59 Of 212 patients with cT2
disease who underwent RC at Fox Chase Cancer Center, 153 (73.2%) patients had either pT3-
T4 or pN+ tumors at RC.60 Therefore, because of the inaccuracy of clinical staging of bladder
cancer, it is imperative that patients with clinical stage T2N0 are not excluded from this trial.
5.4.2.2
Rationale for Including Participants with N1 in Bladder Cancer
Regional lymph node involvement is an important prognostic factor in invasive bladder cancer. 
The 5-year survival in N1-N3 patients in contemporary series is from 13%-29%.61,62 Per the new 
AJCC criteria, N1 patients have been added to the prognostic stage category IIIA and per NCCN 
treatment guidelines, are treated similarly and have similar outcomes as patients with clinical stage 
T3-T4aN0 disease, therefore participants with N1 bladder cancer have been included in this 
protocol.1,2
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5.4.3
Rationale for Choice of Endpoints
EFS is a primary endpoint that captures on-treatment clinical benefit. This is the optimal endpoint 
to capture events that could occur both during the neoadjuvant and adjuvant phases of treatment.
The pCR as one of the primary endpoints will be used to capture the benefit in the neoadjuvant 
part of the treatment.
5.4.3.1
Rationale for pCR as One of the Primary Endpoints
Extensive clinical data demonstrate that achieving a pCR after NAC is associated with increased 
OS in cisplatin eligible patients. In a meta-analysis of 886 patients who received NAC and RC, the 
28.5% of patients who attained a pCR had a relative risk for OS of 0.45 (95% CI = 0.36-0.56; 
P < 0.00001) compared with those who did not achieve a pCR. The relative risk for relapse-free 
survival (RFS) was 0.19 (95% CI = 0.09-0.39; P < 0.00001). There was a 26% and 51% lower
absolute risk of mortality and recurrence, respectively, when pCR was achieved.63
A multicenter assessment of NAC demonstrated pCR rates of approximately 23% irrespective of 
the type of chemotherapy (MVAC vs GC). A Cox regression analysis assessing factors associated 
with OS identified patients achieving pT1N0 status compared with those with residual MIBC 
(pT2), HR = 0.25 (95% CI = 0.16-0.40; P < 0.001).18
In a combined analysis of the Nordic Cystectomy Trials 1 and 2, 449 patients who achieved pCR 
with NAC (22.7%) exhibited an 88.2% 5-year OS.64
The SWOG 8710 Phase 3 study of NAC in 317 patients showed an 85% OS at 5 years associated 
with pCR. Median survival was 77 months for patients receiving NAC and RC compared with 
46 months for RC alone; OS at 5 years was 57% vs 43%, respectively (P = 0.06).11 A retrospective 
analysis of the SWOG data demonstrated that OS was significantly worse for patients with residual 
MIBC after RC.21
Achieving pCR after NAC for MIBC is clearly associated with prolonged OS. The CA045009
study is designed to target a doubling of pCR in the experimental arm.
5.4.3.2
Rationale for Event-free Survival as One of the Primary Endpoints
In the FDA Guidance for Industry/Pathological Complete Response in Neoadjuvant Treatment of
High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval
(2014), EFS is described as an important endpoint for neoadjuvant studies and includes the time
from randomization to progression of disease that precludes surgery, recurrence, or all-cause
death. EFS may also be a realistic endpoint if a large percentage of participants achieve complete
responses and where prolonged survival makes an OS endpoint impractical. While the FDA
guidance is explicitly written only for breast cancer, the principles outlined within provide a
scientific basis for extension to UC.
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5.4.4
Rationale for Open-label Design
This section is not applicable per Protocol Amendment 04. Due to the hydration program and 
the special restrictions for withholding anti-hypertensive in the bempegaldesleukin arm, a placebo-
controlled, double-blinded study is not appropriate for this study.
Participants must have UC of the bladder/MIBC that is deemed potentially curable by RC, and 
must be considered medically fit for RC and be willing to undergo RC as part of the study 
treatment.
For Arm C participants who do not have any neoadjuvant therapy, delaying surgery is not
acceptable.
5.4.5
Rationale for Stratification by Disease State and PD-L1
Stratification by clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1) will help account for any 
potential prognostic outcome differences.
Previous clinical studies with nivolumab monotherapy have shown participants with PD-L1 
positive tumors may have higher response rates than those with negative or indeterminate 
expression. Therefore, participants in the current trial will be stratified by PD-L1 tumor expression 
status, as the effect of PD-L1 tumor expression on the response to bempegaldesleukin and 
nivolumab combination is not yet known.
5.4.6
Duration of Treatment with Nivolumab/Bempegaldesleukin
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the immunotherapy development program indicate 
that most of the responses occur early, with a median time to response of 2 to 4 months, and 
emerging data suggest that benefit can be maintained in the absence of continued treatment.
This protocol includes 3 cycles of neoadjuvant therapy and 12 cycles of adjuvant therapy, which 
comprises approximately 1 year in total treatment duration. The decision to use 3 cycles of 
neoadjuvant therapy was intended to optimize the chance of achieving pCR, and was based, in 
part, on recent data from other neoadjuvant studies with PD-1/PD-L1 inhibitors as discussed in the 
background (Section 3.2).
5.5
Justification for Dose
5.5.1
Justification for Dose of Bempegaldesleukin
This section is not applicable per Protocol Amendment 04. The dose for bempegaldesleukin is 
0.006 mg/kg Q3W taking in consideration the clinical safety profile associated with the robust 
immune system activation observed in the PIVOT-02 study. See Section 3.2.4.2 for additional 
details on PIVOT-02.
5.5.2
Justification for Dose of Nivolumab
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, cHL, SCCHN, and UC, using body weight-normalized dosing (mg/kg), 
and has been safely administered at doses up to 10 mg/kg Q2W. Nivolumab is currently approved 
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for the treatment of various tumors, including melanoma, NSCLC, RCC, cHL, SCCHN, and UC, 
using one of the following regimens: nivolumab 240 mg Q2W, nivolumab 3 mg/kg Q2W, or 
nivolumab 480 mg Q4W.
Nivolumab has been shown to be safe and well tolerated up to a dose level of nivolumab 10 mg/kg 
Q2W. Population PK (PPK) analyses have shown that the PK of nivolumab is linear with 
proportional exposures over a dose range of 0.1 to 10 mg/kg; no differences in PK across 
ethnicities and tumor types were observed. Using the PPK model, the exposures following 
administration of several dosing regimens of nivolumab administered as a flat dose were 
simulated, including nivolumab 360 mg Q3W. The simulated steady state average concentration 
(Cavgss) following administration of nivolumab 360 mg Q3W are expected to be similar to those 
following administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W administered 
to participants weighing 80 kg, the approximate median weight of participants with NSCLC, 
melanoma, and RCC used in the PPK analyses. Given that the Cavgss estimates for nivolumab 
360 mg Q3W are predicted to be similar to those for nivolumab 240 mg Q2W and nivolumab 
3 mg/kg Q2W, the efficacy is predicted to be similar for these regimens. It should be noted that 
the Cmaxss following nivolumab 360 mg Q3W are predicted to be less than those following the 
administration of nivolumab 10 mg/kg Q2W providing sufficient safety margins. Further details 
on nivolumab 360 mg Q3W dosing can be found in the IB.
 
 
 
 
5.5.3
Rationale for Bempegaldesleukin/Nivolumab Combination Dose
This section is not applicable per Protocol Amendment 04. The safety of bempegaldesleukin
as a single agent has been assessed in 5 monotherapy cohorts administered bempegaldesleukin
Q3W (22 patients) at doses ranging from 0.003 to 0.012 mg/kg; a dosing frequency of Q2W (6 
patients) was further explored at 0.006 mg/kg.
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Table 5.5.3-1:
*Not applicable per Protocol Amendment 04. Patient Exposure 
Supporting Combination Dose
Bempegaldesleukin
Dosing Frequency
Nivolumab
(Flat Dosea) 
Dosing Frequency
Bempegaldesleukin
Dose (mg/kg)
No. Patients
Examined for 
Safety
Bempegaldesleukin
Monotherapy
Q3W
n/a
0.003, 0.006,
0.009, 0.012
22
Q2W
n/a
0.006
6
Bempegaldesleukin+
Nivolumab
Q3W
Q2W
0.006
4
Q2W
0.006
3
Q3W
0.006
25
Q2W
0.003
3
Q3W
0.009
3
a Nivolumab Q2W = 240 mg, Q3W = 360 mg.
6
STUDY POPULATION
Not applicable per Protocol Amendment 04, as new enrollment in study has been stopped.
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
Not applicable per Protocol Amendment 04, as new enrollment in study has been stopped.
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent
form (ICF) 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, tumor biopsies, and other requirements of the study
2) Type of Participant and Target Disease Characteristics
a) Not applicable per Protocol Amendment 03 (see new criterion g) below): Participants 
with MIBC, clinical stage T2-T4a, N0 (<10 mm on CT or MRI), M0, diagnosed at TURBT
within 12 weeks of randomization. Variant histology is acceptable if there is a predominant 
urothelial component.
Note: Stained slides from the TURBT or tumor biopsy must be submitted to the vendor for 
confirmation of MIBC prior to randomization.
b) Participant must be deemed eligible for RC by his/her urologist, and must agree to undergo 
RC. For arms A and B, participants must agree to undergo RC after completion of 
neoadjuvant therapy.
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c) Not applicable per Protocol Amendment 03 (see new criterion h) below): Documentation 
of PD-L1 status by immunohistochemistry (IHC) performed by the central lab during the 
screening period; the tumor should be classified as PD-L1 1% or PD-L1 < 1% as 
determined by a central laboratory during the screening period and the results must be 
submitted to IRT prior to randomization. Indeterminate participants are allowed in the 
study. Either a FFPE tissue block or 20 unstained tumor tissue sections with an associated 
pathology report, must be submitted for 
evaluation prior to randomization. The 
tumor tissue sample may be a fresh or recent sample (within 12 weeks) and should be from 
the TURBT or tumor biopsy. No systemic therapy (eg, adjuvant or neoadjuvant 
chemotherapy) should be given after the sample was obtained.
d) A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram or multigated acquisition (MUGA) scan test
e) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
f)
Cisplatin-ineligible participants will be defined by any one of the following criteria:
i)
Impaired renal function (glomerular filtration rate [GFR] 30 but < 60 mL/min)
ii) GFR should be assessed by direct measurement (ie, creatinine clearance) or, if not
available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula)
iii) Common Terminology Criteria for Adverse Events (CTCAE) version 5, Grade 2
hearing loss (assessed per local SOC)
iv) CTCAE version 5, Grade 2 peripheral neuropathy
g) Participants with UC of the bladder, clinical stage T2-T4aN0 (< 15 mm in short axis on 
CT or MRI), M0 or T1-T4aN1 (≥ 15 mm in short axis on CT or MRI), M0, diagnosed at 
TURBT within 12 weeks of randomization. Variant histology is acceptable if there is a 
predominant urothelial component.
Note: Stained slides from the initial TURBT used to make the UC of the bladder/MIBC 
diagnosis and associated pathology report must be submitted to the vendor for 
confirmation of UC of the bladder/MIBC prior to randomization.
h) Documentation of PD-L1 status by IHC performed by the central laboratory during the 
screening period; the tumor should be classified as PD-L1 1% or PD-L1 < 1% as 
determined by a central laboratory during the screening period and the results must be 
submitted to IRT prior to randomization. Indeterminate participants are allowed in the 
study. Either a FFPE tissue block or 20 unstained tumor tissue sections with an associated 
pathology report, must be submitted for 
 evaluation prior to randomization. The 
bladder tumor sample submitted should be from the initial TURBT (obtained within 
12 weeks of randomization) in which the UC of the bladder/MIBC diagnosis was made. 
Submitted tissue sample must not be previously irradiated and systemic therapy must not 
be given after samples are obtained prior to enrollment. 
Note: If despite best efforts, a minimum of 20 unstained slides is not obtainable,
submission of fewer slides may be acceptable in some circumstances following 
discussion with the Medical Monitor.
3) Age and Reproductive Status
a) Not applicable per Revised Protocol 02 [see revised criteria in f i) and g i)]: Male or 
female participants, age 18 years or older at the time of signing the ICF
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b) Not applicable per Revised Protocol 02 [see revised criteria in f iv)]: 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
NOTE: WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements, and still must undergo pregnancy testing as described in 
Section 2.
c) Not applicable per Revised Protocol 02 [see revised criteria in f ix)]: Women must not be 
breastfeeding
d) Not applicable per Revised Protocol 02 [see revised criteria in f vii)]: Women of 
childbearing potential (WOCBP) must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study treatment and for 5 months 
post-treatment completion. Women should use an adequate method(s) of contraception as 
indicated in Appendix 4
e) Not applicable per Revised Protocol 02 [see revised criteria in g ii) and g iv) through 
g vii)]: Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception and fetal protection (Appendix 4) for the duration of treatment with 
study treatment(s) and 7 months post-treatment completion. In addition, male participants must 
be willing to refrain from sperm donation during this time.

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 and the potential of fetal toxicity occurring due to transmission of study drug, 
present in seminal fluid, to a developing fetus, even if the participant has undergone a 
successful vasectomy or if the partner is pregnant. 

The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.

Local laws and regulations may require the use of alternative and/or additional contraception 
methods.
f)
Female Participants 
i)
Females, ages 18 or local age of majority, inclusive
ii) Women who are not of childbearing potential are exempt from contraceptive 
requirements
iii) Women participants must have documented proof that they are not of childbearing 
potential.
iv) WOCBP must have a negative highly sensitive urine or serum pregnancy test as 
required by local regulations pregnancy test (minimum sensitivity 25 IU/L or 
equivalent units of HCG) within 24 hours prior to the start of study treatment.
(1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive

Additional requirements for pregnancy testing during and after study intervention are located 
in Section 2, Schedule of assessments
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
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy
v) WOCBP must agree to follow instructions for method(s) of contraception defined in 
Appendix 4 and as described below and included in the ICF.
vi) WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4)
vii)A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
(1) Is not a WOCBP 
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year), with low user dependency, as described in 
Appendix 4 during the intervention period and for at least 5 months post study 
completion and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction for the same time period
g) Male Participants 
i)
Males, ages 18 or local age of majority, inclusive
ii) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in Appendix 4 and as described below.
iii) Azoospermic males are not exempt from contraceptive requirements and 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 participant has undergone a successful 
vasectomy or if the partner is pregnant.
iv) Not applicable per Protocol Amendment 03 (see new criterion ix) below): 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 during the intervention period 
and for at least 7 months after the last dose of study intervention. 
v) Not applicable per Protocol Amendment 03 (see new criterion x) below): Female 
partners of males participating in the study should be advised to use highly effective 
methods of contraception during the intervention period and for at least 7 months after 
the last dose of study intervention in the male participant.
vi) Not applicable per Protocol Amendment 03 (see new criterion xi) below): Male 
participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, 
oral) even if the participants have undergone a successful vasectomy, during the 
intervention period and for at least 7 months after the last dose of study intervention.
vii)Not applicable per Protocol Amendment 03 (see new criterion xii) below): Male 
participants must refrain from donating sperm during the intervention period and for at 
least 7 months after the last dose of study intervention.
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viii)
Breastfeeding partners should be advised to consult their health care providers 
about using appropriate highly effective contraception during the time the participant 
is required to use condoms
ix) 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 during the 
intervention period and for at least 3 months after the last dose of study intervention.
x) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least 
3 months after the last dose of study intervention in the male participant.
xi) Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from sexual activity or use a male condom during any sexual activity 
(eg, vaginal, anal, oral) even if the participants have undergone a successful vasectomy, 
during the intervention period and for at least 3 months after the last dose of study 
intervention.
xii)Male participants must refrain from donating sperm during the intervention period and 
for at least 3 months after the last dose of study intervention.
6.2
Exclusion Criteria
Not applicable per Protocol Amendment 04, as new enrollment in study has been stopped.
1) Target Disease Exceptions
a) Not applicable per Protocol Amendment 03 (see new criterion d) below): Clinical 
evidence of pathologic LN (≥ 10 mm in short axis) or metastatic bladder cancer
b) Prior systemic therapy, radiation therapy, or surgery for bladder cancer other than TURBT 
or biopsies is not permitted. Prior Bacillus Calmette-Guerin (BCG) or other intravesicular
treatment of NMIBC is permitted if completed at least 6 weeks prior to initiating study 
treatment
c) Evidence of UC in upper urinary tracts (ureters or renal pelvis) or history of previous MIBC 
d) Clinical evidence of ≥N2 or metastatic bladder cancer.
2) Medical Conditions
a) Uncontrolled adrenal insufficiency
b) Major surgical procedure within 14 days prior to initiating study treatment or anticipation 
of the need for a major surgical procedure (other than RC) during the course of the study
c) Severe infection within 4 weeks prior to randomization
d) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been treated, such as basal or squamous cell skin cancer, prostate cancer with evidence 
of undetectable prostate specific antigen (PSA), or carcinoma in situ of the prostate, cervix, 
or breast
e) Any condition (including medical, emotional, psychiatric, or logistical) that, in the opinion 
of the Investigator, would preclude the participant from adhering to the protocol or would 
increase the risk associated with study participation or study drug administration or 
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interfere with the interpretation of safety results (eg, a condition associated with diarrhea 
or acute diverticulitis)
f)
Active infection requiring systemic therapy within 14 days prior to randomization
g) Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics)
h) Known cardiovascular history including unstable or deteriorating cardiac disease within 
the previous 12 months prior to screening including but not limited to the following:
i)
Unstable angina or myocardial infarction
ii) Transient ischemic attack (TIA)/CVA
iii) Congestive heart failure (New York Heart Association [NYHA] Class III or IV)
iv) Uncontrolled clinically significant arrhythmias
i)
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
j)
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
k) History of pulmonary embolism (PE), deep vein thrombosis (DVT), or prior clinically 
significant venous or non-CVA/TIA arterial thromboembolic event (eg, internal jugular 
vein thrombosis) within 3 months prior to randomization 
i)
Participants with a history of a venous or arterial thromboembolic event must be 
asymptomatic for at least 2 weeks prior to randomization and must be receiving a stable 
regimen of therapeutic anticoagulation (low molecular weight heparin [LMWH] or 
direct oral anticoagulation [DOAC]). Note: see section 7.7.2.1 (Restricted Treatments) 
for further guidance.
ii) Unless there is a new medical contraindication observed after Cycle 1 Day 1, a 
participant with a history of venous or arterial thromboembolic event must be 
maintained on therapeutic anticoagulation throughout participation on the treatment 
phase of the study.
l)
Participants with inadequately treated adrenal insufficiency.
m) Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection either 
suspected or confirmed within 4 weeks prior to screening. Acute symptoms must have 
resolved and based on investigator assessment in consultation with the Medical Monitor, 
there are no sequelae that would place the participant at a higher risk of receiving 
investigational treatment.
3) Prior/Concomitant Therapy
a) 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/treatment (See Section 7.7.1 for prohibited therapies)
b) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization) Inhaled or topical steroids, and adrenal replacement steroid 
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doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease
c) Participants who have received a live / attenuated vaccine within 30 days before first 
treatment
d) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, agents that target IL-2 therapy 
or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways
e) Participants currently in other interventional trials, including those for COVID-19, may not 
participate in BMS clinical trials until the protocol-specific washout period is achieved. If 
a study participant has received an investigational COVID-19 vaccine or other 
investigational product designed to treat or prevent COVID-19 prior to screening, 
enrollment must be delayed until the biologic impact of the vaccine or investigational 
product is stabilized, as determined by discussion between the investigator and the Medical 
Monitor.
4) Physical and Laboratory Test Findings
a) White blood cells < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100x103/μL
d) Hemoglobin < 9.0 g/dL
e) Not applicable per Protocol Amendment 03: Serum creatinine > 1.5x upper limit of 
normal (ULN), unless creatinine clearance 40 mL/min (measured or calculated using the 
Cockcroft-Gault formula)
f)
AST/ALT: > 3.0 x ULN
g) Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0x ULN)
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)
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated 
Note: Under certain specific circumstances and only in countries where local regulations 
permit, a person who has been imprisoned may be included or permitted to continue as a 
participant. Strict conditions apply and Bristol-Myers Squibb 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.
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6.3
Lifestyle Restrictions
*Not applicable per Protocol Amendment 04. See Section 7.1.1.1 for hydration guidelines and 
limitations on strenuous activities, long hot showers and sauna use.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. 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, as applicable, 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 Period
Participant Re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized/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 period 
will be permitted (in addition to any parameters that require a confirmatory value).
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.
Testing for asymptomatic COVID-19 by RT-PCR or viral antigen is not required. However, some 
participants may develop suspected or confirmed symptomatic COVID-19, or be discovered to 
have asymptomatic COVID-19 during the screening period. In such cases, participants may be 
considered eligible for the study after meeting all inclusion/exclusion criteria related to active 
infection, and after meeting the following criteria:

At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive RT-PCR or viral antigen test result, and

At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and

Acute symptoms (eg, cough, shortness of breath) have resolved and

In the opinion of the investigator, there are no COVID-19-related sequelae that may place the 
participant at a higher risk of receiving investigational treatment, and 

Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local or 
regional guidelines
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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.
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

Nivolumab Solution for Injection

Not applicable per Protocol Amendment 04. Bempegaldesleukin (NKTR-214) Powder 
for Solution for Injection
An investigational product, also known as investigational medicinal product in some regions, is 
defined 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.
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-investigational 
products.
Per Protocol Amendment 04, all participants receiving bempegaldesleukin plus nivolumab are 
required to discontinue bempegaldesleukin and may continue nivolumab monotherapy. 
Participants in Arm A and Arm B will receive nivolumab monotherapy 360 mg IV Q3W for the 
remainder of the study treatment period.
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Table 7-1:
Study Treatments for CA045009/18-214-13
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or Open Label
Packaging / Appearance
Storage Conditions
(per label)
*Not applicable per 
Protocol Amendment 
04
Bempegaldesleukin 
(NKTR-214) Powder for 
Solution for Injection
0.3 mg, 0.5 mg, or 1 mg 
of rhIL-2 per viala
IP
Open-label
Vial (one or more vials per 
carton)
Refer to the label on
container and/or
pharmacy manual
Nivolumab Solution for
Injectionb
100 mg (10 mg/mL)
IP
Open-label
Vial (multiple vials/carton)
Store at 2-8C.
Protect from light and 
freezing.
a *Not applicable per Protocol Amendment 04. Note: For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer to the same molecule.
b May be labeled as either “BMS-936558-01” or “nivolumab.”
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7.1
Treatments Administered
Per Protocol Amendment 04, all participants receiving bempegaldesleukin plus nivolumab 
are required to discontinue bempegaldesleukin and may continue nivolumab monotherapy.
Participants in Arm A and Arm B will receive nivolumab monotherapy 360 mg IV Q3W for the 
remainder of the study treatment period.
Table 7.1-1:
Selection and Timing of Dose
Study Treatmenta
Unit Dose 
Strength(s)/Dosage 
Level(s)
Dosage Formulation
Frequency of 
Administration
Route of Administration
*Not applicable 
per Protocol 
Amendment 04.
Bempegaldesleukin 
(NKTR-214)b
0.006 mg/kg
q3w
IV
Nivolumab
360 mg 
q3w
IV
a Study agent should be administered in an area with access to resuscitation equipment.
b *Not applicable per Protocol Amendment 04. Bempegaldesleukin (NKTR-214) dose is based on IL-2 content.
7.1.1
Bempegaldesleukin Dosing
This section is not applicable per Protocol Amendment 04. Per Protocol Amendment 04, 
participants receiving bempegaldesleukin plus nivolumab are required to discontinue 
bempegaldesleukin and may continue nivolumab. Each participant’s bempegaldesleukin dose will 
be determined by the participant’s weight in kilograms, which will be determined before the start 
of each cycle. If the participant’s weight is within 10% of the Cycle 1 Day 1 weight, the study drug 
doses do not need to be recalculated depending on institutional guidelines/preference.
Bempegaldesleukin will be administered first before nivolumab. Bempegaldesleukin will be 
administered as an IV infusion over 30 (± 5) minutes at a starting dose of 0.006 mg/kg every 
3 weeks (± 3 days). Bempegaldesleukin infusion must be promptly followed by a flush of diluent 
to clear the line, and administration time should include the time required for flushing. Nivolumab 
administration should start 30 (± 5) minutes after the completion of bempegaldesleukin
administration. 
Participants should be carefully monitored for infusion reactions during bempegaldesleukin
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.6. If the participant experiences a Grade ≥ 2 infusion-related reaction or hypotension 
during the days after bempegaldesleukin dosing, the participant may be monitored overnight at the 
discretion of the Investigator; longer periods of monitoring may be implemented at the discretion 
of the Investigator.
Treatment with bempegaldesleukin may be delayed or reduced as described in Section 7.4. In the 
event that nivolumab is permanently discontinued due to toxicities, see Section 8.1.1.
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Bempegaldesleukin treatment can continue for participants randomized to the bempegaldesleukin 
and nivolumab combination arm in the event that nivolumab is permanently discontinued due to 
toxicities (see Section 8.1.1).
Bempegaldesleukin (NKTR-214) Powder for Solution for Injection is to be administered as an IV 
infusion following reconstitution and dilution as described in the Pharmacy Manual. In-line filters 
(including in-line filter extension sets) must not be used to administer bempegaldesleukin due to 
the extent of drug losses by adsorption on the filter membrane. Bempegaldesleukin infusion must 
be promptly followed by a flush of diluent to clear the line. Care must be taken to assure sterility 
of the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent. 
Bempegaldesleukin infusions prepared in 0.9% NaCl solution or 5% Dextrose solutions are 
compatible with polyvinyl chloride or polyolefin containers and infusion sets, as well as closed-
system transfer devices (CSTDs) when following specific instructions to ensure prepared dose 
accuracy.
Please refer to the Pharmacy Manual/current IB for details regarding preparation, storage, and 
administration.
7.1.1.1
Hydration Guidelines
This section is not applicable per Protocol Amendment 04. Important safety information and 
hydration instructions are to be provided to participants.
Hydration and renal function should be assessed within 24 hours prior to study drug administration 
or as soon as locally feasible (Table 2-2 and Table 2-3). Underlying reasons for decreased oral 
intake (such as nausea) should be addressed and treatment (such as IV hydration) should be 
provided. Participants may receive additional hydration precautions in a participant handout.
For those participants randomized to Arm A (ie, bempegaldesleukin in combination with 
nivolumab), administer at least 1 liter of IV fluid on bempegaldesleukin dosing days (Day 1 of 
cycle). For the next 3 days (Days 2-4) after administration of bempegaldesleukin, participants are 
to be instructed to drink at least 2 liters per day of self-administered oral hydration. Advise 
participants to refrain from activities that may contribute to dehydration (including but not limited 
to, strenuous activity, long hot showers, and saunas) for Days 1 to 4 of each cycle of treatment 
with bempegaldesleukin. Advise participants with orthostatic symptoms to call their treating 
oncologist and consider increasing oral hydration.
Between Days 3 and 5, inclusive, following administration of the first two doses of 
bempegaldesleukin, site personnel must contact the participant (by telephone or clinic visit) at least 
once to remind the participant of the oral hydration guidelines, to assess for any symptomatology 
and compliance with the guidelines, and document the results of the discussion (Table 2-2 and 
Table 2-3). Following subsequent bempegaldesleukin administrations, the oral hydration follow-
up should be conducted as clinically indicated for participants receiving bempegaldesleukin. 
Per clinical judgment, IV fluids may be administered at any time. The Investigator may decide to 
forego administering IV fluids to a participant or adjust the recommendation for self-oral hydration 
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to a particular participant if this is deemed to be in the best interest of the participant (eg, evidence 
of fluid overload). Hydration guidelines should also be provided to the participant.
7.1.2
Nivolumab Dosing
Nivolumab administration should start 30 (± 5) minutes after the completion of bempegaldesleukin
administration in Arm A. Participants should receive nivolumab at a dose of 360 mg as a 30-minute 
infusion on Day 1 of each treatment cycle until progression, unacceptable toxicity, withdrawal of 
consent, completion of 12 cycles of adjuvant treatment or the study ends, whichever occurs first.
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 18 days from the previous dose during Q3W cycles. Premedications are not 
recommended for the first dose of nivolumab. In the event that bempegaldesleukin is permanently 
discontinued due to toxicities, see Section 8.1.1.
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 7.4.6.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. Nivolumab 
treatment can continue for participants randomized to Arm A in the event that bempegaldesleukin
is stopped due to toxicities.
Instructions for dilution and infusion of nivolumab injection may be provided in the clinical 
protocol, pharmacy binder, or Pharmacy Manual.
7.2
Method of Treatment Assignment
The following information is required for participant randomization:

Participant number

Year of birth

PD-L1 status (≥ 1% vs < 1%/ indeterminate)

UC of the bladder/MIBC confirmation

Clinical stage (T2N0 vs T3-T4aN0 vs T1-T4aN1) (see Appendix 9)
Stratified permuted block method will be used for randomization and randomized participants will 
be stratified by clinical T stage and PD-L1 status. Due to the importance of avoiding delays 
associated with obtaining a second tumor sample for evaluation, this study will allow up to 10% 
(total) of randomized participants to be included in the study with indeterminate PD-L1 status.
Participants with clinical stage T1-T4aN1M0 are eligible from Protocol Amendment 03. These 
participants will be randomized in the IRT using a new randomization schedule.
Tumor PD-L1 expression data will be transferred directly from the analyzing laboratory to the IRT 
vendor.

PD-L1 positive (1% tumor cell membrane staining in a minimum of 100 evaluable tumor 
cells)
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
PD-L1 negative/indeterminate (< 1% tumor cell membrane staining in a minimum of 
100 evaluable tumor cells/tumor cell membrane scoring hampered by high cytoplasmic 
staining content).
Study treatment will be administered at the study visits as listed in the Schedule of Activities 
(Section 2).
7.3
Blinding
Not applicable as this is an open-label study; however, PD-L1 will be blinded to investigators but 
provided to the bioanalytical laboratory as appropriate.
The specific treatment to be taken by a participant will be assigned using an Interactive Response 
Technology (IRT). Treatment assignments will be released to the bioanalytical laboratory in order 
to minimize unnecessary analysis of samples.
7.4
Dosage Modification
Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; 
however, the criteria remain unchanged for nivolumab. If bempegaldesleukin or nivolumab 
meet the criteria for dose delay, then administration of both drugs must be delayed until the criteria 
to resume are met (see Table 7.4.1-1). Delay nivolumab and bempegaldesleukin dosing for any 
adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Note: Tumor assessments for all participants should continue as per protocol even if dosing is 
delayed.
Participants who require delay of nivolumab and bempegaldesleukin should be re-evaluated 
weekly or more frequently if clinically indicated and resume treatment with combination of 
bempegaldesleukin and nivolumab when re-treatment criteria are met. Immuno-oncology agents 
are associated with AEs that can differ in severity and duration from AEs caused by other 
therapeutic classes. Bempegaldesleukin and nivolumab are considered an immuno-oncology agent 
in this protocol. Early recognition and management of AEs associated with immuno-oncology 
agents may mitigate severe toxicity.
Discontinuation criteria for nivolumab and bempegaldesleukin are found in Sections 7.4.1 and
8.1.1.
7.4.1
Nivolumab and Bempegaldesleukin Dose Delay, Resume, and 
Discontinuation Criteria
Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; 
however, the criteria remain unchanged for nivolumab. The criteria to delay, resume, and 
discontinue nivolumab and bempegaldesleukin were initially developed using CTCAE v4.03 
definitions of AE grading. In Oct-2020, the nivolumab AE grading criteria and algorithms were 
updated to CTCAE v5, which can be found in Table 7.4.1-1.
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SARS-CoV-2 infection, either confirmed or suspected, requires delay of nivolumab and 
bempegaldesleukin study treatment. If a study participant has received an investigational COVID-
19 vaccine prior to screening, enrollment should be delayed until the full dosing schedule of the 
vaccine has been completed and the impact of the vaccine is stabilized, unless a delay would 
compromise the patient’s health or suitability for enrollment, as determined by the study team.
AE criteria for delaying, resuming, and discontinuing nivolumab and bempegaldesleukin are 
available in Table 7.4.1-1 and Section 8.1.1. Participants may resume treatment with study drug if 
they have completed AE management (ie, corticosteroid taper) or are on ≤10 mg prednisone or 
equivalent.
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. Dose 
reductions for nivolumab are not permitted in this study.
Not applicable per Protocol Amendment 04. Dose delays and reductions are permitted for 
bempegaldesleukin. Bempegaldesleukin may be delayed or reduced to 0.003 mg/kg based on 
observed drug-related toxicities. If the bempegaldesleukin dose is reduced to 0.003 mg/kg, the 
dose level should remain at this level throughout the remainder of the study and will not be re-
escalated.
Not applicable per Protocol Amendment 04. Bempegaldesleukin dosing may resume at the same 
bempegaldesleukin dose or at a lower bempegaldesleukin dose level when toxicity resolves to Grade 
1 or returns to baseline, except for instances where the potential recurrence of the event poses an undue 
risk for the participant. Medical Monitor consultation is required for dose reduction.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Gastrointestinal
Colitis or Diarrhea
Grade 2 
Delay dose
Dosing may resume when AE resolves to baseline.
Grade 3 
Delay dose
Dosing may resume when AE resolves to baseline.
Grade 4 
Permanently 
discontinue
Renal
Serum Creatinine Increased
See bempegaldesleukin-specific 
criteria in Table 7.4.1-2 for 
transient, non-inflammatory 
increased serum creatinine.
Grade 2 or 3 
Nivolumab: Delay 
dosea
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 4 
Permanently 
discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after pneumonitis has resolved to 
≤Grade 1.
Grade 3 or 4 
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Hepatic
AST, ALT, or T.bili Increased
AST or ALT > 3× and ≤ 5× 
ULN or T.bili > 1.5× and ≤3× 
ULN, regardless of baseline 
value
Delay dose
Dosing may resume when laboratory values return to 
baseline.
AST or ALT > 5× ULN or 
T.bili > 3× ULN, regardless of 
baseline value
Permanently 
discontinue 
ALT/AST elevations < 8.0 x ULN in Cycle 1 only, study 
treatment does not need to be discontinued (see Section 
7.4.1.1 for dose modification criteria).
Concurrent AST or ALT > 3× 
ULN and T.bili > 2× ULN, 
regardless of baseline value
Permanently 
discontinue 
Endocrinopathy
Adrenal Insufficiency
Grade 2 adrenal insufficiency
Delay dose
Dosing may resume after adequately controlled with 
hormone replacement.
Grade 3 or 4 adrenal 
insufficiency or adrenal crisis
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming 
nivolumab/bempegaldesleukin therapy. If adrenal 
insufficiency resolves or is adequately controlled with 
physiologic hormone replacement, participant may not 
require discontinuation of nivolumab.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Hyperglycemia
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3)
Delay dose
Dosing may resume if hyperglycemia resolves to 
Grade ≤1 or baseline value, or is adequately controlled 
with glucose-controlling agents.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming therapy. If 
hyperglycemia resolves, or is adequately controlled with 
glucose-controlling agents, participant may not require 
discontinuation of nivolumab or bempegaldesleukin.
Hypophysitis/Hypopituitarism
Symptomatic Grade 1-3 that is 
also associated with 
corresponding abnormal lab 
and/or pituitary scan
Delay dose 
Dosing may resume if endocrinopathy resolves to be 
asymptomatic, or is adequately controlled with only 
physiologic hormone replacement.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming nivolumab or 
bempegaldesleukin therapy. If endocrinopathy resolves or 
is adequately controlled with physiologic hormone 
replacement, participant may not require discontinuation 
of nivolumab or bempegaldesleukin.
Hyperthyroidism or 
Hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if endocrinopathy resolves to be 
asymptomatic, or is adequately controlled with only 
physiologic hormone replacement or other medical 
management.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming nivolumab or 
bempegaldesleukin therapy. If endocrinopathy resolves or 
is adequately controlled with physiologic hormone 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
replacement, participant may not require discontinuation 
of nivolumab or bempegaldesleukin.
Skin
Rash
Grade 2 rash covering > 30% 
body surface area, or Grade 3 
rash 
Delay dose 
Dosing may resume when rash reduces to ≤ 10% body 
surface area. 
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN),
or drug reaction with 
eosinophilia and systemic 
symptoms (DRESS)
Delay dose
Dosing may resume if SJS, TEN, or DRESS is ruled out 
and rash reduces to is ≤ 10% body surface area.
Grade 4 rash or confirmed 
SJS, TEN, or DRESS
Permanently 
discontinue
Neurological
Guillain-Barre Syndrome (GBS)
Any Grade
Permanently 
discontinue
Myasthenia Gravis (MG)
Any Grade
Permanently 
discontinue
Encephalitis
Any Grade encephalitis
Delay dose 
After workup for differential diagnosis (ie, infection, 
tumor-related), if encephalitis is not drug-related, then 
dosing may resume when AE resolves. 
Any Grade drug-related 
encephalitis 
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Myelitis
Any Grade myelitis
Delay dose
After workup for differential diagnosis (ie, infection, 
tumor-related), if myelitis is not drug-related, then dosing 
may resume when AE resolves. 
Any Grade drug-related 
myelitis
Permanently 
discontinue
Neurological (other than GBS, MG, 
encephalitis, or myelitis);
For CVA/TIA, see 
bempegaldesleukin-specific criteria 
in Table 7.4.1-2.
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline. 
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Myocarditis
Symptoms induced from mild 
to moderate activity or 
exertion
Delay dose
Dosing may resume after myocarditis has resolved.
Severe or life threatening, with 
symptoms at rest or with 
minimal activity or exertion, 
and/or where intervention 
indicated
Permanently 
discontinue
Other Clinical AEs
Pancreatitis:
Amylase or Lipase Increased
Grade 3 with symptoms
Delay dose
Note: Grade 3 increased amylase or lipase without signs or 
symptoms of pancreatitis does not require dose delay.
Dosing may resume when participant becomes 
asymptomatic.
Grade 4
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Uveitis
Grade 2 uveitis
Delay dose
Dosing may resume if uveitis responds to topical therapy 
(eye drops) and after uveitis resolves to Grade ≤ 1 or 
baseline. If participant requires oral steroids for uveitis, 
then permanently discontinue study drug.
Grade 3 or 4 uveitis
Permanently 
discontinue
Other Drug-related AE 
(not listed above; See
bempegaldesleukin-specific criteria 
in Table 7.4.1-2 for further 
guidance) (not applicable per 
Protocol Amendment 04).
Grade 2 non-skin AE, except 
fatigue
Nivolumab: Delay 
dosea
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 3 AE: First occurrence 
lasting ≤ 7 days
Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value (unless otherwise requiring permanent 
discontinuation, per Section 8.1.1) with the exception of 
fatigue, where dosing may resume in the presence of 
Grade 2 fatigue.
Grade 3 AE: First occurrence 
lasting > 7 days
Permanently 
discontinue
Recurrence of Grade 3 AE of 
any duration
Permanently 
discontinue
Grade 4 or Life-threatening 
adverse reaction
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed) *Per Protocol Amendment 04, the text below 
related to bempegaldesleukin is not applicable; however, the criteria remain unchanged for nivolumab 
Note: Bempegaldesleukin must be discontinued for participants receiving bempegdesleukin plus nivolumab
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Other Laboratory Abnormalities
Other Drug-related Laboratory 
Abnormality (not listed above)
Grade 3
Delay dose
Exceptions:
No delay required for: 

Grade 3 lymphopenia. 

Grade ≥ 3 asymptomatic amylase or lipase elevation
Permanent Discontinuation for: Grade 3 thrombocytopenia 
> 7 days or associated with bleeding. 
Grade 4
Permanently 
discontinue
Exceptions: The following events do not require 
discontinuation of study drug: 

Grade 4 neutropenia ≤ 7 days

Grade 4 lymphopenia or leukopenia

Grade 4 isolated electrolyte imbalances/abnormalities 
that are not associated with clinical sequelae and are 
responding to supplementation/appropriate 
management within 72 hours of their onset.
Infusion Reactions 
(manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like reactions)
Hypersensitivity Reaction or 
Infusion Reaction
Grade 3 or 4
Permanently 
discontinue
See Section 7.4.6 (Treatment of Bempegaldesleukin-
related or Nivolumab-related Infusion Reactions). 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMS, Bristol Myers Squibb; CTCAE, Common Terminology 
Criteria for Adverse Events; CVA, cerebrovascular accident; DRESS, drug-reaction with eosinophilia and systemic symptoms; GBS, Guillain-Barre Syndrome; 
MS, myasthenia gravis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; TIA, transient ischemic attach; ULN, upper limit of normal.
a *Not applicable per Protocol Amendment 04.If dosing of one drug is delayed, then dosing of both drugs is delayed.
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Table 7.4.1-2:
Bempegaldesleukin-specific Adverse Event Criteria for Delay, Resumption, and Discontinuation of 
Nivolumab and Bempegaldesleukin (if one is delayed, both are delayed)
*Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; however, the criteria remain 
unchanged for nivolumab.
Bempegaldesleukin-specific Criteria for Delay, Resumption, and Discontinuation
Serum Creatinine Increased
(transient, non-inflammatory)
Grade 2, 3, or 4
Delay dosea
For participants who must delay study treatment due to 
Grade ≥ 2 creatinine increase due to a non-inflammatory 
cause, delay retreatment with study drug for approximately 
3-5 days. After the dosing delay, the participant may 
resume study drug when serum creatinine has returned to 
Grade ≤ 1, as assessed within 24 hours prior to redosing 
(or as soon as locally feasible). If inflammatory etiology 
suspected, refer to renal AE management algorithm 
(Appendix 6) for further guidance.
Other Drug-related AE 
(not listed above)
Persistent Grade 2 toxicity, 
except fatigue and asthenia
Delay dosea
Dose delay at the discretion of the Investigator.
Note: Persistent Grade 2 is defined as a Grade 2 AE 
lasting ≥ 3 weeks and ongoing at the time of subsequent 
dosing that is attributed as either “possibly related” or 
“related” to bempegaldesleukin.
TIA/CVA 
All grades
Permanently 
discontinue both drugs
Any new CVA event confirmed by MRI with diffusion 
weighted imaging, regardless of neurological symptoms 
(eg, cryptogenic CVA) and for suspected TIA without 
clear alternative etiology. See Appendix 7.
Abbreviations: AE, adverse event; CVA, cerebrovascular accident; TIA, transient ischemic attack.
a If dosing of one drug is delayed, then dosing of both drugs is delayed.
*Per Protocol Amendment 04, participants are required to discontinue bempegaldesleukin and may continue on nivolumab 
treatment. Advanced Cardiac Life Support (ACLS) and institutional guidelines should be followed for all CVA cases. For participants 
previously treated with bempegaldesleukin plus nivolumab who have a CVA or TIA, the Investigator should discuss risk/ benefit of 
continuing nivolumab. The managements algorithm for CVA or TIA (Appendix 7) is not applicable per Protocol Amendment 04.
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7.4.1.1
Dose Modification Criteria for Bempegaldesleukin and Nivolumab for 
Cycle 1 AST/ALT Elevations
This section is not applicable per Protocol Amendment 04. These recommendations are for 
Cycle 1 only and are not intended to serve as rigid guidelines or to replace clinical judgement.
Subsequent cycles should follow standard Hepatic Adverse Event Management Algorithm 
(Appendix 6).
Rule out alternative etiologies. Consider imaging if obstruction is suspected. If there is a 
non-inflammatory etiology, treat accordingly and continue bempegaldesleukin and nivolumab. 
If ALT/AST increases during monitoring, follow the guidance for the highest levels.
AST or ALT > 3.0 to ≤ 5 × ULN (within first cycle of bempegaldesleukin + nivolumab)
Increase frequency of liver function test (LFT) monitoring to approximately every 3 days and delay 
treatment until lab abnormalities resolve to Grade 1 or baseline.
If no improvement within 7 days, treat with 0.5-1 mg/kg/day prednisone equivalents, and taper 
steroids over at least 1 month before resuming treatment.
ALT or AST > 5.0 to ≤ 8.0 × ULN (within first cycle of bempegaldesleukin + nivolumab)
Increase frequency of monitoring to approximately every 3 days until lab abnormalities resolve to 
Grade 1 or baseline.
Treatment must be delayed until lab abnormalities resolve to Grade 1 or baseline.
If no improvement within 7 days (follow Hepatic Adverse Event Management Algorithm 
[Appendix 6]);

Discontinue bempegaldesleukin + nivolumab

1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least one 
month

Consult gastroenterologist

Consider adding non-corticosteroid immunosuppressive medication if no improvement in 
> 3-5 days, worsens or rebounds while on steroids
ALT or AST > 8.0 × ULN (follow Hepatic Adverse Event Management Algorithm 
[Appendix 6])

Discontinue bempegaldesleukin + nivolumab

Increase frequency of monitoring to approximately 1-2 days

1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least one 
month

Consult gastroenterologist

If no improvement in > 3–5 days, worsens or rebounds, add non-corticosteroid 
immunosuppressive medication
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Please refer to Section 8.1 for discontinuation criteria.
7.4.2
Monitoring and Management of Elevated Hepatic Transaminases
Per Protocol Amendment 04, language for bempegaldesleukin is no longer applicable.  
Elevated hepatic transaminases are an overlapping toxicity that can occur for both 
bempegaldesleukin and nivolumab. The elevations in hepatic transaminases associated with 
bempegaldesleukin typically occur at the time of peak active cytokine concentration in the blood 
(Days 2-4), and are often accompanied by other cytokine-related toxicities such as flu-like 
symptoms, rash or pruritus. The transient elevations in hepatic transaminases are usually mild or 
moderate in severity, not associated with increased total bilirubin, resolve spontaneously without 
treatment, and predominantly occur in Cycle 1 and Cycle 2. Grade 3 laboratory abnormalities with 
these characteristics have been observed in PIVOT-02 during Cycle 1, and participants were able 
to continue study treatment uninterrupted with close laboratory monitoring. For transaminase 
elevations occurring in Cycle 1 consistent with a cytokine related effect without alternative 
etiologies, follow the Cycle 1 hepatic adverse event management guideline (Section 7.4.1.1).
Hepatic events, including elevated liver function tests, have also been observed for nivolumab. 
Most cases were of low or moderate severity. Higher grade abnormalities are concerning for 
immune-mediated hepatitis, and typically occur with a later onset (median time to onset of 
3.3 months). Immune-mediated hepatitis generally results in a quick rise in liver function tests, 
and responds to corticosteroids or immune-modulating agents. For transaminase elevations 
occurring in Cycle 2 onwards potentially involving an immune-mediated mechanism, follow the 
immune-mediated hepatic adverse event management guidelines in the nivolumab Investigator’s 
Brochure or product labeling for appropriate management.
7.4.3
Monitoring and Management of Bempegaldesleukin-induced 
Eosinophilia
This section is not applicable per Protocol Amendment 04. Frequent and significant 
eosinophilia has been observed in participants receiving both single agent bempegaldesleukin and 
bempegaldesleukin plus nivolumab, primarily starting at Cycle 2 or later, consistent with the 
known effect of IL-2 therapy. Clinical data analysis demonstrated that frequency of selected AEs 
(primarily Grade 1 or 2 in severity) such as rash, pruritus, edema, nausea, vomiting, diarrhea, and 
dizziness increased with level of eosinophilia. Isolated cases of suspected hypereosinophilic 
syndrome have been reported.
Absolute eosinophil count (AEC) should be closely monitored per protocol. If study participant is 
suspected to have hypereosinophilic syndrome (symptoms may involve skin, lungs, digestive tract, 
heart, blood and nervous system) with AEC at or above 5000/µL (5x109/L) level, 
bempegaldesleukin treatment may need to be withheld, and the participant should be treated as 
clinically indicated.
7.4.4
Monitoring and Management of Adrenal Insufficiency and Hypophysitis
Adrenal insufficiency and hypophysitis have been observed in participants receiving nivolumab. 
Consider prompt evaluation when participants have signs or symptoms of hypophysitis or adrenal 
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insufficiency which includes levels of early-morning adrenocorticotropic hormone (ACTH), 
cortisol, thyroid-stimulating hormone (TSH), and free thyroxine (T4). Co-management with an 
endocrinologist is recommended for participants with pre-existing adrenal insufficiency.
7.4.5
Management Algorithms for Immuno-oncology Agents
Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; 
however, the criteria remain unchanged for nivolumab. Immuno-oncology agents are 
associated with AEs that can differ in severity and duration from AEs caused by other therapeutic 
classes. Bempegaldesleukin and nivolumab are considered immuno-oncology agents in this 
protocol. Early recognition and management of AEs associated with immuno-oncology agents 
may mitigate severe toxicity. Management Algorithms (see Appendix 6, Appendix 7, Appendix 8,
and the nivolumab IB) have been developed to assist Investigators in assessing and managing the 
following groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological

Myocarditis

CVA

Cytokine-release Syndrome (CRS)
Advanced Cardiac Life Support (ACLS) and institutional guidelines should be followed for all
CVA cases. For participants previously treated with bempegaldesleukin plus nivolumab who have 
experienced a CVA or TIA, the Investigator should discuss risk/ benefit of continuing nivolumab.  
A management algorithm for possible signs and symptoms of CVA or TIA for participants treated 
with bempegaldesleukin in combination with a checkpoint inhibitor is provided in Appendix 7
(not applicable per Protocol Amendment 04).
7.4.5.1
Management Algorithm for Cytokine-release Syndrome
This section is not applicable per Protocol Amendment 04. CRS is a clinical diagnosis with a 
constellation of symptoms often characterized by fever, tachypnea, headache, tachycardia, 
hypotension, rash, and/or hypoxia caused by the release of cytokines. In addition, diarrhea and end 
organ dysfunction can be seen in CRS. Many of these symptoms overlap with known AEs seen in 
bempegaldesleukin and nivolumab combination therapy (ie, pyrexia and hypotension). These 
symptoms may be seen in infusion reactions as well as other known syndromes, such as tumor 
lysis syndrome and macrophage activation syndrome. For suspected CRS of Grade 3 or above, the 
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Investigator is encouraged to contact the Medical Monitor. An algorithm for the management of 
CRS is provided in Appendix 8 (not applicable per Protocol Amendment 04).
7.4.6
Treatment of Bempegaldesleukin-related or Nivolumab-related Infusion 
Reactions
Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; 
however, the criteria remain unchanged for nivolumab. Infusion reactions have been reported 
during bempegaldesleukin and nivolumab infusions. If such a reaction were to occur with either 
the bempegaldesleukin or nivolumab infusion, it might manifest with fever, chills, rigors, 
headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other 
allergic-like reactions.
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 the bedside and monitor the 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 subsequent infusions. Subsequent infusions may be administered at a 
reduced rate (eg, 50% of the original infusion rate).
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
24 hours):

Stop the bempegaldesleukin or nivolumab 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 the bedside and monitor the 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 symptoms recur after restarting the 
bempegaldesleukin or nivolumab infusion, then no further bempegaldesleukin or nivolumab 
will be administered at that visit. Administer diphenhydramine 50 mg IV, remain at the 
bedside, and monitor the participant until resolution of symptoms. 

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 the infusion. If necessary, corticosteroids 
(up to 25 mg of methylprednisolone or equivalent) may be used (see Section 7.7.1 for 
corticosteroid dose equivalents). Subsequent infusions may be administered at a reduced rate 
(eg, 50% of the original infusion rate).
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For Grade 3 or Grade 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 bempegaldesleukin or nivolumab. 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. Nivolumab and 
bempegaldesleukin will be permanently discontinued. The participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Investigators should 
follow their institutional guidelines for the treatment of anaphylaxis. Remain at the bedside 
and monitor the 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).
7.5
Preparation/Handling/Storage/Accountability
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 administered to 
study participants. The investigational product must be administered 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 administered and BMS contacted 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 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Please refer to the current version of the Investigator’s Brochures and/or pharmacy manual for 
complete preparation, storage, and handling information.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and the Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable
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7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability, as well as the 
participant’s medical records and electronic case report form, (eCRF). Study drug will be 
administered in the clinic by trained personnel. Drug accountability should be reviewed by the site 
study staff at each visit. 
This paragraph is not applicable per Protocol Amendment 04 as bempedaledesleukin is 
discontinued from Arm A. Arm A: At least once between Days 3 and 5 (inclusive) following the 
first two infusions of bempegaldesleukin, site personnel must contact the participant (by telephone 
or clinic visit) to remind the participant of the oral hydration guidelines, to assess for any 
symptomatology and compliance with the guidelines, and document the results of the discussion 
(Table 2-2 and Table 2-3). For subsequent doses, the oral hydration follow-up should be conducted 
as clinically indicated for participants receiving bempegaldesleukin.
7.7
Concomitant Therapy
Concomitant medications are recorded at baseline and throughout the treatment of the study in the
appropriate section of the eCRF.
All medications (prescription and over-the-counter [OTC]), vitamin and mineral supplements, 
and/or herbs taken by the participant from Screening through End of Treatment phase will be 
documented and recorded, including start and stop date, dose and route of administration, 
frequency, and indication. Medications taken for a procedure (eg, biopsy) should also be included.
Pre-medications should not be administered prior to the initial administration of 
bempegaldesleukin (Per Protocol Amendment 04, bempegaldesleukin will no longer be 
administered). or nivolumab, but if a participant reports symptoms (such as nausea and/or 
vomiting), prophylactic use of antiemetics may be used.
Any subsequent anti-cancer therapy will be recorded until end of study or death, in the appropriate 
section of the eCRF.
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
AE):

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

Low-dose acetylsalicylic acid (approximately 81 mg/day) should not be combined with 
LMWH or DOAC due to an increased risk of hemorrhage (except as stated in Section 7.7.2.1).

Immunosuppressive agents

Immunosuppressive doses of systemic corticosteroids (except as stated in Section 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 disease under study).
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
Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally.

Recording of prior medications should include prior cancer treatments: previous 
immunotherapy, chemotherapy, targeted therapy, radiation, OTC medications, herbs, and 
dietary supplements.

All medications (prescription and [OTC]), vitamin and mineral supplements, and/or herbs 
taken by the participant from Screening through End of Treatment phase will be documented 
and recorded, including start and stop date, dose and route of administration, frequency, and 
indication. Medications taken for a procedure (eg, biopsy) should also be included.

Pre-medications should not be administered prior to the initial administration of 
bempegaldesleukin or nivolumab, but if a participant reports symptoms (such as nausea and/or 
vomiting), prophylactic use of antiemetics may be used.

Administration of a live COVID-19 vaccine is prohibited within 30 days prior to randomization 
(or screening). Live COVID-19 vaccines should not be used during the study, including the 
treatment period and within 100 days following last dose of IP. 
7.7.1.1
Effect of Bempegaldesleukin on PK of Concomitant Medications
This section is not applicable per Protocol Amendment 04. Bempegaldesleukin causes transient 
increases in circulating cytokines lasting for about one week after bempegaldesleukin dosing in 
the Q3W dosing schedule. Several of these cytokines (IFN-γ, IL-6, IL-10) have the potential to 
decrease the activity of multiple enzymes and drug transporters.65,66 Consequently, treatment with 
bempegaldesleukin may lead to temporary decrease in clearance of drugs that are substrates of 
metabolizing enzymes or drug transporters. Where indicated based on decreased tolerability or the 
occurrence of adverse effects related to a concomitant drug, reduce the dosage of the concomitant 
drug during Days 3 to 8 of each cycle of bempegaldesleukin.
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 prior to 
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.
7.7.2.1
Restricted Treatments
The guidance for anticoagulation and anti-thrombotic therapy for the prevention and treatment of 
venous thromboembolic disease was included to mitigate the potential increased risk of ischemic 
cerebrovascular events (ICEs) observed in participants treated with bempegaldesleukin plus 
nivolumab. Per Protocol Amendment 04 participants will receive nivolumab monotherapy only. 
Nivolumab monotherapy does not appear to be associated with an increased risk of ICE; 
anticoagulation therapy will no longer be mandated for patients enrolled on the study. There are 
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no data suggesting how long the duration of potential increased risk of ICE persists after the 
discontinuation of bempegaldesleukin. Decisions regarding antithrombotic therapy should be 
based on the investigator’s assessment of the risk benefit for each individual patient.
Per protocol amendment 04, the remainder of this section is not applicable.
Participants with a history of a venous or arterial thromboembolic event must be receiving a stable 
regimen of therapeutic anticoagulation (LMWH or DOAC). Additionally:

Use of warfarin (Coumadin) is permitted; however, therapeutic dosing should target a specific 
International Normalised Ratio (INR) stable for at least 4 weeks prior to enrollment. 
Bempegaldesleukin has the potential to down-regulate metabolizing enzymes for warfarin for 
approximately 1 week after administration of each dose of bempegaldesleukin. Due to the 
possibility of drug-drug interactions between warfarin and bempegaldesleukin, frequent 
monitoring of INR and ongoing consideration of dose adjustments are warranted throughout 
the participant’s participation on study.

Unless there is a new medical contraindication observed after Cycle 1 Day 1, a participant with 
a history of venous or arterial thromboembolic event must be maintained on therapeutic 
anticoagulation throughout the participant’s time on study treatment.
7.7.2.2
Imaging Restriction 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 per imaging study. Imaging contraindications and contrast risks are to be considered in 
this assessment. Participants with renal insufficiency are to be assessed as to whether or not they 
should receive contrast and if so, which contrast agent and dose 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, therefore MRI 
contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. This will be outlined in the image manual.
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 standards set by the local Ethics Committee.
7.7.2.3
Blood Pressure Precautions
This section is not applicable per Protocol Amendment 04. Consideration should be given to 
withholding antihypertensive medications including diuretics, as well as other drugs with 
hypotensive properties (eg, alpha-blockers for benign prostatic hyperplasia, particularly when 
therapy involves multiple antihypertensive drugs and classes other than thiazide diuretics. If 
withholding antihypertensive medications, withhold no less than 12 hours and no more than 48 
hours prior to each dose of bempegaldesleukin. Participants who are on medications with 
antihypertensive effects for the treatment of coronary artery disease (CAD) (eg, beta-blockers, Ca 
channel blockers, nitrates, etc) should be able to withhold these drugs prior to initiation of 
treatment.
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Antihypertensive medications may be reinstituted in between doses of bempegaldesleukin at any 
time as clinically indicated (eg, based on blood pressure monitoring results).
In participants receiving beta-blockers, consider a step-wise tapering of doses before initiation of 
bempegaldesleukin to avoid reflex tachycardia. If Grade 2 or higher hypertension is observed in 
any cycle, participants should be monitored more frequently (at least weekly until a new stable 
antihypertensive regimen is identified). Participants may be monitored more frequently at the 
discretion of the investigator as clinically warranted.
7.7.3
Permitted Therapy
Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; 
however, the criteria remain unchanged for nivolumab.
Prophylaxis for flu-like symptoms with either acetaminophen or ibuprofen is permitted on study 
per the Investigator’s discretion. Prophylaxis for flu-like symptoms should be initiated on either 
Day 1 or Day 2 of the dosing cycle and may continue through Day 5 or longer as needed.
Prophylaxis for rash and/or pruritus with anti-histamines is permitted on study per the 
Investigator’s discretion. Prophylaxis for rash and/or pruritus should be initiated on either Day 1 
or Day 2 after dosing of bempegaldesleukin or nivolumab and may continue through Day 5 or 
longer as needed.
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.
7.8
Treatment After the End of the Study
At the end of the study/Period, BMS will not continue to provide BMS supplied study treatment 
to participants/investigators unless BMS chooses to extend the study. The investigator should 
ensure that the participant receives appropriate SOC to treat the condition under study.
BMS reserves the right to terminate access to BMS supplied study treatment if any of the following 
occur: a) the study is terminated due to safety concerns; b) the development of the 
bempegaldesleukin is terminated for other reasons, including but not limited to lack of efficacy 
and/or not meeting the study objectives; c) the participant can obtain medication from a 
government sponsored or private health program. In all cases BMS will follow local regulations.
Per Protocol Amendment 04, BMS is terminating the development of bempegaldesleukin in 
combination with nivolumab. If BMS decides to terminate the study, all sites will be notified and 
given a period of time to discontinue study treatment and transition all participants to commercially 
available SOC treatment. The sponsor may provide alternative mechanisms to receive treatment 
for participants who cannot afford or access commercially available SOC treatments.
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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 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information.

Any clinical adverse event (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 Bristol-Myers Squibb (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, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)

EFS event as defined in Section 9.1.1
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, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In all cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety. See Section 9.2.5, Pregnancy).
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 case report form (CRF) page.
8.1.1
Nivolumab and Bempegaldesleukin Discontinuation Criteria
Per Protocol Amendment 04, participants receiving bempegaldesleukin plus nivolumab are 
required to discontinue bempegaldesleukin and will receive nivolumab monotherapy.
Per Protocol Amendment 04, the text below related to bempegaldesleukin is not applicable; 
however, the criteria remain unchanged for nivolumab.
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Nivolumab and bempegaldesleukin treatment must be permanently discontinued per criteria in 
Table 7.4.1-1. Discontinue nivolumab and bempegaldesleukin for 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 and bempegaldesleukin dosing.

Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions:

Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed.

Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee).
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the BMS 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory studies 
should also continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays.
8.1.2
Post-study Treatment Study Follow-up
In this study, pCR, EFS, and OS are key endpoints of the study. Post-study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed (in this study or a 
rollover study) for collection of survival follow-up data as required and in line with Section 5 until 
death or the conclusion of the study. For each randomized participant, the maximum total duration 
of the study is up to 62 weeks + 100 days of safety follow-up.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol-defined window (see Section 2). At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all 
contacts or is lost to follow-up.
Per Protocol Amendment 04, this section is no longer applicable.  Additional subsequent cancer 
therapy details such as regimen, setting of the regimen, line of therapy, start date and end date of 
each regimen, best response to the regimen, and date of progression after next line of therapy will 
be collected.
Participants who discontinue study treatment may continue to be followed.
8.2
Discontinuation from the Study
Participants who discontinue study treatment will remain in the study and must continue to be 
followed up to 100 days for protocol specified follow-up procedures with documentation of last 
overall survival upon discontinuation. 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.
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
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.

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. Adherence to the study design requirements, including 
those specified in the Schedule of Activities (Section 2), 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 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 
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provided the procedure meets the protocol-defined criteria and has been performed within the 
timeframe defined in the Schedule of Activities (Section 2).
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.
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, 
and 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’s Brochure.
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.
9.1
Efficacy Assessments
Per Protocol Amendment 04, tumor assessments will be determined by investigator.
9.1.1
Definition of Events in EFS
EFS is defined as the time from randomization to any of the following events: progression of
disease that precludes surgery, local or distant recurrence, or death due to any cause. Details on
EFS events are provided below:

Worsening of disease that precludes surgery (as determined by Investigator or Section 9.1.1.2)

If surgery is possible, but not performed for other reasons (eg, participant refuses, AEs), and there 
has been RECIST v1.1 assessed progression in the neoadjuvant period, then it will be considered 
an EFS event (see Section 9.1.2.2).

If surgery is possible but not performed for other reasons (participant refuses or worsening of 
medical condition), then the participant may continue on study treatment and will be considered 
to have an EFS event if and when:

There is RECIST v1.1 defined progression

If there is carcinoma in situ (CIS), high grade Ta, T1, or ≥T2 disease at any time after 
neoadjuvant therapy is completed observed on cystoscopy and confirmed by pathologic 
review after TURBT and/or bladder biopsy (see schedule of cystoscopy in Section 2)

If surgery is attempted but gross resection is abandoned, due to unresectable tumor or 
worsening of disease, then that will be considered an EFS event.

If RC is completed with no or only microscopic residual disease (positive margins, not visible
on imaging), then the participant will continue on study and will be considered to have an EFS
event if and when radiographically (or by biopsy) visible recurrence occurs.
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
If surgery is completed with unequivocal gross residual disease (visible on imaging or by 
biopsy), it will be considered as an EFS event. Equivocal residual disease should be confirmed
by biopsyor confirmed by further progression (RECIST v1.1) at following scan (see Appendix 
10).

Local or distant recurrence or new upper tract tumor confirmed by imaging or biopsy

Death due to any cause
9.1.1.1
Definition of Disease Recurrence
Bladder cancer recurrence will be defined as any unequivocal evidence of new bladder cancer 
lesions that are detected after RC. Biopsy should be employed where required to prove recurrence. 
In cases where recurrence is equivocal and biopsy cannot be performed or were not diagnostic, the 
participant may continue treatment and imaging of suspect lesions should be repeated in 4-8 weeks 
(Section 9.1.2.3).
The first post-surgery assessment will occur within 60 to 90 days after RC and prior to beginning 
post-surgery IO therapy for Arms A and B. Participants who have new LNs defined as short axis
10 mm with growth of ≥5 mm (eg, 9 mm LN grows to 14 mm) or have findings of other new, 
unequivocal non-nodal lesions will be considered as having recurrence. Confirmation of 
recurrence must be attempted as described in Section 9.1.2.2.
Tumor may recur in the following sites:

Local, urothelial tract: Any new UC in ureter or renal pelvis, including lesions thought to be a 
second UC primary, will be considered recurrences, as well as new CIS, Ta high grade, T1 or 
muscle invasive lesion in participants who do not undergo RC.

Local, non-urothelial tract: Any new UC in pelvic soft tissue or involving pelvic nodes below 
the aortic bifurcation.

Distant: Any new non-local recurrence
Unequivocal recurrence of urothelial cancer at any of these sites will be considered an EFS event 
requiring that study treatment be discontinued.
9.1.1.2
Definition of Disease Progression
All participants including those who did not undergo RC due to reasons other than worsening of
disease precluding surgery will be followed by imaging for disease progression according to 
RECIST v1.1 (see Appendix 10). For participants who are undergoing surveillance cystoscopies, 
see Section 9.1.1 above.
9.1.1.3
Definition of pCR
The pCR rate is defined as the proportion of randomized participants with absence of any cancer 
(T0, N0) in pathology specimens after RC, as assessed by blinded pathology review.
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9.1.2
Imaging Assessment for the Study
As per Protocol Amendment 04, images will no longer be submitted to central imaging 
vendor.
All images will be submitted to a central imaging vendor for BICR at any time during the study. 
Copies of additional scans conducted at the time of UC of the bladder/MIBC diagnosis should be 
stored at the sites for possible future analysis, at the Sponsor’s discretion. Sponsor may also request 
additional historical scans to clarify baseline assessment. Prior to scanning first participant, sites 
should be qualified and understand the image acquisition guidelines and submission process as 
outlined in the CA045009 Imaging Manual provided by the central imaging vendor. Screening and 
on study images should be acquired as outlined in Schedule of Activities (Section 2).
Tumor assessments at other time points may be performed if clinically indicated. 
Tumor assessments for all participants should continue as per protocol even if dosing is delayed
or discontinued. Tumor measurements should be made by the same investigator or radiologist for 
each assessment, whenever possible.
9.1.2.1
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis (including excretory imaging), and all other 
known and/or suspected sites of disease should be performed for tumor assessments. Images 
should be acquired with slice thickness of 5 mm or less with no intervening gap (contiguous). 
Every attempt should be made to image each participant using an identical acquisition protocol on 
the same scanner for all imaging time points. Tumor measurements should be made by the same 
investigator or radiologist for each assessment, whenever possible. Change in tumor measurements 
and tumor response to guide ongoing study treatment decisions will be assessed by the investigator 
using the RECIST v1.1 criteria.
If a participant has a contraindication for CT IV contrast, then a non-contrast CT of the chest and 
a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of disease 
should be obtained.
If a participant has a contraindication for both MRI and CT IV contrasts, then a non-contrast CT 
of the chest and a non-contrast MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT IV contrast, then a non-contrast CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease is acceptable.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET-CT 
is increasingly used in clinical care, and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-based 
RECIST v1.1 measurements. However, if a site can document that the CT performed as part of a 
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PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST v1.1 measurements. Note, however, that the 
PET portion of the CT introduces additional data that may bias an investigator if it is not routinely 
or serially performed.
9.1.2.2
BICR Confirmation of Progression or Recurrence
Per Protocol Amendment 04, BICR will be discontinued and all study treatment decisions 
will be based on the investigator’s assessment of tumor images.
See comprehensive Definition of Events in EFS (Section 9.1.1). Not applicable per Protocol 
Amendment 04. All investigator-assessed events require BICR confirmation with the exception
of events from preclusion of surgery due to disease worsening or abandoned surgery do not require 
BICR confirmation.
Not applicable per Protocol Amendment 04. Sites should submit all scans to the central imaging 
vendor on a rolling basis, throughout the duration of the study. The site will inform the central 
imaging vendor when the investigator assessment indicates either (i) unequivocal disease 
progression per RECIST v1.1 criteria (for participants without RC) or (ii) unequivocal evidence 
of disease recurrence after RC, in order for BICR assessment of progression/recurrence to be 
performed. The BICR will be completed and the results provided to the site as specified in the 
imaging vendor documents, provided there are no pending imaging queries to the site. All details 
on the timelines and associated process requirements will be outlined in the Imaging Manual.
Not applicable per Protocol Amendment 04. Participants whose [progression or recurrence] is 
not confirmed by the BICR will be required to continue tumor assessments (if clinically feasible) 
according to the protocol-specified schedule (Section 2) or sooner if clinically indicated. Also, if 
participants discontinue treatment without radiographic [progression or recurrence], tumor 
assessments will continue according to the protocol-specified schedule, as noted in Schedule of 
Activities (Section 2) until progression has been confirmed by BICR (Section 9.1.2.2).
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment.
9.1.2.3
Confirmation and Date of Progression or Recurrence
Per Protocol Amendment 04, BICR will be discontinued and all study treatment decisions 
including progression and recurrence will be based on the investigator’s assessment of tumor 
images.
The first date when progression or recurrence was observed is taken into account regardless of the
method of assessment. Therefore, recurrence will be declared for any lesion when:

Progression or recurrence is unequivocal (eg, multiple new measurable lesions); confirmation
with histology/cytology should be attempted but is not required.

Progression or recurrence is equivocal; for example, LN only, solitary lesion, or disease in the
urothelial tract, confirmation with histology/cytology should be considered if feasible.
Confirmation of a defined lesion in the upper genitourinary tract may be obtained with a
retrograde study and biopsy. If biopsy is not feasible, a follow-up CT or MRI scan may be used
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to confirm recurrence. Follow-up (confirmatory) scan should occur 4 to 8 weeks after the initial
scan. The date of the initial scan showing recurrence (or a suspect lesion, later shown to be a
recurrence) will count as the date of recurrence.

Any pathological evidence of new bladder cancer denotes recurrence.

A suspicious urine cytology (eg, positive Urovision or similar urine assay) alone does not
constitute the basis for recurrence of disease, but should prompt for further investigation, 
(eg, radiological confirmation). Tumor markers or auto-antibodies alone cannot be used to
document recurrence. Biopsyand/or imaging is required to establish recurrence.

If both pathology and imaging were done and recurrence or bladder cancer confirmed, the date
of recurrence is the date of which ever examination came first.

New NMIBC in participants who do not undergo RC would be progression.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 
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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
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Serious Adverse Drug Reactions section in the IB represent the Reference Safety Information to 
determine expectedness of SAEs for expedited reporting.

The collection of non-serious AEs (with the exception of non-serious AEs related to SARS-
CoV-2 infection) should begin at initiation of study treatment. All SAEs, and 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 
discontinuation of dosing.

All SAEs must be collected from the time of signing the consent, including those thought to 
be associated with protocol-specified procedures and within 100 days of discontinuation of 
dosing.

For participants randomized to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of randomization. For participants in Arm C, SAEs should 
be collected for 100 days following RC.

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, (eg, a follow-up skin biopsy).

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module.

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 or designee within 24 hours
of updated information being available.

CVA (any grade) is considered an AEOSI and should be assessed for seriousness using the 
standard seriousness definition. However, all CVAs are required to follow the timelines for 
SAE reporting (eg, 24 hours). CVA management guidelines, provided in Appendix 7, are no 
longer applicable per Protocol Amendment 04. 
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.
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 
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collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known AEs, when appropriate for the program or protocol.
All nonserious AEs (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 adjuvant therapy for Arms A and B and 100 days from RC for Arm C. For participants who do 
not continue adjuvant therapy in Arms A and B, AEs and/or SAEs should be collected for a period 
of 100 days following RC.
Every AE must be assessed by the investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the participant’s case report form.
9.2.3
Follow-up of AEs and SAEs

Nonserious 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 nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious 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, 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, 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.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 9.2).
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 Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws including European Directive 2001/20/EC and FDA Code of 
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Federal Regulations 21 CFR Parts 312 and 320. A Suspected, Unexpected Serious Adverse 
Reaction (SUSAR) 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 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.
Serum or urine pregnancy tests will be performed on women of childbearing potential according 
to the Schedule of Activities. A negative pregnancy test result must be obtained before the 
administration of the study drug(s).
A pregnancy test does not need to be performed on women who are postmenopausal. A definition 
of post-menopausal can be found in Appendix 4.
If a female participant becomes pregnant, administration of the study drug(s) must be discontinued. 
Requirements for reporting a pregnancy are provided in Appendix 3. 
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.
If any sexual activity (eg, vaginal, anal, oral) has occurred between a male participant and a 
pregnant WOCBP partner(s), the information should be reported to the Sponsor or designee, even 
if the male participant has undergone a successful vasectomy. In order for Sponsor or designee to 
collect any pregnancy surveillance information from the female partner, the female partner(s) must 
sign an informed consent form for disclosure of this information. Information on the pregnancy 
will be collected on the Pregnancy Surveillance Form.
9.2.6
Immune-mediated Adverse Events
Immune-mediated AEs (IMAEs) 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 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
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This paragraph is not applicable per Protocol Amendment 04. Additional information may 
also be collected on select AEs primarily related to bempegaldesleukin, including hypotension, 
capillary leak syndrome, and eosinophilic disorders. A list of relevant AE terms will be maintained 
by the Medical Surveillance Team/Drug Safety Committee or equivalent.
9.2.7
Adverse Events of Special Interest (AEOSI)
CVA (any grade) is considered an AEOSI and should be assessed for seriousness using the 
standard seriousness definition. However, all CVAs are required to follow the timelines for SAE
reporting (eg, 24 hours). CVA management guidelines, provided in Appendix 7, are no longer 
applicable per Protocol Amendment 04.
9.2.8
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious 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 versus low hemoglobin value).
9.2.9
Potential Drug-induced Liver Injury (DILI)
Specific criteria for identifying potential DILI have not been identified for this protocol. Standard 
medical practice in identifying and monitoring hepatic issues should be followed.
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:

Treatment-emergent ALT or AST > 3 times ULN ( >2x baseline AND >3x ULN for 
participants with baseline elevation),
AND

Total bilirubin > 2 times ULN (>2x baseline AND >2x ULN for participants with baseline 
elevation) or clinical jaundice, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND
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
No other immediately apparent possible causes of elevated liver enzymes and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug (s) known to be hepatotoxic.
9.2.10
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 nonserious or serious AE, as appropriate, and reported accordingly.
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). All instances of accidental 
overdose and/or dosing errors should be reported on the Dosage Administration Record eCRF.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
Vital Signs and Oxygen Saturation
Vital sign measurements will be recorded according to the Schedule of Activities (Section 2). Vital 
signs include pulse rate, systolic and diastolic blood pressure, and temperature. Pulse oximetry 
will also be included and at baseline only. It is preferred that the same arm be used for all blood 
pressure readings, if possible. Instructions for more frequent vital sign monitoring after completion 
of study drug administration are provided in Section 2.
9.4.2
Physical Examinations
Refer to Schedule of Activities (Section 2).
9.4.3
Electrocardiograms
All participants will have 12-lead electrocardiogram (ECG) done during screening and treatment 
as specified in the Schedule of Activities (Section 2).
9.4.4
Echocardiogram
Standard echocardiogram will be performed to assess cardiac function and LVEF according to the 
Schedule of Events. A MUGA scan can be performed to assess cardiac function and LVEF if a 
standard echocardiogram cannot be performed.
9.4.5
Pregnancy Tests
Serum or urine pregnancy tests will be performed on women of childbearing potential according 
to the Schedule of Activities (see Section 2). A negative pregnancy test result must be obtained 
within 24 hours prior to administration of the study drug(s).
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A pregnancy test does not need to be performed on women who are postmenopausal. A definition 
of post-menopausal can be found in Appendix 4. If a female participant becomes pregnant, 
administration of the study drug(s) must be discontinued.
Guideline to be followed in case of pregnancy and reporting requirements are provided in Section
9.2.5.
9.4.6
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.4.7
Clinical Safety Laboratory Assessments
As of Protocol Amendment 04,  clinical safety laboratory assessments will be performed 
locally per the Schedule of Activities (Section 2) and will not be required to be submitted to 
central laboratory.
A list of the clinical laboratory analyses to be tested is provided in Table 9.4.7-1.
All clinical safety laboratory assessments will be performed locally per the Schedule of Activities 
(Section 2).
Investigators should document their review of each laboratory safety report.
The Investigator or a qualified Sub-Investigator will review all laboratory results for clinical 
significance. Any laboratory result deemed clinically significant (ie, is associated with signs and 
symptoms, requires treatment, or requires follow up) will be recorded as an AE as described in 
Section 9.2.
Table 9.4.7-1:
Clinical Safety Laboratory Assessments
Hematology CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Direct bilirubin
Alkaline phosphatase
Lactate dehydrogenase (LDH)
Creatinine
Blood urea nitrogen (BUN) or serum urea
Uric acid
Total Protein
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Creatine kinase
TSH, free T3 and free T4 - screening 
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Table 9.4.7-1:
Clinical Safety Laboratory Assessments
Glucose
TSH, with reflexive fT3 and fT4 if TSH is abnormal -
on treatment
Creatinine clearance (CLcr)- screening only
Lipase and /or amylase
Serology
Serum for hepatitis C antibody, hepatitis B surface antigen, (screening only)
HIV-1 and -2 antibody where mandated by local requirements (screening only) See Appendix 11
Other Analyses
Urine or Serum Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG) 
Follicle stimulating hormone (FSH) (screening only; required to confirm menopause in women < age 55) 
Urinalysis - screening only and as clinically indicated.a
a Urine dipstick can be done and if abnormal, perform microanalysis.
 
 
 
 
 
 
 
 
 
 
 
 
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9.7
Pharmacogenomics
Not applicable
 
 
 
 
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10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
Per Protocol Amendment 04 this section is not applicable. 
The sample size (N = 540 across 3 arms) of the study accounts for the 2 primary efficacy 
comparisons:
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
pCR comparison of Arm A vs Arm C in all randomized participants

EFS comparison of Arm A vs Arm C in all randomized participants
The overall 2-sided alpha for this study is 0.05. For sample size determination this is split with 
0.001 for the pCR comparison and 0.049 for the EFS comparison.
According to the original protocol assumption from 2019, the accrual rate of 17 participants per 
month estimated an accrual period of approximately 32 months for completion. Based on the 
revised accrual projection from April 2021 and the impact of COVID-19, the accrual period will 
take approximately 43 months to complete.
Sample size consideration for the pCR primary comparison of Arm A vs Arm C
Assuming the pCR rate for the experimental and the control arms are 36% and 15% respectively,11
a total of 360 participants (180 per arm) will provide approximately 90% power for the 2-sided 
test at overall significance level of 0.001. The analysis will occur when all randomized participants 
will be eligible for pCR evaluation (approximately 4 months after the last participant is 
randomized).
Sample size consideration for the EFS primary comparisons of Arm A vs Arm C
Among the approximately 360 randomized participants (180 per arm), approximately 156 EFS 
events provide at least 88% power to detect a HR of 0.6 with an overall type 1 error of 0.049 
(2-sided). The EFS distribution is assumed to be piecewise exponential with the following 
landmark values for the control group (Arm C): EFS rates of 43% at 36 months, 37% at 60 months 
and 25% at 120 months. These assumptions are based on the control arm (ie, local radical therapy 
alone without neoadjuvant therapy) of MRC/EORTC BA06 Phase 3 study72 incremented by 5% 
to account for the fact that a subset of participants did not undergo RC as definitive treatment in 
that study. Proportional hazard is modeled for the treatment effect. The calculation accounts for 
approximately 11% drop out during study duration (exponential with 5% by 12 months).
Two interim analyses for EFS are planned and corresponding stopping boundaries will be based 
on an O’Brien and Fleming alpha spending function. The first will take place at the time of final 
pCR analysis (based on the assumptions, approximately 101 EFS events in Arms A and C will 
occur at this time). The second interim analysis will take place when approximately 85% of the 
total number of events have occurred (approximately133 EFS events in Arms A and C). If the first 
interim analysis is performed exactly at 101 events, the boundary in terms of statistical significance 
for declaring superiority would be 0.01. If the second interim analysis is performed exactly at 
133 events, the boundary in terms of statistical significance for declaring superiority would be 
0.026. The boundary for declaring superiority in terms of statistical significance for the final 
analysis after 156 events in Arms A and C would be 0.04. The final analysis of EFS is projected 
to occur approximately 65 months after the start of the study (approximately 43 months accrual 
and 22 months follow-up). Given the slowdown in events rate observed after 24 months in
historical data, which could prevent the analysis to be performed in a reasonable time window, if 
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the 156th event in Arms A and C has not occurred 24 months after randomization of the last 
participant, then the final EFS analysis will take place at that time. In such a case, the final analysis 
boundary will be recalculated based on the actual updated final number of events.
Sample size calculations are summarized in Table 10.1-1.
Table 10.1-1:
Sample Size Calculations per Comparison for Primary Endpoints
*Not applicable per Protocol Amendment 04.
Endpoints
pCR (Arm A vs C)
EFS (Arm A vs C)
Accrual Duration
43 months
43 months
Power
90%
88%
Alpha
0.001 (2-sided)
0.049 (2-sided)
Hypothesized Rates Control vs 
Experimental
pCR: 15% vs 36%
EFS at 36 mo: 43% vs 60%
EFS at 60 mo: 37% vs 55%
EFS at120 mo: 25% vs 44%
Hypothesized Hazard Ratio
-
0.60
pCR Final/
EFS Interim Analysis 1
~47 months (accounts for 
4 months to get pCR on all 
participants)
~47 months
101 events in Arms A and C (65% I)
EFS Interim Analysis 2
~56 months
133 events in Arms A and C (85% I)
EFS Final Analysis
~65 months
156 events in Arms A and C
Sample size for the comparison
~360 randomized participants in 2 treatment groups
Total Sample Size
540 randomized participants (180/group)
East version 6.4 was used for sample size/power computations
Assumptions of treatment effect for the overall survival comparison of Arm A vs Arm C
Among the approximately 360 randomized participants, approximately 156 OS events provide 
88% power to detect a HR of 0.6 with an overall type 1 error of 0.049 (two-sided). The OS 
distribution is assumed to be piecewise exponential with the following landmark values for the 
control group: OS rates of 55% at 36 months, 48% at 60 months and 35% at 120 months. These 
assumptions are based on the control arm (ie, local radical therapy alone without neoadjuvant 
therapy) of MRC/EORTC BA06 Phase 3 study incremented by 5% to account for the fact that a 
subset of participants did not undergo RC as definitive treatment in that study.72 Proportional 
hazard is modeled for the treatment effect without dropout.
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Two interim analyses are planned and corresponding stopping boundaries will be based on an 
O’Brien and Fleming alpha spending function. The first will take place at the time of second EFS 
analysis (approximately after 133 EFS events in Arms A and C). At that time, approximately 
109 OS events in Arms A and C are expected. The second interim analysis will take place at the 
time of final EFS analysis (approximately 156 EFS events in Arms A and C). At that time,
approximately 84% of the total number of OS events will have occurred (approximately 131 OS 
events in Arms A and C). In case EFS reaches significance at an interim analysis, the subsequent 
OS analyses timing will be based on the OS number of events described above. The final analysis 
of OS will take place when 156 OS events in Arms A and C are observed, and it is projected to 
occur approximately 86 months after the start of the study (approximately 43 months accrual and 
43 months follow-up). If the 156th event in Arms A and C has not occurred 44 months after 
randomization of the last participant, then the final OS analysis will take place at that time. In such 
case, the final analysis boundary will be re-calculated based on the actual updated final number of 
events.
10.2
Populations for Analyses
For purposes of main analyses, the following populations are defined:
Table 10.2-1:
Analysis Populations
Population
Description
All enrolled participants
All participants who signed an informed consent form and were registered into 
the IRT
All randomized participants
All participants who were randomized to any treatment arm in the study
All treated participants
All randomized participants who either received at least one dose of any study 
medication or underwent radical cystectomy
10.3
Statistical Analyses
Per Protocol Amendment 04, the Sponsor is terminating the development of 
bempegaldesleukin in combination with nivolumab. This trial will be unblinded and no
hypothesis testing will be performed. The efficacy endpoints of pCR, EFS, and OS will be 
summarized descriptively in all randomized subjects. Details will be included in the SAP.
A description of the participant population will be included in a statistical output report.
Below is a summary of planned statistical analyses of the primary and secondary endpoints.
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Table 10.3-1:
Efficacy Analyses
*Not Applicable per Protocol Amendment 04.
Endpoint
Statistical Analysis Methods
Primary
Pathological Complete Response (pCR) in Arm A vs 
Arm C
The pCR rate is defined as the proportion of 
randomized participants with absence of any cancer 
(T0, N0) in pathology specimens after RC, as assessed 
by blinded pathology review.
pCR rates and corresponding 95% exact CIs will be 
calculated using the Clopper Pearson method for each 
treatment group in the all randomized participants 
population. Participants who do not undertake surgery 
will be counted as non-pCR and will be included in 
the denominator.
pCR rates will be compared using a 2-sided stratified 
Cochran Mantel Haenszel (CMH) test. Associated 
odds ratio and estimate of the difference with 99.9% 
and 95% CI will be calculated.
Event-Free Survival (EFS) in Arm A vs Arm C 
EFS is defined as time from randomization to any of 
the following events: progression of disease that 
precludes surgery, local or distant recurrence, or death 
due to any cause. Participants who die without a 
reported progression/disease recurrence will be 
considered to have experienced an event on the date of 
their death. Participants who did not report 
progression/recurrence of disease or die will be 
censored on the date of their last evaluable tumor 
assessment. Participants who did not have any on study 
tumor assessments and did not die will be censored on 
their date of randomization. Further details on the 
censoring rules for consideration of subsequent 
therapies will be described in the Statistical Analysis 
Plan (SAP).
EFS will be analyzed in the all randomized 
participants population.
EFS will be compared between 2 arms with a 
stratified 2-sided log rank test. The hazard ratio and 
the corresponding 95% and (100-adjusted alpha)% CI
will be estimated in a stratified Cox proportional 
hazards model using the randomized arm as a single 
covariate. The EFS curves for each randomized arm 
will be estimated using the Kaplan-Meier (KM) 
product-limit method. In addition, EFS rates at 
specific time points will be estimated using KM 
estimates on the EFS curve for each randomized arm. 
Associated 2-sided 95% CIs will be calculated using 
the Greenwood formula (using log-log 
transformation). The EFS endpoint will be analyzed 
by BICR assessment (primary analysis) as well as by 
investigator (ie, all events assessed by the 
investigator)as sensitivity analysis. In the primary 
analysis by BICR assessment, type of events that can 
only be assessed by investigator (see Section 9.1, eg,
worsening of disease precluding surgery, abandoned 
resection due to unresectable disease) will be 
considered as events.
Additional sensitivity analysis on EFS will also be 
performed, and details will be included in the SAP
.
Secondary
pCR in Arm B vs Arm C
Same definition as the corresponding primary endpoint.
Similar analyses of pCR in Arm B vs Arm C will be 
conducted. The hypothesis testing will only be 
performed if the higher hierarchical endpoints are 
met, as described in the SAP.
EFS in Arm B vs Arm C 
Same definition as the corresponding primary endpoint.
Similar analyses of EFS in arm B vs arm C will be 
conducted. The hypothesis testing will only be 
performed if the higher hierarchical endpoints are 
met, as described in the SAP.
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Table 10.3-1:
Efficacy Analyses
*Not Applicable per Protocol Amendment 04.
Endpoint
Statistical Analysis Methods
OS in Arm A vs Arm C and in Arm B vs Arm C
OS is defined as the time between the date of 
randomization and the date of death due to any cause. 
For participants still alive, OS is censored at the last 
date the participant is known to be alive.
OS will be analyzed in the all randomized participants 
population. The same analyses as described for EFS 
analyses will be performed for OS. The hypothesis 
testing will only be performed if the higher 
hierarchical endpoints are met, as described in the 
SAP.
pCR in Arm A vs Arm B
Same definition as the corresponding primary endpoint.
pCR rates and corresponding 95% exact CIs will be 
calculated using the Clopper Pearson method for each 
treatment group in the all randomized participants 
population.
Associated odds ratio and estimate of the difference 
with 95% CI will be calculated.
EFS in Arm A vs Arm B 
Same definition as the corresponding primary endpoint
The EFS curves for each randomized arm will be 
estimated using the Kaplan-Meier (KM) product-limit 
method. In addition, EFS rates at specific time points 
will be estimated using KM estimates on the EFS 
curve for each randomized arm. Associated 2-sided 
95% CIs will be calculated using the Greenwood 
formula (using log-log transformation).
The hazard ratio and the corresponding 95% will be
estimated in a stratified Cox proportional hazards 
model using the randomized arm as a single covariate. 
The stratification factors for analysis are the following:

Clinical Stage (T2N0 vs T3-T4aN0 vs T1-T4aN1)

PD-L1 status (1% vs < 1%/indeterminate)
Text related to alpha spending and hierarchical testing in the following paragraphs is not applicable 
in Protocol Amendment 04. The overall 2-sided alpha for this study is 0.05, which is split with 
0.001 for pCR and 0.049 for EFS for both Arm A vs Arm C comparison. 
No formal powered comparison of Arm A versus Arm B is planned, therefore, it may not be 
possible to draw any conclusion from the trial results about the superiority of Arm A compared to 
Arm B.
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To control the type I error rate, the following hierarchical testing approach will be implemented:
1) pCR: A vs C will be first tested at 0.001 alpha (two-sided)
2) pCR: B vs C will be tested at 0.001 alpha (two-sided) if i. was significant
3) EFS: A vs C will be tested at 0.049 (or 0.05 if ii. was significant) alpha (two-sided)
4) EFS: B vs C will be tested if iii. was significant and with the same alpha (two-sided)
5) OS: A vs C will be tested if iv. was significant and with the same alpha (two-sided)
6) OS: B vs C will be tested if v. was significant and with the same alpha (two-sided)
This approach has a graphical representation, which is illustrated in Figure 10.3-1.
Figure 10.3-1:
*Not Applicable per Protocol Amendment 04. Graphical 
Representation of the Statistical Testing Approach
Given EFS and OS endpoints are tested hierarchically using a group sequential approach, the 
overall hierarchical testing approach will be used where each endpoint/comparison will have its 
own specific Lan-DeMets alpha spending function with the O’Brien-Fleming type of boundaries.73
Additional details around the interim analysis schedule is provided in Section 10.3.3.
10.3.1
Safety Analyses
All safety analyses will be performed on the all treated participants population.
Table 10.3.1-1:
Safety Analyses
Endpoint
Statistical Analysis Methods
Secondary
Descriptive statistics of safety will be presented using NCI CTCAE version 5.0 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 5.0 criteria by system organ class and 
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Table 10.3.1-1:
Safety Analyses
Endpoint
Statistical Analysis Methods
preferred term. On-study laboratory parameters including hematology, chemistry, liver 
function, and renal function will be summarized using worst grade NCI CTCAE v 5.0 
criteria.
Additional safety analyses will be described in the statistical analysis plan finalized before 
first database lock.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3.3
Interim Analyses
Per Protocol Amendment 04 this section is not applicable.
Several interim analyses are planned for efficacy. Table 10.3.3-1 gives an overview of interim 
analyses purpose and timing.
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Table 10.3.3-1:
Interim Analyses Schedule
*Not Applicable per Protocol Amendment 04.
Analysis
Purpose
Analysis Trigger
Projected 
Timinga
Number of 
Participants/Events
Final pCR
Interim EFS 1
Demonstrate 
significant 
improvement in pCR 
and EFS
All randomized 
participants who 
underwent RC have 
pCR evaluation
~47 months
pCR: all randomized 
participants (~360 in 
Arms A and C)
EFS: ~101 events 
(Arms A and C)
Interim EFS 2
Interim OS 1
Demonstrate 
significant 
improvement in EFS 
and OS
~133 EFS events in 
arms A and C
~56 months
EFS: ~133 events
(Arms A and C)
OS: ~109 events (Arms 
A and C)
Final EFS
Interim OS 2
Demonstrate 
significant 
improvement in EFS 
and OS
~156 EFS events in 
arms A and C
~65 months
EFS: ~ 156 events 
(Arms A and C)
OS: ~131 events (Arms 
A and C)
Final OS
Demonstrate 
significant 
improvement in OS
~156 OS events in 
arms A and C
~86 months
OS: ~156 events (Arms 
A and C)
a Approximate projected timing from the start of randomization
10.3.4
Interim Analyses for EFS
Per Protocol Amendment 04 this section is not applicable.
Two interim analyses for efficacy of EFS are planned. The first will take place at the time of final 
pCR analysis (approximately after 101 EFS events in Arms A and C). The second interim analysis 
will take place when approximately 85% of the total number of events have occurred 
(approximately 133 events in Arms A and C). Details are provided in Section 10.3.3. There is no 
futility analysis for EFS.
10.3.5
Interim Analyses for OS
Per Protocol Amendment 04 this section is not applicable.
Two interim efficacy analyses of OS are planned. The first will take place at the time of EFS 
interim analysis 2 (approximately after 133 EFS events in Arms A and C). The second OS interim 
analysis will take place at the time of final EFS analysis. In case EFS reaches significance at an 
interim analysis, the subsequent OS analyses timing will be based on the OS number of events 
(approximately 109 OS events in Arms A and C for interim 1 and 131 OS events in Arms A and 
C for interim 2). There is no futility analysis for OS.
These interim comparisons for EFS and OS will allow for early formal testing for superiority, and 
the boundaries for declaring superiority will be derived based on the actual number of events using 
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Lan-DeMets spending function with O’Brien and Fleming type of boundary in EAST version 6 
based on the information fraction observed.
An independent statistician external to BMS will perform interim analyses (in conjunction with a 
review by the Data Monitoring Committee). The SAP will further describe the planned interim 
analyses.
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11
REFERENCES
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25 Galsky MD, Stensland K, Moshier EL, Sfakianos J, McBride RB, Tsao C-K, et al. 
Effectiveness of adjuvant chemotherapy (AC) versus observation in patients with >= pT3 
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26 Bajorin DF, Witjes JA, Gschwend J, et al. First results from the phase 3 CheckMate 274 trial 
of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk 
muscle-invasive urothelial carcinoma (MIUC).J Clin Oncol 2021;39(6_suppl):391-391.
27 Powles T, Kockx M, Rodriguez-Vida A. et al. Clinical efficacy and biomarker analysis of 
neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 
2019;25:1706-14.
28 Necchi A, Raggi D, Gallina A, et al. et al. Updated Rresults of PURE-01 with Ppreliminary 
Aactivity of Nneoadjuvant Ppembrolizumab in Ppatients with Mmuscle-invasive Bbladder 
Ccarcinoma with Vvariant Hhistologies. Eur Urol. 2019 Nov 82020;77:439-46.
29 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
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30
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31
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tumor escape. Nat Immunol. 2002;3(11):991-8.
32
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2005;23:515-48.
33 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. 
2000;192(7):1027-34.
34 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239-45.
35 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-20.
36 Nivolumab (BMS-936558) Investigator Brochure, Version 19. Bristol Myers Squibb 
Company; 29-Jun-2020. Document Control No. 930038243.
37 Sharma P, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after 
platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017 
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38 Charych DH, Hoch U, Langowski JL, et al. NKTR-214, an engineered cytokine with biased 
IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. 
Clinical Cancer Research. 2016;22:680 690.
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39 Charych DH, Rubas W, Dixit V, et al. Immune memory in nonclinical models after treatment 
with NKTR-214, an engineered cytokine biased towards expansion of CD8+ T cells in tumor. 
Poster presented at the Annual Meeting of the American Society of Clinical Oncology 
(ASCO); 2016b Jun 3-7; Chicago, IL.
40 Parisi G, Saco JD, Salazar FB, et al. Persistence of adoptively transferred T cells with a 
kinetically engineered IL-2 receptor agonist. Nat Commun 2020;11:660.
41 Sharma M, Khong H, Fa’ak F, et al. Bempegaldesleukin selectively depletes intratumoral 
Tregs and potentiates T cell-mediated cancer therapy. Nat Commun 2020;11:661.
42 Diab A, Tannir N, Cho D, et al. Pivot̺02: Preliminary safety, efficacy and biomarker results
from the Phase 1/2 study of CD-122̺biased agonist NKTR-214 plus nivolumab in patients 
with locally advanced/metastatic solid tumors. Paper presented at the Society for 
Immunotherapy of Cancer Annual Meeting, November 10-12, 2017, National Harbor, MD.
43 Bempegaldesleukin (NKTR-214) Investigator Brochure, Version 9. Nektar Therapeutics. 
2021. Document Control No. 930127258.
44 Diab A, Tannir NM, Bentebibel SE, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in 
patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and 
immune activation (PIVOT-02). Cancer Discov 2020;10:1158-73.
45 Diab A, Hurwitz ME, Cho DC, et al. NKTR-214 (CD-122-biased agonist) plus nivolumab in 
patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. Presented at 
Annual Meeting of the American Society of Clinical Oncology (ASCO); June 1-5, 2018a; 
Abstract #3006, Chicago, IL.
46 Diab A, Puzanov I, Maio, M. Clinical activity of BEMPEG plus NIVO in previously untreated 
patients with metastatic melanoma: updated results from the Phase 1/2 PIVOT-02 study. Paper 
presented at Annual Meeting of the Society for Immunotherapy of Cancer (SITC); 2019 Nov 
6 10; National Harbor, MD.
47 Siefker-Radtke AO, Fishman M, Balar V, et al. NKTR-214 + nivolumab in first-line 
advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02. Presented 
at Annual Meeting of the American Society of Clinical Oncology Genitourinary Cancers 
Symposium (ASCO-GU); February 14 16, 2019; San Francisco, CA.
48 Tolaney S, Baldini C, Spira A, et al. Clinical activity of BEMPEG plus NIVO observed in 
metastatic TNBC: Preliminary results from the TNBC cohort of the Ph1/2 PIVOT-02 study. 
Poster presented at the 2019 CRI-CIMT-EATI-AACR International Cancer Immunotherapy 
Conference, 26 September 2019, Paris, France.
49 https://news.bms.com/news/details/2022/Nektar-and-Bristol-Myers-Squibb-Announce-
Update-on-Clinical-Development-Program-for-Bempegaldesleukin-BEMPEG-in-
Combination-with-Opdivo-nivolumab/default.aspx.
50 Feifer AH, Taylor JM, Tarin TV, and Herr WH. Maximizing Cure for Muscle Invasive Bladder 
Cancer: Integration of Surgery and Chemotherapy. Eur Urol. 2011; 59(6): 978–984.
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51 Dotan ZA, Kavanagh K, Yossepowitch O, et al. Positive surgical margins in soft tissue 
following radical cystectomy for bladder cancer and cancer specific survival. J Urol. 2007; 
178:2308–2312.
52 Herr HW. Extent of pelvic lymph node dissection during radical cystectomy: where and why! 
Eur Urol. 2010; 57:212–213. [PubMed: 19896263]
53 Roth B, Wissmeyer MP, Zehnder P, et al. A new multimodality technique accurately maps the 
primary lymphatic landing sites of the bladder. Eur Urol 2010;57:205–11.
54 Chang SS, Bochner BH, Roger Chou R, et al. 2017. Treatment of Non-Metastatic Muscle-
Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline. The Journal Of Urology. 198, 
552-559
55 Dhar NB, Klein EA, Reuther AM, Thalmann GN, Madersbacher S, Studer UE. Outcome after 
radical cystectomy with limited or extended pelvic lymph node dissection. The Journal of 
Urology. 2008;179(3):873–878.
56 National Comprehensive Cancer Network Guidelines for Bladder Cancer. (Accessed Sep-
2018, https://www.nccn.org/professionals/physician_gls/default.aspx#site)
57 Bajorin DF and Herr HW. Kuhn’s Paradigms: are those closest to treating bladder cancer the 
last to appreciate the paradigm shift? JCO 2011;29(16):2135-7
58 Griffiths, G, International Phase III Trial Assessing Neoadjuvant Cisplatin, Methotrexate, and 
Vinblastine Chemotherapy for Muscle-Invasive Bladder Cancer: Long-Term Results of the 
BA06 30894 Trial. J Clin Oncol. 2011 Jun 1; 29(16): 2171–2177. Published online 2011 Apr 
18. doi: 10.1200/JCO.2010.32.3139
59 Dickstein RJ, Grossman HB, Pretzsch SM, et al: Can we reliably identify patients for radical 
cystectomy with neoadjuvant chemotherapy? Presented at the Annual Meeting of the Society 
of Urologic Oncology, Bethesda, MD, December 9-10, 2010 (abstr 23).
60 Canter D, Long C, Kutikov A, et al. Clinicopathological outcomes after radical cystectomy for 
clinical T2 urothelial carcinoma: Further evidence to support the use of neoadjuvant 
chemotherapy. 2011; BJU Int 107:58-62.
61 Dalbagni G, Genega E, Hashibe M, et al. Cystectomy for bladder cancer: a contemporary 
series. J Urol 2001;165:1111-6.
62 Mills RD, Turner WH, Fleischmann A, et al. Pelvic lymp node metastasis from bladder cancer: 
outcome in 83 patients after radical cystectomy and pelvic lymphadenectomy. J Urol 
2001;166:19-23.
63 Petrelli F, Coinu A, Cabiddu M, et al. Correlation of pathologic complete response with 
survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-
analysis. Eur Urol. 2014;65(2):350-7.
64 Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, et al. Pathologic downstaging is a surrogate 
marker for efficacy and increased survival following neoadjuvant chemotherapy and radical 
cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol. 2012 Jun;61(6):1229-38
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65 Haas CE, Nelsen JL. Drug-cytokine interactions. In Piscitelli SC, Rodvold KA, eds. Drug 
Interactions in Infectious Diseases. Human Press Inc, Totowa NJ, USA. 2005 pp 431-461.
66 Zídek Z, Anzenbacher P, Kmoníčková E. Current status and challenges of cytokine 
pharmacology. Br J Pharmacol 2009;157:342-61.
 
 
 
 
 
 
 
 
72 International Collaboration of Trialists on behalf of the Medical Research Council Advanced 
Bladder Cancer Working Party et al. J Clin Oncol 2011; 9: 16; 2171-2177.
73 Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-sequential 
trials. Statist. Med 2010;29:219-28.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ACLS
Advanced Cardiac Life Support 
AE
adverse event
AEC
Absolute eosinophil count 
AEOSI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
AEC
Absolute eosinophil count 
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
HCG
human chorionic gonadotrophin
Bcl-xL
B-cell lymphoma-extra large
BICR
Blinded independent central review
BMS
Bristol-Myers Squibb
BP
blood pressure
BTLA
B and T lymphocyte associated
BUN
blood urea nitrogen
Cavgss
steady state average concentration
CAD
coronary artery disease
CBC
complete blood count
CD8+
CD8 positive
CD 122
interleukin-2 receptor subunit beta
CD-28
cluster of differentiation 28
CFR
Code of Federal Regulations 
cHL
classical Hodgkin’s lymphoma
CI
confidence interval
CLcr
creatinine clearance
Cmaxss
steady-state peak concentrations
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Term
Definition
CMH
Cochran-Mantel Haenszel 
CMV
cytomeglovirus
COVID-19
coronavirus disease 2019
CR
complete response
CRC
Colorectal cancer
CRF
Case Report Form, paper or electronic
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events 
CTLA-4
cytotoxic T-lymphocyte–associated antigen 4
CVA
cerebrovascular accident 
Cavgss
simulated steady state average concentration
DFS
Disease free survival
dL
deciliter
DLT
dose-limiting toxicity
DMC
Data monitoring committee
DNA
deoxyribonucleic acid
DOAC
direct oral anticoagulation
DWI
diffusion-weighted imaging
ECG
electrocardiogram
ECHO
echocardiogram
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
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Term
Definition
FDA
Food and Drug Administration
FFPE
Formalin-Fixed Paraffin-Embedded
FSH
follicle stimulating hormone
g
gram
GC
gemcitabine and cisplatin 
GFR
glomerular filtration rate
h
hour
H&E
hematoxylin and eosin
HBsAg
hepatitis B surface antigen
HCC
Hepato cellular carcinoma
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
hazard ratio
IB
Investigator’s brochure
ICE
ischemic cerebrovascular event (ICE)
ICF
Informed consent form
ICOS
inducible T-cell costimulator
ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
interferon-γ
IHC
immunohistochemistry 
IL-2
interleukin-2
IL-2Rβγ
IL-2-receptor beta gamma subunit
IMAE
Immune mediated adverse event
INR
international normalised ratio
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Term
Definition
IO
Immuno Oncology
IP
investigational products
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intention-to-treat
IV
intravenous
kg
kilogram
L
liter
LDH
lactate dehydrogenase
LFT
liver function test
LMWH
low molecular weight heparin
LN
lymph node
LVEF
left ventricular ejection fraction
mg
milligram
MIBC
muscle-invasive bladder cancer
min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition
MVAC
methotrexate, vinblastine, doxorubicin, cisplatin
g
microgram
N
number of subjects or observations
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Term
Definition
NAC
neoadjuvant chemotherapy 
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
NCDB
National Cancer Data Base
NK
natural killer
NKTR
Nektar Therapeutics
NKTR-214
bempegaldesleukin
NMIBC
non-muscle invasive bladder cancer
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over the counter
PBMC
peripheral blood mononuclear cell
pCR
pathologic complete response
PD
Progressive disease
PD-1
programmed cell death protein-1
PD-L1
programmed death ligand 1
PEG
polyethylene glycol
PET
positron emission tomography
PFS
progression-free survival
PGC
paclitaxel, gemcitabine, and cisplatin 
PK
pharmacokinetics
PLND
pelvic lymph node dissection
PPK
population pharmacokinetics
PO
per os (by mouth route of administration)
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Term
Definition
PR
partial response
PSA
Prostate Specific Antigen 
Q2W
every two weeks
Q3W
every three weeks
RC
Radical Cystectomy
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RFS
relapse-free survival 
RP2D
recommended Phase 2 dose
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SD
standard deviation
SOC
standard of care
SOGUG
Spanish Oncology Genitourinary Group
t
temperature
T
time
T cell
regulatory T cell
TCR
T cell receptor
TIA
Transient ischemic attack
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Term
Definition
TME
tumor microenvironment
TNM
tumor, node, and metastasis
Tregs
regulatory T cells
TSH
thyroid-stimulating hormone
TURBT
Transurethral Resection of Bladder Tumor
UC
urothelial carcinoma
ULN
upper limit of normal
US
United States of America
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 GuidelinesGood 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 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. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee.
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. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. 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. Certain CRF pages and/or electronic files may serve as the source 
documents:
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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.
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.
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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.

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.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
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)
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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.  
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 9.2.9 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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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
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.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure

End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
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human teratogenicity or fetotoxicity. This should be evaluated in context of safety margins 
from the no-observed adverse effect level (NOAEL) or the time required for 5 half-lives of the 
IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b 

oral (birth control pills)

intravaginal (vaginal birth control suppositories, rings, creams, gels)

transdermal 

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy

Progestogen-only hormonal contraception associated with inhibition of ovulation (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol)b 

oral 

injectable 

Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol) b,c

Bilateral tubal occlusion

Vasectomized partner 
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.
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
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 treatment. 
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.

Continuous abstinence must begin at least 30 days prior to initiation of study therapy

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 

Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
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 treatment, 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. 
c 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
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.

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 (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
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Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
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
ECOG (ADULT) PERFORMANCE STATUS SCALES
PERFORMANCE STATUS CRITERIA: ECOG Score 
ECOG (Zubrod) 
Score 
Description
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 alight or 
sedentary nature, e.g., 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.
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APPENDIX 6
MANAGEMENT ALGORITHMS
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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APPENDIX 7
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM *PER PROTOCOL AMENDMENT 
04 NO LONGER APPLICABLE.
The table below provides a management algorithm for possible signs/symptoms of CVA for 
participants treated with the combination of bempegaldesleukin with a checkpoint inhibitor. This 
general guideline constitutes guidance to the Investigator and may be supplemented by clinical 
judgement of the Investigator and/or discussions with the Medical Monitor representing the 
Sponsor.
CEREBROVASCULAR ACCIDENT
ADVERSE EVENT MANAGEMENT ALGORITHM
This guideline pertains to all participants receiving bempegaldesleukin (NKTR-214) in 
combination with nivolumab.
For unexplained neurological symptoms (such as hemiparesis, confusion, dysarthria, or visual 
disturbances) that may be associated with CVA:

Recommend following the Advanced Cardiac Life Support (ACLS) Adult Suspected 
Stroke Algorithm that includes time-sensitive assessment and rtPA use guidance.a

Perform neurological imaging with DWI MRI as soon as feasible after the initial presentation
of symptoms, preferably within 24 hours, or as indicated following an acute intervention. 
DWI MRI is preferred, but if contraindicated, alternative imaging modalities may be used.
If imaging is consistent with a CVA, proceed to the following:
1
For any new CVA event confirmed by imaging (DWI MRI preferred unless 
contraindicated), regardless of neurological symptoms (eg, cryptogenic CVA), and for 
suspected TIA without clear alternative etiology:

Discontinue study treatment for participants receiving bempegaldesleukin in 
combination with a checkpoint inhibitor (ie, nivolumab).
2
Neurology consultation recommended.
3
Perform pertinent laboratory assessments including coagulation (D-dimer, complete 
blood count with differential, serum blood urea nitrogen, and creatinine)
 
, preferably by central laboratory testing. Local laboratory 
testing is allowed when central laboratory testing is not possible.
4
Consider cardiac echocardiogram (trans-esophageal as appropriate) to evaluate for 
potential source of emboli.
Abbreviations: ACLS, Advanced Cardiac Life Support; CVA, cerebrovascular accident; DWI, diffusion-weighted 
imaging; MRI, magnetic resonance imaging; rtPA, recombinant tissue plasminogen activator; TIA, transient ischemic 
attack.
a ACLS-algorithms.com. Adult Stroke Algorithm, (ACLS) Advanced Cardiac Life Support [Internet]; 2021 [cited 5 
May 2021]. Available from: https://acls-algorithms.com/adult-stroke-algorithm/. Additional consideration to the 
above CVA management guidelines for adolescent study population: rtPA use is not approved in this age group for 
acute ischemic stroke indication. Follow age-appropriate institutional guidelines for antithrombotic therapies for 
emergency ischemic stroke management.
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APPENDIX 8
CYTOKINE RELEASE SYNDROME (CRS) MANAGEMENT 
ALGORITHM *PER PROTOCOL AMENDMENT 04 NO LONGER 
APPLICABLE.
A management algorithm for cytokine-release syndrome (CRS) for participants treated with 
bempegaldesleukin is provided below. This general guideline constitutes guidance to the 
Investigator and may be supplemented by discussions with the Medical Monitor representing the 
Sponsor.
As a general principle, differential diagnoses should be diligently evaluated according to standard 
medical practice. Non-inflammatory etiologies should be considered and appropriately treated.
For patients with suspected CRS:
For Grade 1 or Grade 2 events, implement supportive care, including management of isolated 
symptoms based on institutional practices
Consider admitting the patient for monitoring and to provide supportive care, including management 
of isolated symptoms based on institutional practices and protocol management guideline 
(eg, hydration management guidelines in Section 7.1.1.1).
For patients with a persistent or worsening clinical condition after initial treatment of CRS, 
re-evaluate for other contributing conditions. It is particularly important to reassess the patient for 
coexisting infections, cardiac, pulmonary, thromboembolic, and other complications.
Grading Assessment per 
CTCAE Version 5.0
Treatment Measures Recommended
CRS 
Grade 3 
Hypotension 
managed with 
1 pressor
Hypoxia requiring 
> 40% O2
Vasopressin administration should be considered if the 
hypotensive event is refractory to > 3 L of fluid resuscitation.
Oxygen therapy (nasal canula, non-invasive positive pressure 
ventilation, etc.) for respiratory symptoms with consideration 
of intubation for a patient with severe respiratory 
manifestations.
Supportive care for renal, hepatic and other organ function 
deteriorations.
Steroid therapy should be considered (eg, hydrocortisone 
100 mg every 8 hours, dexamethasone 10 mg up to 4 times 
daily, 1 to 2 mg/kg/day methylprednisone IV or PO 
equivalent).
High-dose steroid (eg, solumedrol 2 mg/kg up to 1 gram daily 
for 3 days) may be considered for severe CRS that failed to 
respond after repetitive steroid treatments.
For severe CRS cases that require simultaneously aggressive 
management of hypotension, oxygenation and cardiac 
telemetry, consult Intensivist for ICU evaluation.
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APPENDIX 9
DEFINITIONS OF AJCC TNM
The American Joint Committee for Cancer (AJCC) TNM Staging System is based on the extent 
of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M). 
Adapted from Amin, M.B., Edge, S., Greene, F., Byrd, D.R., Brookland, R.K., Washington, M.K., 
et al. (Eds.) (2017). AJCC Cancer Staging Manual, 8th Edition. Switzerland:Springer International 
Publishing.
Table 1:
Definition of Primary Tumor (T)
T Category
T Criteria
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Ta
Non-invasive papillary carcinoma
Tis
Urothelial carcinoma in situ: “flat tumor”
T1
Tumor invades lamina propria (subepithelial connective tissue)
T2
Tumor invades muscularis propria
pT2a
Tumor invades superficial muscularis propria (inner half)
pT2b
Tumor invades deep muscularis propria (outer half)
T3
Tumor invades perivesical soft tissue
pT3a
Microscopically
pT3b
Macroscopically (extravesical mass)
T4
Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, 
uterus, vagina, pelvic wall, abdominal wall
T4a
Extravesical tumor invades directly into prostatic stroma uterus, vagina
T4b
Extravesical tumor invades pelvic wall, abdominal wall
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Table 2:
Definition of Regional Lymph Node (N)
N Category
N Criteria
NX
Lymph nodes cannot be assessed
N0
No lymph node metastasis
N1
Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and 
external iliac or sacral lymph node
N2
Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and 
external iliac or sacral lymph node metastasis 
N3
Lymph node metastasis to the common iliac lymph nodes
Table 3:
Definition of Distant Metastasis (M)
M Category
M Criteria
M0
No distant metastasis
M1
Distant metastasis
M1a
Distant metastasis limited to lymph nodes beyond the common iliacs
M1b
Non-lymph-node distant metastasis
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APPENDIX 10
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or 2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions

Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.

Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.

Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
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default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.

Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 

Non-CR/Non-PD: Persistence of one or more non-target lesion(s)

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
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if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
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CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE 
= inevaluable.
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR = complete response, PD = progressive disease and NE = inevaluable.
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCE: 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 11
COUNTRY SPECIFIC REQUIREMENTS
Any Countries Where Exclusion of HIV Positive Participants Is Locally Mandated
Original Language/Section 
Number
Country-specific language
Section 2 Flow Chart/Time
and Events Schedule, Table 2-
1: Screening Assessments-
LaboratoryTests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 2)j 
“Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS)”to be 
replaced with “Positive test for HIV”.
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APPENDIX 12
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 03, 26-Aug-2021
Revisions made to include the addition of participants with high-risk urothelial carcinoma (UC) of 
the bladder with N1 disease and muscle-invasive bladder cancer (MIBC), addition of nivolumab 
+ bempegaldesleukin vs nivolumab secondary endpoint comparisons, and the updated alpha 
allocation for the pathologic complete response (pCR) and event free survival (EFS) primary 
endpoints. Additional revisions made to align with Nivolumab and Bempegaldesleukin program 
standards. Other updates have also been made to align with changes to safety assessments 
including safety management algorithms. Guidance for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) status as well as coronavirus disease 2019 (COVID-19) vaccine has 
also been included. This amendment incorporates the changes from the approved Administrative 
Letter 03.
Revisions are applicable to future participants enrolled in the study, and where applicable, to all 
participants currently enrolled.
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Title Page

Revised to include the National Clinical 
Trial (NCT) Number and Universal 
Trial Number (UTN)

Updated study contact information

Updated study title to include 
bempegaldesleukin

Bristol-Myers Squibb locations updated
To provide current information for 
the study
Synopsis
Updated synopsis to match relevant protocol 
revisions
Reflect changes in protocol body 
as summarized below
Table 2-1 Screening 
Procedural Outline
Notes section updated for: Informed 
Consent, UC of the bladder/MIBC 
Confirmation, Tumor Sample Submission, 
Oral Hydration Follow-up (Arm A only), 
Adverse Event (AE) and Serious Adverse 
Event (SAE) Assessments, Concomitant 
Medication Use, Clinical Laboratory Testing
To provide consistency

Updated Medical History notes to 
include T1 stage

Clarified staging to include N0, N1, or 
M0 
Revised to incorporate updates to 
patient population
Body Imaging notes updated to 35 days 
(from 28 days) prior to randomization
To provide clarification and 
increase the body imaging window 
at screening 

Added UC of the bladder to MIBC 
Confirmation
Revised to incorporate updates to 
patient population
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Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale

Added Tumor Tissue Assessment 
procedure
Updated Prior and Concomitant Medication 
Review/Use
Include vaccine use
Table 2-1 Screening 
Procedural Outline
Table 2-2 Pre-surgery 
(Neoadjuvant) Procedures 
and Assessments (Arm A + 
Arm B)
Table 2-3 Post-surgery 
(Adjuvant) Procedures and 
Assessments (Arm A and 
Arm B)
Table 2-4 Long-term 
Follow-up Assessments 
(Arm A and Arm B)
Table 2-5 Study 
Assessments - Arm C
Added “Measurements, Vital Signs, and 
Performance Status” to Physical 
Examination
To provide clarification
Table 2-2 Pre-surgery 
(Neoadjuvant) Procedures 
and Assessments (Arm A + 
Arm B)

Updated Cycle 2 and 3 to include “Day 
3-5”

Updated Day 8 to include -1 day 
window

Updated Clinical Laboratory Testing 
procedure to include Day 8 collection; 
updated Notes to include instruction on 
when to repeat testing
Revised to align with language for 
BMS program updates 

Concomitant Medication Use added 
note to record at each visit

Added note to complete 
 
 assessments within 14 days 
prior to radical cystectomy (RC)
To provide clarification
Body Imaging updated from “within 
4 weeks of completion of last dose of 
neoadjuvant therapy” to “after completion of 
last dose”
Revised to provide flexibility of 
scheduling procedures as well as 
provide clarification
Deleted footnotes:

“All participants are required to have a 
visit at 60-90 days after RC to collect 
data related to RC and imaging is 
required at this visit. Participants who 
do not undergo RC for reasons other 
than disease progression, they may start 
their planned post-surgical treatment 
Updated to provide clarification 
and align with Table 2-3 Post-
surgery (Adjuvant) Procedures and 
Assessments (Arm A and Arm B)
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Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
following the first post-baseline tumor 
assessment.”

“If patients are dosed on a Thursday, 
Day 3 procedures may be done on Day 
2”

“Arm A only”
Table 2-2 Pre-surgery 
(Neoadjuvant) Procedures 
and Assessments (Arm A + 
Arm B)
Table 2-3 Post-surgery 
(Adjuvant) Procedures and 
Assessments (Arm A and 
Arm B)
Oral Hydration Follow-up notes: added 
instruction for sites to document the results 
of discussing hydration guidelines with 
participants
Added clarification on 
expectations for hypotension and 
syncope mitigation
Table 2-2 Pre-surgery 
(Neoadjuvant) Procedures 
and Assessments (Arm A + 
Arm B)
Table 2-3 Post-surgery 
(Adjuvant) Procedures and 
Assessments (Arm A and 
Arm B)
Table 2-4 Long-term 
Follow-up Assessments 
(Arm A and Arm B)
Table 2-5 Study 
Assessments - Arm C
Section 3.3.3 
Bempegaldesleukin and 
Nivolumab Benefit and 
Risk Assessment
Section 7.4.1 Nivolumab 
and Bempegaldesleukin 
Dose Delay, Resume, and 
Discontinuation Criteria
 

AE and SAE Assessments: added 
SARS-CoV-2 language

Updated to include benefit and risk 
considerations if participants had 
COVID-19

Added criteria for delaying treatment in 
case of SARS-CoV-2 infection
Participant safety management due 
to COVID-19
Table 2-3 Post-surgery 
(Adjuvant) Procedures and 
Assessments (Arm A and 
Arm B)

Updated post-surgery adjuvant Cycle 1 
“120 days” to “60 to 120 days”

Updated Notes header to delete “If a 
dose is delayed, then the procedures 
associated with that visit are delayed 
(with the exception of tumor 
assessments), which should continue per 
schedule;” added reference to footnote 
“d” to table column headers
To provide clarification
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Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale

Concomitant Medication Use added 
note to record at each visit

Cystoscopy notes updated to include 
information for participants who do not 
undergo RC

Added note for Clinical Laboratory 
Testing to include reference to Section 
9.4.7

Updated Body Imaging language to 
include RC; clarified tumor assessment 
frequency

Updated footnote “b” to clarify RC or 
cystoscopy

Footnote “e” added for participants who 
do not have RC

Cystoscopy language updated to include 
window for monitoring disease 
recurrence (every 12 weeks ± 7 days 
and every 24 weeks ± 14 days)

Updated footnote “c” to include 
windows
Revised to provide flexibility of 
scheduling procedures as well as 
provide clarification
Moved Submission of Tissue for pCR 
procedure 
 to 
Efficacy Assessments
For clarification of the two tissue 
collections occurring at the same 
time point
Table 2-3 Post-surgery 
(Adjuvant) Procedures and 
Assessments (Arm A and 
Arm B)
Table 2-4 Long-term 
Follow-up Assessments 
(Arm A and Arm B)
Table 2-5 Study 
Assessments - Arm C
Section 5.1.2.2 Surgery 
(Radical Cystectomy)

Clarified that maximal transurethral 
resection of bladder tumor (TURBT) to 
be performed at the time of the first 
cystoscopic examination (instead of first 
"on treatment" cystoscopy)

Added language on when monitoring 
should begin for participants who do not 
undergo RC
To provide clarification
Table 2-3 Post-surgery 
(Adjuvant) Procedures and 
Assessments (Arm A and 
Arm B)
Table 2-4 Long-term 
Follow-up Assessments 
(Arm A and Arm B)
Table 2-5 Study 
Assessments - Arm C
Added window of ± 7 days for completion 
of 
assessments
Revised to provide flexibility of 
scheduling procedures as well as 
provide clarification
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Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-4 Long-term 
Follow-up Assessments 
(Arm A and Arm B)

Updated Notes for AE Assessments

Concomitant Medication Use added 
note to record at each visit; removed 
collection at Survival Follow-up Every 
3 months

Updated “CBC w/Differential, 
Chemistry Panel, Endocrine Testing” to 
“Clinical Laboratory Testing”

Pregnancy Test updated to specify 
serum or urine and requirements
To provide clarification
Added Survival Status to Efficacy 
Assessments
Revised to align with most recent 
language for BMS program 
updates
Updated Body Imaging notes from every 
24 weeks ± 1 week to 2 weeks; specified 
maximum of 5 years “from the date of 
randomization”
To provide clarification and 
flexibility of scheduling
Cystoscopy language updated to include 
window for monitoring disease recurrence 
(every 12 weeks ± 7 days and every 
24 weeks ± 14 days)
Revised to provide flexibility of 
scheduling procedures as well as 
provide clarification
Deleted footnote that stated “Including 
details on subsequent therapy such as start 
and stop dates, best response, date of 
progression”
Removed duplication of 
information included in the Notes 
section
Table 2-5 Study 
Assessments - Arm C
Updated Notes for Concomitant Medication 
use to record at each visit
To provide clarification
Updated SAE Assessment to be performed 
continuously “until 100 days from RC”
To provide clarification for SAE 
collection for Arm C participants

Body Imaging language updated to 
include RC, clarified tumor assessments 
frequency
 
To provide clarification
Cystoscopy language updated:

To include window for monitoring 
disease recurrence (every 12 weeks 
± 7 days and every 24 weeks ± 14 days)

To add “for reasons other than 
progression”

Revised to provide flexibility 
of scheduling procedures as 
well as provide clarification

To provide clarification
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Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Added note to complete 
 
assessments within 14 days prior to RC
To provide clarification for 
completing 
 
assessment 
Table 2-4 Long-term 
Follow-up Assessments 
(Arm A and Arm B)
Table 2-5 Study 
Assessments - Arm C
Notes updated for Subsequent Anti-cancer 
Therapy
Revised to align with most recent 
language for BMS program 
updates 
Section 3 Introduction
Included updated tumor staging system 
groups
Provided further clarification 
Updated description of this study to include 
participants with UC of the bladder
Revised to align with updated 
patient population
Section 3.2.1 
Epidemiology/Indication

Updated background on patients with 
bladder cancer

Updated Management of UC, including 
MIBC section to include UC of the 
bladder information 

Added results from CheckMate-274
study
More recent dataset
Section 3.2.3 
Bempegaldesleukin

Updated references

Updated clinical experience data with 
data from final database locks
Updated references to reflect final 
publications
Section 3.2.4.1 Study 15-
214-01 (EXCEL; 
Bempegaldesleukin 
Monotherapy)

Added text to clarify bempegaldesleukin 
dose of 0.006 mg/kg was tolerated well 
and that the MTD was determined to be 
0.009 mg/kg

Deleted management guidelines to 
mitigate the risk of hypotension
Revised to align with most recent 
language for BMS program 
updates 
Provided additional information on best 
overall response for 28 patients evaluated in 
Study 15-214-01
More recent dataset
Section 3.2.4.2 Study 16-
214-02 (PIVOT-02; 
Bempegaldesleukin and 
Nivolumab Combination 
Therapy)

Replaced Oct-2018 data with Oct-2020 
data for PIVOT-02 study

Updated tumor response to include data 
from Jan-2019
More recent dataset
Updated to include text on serious events of 
cerebrovascular accident (CVA)
Revised to align with most recent 
language for BMS program 
updates 
Section 3.2.4.3 Pooled 
Safety Analysis of 
Participants with 
Bempegaldesleukin and 
Nivolumab Exposure
Section added; as a result of the added 
section, the following section was re-
numbered 
Revised to align with language for 
BMS program updates 
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Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.2.4.4 Observed 
Events of Cerebrovascular 
Accident
Updated to include section on initial and 
updated analysis of CVA accidents in 
PIVOT-02
Added and updated data and 
information to align with 
Bempegaldesleukin Investigator’s 
Brochure (IB) v9
Section 3.3.3 
Bempegaldesleukin and 
Nivolumab Benefit and 
Risk Assessment
Sentence added regarding benefit and risk 
considerations for COVID-19
Participant safety management due 
to COVID-19
Added non-live COVID-19 vaccination text
Address 
for the benefit-risk of COVID-19 
vaccination during participation in 
the clinical trial
Section 4 Objectives and 
Endpoints
Section 9.1.1.3 Definition 
of pCR
Table 10.3-1 Efficacy 
Analyses
Pathologic complete response definition 
updated from "T0, N0, M0" to "T0, N0"
Updated to remove M0 from 
definition
Section 4 Objectives and 
Endpoints

Primary and secondary objectives 
updated to add "in all randomized 
participants," where applicable

Updated the secondary objective to 
compare the pCR rate of neoadjuvant 
nivolumab monotherapy to standard of 
care to delete “at the time of surgery”
 
 
 
To provide clarification
Added secondary objectives and endpoints 
to evaluate (descriptively) the pCR rate and 
EFS of neoadjuvant nivolumab + 
bempegaldesleukin versus neoadjuvant 
nivolumab followed by adjuvant nivolumab 
in all randomized participants
Better comprehend final study 
results
Section 5.1 Overall Design
Figure 5.1-1 Study Design 
Schematic
Include updated stratification factors, added 
high-risk UC of the bladder to the patient 
population in the study design
T1-T4aN1 (high-risk UC of the 
bladder) participants were added 
to the study design
Protocol Amendment No.: 04
Date: 10-Jun-2022
221
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5.0
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Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Figure 5.1-1 Study Design 
Schematic
Study schematic updated from “Muscle 
invasive/resectable urothelial carcinoma” to 
“High-risk UC/muscle-invasive/resectable 
bladder cancer”
To provide clarification
Section 5.1.1 Screening 
Period
Updated text to specify tissue sample 
requirements prior to randomization 
To provide clarification
Section 5.1.2.2 Surgery 
(Radical Cystectomy)
Updated text to specify timing of RC for 
participants in Arms A, B, and C
To provide clarification
Updated text for pathology slides to include 
hematoxylin and eosin (H&E) and relevant 
immunohistochemistry (IHC)
Cystoscopy language updated to include 
window for monitoring disease recurrence 
(every 12 weeks ± 7 days and every 
24 weeks ± 14 days)
Revised to provide flexibility of 
scheduling procedures as well as 
provide clarification
Section 5.1.2.3 Adjuvant 
(Post-surgical Treatment)

Updated post-surgery adjuvant Cycle 1 
“120 days” to “60 to 120 days”
To provide clarification
Section 5.1.4.1 Blinded 
Pathology and Radiology 
Review

Added text to clarify that stained slides 
from the initial TURBT will be used to 
clinically diagnose UC of the 
bladder/MIBC

Updated radiology review text
To provide clarification
Section 5.3 End of Study 
Definition

Updated final analysis for primary 
endpoint pCR to 47 months from 
36 months

Updated final analysis for primary 
endpoint EFS to 65 months from 
54 months
Revised study accrual projections
Section 5.4 Scientific 
Rationale for Study Design
Section 5.4.2 Rationale for 
Study Comparator and 
Study Population
Added N1 stage to these sections
Added participants with high-risk 
UC of the bladder; addition of the 
N1 stage
Section 5.4 Scientific 
Rationale for Study Design
Updated recurrence rate for patients 
diagnosed with UC
More recent dataset
Section 5.4.2.2 Rationale 
for Including Participants 
with N1 in Bladder Cancer
Added section
Addition of the N1 stage
Section 5.4.5 Rationale for 
Stratification by Disease 
State and PD-L1
Section 7.2 Method of 
Treatment Assignment
Updated clinical stage stratification factors
Revised to align with updated 
patient population
Protocol Amendment No.: 04
Date: 10-Jun-2022
222
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 6.1 Inclusion 
Criteria
Revised inclusion criteria 2)a with 2)g and 
2)c with 2)h 
To provide clarification
Revised inclusion criteria 3)g)iv with 3)g)ix, 
3)g)v with 3)g)x, 3)g)vi with 3)g)xi, and 
3)g)vii with 3)g)xii 
Updated contraception 
requirements for 
bempegaldesleukin
Section 6.2 Exclusion 
Criteria
Updated exclusion criterion 1)a with 1)d
Align with updated participant 
population of high-risk UC
Added exclusion criteria 2)m and 3)e
Clarify expectations for eligibility 
for participants with suspected or 
confirmed symptomatic COVID-
19
Updated exclusion criterion 4)e to not 
applicable
To provide clarification and 
remove inconsistency with 
inclusion criterion 2)f
Section 6.4.1 Retesting 
During Screening Period
Added COVID-19 language
Clarify expectations for retesting 
for participants with suspected or 
confirmed symptomatic COVID-
19
Table 7-1 Study Treatments 
for CA045009/18-214-13
Updated to include available presentations of 
bempegaldesleukin 
Include potency for commercial 
supply of bempegaldesleukin
Deleted footnote “0.65 mg to be available 
only after local CMC regulatory 
requirements are fulfilled per region”
To provide clarification
Section 7.1.1 
Bempegaldesleukin Dosing
Added sentence "Bempegaldesleukin 
treatment can continue for participants 
randomized to the bempegaldesleukin and 
nivolumab combination arm in the event that 
nivolumab is permanently discontinued due 
to toxicities."
Revised to align with most recent 
language for BMS program 
updates 
Section 7.1.1.1 Hydration 
Guidelines
Section 7.6 Treatment 
Compliance
Added text to instruct participants on 
hydration and when to contact the treating 
oncologist
Added clarification on 
expectations for hypotension and 
syncope mitigation
Updated to include instruction for sites to 
document the results of discussing hydration 
guidelines with participants
Section 7.1.1.1 Hydration 
Guidelines
Deleted last sentence “Advise participants 
with orthostatic symptoms to call their 
treating oncologist and consider increasing 
oral hydration.”
Removed duplicate text in section
Section 7.1.2 Nivolumab 
Dosing
Added sentence "In the event that 
bempegaldesleukin is permanently 
discontinued due to toxicities, see 
Section 8.1.1."
Revised to align with most recent 
language for BMS program 
updates 
Protocol Amendment No.: 04
Date: 10-Jun-2022
223
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Deleted "Nivolumab treatment can continue 
for participants randomized to NKTR-214 
and nivolumab combination arm in the event 
that NKTR-214 is permanently discontinued 
due to toxicities, as noted above"
Removed duplicate text in section
Section 7.2 Method of 
Treatment Assignment
Added statement regarding new 
randomization schedule for participants with 
clinical stage T1-T4aN1M0
New randomization list needed for 
N1 participants
Section 7.4 Dosage 
Modification
Added second sentence in first paragraph
Revised to align with most recent 
language for BMS program 
updates
Added last sentence to reference 
discontinuation criteria in Section 8.1.1
To provide clarification
Section 7.4.1 Nivolumab 
and Bempegaldesleukin 
Dose Delay, Resume, and 
Discontinuation Criteria
Updated section title
Revised to align with most recent 
language for BMS program 
updates
Updated section to include statement 
regarding development and updating of 
management algorithms 
Updated study treatment dose 
delay, resume, and discontinuation 
criteria to align with the current 
CTCAE v5 and to align with 
Bempegaldesleukin IB v9 and 
Nivolumab IB v19 Addendum 01
Added: 

Table 7.4.1-1 Adverse Event Criteria for 
Delay, Resumption, and 
Discontinuation of Nivolumab and 
Bempegaldesleukin 

Table 7.4.1-2 Bempegaldesleukin-
specific Adverse Event Criteria for 
Delay, Resumption, and 
Discontinuation of Nivolumab and 
Bempegaldesleukin (if one is delayed, 
both are delayed)
Added SARS-CoV-2 infection and COVID-
19 vaccine language
Participant safety management due 
to COVID-19
Updated to include corticosteroid taper text
Revised to align with most recent 
language for BMS program 
updates
Section 7.4.1.1 Dose 
Modification Criteria for 
Bempegaldesleukin and 
Nivolumab for Cycle 1 
AST/ALT Elevations
Removed “Grade 2” and “Grade 3” sub 
headers
Revised to bridge 
bempegaldesleukin and nivolumab 
protocol updates to align with 
CTCAE v5 language
Updated “Grade 0-1” to “Grade 1 or 
baseline”
Section 7.4.3 Monitoring 
and Management of 
Updated last sentence to specify that 
bempegaldesleukin may need to be withheld 
and participant should be treated as 
Revised to align with most recent 
language for BMS program 
updates 
Protocol Amendment No.: 04
Date: 10-Jun-2022
224
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Bempegaldesleukin-
induced Eosinophilia
clinically indicated, if participant is 
suspected to have hypereosinophilic 
syndrome
Section 7.4.5 Criteria to 
Resume Bempegaldesleukin 
and/or Nivolumab
Section was deleted. As a result, the 
following sections were re-numbered.
Revised to align with Table 7.4.1-
1
Section 7.4.6 Management 
Algorithms for Immuno-
oncology Agents
Added reference to CVA and cytokine-
release syndrome (CRS) management 
algorithms
Revised to align with most recent 
language for BMS program 
updates 
Section 7.4.6.1 
Management Algorithm for 
Cytokine-release Syndrome
Section added
To align with Bempegaldesleukin 
IB v9 on the management of this 
potential risk
Section 7.4.7 Treatment of 
Bempegaldesleukin-related 
or Nivolumab-related 
Infusion Reactions
Added text “Subsequent infusions may be 
administered at a reduced rate (eg, 50% of 
the original infusion rate)” for Grade 1 and 
Grade 2 symptoms
To align with Bempegaldesleukin 
IB v9
Section 7.7.1 Prohibited 
and/or Restricted 
Treatments
Added language for COVID-19 vaccines
Participant safety management due 
to COVID-19
Section 7.7.1.1 Effect of 
Bempegaldesleukin on PK 
of Concomitant 
Medications
Clarified effect of bempegaldesleukin on 
pharmacokinetics of concomitant 
medications
To align with Bempegaldesleukin 
IB v9
Section 7.7.2.3 Blood 
Pressure Precautions
Updated text for alpha-blockers
Revised to align with most recent 
language for BMS program 
updates 
Clarified that antihypertensive medications 
may be reinstituted "at any time" as 
clinically indicated for bempegaldesleukin
Section 8.1 Discontinuation 
from Study Treatment
Replaced bullet point for “Disease 
progression” with “EFS event as defined in 
Section 9.1.1”
To provide clarification
Section 8.1.1 Nivolumab 
and Bempegaldesleukin 
Discontinuation Criteria
Updated to remove redundant criteria listed 
in Table 7.4.1-1
Revised to bridge 
bempegaldesleukin and nivolumab 
protocol updates to align with 
CTCAE v5 language
Section 9.1.1 Definition of 
Events in EFS
Removed references to BICR confirmation 
Clarification that primary EFS 
analysis will be based on BICR 
assessment and analysis by 
investigator will be conducted as a 
sensitivity
Updated definition for carcinoma in situ 
To provide clarification
Section 9.1.1.1 Definition 
of Disease Recurrence
Updated window for first post-surgery 
assessment from "120 days" to "60 to 
90 days" after RC
Revised to provide flexibility of 
scheduling procedures as well as 
provide clarification
Protocol Amendment No.: 04
Date: 10-Jun-2022
225
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Definition of new lymph node updated to 
include "growth of ≥ 5 mm"
To provide clarification
Section 9.1.1.2 Definition 
of Disease Progression
Updated first sentence to clarify RECIST 
v1.1 should be used to evaluate disease 
progression
To provide clarification
Section 9.1.2.2 BICR 
Confirmation of 
Progression or Recurrence
Added statement regarding events that 
require BICR confirmation
To provide clarification
Updated language on unequivocal disease 
progression/recurrence
Section 9.2.1 Time Period 
and Frequency for 
Collecting AE and SAE 
Information
Added collection for AEs related to SARS-
CoV-2
Participant safety management due 
to COVID-19 
Updated language to specify SAE collection 
for Arm C participants
To provide clarification
Section 9.2.2 Method of 
Detecting AEs and SAEs
Added language for collection of AEs 
following radical cystectomy
To provide clarification
Section 9.2.3 Follow-up of 
AEs and SAEs
 
 
Added SARS-Cov-2 language
Participant safety management due 
to COVID-19
Section 9.2.5 Pregnancy
Updated first sentence of last paragraph to 
remove instructional text that was 
inadvertently included in Revised Protocol 
01
Removal of model document 
instructional text
Table 9.4.7-1 Clinical 
Safety Laboratory 
Assessments
Updated "Fasting glucose" to "Glucose"
Revised to align with most recent 
language for BMS program 
updates 
Added table note for urinalysis
To provide clarification 
Protocol Amendment No.: 04
Date: 10-Jun-2022
226
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Protocol Amendment No.: 04
Date: 10-Jun-2022
227
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.1: Sample Size 
Determination

Updated accrual projection for study

Updated final analysis of OS from 
74 months to 86 months after study start
Revised study accrual projections

Updated 2-side alpha for pCR from 
0.015 to 0.001 and EFS from 0.035 to 
0.049

Updated pCR rate for experimental arm 
from 30% to 36%; updated power for 
control arm from 81% to 90%

Updated 2-sided power for pCR from 
81% to 90%; updated overall 
significance level from 0.015 to 0.001

Updated EFS power from 85% to 88% 
and type I error from 0.035 to 0.049

Updated boundary for statistical 
significance superiority from 0.006 to 
0.01 for first interim analysis of EFS 
endpoint

Updated boundary for statistical 
significance superiority from 0.018 to 
0.026 for second interim analysis of 
EFS endpoint

Updated boundary for statistical 
significance superiority from 0.029 to 
0.04 for final analysis of EFS endpoint

Updated power from 85% to 88% and 
type I error from 0.035 to 0.049 for OS 
events
Updated statistical design to adjust 
alpha allocation between pCR and 
EFS endpoints 
 
Added text about MRC/EORTC BA06
Phase 3 study
To provide clarification
Protocol Amendment No.: 04
Date: 10-Jun-2022
228
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Table 10.1-1: Sample Size 
Calculations per 
Comparison for Primary 
Endpoints

Updated Accrual Duration, pCR 
final/EFS Interim Analysis 1, EFS 
Interim Analysis 2, and EFS Final 
Analysis
Revised study accrual projections

Updated power from 81% to 90% for 
pCR and 85% to 88% for EFS

Updated Alpha from 1.5% to 0.001 for 
pCR and 3.5% to 0.049 for EFS

Updated Hypothesized Rates Control vs 
Experimental from 30% to 36% for pCR
Updated statistical design
Section 10.3: Statistical 
Analysis

Removed “including subgroups of age, 
gender and race” from first sentence

Updated overall 2-sided alpha for pCR 
from 0.015 to 0.001 and EFS from 
0.035 to 0.049

Added hierarchical testing approach to 
control type I error rate for pCR, EFS, 
and OS

Removed sentence “Further details on 
the methodology and testing strategy for 
the control of the type I error rate 
(including OS endpoint) will be 
described in the statistical analysis 
plan.”
Updated statistical design
Updated clinical stage stratification factors
Revised to align with updated 
study design
Added language regarding no planned 
formal powered comparison of Arm A vs 
Arm B
To provide clarification
Table 10.3-1: Efficacy 
Analyses
Updated CI to include 99.9% for Cochran 
Mantel Haenszel test
Updated statistical design

Removed reference to BICR assessment 
for EFS endpoint

Added text to clarify EFS Statistical 
Analysis Method to include BICR and 
investigator assessments
Clarification that primary EFS 
analysis will be based on BICR 
assessment and analysis by 
investigator will be conducted as a 
sensitivity
Added secondary endpoints to include pCR 
in Arm A vs Arm B and EFS in Arm A vs 
Arm B
Secondary objectives added to 
better comprehend the final study 
results
Figure 10.3-1: Graphical 
Representation of the 
Statistical Testing 
Approach
Added graphical representation of the 
statistical testing approach
Updated statistical design
Protocol Amendment No.: 04
Date: 10-Jun-2022
229
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Protocol Amendment 03
Section Number & 
Title
Description of Change
Brief Rationale
Table 10.3.3-1 Interim 
Analyses Schedule
Updated Projected Timing column for all 
analysis time points
Revised study accrual projections
Section 11 References
Updated references to remove duplicates in 
section and throughout protocol
Remove duplicate references
Appendix 2 Study 
Governance Considerations
Updated first paragraph in Monitoring 
section to include remote monitoring
To provide clarification
Added new subsection on dissemination of 
study data
Appendix 6 Management 
Algorithms
Updated the immuno-oncology (IO) agent 
management algorithms to align with 
CTCAE v5
Updated IO management 
algorithms for immune-mediated 
AEs to align with current CTCAE 
v5 and the updated Nivolumab IB 
v19 Addendum 01.
Appendix 7 
Cerebrovascular Accident 
Adverse Event 
Management Algorithm
Updated CVA management algorithm
To clarify CVA and TIA 
algorithms and to align with 
Bempegaldesleukin IB v9
Appendix 8 Cytokine 
Release Syndrome (CRS) 
Management Algorithm
Added new appendix for CRS management 
algorithm. As a result, the following 
appendices were re-numbered.
Added new Appendix and align 
with Bempegaldesleukin IB v9
Appendix 11 Country 
Specific Requirements

Updated sentence to “Any countries 
where exclusion of”

Corrected exclusion criterion referenced 
in table
To provide clarification
Removed “Discontinuation of treatment due 
to pregnancy” row 
Protocol has stricter language
All
Updated NKTR-214 to bempegaldesleukin
Revised to align with most recent 
language for BMS program 
updates
All
Minor typographical errors were corrected, 
and edits were made for consistency and 
clarity 
Minor, therefore have not been 
summarized
Protocol Amendment No.: 04
Date: 10-Jun-2022
230
6.0
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930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Overall Rationale for the Revised Protocol 02, 05-Mar-2020
Revisions made to include CVA mitigation. Additional revisions made to align with Nivolumab 
and NKTR-214 essential protocol elements updates. Revisions are applicable to future participants 
enrolled in the study, and where applicable, to all participants currently enrolled.
Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Synopsis
Updated synopsis
Reflect changes in protocol body as 
summarized below
Section 2: Schedule of 
activities
Specificity added to body imaging 
language 
Removed “60-90 days after RC” in 
Table 2-4 Long-term Follow-up 
Assessments
Updated MIBC confirmation to include 
H&E and/or IHC stained slides
Updated Table 2-2: Day 8 
 
 Arm A
Clarification
Tables 2-2, 2-3: Oral hydration 
follow-up
Section 7.1.1.1: Hydration 
guidelines
Section 7.6: Treatment 
compliance
Updated to include hydration 
compliance contact
CVA mitigation
Tables 2-4, 2-5: Subsequent 
therapy
Added notes to subsequent therapy
Revised to align with most recent 
language for BMS program updates
Tables 2-2, 2-3: Clinical 
laboratory testing
Added language to include renal 
function assessment
Safety and clarifications
Section 3: Introduction
Replaced “NKTR-214” with 
“bempegaldesleukin” where applicable
Revised to align with most recent 
language for BMS program updates
Section 3.2: Background
Updated NKTR-214 mechanism of 
action 
Updated clinical experience with 
NKTR-214
Added observed events of 
cerebrovascular accident in PIVOT-02 
study
More recent dataset
Section 3.3: Benefit-risk 
assessment
Updated NKTR-214 safety profile 
language
Updated NKTR-214 and nivolumab 
benefit and risk assessment
More recent dataset
Protocol Amendment No.: 04
Date: 10-Jun-2022
231
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Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 5.1: Overall design
Updated Figure 5.1-1 Study design 
schematic
Visual clarity of study design 
schematic   
Section 5.1.2: Treatment period
Updated details for diagnostic slides in 
surgery (RC) section
Clarification
Section 5.1.4.1: Blinded 
Pathology and Radiology 
Review
Language added in Pathology Review
Clarification
Section 5.2: Number of 
participants
Updated screen fail rate from 20 to 
25%
More recent dataset
Section 5.3: End of study 
definition
Section 5.4.3: Rationale for 
choice of endpoints
Removed reference to “co-primary” 
terminology
Reflect update 
 
Section 5.4.5: Rationale for 
stratification by disease state 
and PDL-1
Updated stratification from “pT2 vs 
pT3/T4a” to “clinical stage (T2 vs 
T3/T4a)”
Clarification
Section 6: Study population
Updated age and reproductive status
Revised to align with most recent 
language for BMS program updates
Section 6.2: Exclusion criteria
Updated to remove “or UC not 
confined to the bladder” in exclusion 
1c
Added CVA exclusion criteria
Added adrenal insufficiency exclusion
Correction of typographical error 
CVA mitigation
Safety and clarification
Section 7 
Updated study treatments table
Updated “pharmacy reference sheet” to 
“pharmacy manual”
Updated NKTR-214 dosing
Clarification
Section 6.3: Lifestyle 
restrictions
Updated text to state “strenuous 
activities” and “long, hot showers”
CVA mitigation and IB update
Protocol Amendment No.: 04
Date: 10-Jun-2022
232
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 7.1: Treatments 
administered
Updated hydration guidelines
Section 7.2: Method of 
treatment assignment
Updated to reference Appendix 8
Updated stratification language
Clarification
Section 7.4: Dose modification
Added language for nivolumab and 
NKTR-214 dose delay and reduction 
criteria
Added dose modification criteria for 
Cycle 1 AST/ALT elevations
Added monitoring and management of 
elevated hepatic transaminases
Added monitoring and management of 
adrenal insufficiency hypophysitis
Updated criteria to resume NKTR-214 
and/or nivolumab
Added myocarditis management 
algorithm 
Safety and clarifications
Section 7.7: Concomitant 
therapy
Updated prohibited and/or restricted 
treatments
Added effect of NKTR-214 on PK of 
concomitant medications section
Added restricted treatments section
Updated blood pressure precautions
CVA mitigation
Section 7.7.2.2: Imaging 
restriction and precautions
Updated restriction and precautions 
section
Revised to align with most recent 
language for BMS program updates
Section 8: Discontinuation 
criteria
Updated nivolumab and NKTR-214 
discontinuation criteria
Updated post-study treatment study 
follow-up
Safety and clarification
Section 9.1: Efficacy 
assessments
Updated methods of measurements
Clarification
Section 9.2: Adverse events
Updated time period and frequency for 
collecting AE and SAE information to 
include AEOSI bullet 
Added AEOSI section 9.2.7
CVA mitigation
Section 9.2.5: Pregnancy
Removed language about terminated 
pregnancy
Revised to align with most recent 
language for BMS program updates
Section 9.2.6: Immune-
mediated adverse events
Moved section from 9.2.1 to 9.2.6  
Revised to align with most recent 
language for BMS program updates
Protocol Amendment No.: 04
Date: 10-Jun-2022
233
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 9.4.1: Vital signs and 
oxygen saturation
Removed “oral” from temperature
assessment
Clarification
Table 9.4.7-1: Clinical safety 
laboratory assessments
Added “or serum urea” to BUN
Removed 
“screening 
only” 
from 
albumin
Updated to reference Appendix 10
Clarification
Section 10.1: Sample size 
determination
Section 10.3: Statistical 
analyses
Added “2-sided” to alpha
Updated text for EFS interim analyses 
to 
remove 
“upper 
tract 
tumor 
recurrence”
Clarification
Table 10.2-1: Analysis 
populations
Added language to description of all 
treated participants
Clarification
Section 12: Appendix 1
Added definitions of AEOSI, ASCO, 
DOAC, DWI, EOI, H&E, IB, INR, 
LFT, LMWH, NKTR-214, TSH
Clarification
Section 12: Appendices
Updated 
study 
governance 
considerations (Appendix 2)
Updated 
women 
of 
childbearing 
potential definitions and methods of 
contraception (Appendix 4)
Revised to align with most recent 
language for BMS program updates
Protocol Amendment No.: 04
Date: 10-Jun-2022
234
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Updated country specific requirements 
(Appendix 10)
Section 12: Appendices
Added myocarditis treatment algorithm 
to Appendix 6
Added Appendix 7: CVA algorithm
Safety; revised to align with most 
recent language for BMS program 
updates 
Section 12: Appendix 5
Updated appendix title to remove “and 
Lansky (adolescents)”
Clarification
All
Updated header to replace “pegylated 
human 
recombinant 
Interleukini-2” 
with “bempegaldesleukin”
Moved “NKTR-214” from left to right 
side of header
Revised to align with most recent 
language for BMS program updates
All
Re-numbering of sections or appendices 
due to insertion of additional sections
Minor 
typographical 
errors 
were 
corrected and edits were made for 
consistency and clarity 
Insertion or relocation of sections or 
appendices in protocol, as mentioned 
above
Minor, therefore have not been 
summarized
Protocol Amendment No.: 04
Date: 10-Jun-2022
235
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Overall Rationale for the Revised Protocol 01, 21-Jan-2019
Revisions made 
. Additional revisions made to align with 
BMS policy and nivolumab/NKTR-214 program updates. Revisions are applicable to future 
participants enrolled in the study, and where applicable, to all participants currently enrolled.
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 2
Specificity added to pregnancy 
language 
Clarification
Table 2-1 and Section 6.1 
Inclusion Criteria
Section 5.1 Study Design
Section 7.2 Method of 
Treatment Assignment
Updated language to emphasize receipt 
of MIBC confirmation prior to 
randomization added to screening table.
Confirmation of pathologic diagnosis 
added to ensure enrollment of 
intended patient population.
Table 2-1
Section 6.1 Inclusion Criteria
Tumor tissues submission criteria
“non-evaluable” was removed from 
previously acceptable PD-L1 
classification; “indeterminate/non-
evaluable”.
Tumor tissue samples must be 
evaluable
Samples have “indeterminate”
PD-L1 expression when a sample is 
otherwise evaluable.
Table 2.1 Screening
Section 9.4.3 SoA / ECG
Medical Monitor approval removed for 
abnormal baseline ECG abnormalities.
Investigator to use existing 
Inclusion/Exclusion criteria and 
clinical judgment.
Table 2.2
Treatment 
SoA
Treatment changed for Cycle 1: 
(Day 5± 1day) replaced (Day 4-7)
Provide clarification
Table 2-3
Specified “once consent has been 
obtained” to heading
Wording for timeframe to begin Cycle 
1 changed from “within 60-120 days to 
“within 120 days”
Participants who have not completed 
radical cystectomy, must be 
reconsented before receiving 
adjuvant therapy
Provide clarification
Clinical Experience
Section 3.2.4.2
Updated PIVOT-02 data (07Ma018)
More recent dataset
Section 5.1.4
Data Monitoring Committees
The following sentence was added:
“When required, adjudicated events 
will be submitted to the DMC and 
Health Authorities for review on a 
specified timeframe in accordance with 
the adjudication documentation”
Required text for studies involving 
external committees
Section 5.4.6
Scientific Rationale
Updated rationale for duration of 
treatment with NKTR-214
Aligned with hypothesized MoA
Section 6.1
Inclusion Criteria
Removed procedural time frames from 
Inclusion/Exclusion criteria (still 
Not necessary to define the 
population
Protocol Amendment No.: 04
Date: 10-Jun-2022
236
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
applicable in SoA, e.g. CT within 
28 days)
Section 6.1 
Inclusion Criteria
Removed “Life expectancy ≥ 12 weeks
Inclusion criterion deemed irrelevant 
for this study population
Section 6.1
Inclusion Criteria 
Window tissue submission increased 
from 8-12 weeks
Loosens time frame for archived 
tissue sample
Section 6.1 
Inclusion Criteria
Added text to address fetal protection. 
Participants still must undergo monthly 
pregnancy testing
Added contraception exception for 
abstinent WOCBP and removed 
exception for Azoospermic males
Updated BMS policy addressing 
WOCBP and Clinical Trials 
Risk of drug(s) passing into seminal 
fluid
Section 6.2
Exclusion Criteria
Adjusted arrhythmia criteria
Clinical judgment
Section 7.3
Blinding
Added standard blinding language
To allow limited 
 lab personnel to 
view treatment allocation
Section 7.4.1
Dose Delay
Updated NKTR-214 dose delay criteria
Section 7.4.3 Resumption
Added criteria to resume NKTR-214 
and/or Nivolumab from Nivolumab 
program language.
Added: Grade ≥3 adrenal insufficiency 
requires discontinuation.
Clarification
Section 7.4.5
Infusion Reactions
Removed mandatory Medical Monitor 
contact for Grade 3+ infusion reaction
Clinical judgment and generally 
covered by 24 hour SAE reporting
Section 7.6
Compliance
Added compliance language
Standardization
Section 7.7.2.2
Blood Pressure Precautions
“5-10 days” to restart hypertensive 
medications was replaced with “as 
clinically indicated”
Clinical Judgement
Section 8.1.1
Discontinuation Criteria
Specified: Grade ≥ 3 adrenal 
insufficiency requires discontinuation 
regardless of control with hormone 
replacement
Removed mandatory Medical Monitor
approval for partial discontinuations
to 
specify dosing interruptions 
permission
Clinical Judgement
Section 8.1.2
Post Treatment Follow-up
Added text to take into account 
roll-over studies
Allow continuation into roll-over 
study when applicable
Section 9.2.1
Immune-Mediated AEs
Added imAE language aligned with 
Nivolumab program and NKTR-214 
select AE language
Specifies additional data may be 
collected
Protocol Amendment No.: 04
Date: 10-Jun-2022
237
6.0
Approved
930131308
5.0
v
Approved
1.0
v

Clinical Protocol
CA045009/18-214-13
BMS-986321 
bempegaldesleukin (NKTR-214)
Summary of Key Changes for Revised Protocol 01
Section Number & Title
Description of Change
Brief Rationale
Section 9.2.6
Pregnancy
Text added to address fetal protection
Removed mandatory discontinuation 
(i.e. if pregnancy has ended)
Updated BMS policy
Section 9.2.8
DILI
Adjusted DILI definition
To account for patients with baseline 
transaminase elevations
Section 9.3 
Overdose
Added overdose definition
To align with appendix update
Section 10
Number of Participants
Number of participants changed from 
160 to 180 
Typo corrected; 180 is correct 
number
Appendix 3
Adverse Events
Text added to AE definition of events 
not meeting the AE definition:
Anticipated day-to-day fluctuations of 
pre-existing disease(s) or condition(s) 
present or detected at the start of the 
study that do not worsen.
The following paragraph was removed 
from definition of SAE:
Any component of a study endpoint that 
is considered related to study therapy 
should be reported as SAE (e.g., death is 
an endpoint, if death occurred due to 
anaphylaxis, 
anaphylaxis 
must 
be 
reported).
Correction made; text inadvertently 
dropped from previous version
Not applicable for oncology studies; 
only applies to protocols with 
endpoints that are excluded from 
regular reporting as SAE's.
Appendix 4
WOCBP
Replaced with nivolumab program 
specific appendix
Alignment 
Appendix 9
Country Specific
Added appendix for HIV testing
Required 
appendix 
based 
on 
Nivolumab program; inadvertently 
left out of previous version
Protocol Amendment No.: 04
Date: 10-Jun-2022
238
6.0
Approved
930131308
5.0
v
Approved
1.0
v