A Phase 3, Randomized, Open-label Study of NKTR-214 Combined With Nivolumab Versus Nivolumab in Participants With Previously Untreated Unresectable or Metastatic Melanoma
Phase: PHASE3
Conditions: Melanoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
 
A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus Nivolumab 
in Participants with Previously Untreated Unresectable or Metastatic Melanoma 
 
 
NCT Number: NCT03635983 
Document Date (Date in which document was last revised): May 19, 2022 

Page:
1
Protocol Number:
CA045001/17-214-08
IND Number:
139,237
EX-US
Non-IND
EUDRACT Number:
2018-001423-40
Date:
25-May-2018
Revised Date:
19-May-2022
CLINICAL PROTOCOL CA045001/17-214-08
A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus 
Nivolumab in Participants with Previously Untreated Unresectable or Metastatic Melanoma 
Protocol Amendment 03
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-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).
©2022 Bristol-Myers Squibb Company
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 03
19-May-2022
Key changes include:
•
Participants who are currently receiving bempegaldesleukin plus
nivolumab are required to discontinue bempegaldesleukin and may 
continue nivolumab monotherapy.
•
Nivolumab monotherapy dose for participants in Arm A and Arm B 
will be 480 mg IV (intravenous) Q4W (every four weeks) 
(participants < 40 kg: weight-based 6 mg/kg IV Q4W).
•
Maximum duration of the study is up to 2 years +100 days from the 
randomization of the last participant.
•
Tumor assessment evaluated by the Investigator only.
•
No further formal overall survival (OS) analyses will be performed.
•
Secondary and exploratory objectives except biomarker parameters 
will no longer be applicable. Biomarker sample collection will not be 
applicable. However, exploratory biomarker analysis on previously 
collected samples may be conducted.
Protocol 
Amendment 02
26-Aug-2021
Key changes include:
•
Clarified tumor tissue requirement.
•
Updated study treatment dose delay, resumption, and discontinuation, 
and adverse events management for NCI CTCAE version 5. Added 
permanent discontinuation criteria for bempegaldesleukin treatment 
related to CVA and TIA. Updated CVA management algorithm 
(Appendix 7).
•
Added cytokine release syndrome information and
management/algorithm (Appendix 11).
•
Updated projection of analysis times based on updated enrollment 
projection.
•
Added additional information on PFS assumptions and provided the 
estimated median PFS by arm.
•
Added provisional language for conducting OS final analysis at 60 
months after last participant randomized if the planned OS event 
number is not reached by then.
•
Added additional sensitivity analyses for PFS and OS to account for 
potential non-proportional hazards in efficacy analyses.
•
Added information for SARS-C0V-2 infection and vaccine.
•
Updated Appendix 10 to include German-specific information 
(ca045001-revprot00a-de-specific and ca045001-revprot00b-de-
specific).
Incorporated Administrative Letter 03 and German-specific 
Administrative Letter 04.
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
4
Document
Date of Issue
Summary of Change
German-
specific 
Administrative 
Letter 04
24-Aug-2020
Addresses 3 clarifications/inconsistencies of Revised Protocol 00b 
Germany Specific (dated 06-May-2020):
•
In Section 7.4.1, removed the paragraph relating to Grade 3 or greater 
AEs that cause dose delay that was erroneously not removed.
•
In Section 9.8.3, removed the paragraph relating to a Grade 3 drug-
related AE that results in a dose delay that was erroneously not 
removed.
Administrative 
Letter 03
09-Jul-2020
Addressed 4 clarifications/inconsistencies of Revised Protocol 01 in regard 
to:
•
In Section 7.4.1, removed the paragraph relating to Grade 3 or greater 
AEs that cause dose delay that was erroneously not removed.
•
In Section 9.8.3, removed the paragraph relating to a Grade 3 drug-
related AE that results in a dose delay that was erroneously not 
removed. 
Revised 
Protocol 01
24-Feb-2020
•
The sections on 
Biomarker assessment were revised.
•
Nektar program updates were added.
•
Study Design and Schema image were updated to include AJCC M 
stage change.
•
Internal inconsistencies were corrected.
•
Statistical analysis was updated to include one additional interim 
analysis of OS.
•
DoCR was removed as an Endpoint.
•
Appendices 2, 3, 4 and 6 were modified to include the latest updates.
•
Appendix 7 was added to include cerebrovascular accident 
management algorithm. As a result following Appendices were 
renumbered.
•
Appendix 8 was revised to include Mucosal Melanoma of the Head and 
Neck TNM definitions.
•
Appendix 10 was updated to include German-specific, Czech-specific 
and Ireland-specific amendments (ca045001-revprot00a).
•
Changes as per Admin Letter 01 and 02.
Administrative 
Letter 02
17-Sep-2018
Addresses four clarifications/inconsistencies of the protocol in regard to:
•
Clarification on the brain imaging screening window in Table 2-1 and 
section 6.1 Exclusion Criteria
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
5
Document
Date of Issue
Summary of Change
Administrative 
Letter 01
08-Jun-2018
To correct study number to CA045001/17-214-08
Original 
Protocol
25-May-2018
Not applicable
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03:
The addition of bempegaldesleukin to nivolumab did not result in a statistically significant 
improvement in progression free survival (PFS) (Hazard Ratio [HR] 1.09, 97% Confidence 
Interval [CI], 0.88-1.35) or objective response rate (ORR) compared to nivolumab monotherapy, 
and the significance threshold for overall survival (OS) was also not crossed at an interim analysis.
Given there was no additional clinical benefit in the doublet therapy arm compared to the
monotherapy arm for the primary endpoints of PFS and ORR, Bristol-Myers Squibb Company 
(BMS) and Nektar, in consultation with the Data Monitoring Committee (DMC), decided to 
unblind the trial and to perform no additional formal analyses for the OS endpoint. Furthermore, 
there was added toxicity with bempegaldesleukin plus nivolumab compared to nivolumab 
monotherapy, including a higher incidence of drug-related adverse events (AEs), drug-related 
serious adverse events (SAEs), and drug-related AEs leading to study treatment discontinuation.
Given that additional toxicities with no added efficacy were observed in the experimental arm, 
participants receiving bempegaldesleukin plus
nivolumab are required to
discontinue 
bempegaldesleukin and may continue nivolumab monotherapy.
On 14-Apr-2022, BMS and Nektar announced a joint decision to end the clinical development 
program for bempegaldesleukin in combination with nivolumab.
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 03
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated title to remove PIVOT-
IO-001.
This is a correction.
Summary
Updated text.
To align the Summary with 
updates made to the full 
protocol.
Table 2-2: On-Study Activities 
(CA045001)
Added that text related to 
bempegaldesleukin is not 
applicable.
No longer applicable as 
bempegaldesleukin will not be 
administered.
Table 2-2: On-Study Activities 
(CA045001)
Added new row for ‘Administer 
Study Drug.’
To remove bempegaldesleukin 
and include updated nivolumab 
dose at 480 mg IV (intravenous) 
Q4W (every four weeks).
Table 2-2: On-Study Activities 
(CA045001)
Added that the following 
sections are not applicable per 
Protocol Amendment 03: 
Administer Study Drug, 
Sections are no longer 
applicable as bempegaldesleukin 
will no longer be administered
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Administer Fluids, Review 
Hydration Guidelines with 
Participants, Oral Hydration 
Follow-up, Biomarker 
Assessments, Biomarker Sample
Collection, Stool Sample 
Collection, Tumor Biopsy, 
Table 2-2: On-Study Activities
(CA045001)
•
Updated body and brain
imaging to include that 
Investigator assessment will 
be used instead of blinded 
independent central review 
(BICR).
•
Updated body and brain
imaging assessment to 
include that imaging 
assessment will be 
performed per schedule of 
local standard of care 
(SOC).
Primary endpoints of PFS and 
ORR by BICR assessment were 
completed. Investigator tumor 
assessment will continue.
Table 2-3: Long-term 
Procedural Follow-Up 
(CA045001)
Added that the following 
sections were not applicable per 
Protocol Amendment 03:
Subsequent Anti-Cancer 
Therapy, 
 
Biomarker 
Assessments (Blood PD 
Sampling and Tumor Biopsy)  
 
. 
Additional biomarker sample 
collection will not be applicable. 
However, exploratory biomarker 
analysis may be conducted.
Updated body and brain imaging 
to include that Investigator 
Primary endpoints of PFS and 
ORR by BICR assessment were 
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
assessment will be used instead 
of BICR.
completed. Investigator tumor 
assessment will continue.
Added that footnote b is not 
applicable per Protocol 
Amendment 03.
No further formal OS analyses 
will be conducted.
Section 3: Introduction
Added details on how 
Investigators can proceed with 
study treatments.
Participants are required to 
discontinue bempegaldesleukin.
Section 3.1.1: Research 
Hypothesis
Added that section is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin.
Section 3.3.3: 
Bempegaldesleukin and 
Nivolumab Benefit and Risk 
Assessment
Added that bempegaldesleukin 
did not show a benefit.
Given that additional toxicities 
with no added efficacy were 
observed in the experimental 
arm, the risk benefit was 
updated.
Section 4: Objectives and 
Endpoints
Added that secondary and 
exploratory endpoints except 
biomarker sample collection are 
not applicable per Protocol 
Amendment 03.
Additional data for secondary 
and exploratory objectives,
except biomarker parameters, 
will not be captured.
Section 5.1: Overall Design
Added that original treatments 
are not applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin.
Figure 5.1-1: Study Schematic
Added that per Protocol 
Amendment 03 participants in 
Arm A are required to
discontinue bempegaldesleukin 
and continue nivolumab 
monotherapy.
Participants are required to 
discontinue bempegaldesleukin.
Adjusted maximum study 
duration from 5 years to 2 years 
+100 days.
Since further formal OS 
analyses will not be conducted 
the maximum study duration is 
being shortened to the 
nivolumab treatment period (2 
years) +100 days for safety 
follow-up.
Section 5.1.2: Treatment Period
Added details on how 
Investigators can proceed with 
study treatments.
Participants receiving 
bempegaldesleukin plus 
nivolumab should discontinue 
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
bempegaldesleukin and will 
receive nivolumab monotherapy.
Section 5.1.3: Long-term 
Follow-up
Adjusted maximum study 
duration from 5 years to 2 years 
+100 days.
Since further formal OS 
analyses will not be conducted 
the maximum study duration is 
being shortened to the 
nivolumab treatment period (2 
years) +100 days for safety 
follow-up.
Added that formal survival
analysis is not applicable per 
Protocol Amendment 03.
No further formal OS analyses 
will be conducted.
Section 5.3: End of Study 
Definition
Added that OS analyses will not 
be performed.
No further formal OS analysis 
will be performed.
Added text that the total 
duration of the study for the OS 
endpoint is not applicable per 
Protocol Amendment 03.
Since further formal OS 
analyses will not be conducted 
the maximum study duration is 
being shortened to the 
nivolumab treatment period (2 
years) +100 days for safety 
follow-up.
Section 5.4.5: Rationale for 
Open-Label Design
Section 5.5.1: Justification for 
Dose of Bempegaldesleukin
Section 5.5.3: Rationale for 
Bempegaldesleukin/Nivolumab 
Combination Dose
Added that section is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin.
Section 5.4.7: Duration of 
Treatment with Nivolumab/ 
Bempegaldesleukin
Added that paragraph referring 
to bempegaldesleukin is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin.
Section 5.5.2: Justification for 
Dose of Nivolumab
•
Added that participants can 
continue on nivolumab 
monotherapy.
•
Updated dose of nivolumab 
to 480 mg IV Q4W.
•
Added that participants < 40 
kg will be administered a 
Changed dose for participants 
continuing nivolumab 
monotherapy to the approved 
nivolumab dose.
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
body weight adjusted 
nivolumab dose of 6 mg/kg 
IV Q4W.
Section 5.5.4: Justification for 
Dose for Adolescents
•
Updated dose of nivolumab 
to 480 mg IV Q4W.
•
Changed weight base for 
nivolumab from 4.5 mg/kg 
IV Q3W (every three 
weeks) to 6 mg/kg IV Q4W.
Changed dose for participants 
continuing nivolumab 
monotherapy to the approved 
nivolumab dose.
Section 6.3: Lifestyle 
Restrictions
Added that section is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin.
Section 7: Treatment
•
Added that participants can 
continue on nivolumab 
monotherapy.
•
Updated dose of nivolumab 
to 480 mg IV Q4W.
•
Added weight base for 
nivolumab of 6 mg/kg IV 
Q4W.
Changed dose for participants 
continuing nivolumab 
monotherapy to the approved 
nivolumab dose.
Section 7.1: Treatments 
Administered
•
Added that participants can 
continue on nivolumab 
monotherapy.
•
Updated dose of nivolumab 
to 480 mg IV Q4W.
•
Changed weight base for 
nivolumab from 4.5 mg/kg 
IV Q3W to 6 mg/kg IV 
Q4W.
Changed dose for participants 
continuing nivolumab 
monotherapy to the approved 
nivolumab dose. 
Section 7.1.1: 
Bempegaldesleukin Dosing 
Section 7.4.1.1: Dose 
Modification Criteria for 
Bempegaldesleukin and 
Nivolumab for Cycle 1 
ALT/AST Elevations
Added that this section is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin.
Protocol Amendment No.: 03
Date: 19-May-2022
10
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 7.4.3.1: 
Bempegaldesleukin-induced 
Eosinophilia
Section 7.4.3.2: Eosinophilic 
Disorders
Section 7.4.5.2: Management 
Algorithm for Cytokine-Release 
Syndrome
Section 7.1.1.1: Hydration 
Guidelines
Added that this section is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin 
and hydration guidelines were 
only relevant for 
bempegaldesleukin 
administration.
Section 7.1.2: Nivolumab 
Dosing
•
Added that participants can 
continue on nivolumab 
monotherapy.
•
Updated dose of nivolumab 
to 480 mg IV Q4W.
•
Changed weight-based 
dosage for nivolumab from 
4.5 mg/kg IV Q3W to 6 
mg/kg IV Q4W, and added 
details on infusion.
Changed dose for participants 
continuing nivolumab 
monotherapy to the approved 
nivolumab dose.
Section 7.3: Blinding
Added that treatment assignment 
will not be blinded to Sponsor.
Sponsor has been unblinded to 
treatment assignment since no 
further formal efficacy analyses 
have been conducted.
Section 7.4: Dosage 
Modification
Section 7.4.1: Nivolumab and 
Bempegaldesleukin Dose Delay, 
and Discontinuation Criteria
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 03.
Participants are required to 
discontinue bempegaldesleukin.
Protocol Amendment No.: 03
Date: 19-May-2022
11
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 7.6: Treatment 
Compliance
Section 7.7.4.2: Restricted 
Treatments
Section 7.7.5: Permitted 
Therapy
Section 7.4.5.1: Management 
Algorithms for Immuno-
Oncology Agents
•
Added that text related to 
bempegaldesleukin is not 
applicable.
•
Adjusted that the 
management algorithm for 
bempegaldesleukin can be 
found in Appendix 7.
Participants are required to 
discontinue bempegaldesleukin.
Section 7.7.4.2: Restricted 
Treatments
Added text stating that 
anticoagulation therapy will no 
longer be mandated for 
participants enrolled in this 
study.
Participants are required to 
discontinue bempegaldesleukin.
Section 7.7.4.4: Blood Pressure 
Precautions
Added that section is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin 
and blood pressure precautions 
were only relevant for 
bempegaldesleukin.
Section 7.8: Treatment After the 
End of the Study
Added that participants will 
receive SOC nivolumab after the 
end of the study.
Participants are required to 
discontinue bempegaldesleukin
and will receive SOC nivolumab
monotherapy.
Section 8.1: Discontinuation 
from Study Treatment
Removed that radiographic 
assessment needs to be 
submitted to a central imaging 
vendor.
Primary endpoints of PFS and 
ORR by BICR assessment were 
completed. Investigator tumor 
assessment will continue.
Section 8.1.1: Nivolumab and 
Bempegdesleukin 
Discontinuation Criteria
Section 8.1.2: Criteria to 
Resume Bempegaldesleukin 
and/or Nivolumab
Added that text related to 
bempegaldesleukin is not 
applicable.
Participants are required to 
discontinue bempegaldesleukin.
Protocol Amendment No.: 03
Date: 19-May-2022
12
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 8.1.3: Treatment 
Beyond Progression
Removed that radiographic 
assessment needs to be 
submitted to a central imaging 
vendor.
Primary endpoints of PFS and 
ORR by BICR assessment were 
completed. Investigator tumor 
assessment will continue.
Section 8.1.4: Post Study 
Treatment Study Follow-up
Added to refer to Section 5.1 for 
details and that section is not 
applicable.
Since further formal OS 
analyses will not be conducted 
this section is not applicable.
Section 8.2: Discontinuation 
from the Study
Added that participants will be 
followed up to 100 days for 
protocol specified follow-up 
procedures with documentation 
of last overall survival.
Since further formal OS 
analyses will not be conducted 
the maximum study duration is 
being shortened to the 
nivolumab treatment period (2 
years) +100 days for safety 
follow-up.
Section 9.1: Efficacy 
Assessments
BICR is replaced with 
Investigator assessment to 
determine response and disease 
progression. 
Primary endpoints of PFS and 
ORR by BICR assessment were 
completed. Investigator tumor 
assessment will continue.
Section 9.1.1: Imaging 
Assessments for the Study
Section 9.1.1.3: BICR 
Confirmation of Progression
Section 9.1.2: Assessment for 
the Study
Added that imaging will not be 
submitted to imaging core lab. 
Primary endpoints of PFS and 
ORR by BICR assessment were 
completed. Investigator tumor 
assessment will continue.
Section 9.2.1: Time Period and 
Frequency for Collecting AE 
and SAE Information
Removed reference to Appendix 
7.
Since participants are required 
to discontinue 
bempegaldesleukin, Appendix 7
is not applicable.
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 9.6: Pharmacodynamics
Added that in biomarker sample 
collection 
 
Table 9.8.2-2 will not be 
applicable per Protocol 
Amendment 03.
Additional biomarker sample 
collection will not be applicable. 
However, exploratory biomarker 
analysis may be conducted.
Section 9.8: Biomarkers
Section 9.8.1: Additional 
Research Collection
Added that in biomarker sample 
collection 
 
Table 9.8.2-2 will not be 
applicable per Protocol 
Amendment 03.
Additional Research collection 
is not applicable. 
Additional biomarker sample 
collection will not be applicable. 
However, exploratory biomarker 
analysis may be conducted.
Table 9.8.2-2: Biomarker 
Sampling Schedule: All 
Participants after Randomization 
into 
 is 
Completed
Added that in biomarker sample 
collection Table 9.8.2-2 will not 
be applicable per Protocol 
Amendment 03.
Additional biomarker samples 
will not be collected.
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 9.8.3: Tumor Tissue 
Specimens
Section 9.8.4: Tumor Gene 
Expression and Mutation 
Analyses
Section 9.8.5: Peripheral 
Biomarkers
Section 9.8.6: Whole Blood for 
Genetic Analysis
Section 9.8.7: Exploratory 
Serum and Plasma Biomarkers
Section 9.8.8: Plasma ctDNA
Section 9.8.9: Serum MicroRNA 
(miRNA)
Section 9.8.10: Myeloid Derived 
Suppressor Cells
Section 9.8.11: Peripheral Blood 
Mononuclear Cells and Whole 
Blood Immunophenotyping 
Section 9.8.12: Microbiome 
Analysis
Added that exploratory analysis 
of selected biomarkers as per 
Section 9.8 may be conducted.
Additional biomarker sample 
collection will not be applicable. 
However, exploratory biomarker 
analysis may be conducted.
Section 10: Statistical 
Considerations
Added that OS analyses will not 
be conducted.
No further formal OS analysis 
will be performed. 
Section 10.3: Statistical 
Analyses
Added that exploratory analysis 
of selected biomarkers as per 
Section 9.8 may be conducted.
This analysis may help to 
understand the mechanism of 
action.
Protocol Amendment No.: 03
Date: 19-May-2022
15
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321
Bempegaldesleukin (NKTR-214) and Nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03
Section Number & Title
Description of Change
Brief Rationale
Section 10.3.4: Interim Analyses
Added that OS analyses will not 
be conducted.
No further formal OS analysis 
will be performed.
Appendix 7: Cerebrovacular 
Accident Adverse Event 
Management Algorithm for the 
Combination of 
Bempegaldesleukin with 
Checkpoint Inhibitors
Added that Appendix 7 is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin; 
therefore, algorithm is not 
applicable.
Appendix 10: Country Specific 
Requirements/Differences
Added Sweden to adolescent 
exclusion.
 
Added that oral hydration is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin; 
therefore, oral hydration 
requirements are not applicable.
Appendix 11: Cytokine-Release 
Syndrome (CRS) Management 
Measures/Algorithm
Added that Appendix 11 is not 
applicable per Protocol 
Amendment 03.
Participants are required to 
discontinue bempegaldesleukin; 
therefore, CRS is not applicable.
Protocol Amendment No.: 03
Date: 19-May-2022
16
Approved
4.0
v
Approved
1.0
v

TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
DOCUMENT HISTORY .............................................................................................. 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 03: ............................ 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 03 ................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
1 SUMMARY ............................................................................................................... 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Melanoma Background / Current Therapies ........................................... 
 
3.2.2 Nivolumab Mechanism of Action ............................................................. 
 
3.2.3 Bempegaldesleukin Mechanism of Action ............................................... 
 
3.2.4 Clinical Experience with Nivolumab ....................................................... 
 
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 ..................................................................................... 
 
5.1.3 Long-Term Follow-Up ............................................................................. 
 
5.1.4 Data Monitoring Committee and Other External Committees ................ 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
5.4.1 Rationale for the Combination of Bempegaldesleukin and Immune 
Checkpoint Inhibitors.................................................................................. 
 
5.4.2 Rationale for Study Comparator and Study Population .......................... 
 
5.4.3 Rationale for Inclusion of Adolescent Participants ................................. 
 
5.4.4 Rationale for Choice of Endpoints ........................................................... 
 
5.4.5 Rationale for Open-Label Design ............................................................ 
 
5.4.6 Rationale for Stratification by M Staging, BRAF, and PD-L1 ................ 
 
5.4.7 Duration of Treatment with Nivolumab/Bempegaldesleukin ................... 
 
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Clinical Protocol
NKTR-214 / BMS-986321
CA045001/17-214-08
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
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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 .......... 
 
5.5.4 Justification for Dose for Adolescents ..................................................... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 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, Reduction, and 
Discontinuation Criteria ............................................................................. 
 
7.4.1.1 Dose Modification Criteria for Bempegaldesleukin and Nivolumab 
for Cycle 1 ALT/AST Elevations ........................................................... 
 
7.4.2 Monitoring and Management of Elevated Hepatic Transaminases ........ 
 
7.4.3 Monitoring and Management of Eosinophilia ......................................... 
 
7.4.3.1 Bempegaldesleukin-induced Eosinophilia ...................................... 
 
7.4.3.2 Eosinophilic Disorders ................................................................... 
 
7.4.4 Monitoring and Management of Adrenal Insufficiency and Hypophysitis
..................................................................................................................... 
 
7.4.5 Management Algorithms for 
Cytokine-
Release Syndrome ....................................................................................... 
 
7.4.5.2 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 
 
7.6 Treatment Compliance ...................................................................................... 
 
7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Palliative Therapy .................................................................................... 
 
7.7.3 Prior and Concomitant Medications ....................................................... 
 
7.7.3.1 COVID-19 Vaccination ................................................................... 
 
7.7.4 Other Restrictions and Precautions ......................................................... 
 
7.7.4.1 Restricted Treatments ..................................................................... 
 
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Clinical Protocol
NKTR-214 / BMS-986321
CA045001/17-214-08
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
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7.7.4.2 Restricted Treatments ..................................................................... 
 
7.7.4.3 Imaging Restriction and Precautions ............................................. 
 
7.7.4.4 Blood Pressure Precautions ........................................................... 
 
7.7.5 Permitted Therapy ................................................................................... 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION AND RESUMPTION CRITERIA ....................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Nivolumab and Bempegaldesleukin Discontinuation Criteria ................ 
 
8.1.2 Criteria to Resume Bempegaldesleukin and/or Nivolumab ..................... 
 
8.1.3 Treatment Beyond Progression ................................................................ 
 
8.1.4 Post Study Treatment Study Follow-up.................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Imaging Assessments for the Study .......................................................... 
 
9.1.1.1 Methods of Measurement ................................................................ 
 
9.1.1.2 Imaging and Clinical Assessment ................................................... 
 
9.1.1.3 BICR Confirmation of Progression ................................................ 
 
9.1.2 Imaging Assessment for the Study............................................................ 
 
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 ................................................................................................ 
 
9.2.7 Adverse Events of Special Interest (AESI/AEOSI) ................................... 
 
9.2.8 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.9 Potential Drug Induced Liver Injury ....................................................... 
 
9.2.10 Other Safety Considerations .................................................................. 
 
9.3 Overdose ........................................................................................................... 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Vital Signs and Oxygen Saturation .......................................................... 
 
9.4.2 Electrocardiograms ................................................................................. 
 
9.4.3 Echocardiogram ...................................................................................... 
 
9.4.4 Pregnancy Tests ....................................................................................... 
 
9.4.5 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.6 Imaging Safety Assessment ...................................................................... 
 
9.6 Pharmacodynamics ........................................................................................... 
 
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Clinical Protocol
NKTR-214 / BMS-986321
CA045001/17-214-08
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
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9.7 Pharmacogenomics ........................................................................................... 
 
9.8 Biomarkers ........................................................................................................ 
 
9.8.1 Additional Research Collection ............................................................... 
 
9.8.2 Biomarker Sampling Schedule ................................................................. 
 
9.8.3 Tumor Tissue Specimens .......................................................................... 
 
9.8.4 Tumor Gene Expression and Mutation Analyses ..................................... 
 
9.8.5 Peripheral Biomarkers ............................................................................. 
 
9.8.6 Whole Blood for Genetic Analysis ........................................................... 
 
9.8.7 Exploratory Serum and Plasma Biomarkers ........................................... 
 
9.8.8 Plasma ctDNA .......................................................................................... 
 
9.8.9 Serum MicroRNA (miRNA) ...................................................................... 
 
9.8.10 Myeloid Derived Suppressor Cells ........................................................ 
 
9.8.11 Peripheral Blood Mononuclear Cells and Whole Blood 
Immunophenotyping .................................................................................... 
 
9.8.12 Microbiome Analysis ............................................................................. 
 
9.9 Medical Resource Utilization and Health Economics ...................................... 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 Sample Size Justification for ORR Estimate .......................................... 
 
10.1.2 Sample Size Justification for PFS Comparison ..................................... 
 
10.1.3 Sample Size Justification for OS Comparison ....................................... 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
10.3.3 Other Analyses ....................................................................................... 
 
10.3.3.3 Missing Data ................................................................................. 
 
10.3.4 Interim Analyses ..................................................................................... 
 
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) AND LANSKY (ADOLESCENTS) 
PERFORMANCE STATUS SCALES ................................................................... 
 
APPENDIX 6 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0 ......................................................................................................... 
 
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Clinical Protocol
NKTR-214 / BMS-986321
CA045001/17-214-08
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
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APPENDIX 7 *NOT APPLICABLE PER PROTOCOL AMENDMENT 03 
CEREBROVASCULAR ACCIDENT ADVERSE EVENT MANAGEMENT 
ALGORITHM FOR THE COMBINATION OF BEMPEGALDESLEUKIN 
WITH CHECKPOINT INHIBITORS .................................................................... 
 
APPENDIX 8 AJCC MELANOMA STAGING (CANCER STAGING MANUAL 
8TH EDITION) ....................................................................................................... 
 
APPENDIX 9 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
 ........................ 
 
APPENDIX 10 COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES ............ 
 
APPENDIX 11 *NOT APPLICABLE PER PROTOCOL AMENDMENT 03 
CYTOKINE-RELEASE SYNDROME (CRS) MANAGEMENT 
MEASURES/ALGORITHM .................................................................................. 
 
APPENDIX 12 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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Clinical Protocol
NKTR-214 / BMS-986321
CA045001/17-214-08
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
Date: 19-May-2022
21
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
1
SUMMARY
Protocol Title: A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with 
Nivolumab Versus Nivolumab in Participants with Previously Untreated Unresectable or 
Metastatic Melanoma
Study Phase: 3
Rationale:
Activation 
of 
programmed 
cell 
death 
protein-1 
(PD-1) 
pathway 
inhibits 
the 
cluster of differentiation 28
(CD-28)-mediated upregulation of cytokines, inhibits T cell 
activation, and inhibits the expansion of previously activated cells. Blockade of the PD-1 pathway 
has demonstrated clinical activity across multiple tumor types including melanoma. An 
accumulating body of evidence supports that low levels of tumor infiltrating lymphocytes (TILs) 
in pretreatment biopsies predict poor clinical response to PD-1 pathway blockade. NKTR-214 
(bempegaldesleukin) promotes biased signaling through the IL-2 intermediate affinity receptor (IL 
2Rβγ) as opposed to the high affinity receptor (IL-2Rαβγ) found on regulatory T-cells (Tregs). 
Bempegaldesleukin increases intra-tumoral CD8+ lymphocytes and natural killer cells as well as 
the number of PD-1+ CD8+ cells in the tumor and peripheral blood. The biologic activity of 
bempegaldesleukin makes it a potentially promising immunotherapy to combine with checkpoint 
inhibitors that target and inhibit the PD-1/PD-L1 pathway.
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
The current study aims to demonstrate that treatment with bempegaldesleukin in combination with
nivolumab will be efficacious in participants with unresectable or metastatic melanoma that is 
previously untreated. 
The addition of bempegaldesleukin to nivolumab did not result in a statistically significant 
improvement in PFS (HR 1.09, 97% CI, 0.88-1.35) or ORR compared to nivolumab monotherapy
as assessed by Blinded Independent Central Review (BICR), and the significance threshold for OS 
was also not crossed at the combined first and second OS analyses. Furthermore, there was added 
toxicity with bempegaldesleukin plus nivolumab compared to nivolumab monotherapy including 
Protocol Amendment No.: 03
Date: 19-May-2022
22
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
a higher incidence of drug-related adverse events (AEs), drug-related serious adverse events 
(SAEs) and drug-related AEs leading to study treatment discontinuation.
Given that additional toxicities with no added efficacy were observed in the experimental arm, per 
Protocol Amendment 03, participants who are currently 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 at 480 mg 
IV Q4W. Participants < 40 kg will be administered a body weight adjusted nivolumab dose of 6 
mg/kg IV Q4W.
Study Population: Males and females, ages 12 years or older, except where local regulations 
and/or institutional policies do not allow for participants < 18 years of age (pediatric population) 
to participate. For those sites, the eligible participant population is ≥18 years of age, or age of 
majority. Adolescents are not eligible for the 
due to the blood sampling 
and biopsy requirements.
Key eligibility criteria
Inclusion
•
Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status 
of ≤ 1 (adults 18 years or older)/Lansky Performance Score ≥ 80% (minors ages 12-17 only)
•
Histologically confirmed stage III (unresectable) or stage IV melanoma, as per American Joint 
Committee on Cancer (AJCC) staging system, 8th edition 
•
Treatment-naïve participants (ie, no prior systemic anticancer therapy for unresectable or 
metastatic melanoma) with the exception of prior adjuvant and/or neoadjuvant treatment for 
melanoma with approved agents (eg, proto-oncogene B-Raf [BRAF]/mitogen-activated 
protein [MEK] inhibitors, ipilimumab, nivolumab, pembrolizumab or interferon). Participants 
who have had recurrence within the 6 months of completing adjuvant or neoadjuvant treatment 
are not eligible.
•
Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria
•
All participants must have tissue submitted during the screening period to allow for participant
enrollment into the study. Tissue submitted should be from an unresectable primary tumor 
lesion or any metastatic site. The tumor tissue should be from a site not previously irradiated 
and with no intervening treatment between time of acquisition and enrollment. Central lab must 
provide IRT with the results of PD-L1 testing prior to randomization. Either a formalin-fixed, 
paraffin-embedded (FFPE) tissue block or 20 unstained tumor tissue sections, with an 
associated pathology report, must be submitted to the core laboratory for inclusion. FFPE tissue 
block and unstained slides submitted should be from biopsy obtained within 6 months prior to 
enrollment. Unstained slides should be sectioned within 3 months prior to submission. 
Submission of an FFPE block is strongly preferred but unstained slides are also acceptable.
Tissue may be from a core biopsy, punch biopsy, excisional or incisional biopsy, or surgical 
specimen; fine needle aspiration and other cytology samples are not acceptable. Biopsies of 
bone lesions that do not have a soft tissue component are also unacceptable for submission. 
Protocol Amendment No.: 03
Date: 19-May-2022
23
Approved
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Medical Monitor (or designee) can be consulted for eligibility if subjects have less than 20 
unstained slides.
−
In order to be randomized, a participant must be classified as PD-L1 positive (≥1% tumor 
cell membrane staining) vs PD-L1 negative (< 1% tumor cell membrane staining) or PD-
L1 indeterminate (tumor cell membrane scoring hampered by high cytoplasmic staining or 
melanin content) based on the PD-L1 immunohistochemistry (IHC) 28-8 pharmDx assay. 
If only an insufficient amount of tumor tissue from an unresectable or metastatic site is 
available from prior to the start of the Screening phase, then a fresh biopsy will be required 
during the screening phase for performance of biomarker analyses. Non-evaluable 
participants are not eligible for randomization.
•
 
 
 Note: If the participant has > 1 lesion, 
the lesion planned for biopsy while on treatment cannot be designated as a target lesion at 
baseline. Additional target lesions should be available for radiographic efficacy assessments. 
If the participant has only 1 lesion that is measurable and amenable to biopsy, the lesion must 
be greater than 2.0 cm and the biopsy cannot be excisional. (Note: These same lesion criteria 
apply for patients who consent to the optional biopsy in the main study.)
•
Participants must have known BRAF V600 mutation status or consent to BRAF V600 mutation 
testing per local institutional standards by approved methodology during the Screening period.
Exclusion
•
Active brain metastases or leptomeningeal metastases. Participants with brain metastases are 
eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence 
of progression for at least 8 weeks after treatment is complete and within 28 days prior to 
randomization. There must also be no requirement for immunosuppressive doses of systemic 
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study 
treatment administration. Stable dose of anticonvulsants is allowed. Treatment for central 
nervous system (CNS) metastases may include stereotactic radiosurgery (eg, GammaKnife, 
CyberKnife, or equivalent) or neurosurgical resection. Participants with CNS metastases 
treated by neurosurgical resection or brain biopsy performed within 28 days prior to 
randomization are not eligible. Participants who received whole brain radiation therapy are not 
eligible.
•
Uveal melanoma is excluded.
Objectives and Endpoints:
Per Protocol Amendment 03, the secondary and exploratory objectives except biomarker 
parameters are no longer applicable. Biomarker sample collection will not be applicable per 
Protocol Amendment No.: 03
Date: 19-May-2022
24
Approved
4.0
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment 03. However, exploratory analysis of biomarkers on previously collected 
specimens as per section 9.8 may be conducted.
Objective
Endpoint
Primary
•
To compare the objective response rate (ORR) using 
RECIST 1.1 of bempegaldesleukin combined with 
nivolumab and that of nivolumab monotherapy in 
participants with previously untreated unresectable or 
metastatic melanoma
•
ORR by Blinded Independent Central 
Review (BICR)
•
To compare progression-free survival (PFS) using 
RECIST 1.1 of bempegaldesleukin combined with 
nivolumab and that of nivolumab monotherapy in 
participants with previously untreated unresectable or 
metastatic melanoma 
•
PFS by BICR
•
To compare overall survival (OS) of bempegaldesleukin
combined with nivolumab and that of nivolumab 
monotherapy in participants with previously untreated 
unresectable or metastatic melanoma
•
OS
Secondary
•
To evaluate efficacy of bempegaldesleukin combined 
with nivolumab and that of nivolumab monotherapy 
•
Clinical Benefit Rate (CBR) duration of 
response (DOR), time to response (TTR), 
evaluated by BICR per RECIST 1.1
•
ORR, PFS, CBR, DOR, TTR - evaluated by 
investigator per RECIST 1.1
•
To evaluate the association between PD-L1 expression on 
tumor cells ( ≥1% or < 1%/indeterminate) and efficacy 
measures including PFS and ORR by BICR and OS
•
PFS and ORR by BICR and OS in 
biomarker population
•
To evaluate the safety and tolerability of 
bempegaldesleukin combined with nivolumab and that of 
nivolumab monotherapy 
•
Safety and tolerability
Exploratory
•
To characterize the effect of nivolumab when 
administered as monotherapy and in combination with 
•
Biomarker parameters
Protocol Amendment No.: 03
Date: 19-May-2022
25
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Objective
Endpoint
bempegaldesleukin on immune cell populations and 
markers of immune activation.
•
To assess efficacy of bempegaldesleukin combined with 
nivolumab and nivolumab monotherapy based on tumor 
mutation burden and blood-based tumor mutation burden
•
PFS, OS, ORR in biomarker population
•
To evaluate PFS after the next line of treatment (PFS2) of 
bempegaldesleukin combined with nivolumab and that of 
nivolumab monotherapy in participants with previously 
untreated unresectable or metastatic melanoma
•
PFS2 by investigator per RECIST 1.1
Overall Design:
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable. 
This is a multicenter, randomized, open-label, Phase 3 study that will evaluate the efficacy and 
safety of bempegaldesleukin in combination with nivolumab compared with nivolumab 
monotherapy in adult and adolescent (≥ 12 years of age) participants with previously untreated 
unresectable or metastatic melanoma. The study is divided into a Screening period, a Treatment 
period, and a Long-Term Follow-up period.
 
 
Randomization (1:1) will be stratified by:
•
PD-L1 tumor expression status (≥1% vs < 1% or indeterminate) based on the PD-L1 IHC 28-
8 pharmDx assay
•
BRAF mutation status (V600 mutation positive vs wild type)
•
AJCC 8th edition M stage [M0 / M1any[0] (Stage III any LDH or Stage IV Normal LDH) vs 
M1any[1] (Stage IV Elevated LDH)] based on the screening imaging and laboratory test 
results.
The treatment period of the study is divided into multiple treatment cycles with associated 
evaluations and procedures. One cycle of treatment is defined as 3 weeks. Results of the 
Protocol Amendment No.: 03
Date: 19-May-2022
26
Approved
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
assessments must be reviewed and documented before administering the first dose of the next 
cycle. In certain circumstances, participants with progressive disease (PD) per RECIST 1.1 but 
with otherwise stable or improved performance and clinical status may continue to be treated in 
the event of a perceived benefit per Investigator; see the full protocol for treatment beyond 
progression criteria.
Long-term follow-up should continue until withdrawal of consent, death, or study termination by 
the Sponsor. The maximum total duration of the study is up to 2 years +100 days after 
randomization of the last participant. 
Number of Participants:
Approximately 764 participants with previously untreated unresectable or metastatic melanoma 
will be randomized (1:1) to 1 of 2 treatment arms.
Treatment Arms and Duration:
Participants will be randomized (1:1) to 1 of 2 treatment arms:
•
Arm A: Bempegaldesleukin 0.006 mg/kg IV Q3W + nivolumab 360 mg IV Q3W
(sequential)
•
Arm B: Nivolumab 360 mg IV Q3W
Note: Nivolumab dosing in both arms for participants < 40 kg will be 4.5 mg/kg (weight based).
Per Protocol Amendment 03, participants who are currently 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 at 480 mg 
IV Q4W. Participants < 40 kg will be administered a body weight adjusted nivolumab dose of 6 
mg/kg IV Q4W.
Participants will be treated until disease progression, death, unacceptable toxicity, symptomatic 
deterioration, the Investigator’s decision to discontinue treatment, the participant’s decision to 
discontinue treatment or withdraw consent, the participant is lost to follow up, BMS and Nektar 
Therapeutics decide to terminate the study, or for a maximum of 24 months of treatment. The total 
maximum duration of the study is up to 2 years +100 days after randomization of the last 
participant.
Study Schematic
This study schematic is not applicable per Protocol Amendment 03.
Protocol Amendment No.: 03
Date: 19-May-2022
27
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Per Protocol Amendment 03:
•
Participants who have completed therapy and are currently in survival follow-up should 
discontinue from the study immediately if AE reporting requirements have been fulfilled 
as per Section 9.2.3. Documentation of last overall survival should occur upon 
discontinuation.
•
Participants who have completed therapy and are currently within the 100 days safety 
follow-up should discontinue from the study once they complete the safety follow up 100 
days after the last dose of study treatment if AE reporting requirements have been fulfilled 
as per Section 9.2.3. Documentation of last overall survival should occur upon 
discontinuation.
•
Participants in Arm A are required to discontinue bempegaldesleukin and may continue 
nivolumab monotherapy. Participants receiving treatment in Arm A and Arm B will receive 
nivolumab monotherapy on study at 480 mg IV Q4W. Participants < 40 kg will be 
administered a body weight adjusted nivolumab dose of 6 mg/kg IV Q4W.
•
All participants will have 100 days safety follow-up or until AE reporting requirements 
have been fulfilled as per Section 9.2.3. Documentation of last overall survival should 
occur upon discontinuation. The Sponsor will close the study once the last participant has 
completed the safety follow-up.
Population:
• Treatment naïve (1L setting)
• Unresectable stage III or stage IV
Stratification factors:
• PD-L1 ≥ 1% v. PD-L1 < 1 % / 
indeterminate
• BRAF mut v. WT
• M0 / M1 any[0] vs M1any[1] 
Randomization 
1 1
N=764
Screening
Arm A
NKTR-214 0.006 mg/kg IV Q3W
and
Nivolumab 360 mgb IV Q3W
Arm B
Nivolumab 360 mgb IV Q3W
b Nivolumab dosing in both arms for participants < 40 kg will be weight-based 4.5 mg/kg IV Q3W.
c Treatment beyond progression may be permitted if protocol criteria met.
d Maximum treatment duration of 24 months.
e Progression determined by investigator with BICR confirmation.
Treat until 
RECIST 1.1 
progression or 
unacceptable 
toxicity c,d,e
Treat until RECIST 
1.1 progression or 
unacceptable 
toxicity c,d,e
Follow-Up
Treatment
Follow-up for 
safety, RECIST 
1.1 
progression, 
and survival
Endpoints
• Primary
•
ORR by BICR
•
PFS by BICR
•
OS
• Secondary:
•
ORR and PFS by investigator
•
PFS and ORR by BICR in BM 
population
•
OS in BM population
•
Safety/tolerability
Protocol Amendment No.: 03
Date: 19-May-2022
28
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Study Treatment:
Study Drug for CA045001
Medication
Potency
IP/Non-IP
*Not applicable per Protocol Amendment 03
Bempegaldesleukin (NKTR-214) Powder for 
Solution for Injection
1.0 mg of rhIL-2 (IL-2) per vial
IP
Nivolumab Solution for Injection
100 mg (10 mg/mL)
IP
Note: For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer to the same molecule
Data Monitoring Committee: Yes
Protocol Amendment No.: 03
Date: 19-May-2022
29
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA045001)
Procedurea
Screening Visit
Notes
Eligibility Assessments
Informed Consent
X
Register in Interactive Response System to obtain participant number. 
Inclusion/Exclusion Criteria
X
Must be confirmed prior to randomization. 
Medical History
X
All medical history relevant to the disease under study including smoking history, alcohol use, 
AJCC M stage, and BRAF mutation status.
Tumor Sample Submission
X
All participants must have tissue submitted during the screening period to allow for participant 
enrollment into the study. Tissue submitted should be from an unresectable primary tumor lesion or 
any metastatic site. The tumor tissue should be from a site not previously irradiated and with no 
intervening treatment between time of acquisition and enrollment. Central lab must provide IRT 
with the results of PD-L1 testing prior to randomization. Either a formalin-fixed, paraffin-
embedded (FFPE) tissue block or 20 unstained tumor tissue sections, with an associated pathology 
report, must be submitted to the core laboratory for inclusion. FFPE tissue block and unstained 
slides submitted should be from biopsy obtained within 6 months prior to enrollment. Unstained 
slides should be sectioned within 3 months prior to submission. Submission of an FFPE block is 
strongly preferred but unstained slides are also acceptable. Tissue may be from a core biopsy, 
punch biopsy, excisional or incisional biopsy, or surgical specimen; fine needle aspiration and other 
cytology samples are not acceptable. Biopsies of bone lesions that do not have a soft tissue 
component are also unacceptable for submission. The Medical Monitor (or designee) can be 
consulted for eligibility if subjects have less than 20 unstained slides.
In order to be randomized, a participant must have quantifiable PD-L1 tumor expression (≥ 1% 
[positive] or < 1% [negative] tumor cell membrane staining) or be classified as PD-L1 
indeterminate. Non-evaluable participants are not eligible for randomization. The analytical 
laboratory must provide IRT with confirmation of the related results prior to randomization.
 
 Note: If the participant has > 1 lesions, the lesion 
planned for biopsy while on treatment cannot be designated as a target lesion at baseline. Additional
target lesions should be available for radiographic efficacy assessments. If the participant has only 
one lesion that is measurable and amenable to biopsy, the lesion must be greater than 2.0 cm and the 
biopsy cannot be excisional. Note: These same criteria that apply for lesion selection also apply to 
participants who consent to the optional biopsy in the main study. Please refer to Section 9.8.3 for 
additional information.
Protocol Amendment No.: 03
Date: 19-May-2022
30
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-1:
Screening Procedural Outline (CA045001)
Procedurea
Screening Visit
Notes
Safety Assessments
Physical Examination, Measurements, Vital 
Signs, Pulse Oximetry, Performance Status 
X
Must be collected within 14 days prior to randomization. Includes height, weight, Performance 
Status (Appendix 5), BP, Heart rate, Temperature, Pulse Oximetry.
Prior and Concomitant Medication Use
X
Must be collected within 14 days prior to randomization. 
Document vaccine use within 30 days prior to randomization. 
Serious Adverse Events Assessment
X
Collected from time of consent. All AEs (SAEs or non-serious AEs) associated with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection collected from time of consent.
See Section 9.2 and Appendix 3 for further details.
ECG
X
Within 14 days of randomization. See Section 9.4.2. 
Echocardiogram or MUGA
X
Left Ventricular Ejection Fraction must be >45% within 60 days 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 judgment.
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.
Refer to Table 9.4.5-1 for a list of laboratory tests to conduct
Pregnancy Test 
X
Serum or urine test (minimum sensitivity 25 IU/L or equivalent units of HCG) is required to be done 
at Screening and within 24 hours prior to first dose of study therapy in women of childbearing 
potential (WOCBP). 
BRAF mutation testing 
X
Results from BRAF mutation testing per local institutional standard required for entry into IRT by 
the site prior to randomization.
Note: Results from NRAS/CKIT mutation testing and prior gene expression profiles for risk 
stratification should be recorded if available.
Protocol Amendment No.: 03
Date: 19-May-2022
31
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-1:
Screening Procedural Outline (CA045001)
Procedurea
Screening Visit
Notes
Tumor Assessment
Body Imaging
X
Contrast-enhanced CT of the chest; contrast-enhanced CT or MRI of the abdomen, and pelvis; and 
all known sites of disease within 28 days prior to randomization. See Section 9.1.1 for further details.
Brain Imaging
X
MRI of the brain without and with contrast is required for participants at baseline within 28 days 
prior to randomization. CT of the Brain (without and with contrast) can be performed if MRI is 
contraindicated. See Section 9.1.1 for further details. 
a Some assessments referred to in this section may not be captured as data in the CRF. 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.
Protocol Amendment No.: 03
Date: 19-May-2022
32
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
Study Drug
Randomize
X
Administer Study 
Drug
X
X
X
Arm A: Nivolumab 480 mg IV Q4W.
Arm B: Nivolumab 480 mg IV Q4W.
Note: Nivolumab dosing for participants < 40 kg on both arms will be 
6 mg/kg IV Q4W.
In both Arm A and Arm B: Participants may be dosed no less than 
25 days from the previous dose.
*Not applicable 
per Protocol 
Amendment 03
Administer Study 
Drug
X
X
X
Not applicable per Protocol Amendment 03. 
The first dose must be administered within 3 calendar days following 
randomization.
Arm A: Bempegaldesleukin 0.006 mg/kg IV Q3W + Nivolumab 360 
mg IV Q3W. Refer to Section 7.1.1 for sequential dosing instructions. 
Arm B: Nivolumab 360 mg IV Q3W
Note: Nivolumab dosing for participants < 40 kg on both arms will be 
4.5 mg/kg IV Q3W.
If the participant’s weight on the day of dosing differs by > 10% from 
baseline or previous dose, the dose must be recalculated. For 
Nivolumab - All doses should be rounded to the nearest milligram. For 
bempegaldesleukin - All doses should be rounded to the second decimal 
digit (hundredths place).
In both Arm A and Arm B: Participants may be dosed no less than 
18 days from the previous dose.
*Not applicable 
per Protocol 
Amendment 03
X
X
X
Not applicable per Protocol Amendment 03.
Protocol Amendment No.: 03
Date: 19-May-2022
33
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
Administer fluids
Arm A only. May be withheld if deemed in the best interest of the 
participant by the Investigator. Refer to Section 7.1.1.1 for additional 
information. 
*Not applicable 
per Protocol 
Amendment 03
Review Hydration 
Guidelines with 
Participants
X
X
X
Not applicable per Protocol Amendment 03. 
Arm A only. Hydration Guidelines should be reviewed at each dosing 
visit
*Not applicable 
per Protocol 
Amendment 03
Oral Hydration 
Follow-up
X
X
Not applicable per Protocol Amendment 03. 
For the first two doses of bempegaldesleukin, between Days 3 and 5 
following infusion, 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. 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
Targeted Physical 
Examination, 
Measurements, 
Vital Signs and 
Performance Status
X
Vital 
Signs 
Only
X
X
•
Weight
•
BP
•
Heart rate
•
Temperature
•
Performance Status (Appendix 5)
Protocol Amendment No.: 03
Date: 19-May-2022
34
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
Arm A and Arm B: Day 1 vital signs for each cycle should be 
monitored at the following intervals:
•
Predose
•
Within 30 minutes of completion of nivolumab administration
Adverse Events 
Assessment 
(including SAEs)
Continuously
All AEs (SAEs or non-serious AEs), including those associated with SARS-
CoV-2 infection, must be collected continuously during the treatment 
period. Refer to Section 9.2.1 for the timing of AE/SAE collection.
Concomitant 
Medication Use
X
X
X
X
Record at each visit. 
Laboratory Tests
Pregnancy Test 
X
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 women of childbearing potential (WOCBP).
Clinical Laboratory 
Testing
X
X
X
Refer to Section 9.4.5 Clinical Safety Laboratory Assessments for list of 
laboratory tests 
See Table 9.4.5-1.
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 dosing, though renal function (ie, serum creatinine) must be 
assessed within 24 hours prior to dosing with bempegaldesleukin or as 
soon as locally feasible. For the first dose visit, labs need not be 
repeated if they were performed within 72 hours and the results are 
available and have been reviewed for eligibility.
Protocol Amendment No.: 03
Date: 19-May-2022
35
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
Efficacy Assessments
Body Imaging
Prior to Protocol Amendment 03, contrast-enhanced CT of the 
chest, CT or MRI of the abdomen, pelvis, and all known and 
suspected sites of disease should be performed every 9 weeks 
(± 7 days) from randomization up to Week 54 and then every 
12 weeks (± 7 days). Per Protocol Amendment 03, tumor 
assessments will continue per schedule of local standard of 
care (SOC). 
Tumor assessment for progression will not be based on 
imaging performed for biopsy in Cycle 2.
Tumor assessment schedule should be maintained regardless 
of dose delays.
Use same imaging method as was used at Screening.
Per Protocol Amendment 03, any participant remaining on treatment 
will continue imaging per Section 9.1.1. Imaging will be performed per 
SOC and images will no longer be submitted (BICR).
All study treatment decisions will be based on the Investigator’s 
assessment of tumor images. 
See Section 9.1.1 for additional details.
Brain Imaging
Prior to Protocol Amendment 03, participants with a history of 
brain metastasis or symptoms should have surveillance MRI 
with and without contrast per standard of care (first assessment 
at 9 weeks (± 7 days) from randomization, and then 
approximately every 12 weeks (± 7 days), or sooner if 
clinically indicated. CT of the brain (without and with 
contrast) can be performed if MRI is contraindicated. Per 
Protocol Amendment 03, brain imaging will be done per
schedule of local SOC.
Per Protocol Amendment 03, any participant remaining on treatment 
will continue imaging per Section 9.1.1. Imaging will be performed per 
SOC and images will no longer be submitted for BICR.
See Section 9.1.1 for further details.
*Not applicable 
per Protocol 
Amendment 03
Biomarker 
Assessments
Not applicable per Protocol Amendment 03.
Please review specimen collection schedule prior to each 
cycle as specified in Sections 
 9.8
Protocol Amendment No.: 03
Date: 19-May-2022
36
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
*Not applicable 
per Protocol 
Amendment 03
Biomarker Sample 
Collection
Not applicable per Protocol Amendment 03.
See Notes
Not applicable per Protocol Amendment 03.
See Section 9.8.2.
 
Table 9.8.2-2 Biomarker Sampling Schedule: All Participants not 
Enrolled into the 
.
Tumor biopsy: Required for the 
 during Cycle 
1 but optional for subsequent participants.
If clinically feasible, the lesion for biopsy during Cycle 1 would be the 
same lesion that was biopsied at baseline. If the participant has only one 
lesion that is measurable and amenable to biopsy, the lesion must be 
greater than 2.0 cm and the biopsy cannot be excisional. If the 
participant has > 1 measurable lesion, the lesion planned for biopsy 
while on treatment cannot be designated as a target lesion at baseline. 
Additional target lesions should be available for radiographic efficacy 
assessments. Note: These same criteria that apply for lesion selection 
also apply to participants who consent to the optional biopsy in the main 
study. Please refer to Section 9.8.3 for additional information.
*Not applicable 
per Protocol 
Amendment 03
Stool sample 
collection
Not applicable per Protocol Amendment 03.
See Notes
*Not applicable 
per Protocol 
Amendment 03
Tumor biopsy
Not applicable per Protocol Amendment 03. 
See Notes
Protocol Amendment No.: 03
Date: 19-May-2022
37
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
Protocol Amendment No.: 03
Date: 19-May-2022
38
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-2:
On-Study Activities (CA045001)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Procedure
Cycle 1 Onlya
Cycle 2 Onlya
Cycle 3 and 
Beyonda
Notes
Day 
1
Day 
3-5
Day 8
(± 1 day)
Day 1
(± 3 days)
Day
3-5
Day 1
(± 3 days)
a 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.
Protocol Amendment No.: 03
Date: 19-May-2022
39
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-3:
Long-term Procedural Follow-Up (CA045001)
Procedure
Follow-up
Visit 1 (± 7 days)a
Follow-up
Visit 2 (± 7 days)a
Survival Follow-up
Every 3 months
(± 14 days)b
Notesc
Safety Assessments
Vital Signs
X
X
Vital Signs: BP, Heart rate, and temperature
Adverse Events Assessments 
(Including SAEs)
X
X
SAEs to be collected after the 100-day safety visit if 
the SAE is deemed to be related or residual 
toxicities are persisting.
All AEs (SAEs or 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.
Performance Status
X
X
Review of Concomitant 
Medications 
X
X
*Not applicable per Protocol 
Amendment 03
Subsequent Anti-Cancer Therapy 
X
X
X
Not applicable per Protocol Amendment 03. 
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 to 
subsequent anti-cancer therapies will be collected.
Laboratory Tests
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.
Clinical Laboratory Testing
See Notes
See Notes
During Safety Follow-up Visit 1 and during Safety
Follow-up Visit 2, if toxicities are present.
Refer to Table 9.4.5-1, Clinical Safety Laboratory 
Assessments for list of laboratory tests
Protocol Amendment No.: 03
Date: 19-May-2022
40
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-3:
Long-term Procedural Follow-Up (CA045001)
Procedure
Follow-up
Visit 1 (± 7 days)a
Follow-up
Visit 2 (± 7 days)a
Survival Follow-up
Every 3 months
(± 14 days)b
Notesc
*Not applicable per Protocol Amendment 03 Biomarker Assessments
*Not applicable per Protocol 
Amendment 03
Blood PD Sampling
Not applicable per Protocol Amendment 03. 
See Notes
Not applicable per Protocol Amendment 03.
See Section 9.8.2.
 
Table 9.8.2-2 Biomarker Sampling Schedule: All 
Participants not Enrolled into the 
 
Tumor biopsy: Optional at progression.
*Not applicable per Protocol 
Amendment 03
Tumor biopsy
Not applicable per Protocol Amendment 03. 
See Notes
Efficacy Assessments
Body Imaging 
Prior to Protocol Amendment 03,only for participants without 
Investigator-assessed progression. Contrast enhanced CT of the chest, CT 
or MRI of the abdomen, pelvis, and all known and suspected sites of 
Per Protocol Amendment 03, any participant 
remaining on follow-up will continue imaging per 
Protocol Amendment No.: 03
Date: 19-May-2022
41
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-3:
Long-term Procedural Follow-Up (CA045001)
Procedure
Follow-up
Visit 1 (± 7 days)a
Follow-up
Visit 2 (± 7 days)a
Survival Follow-up
Every 3 months
(± 14 days)b
Notesc
disease should continue every 9 weeks (± 7 days) from randomization up 
to Week 54 and then every 12 weeks (± 7 days). Per Protocol Amendment 
03, tumor assessments will continue per the schedule of local standard of 
care (SOC).
Section 9.1.1. Imaging will be performed per SOC 
and images will no longer be submitted for BICR.
See Section 9.1.1 for further details. 
Brain Imaging
Prior to Protocol Amendment 03, only for participants without BICR-
confirmed progression. Participants with a history of brain metastasis or 
symptoms should continue to have surveillance MRI with and without 
contrast per standard of care every 12 weeks (± 7 days), or sooner if 
clinically indicated. CT of the brain (without and with contrast) can be 
performed if MRI is contraindicated. Per Protocol Amendment 03, brain
imaging will be done per the schedule of local SOC.
Per Protocol Amendment 03, any participant 
remaining on follow-up will continue imaging 
per Section 9.1.1. Imaging will be performed per 
SOC and images will no longer be submitted for 
BICR.
See Section 9.1.1 for further details.
Survival Status
X
X
X
Protocol Amendment No.: 03
Date: 19-May-2022
42
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 2-3:
Long-term Procedural Follow-Up (CA045001)
Procedure
Follow-up
Visit 1 (± 7 days)a
Follow-up
Visit 2 (± 7 days)a
Survival Follow-up
Every 3 months
(± 14 days)b
Notesc
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 Not applicable per Protocol Amendment 03. 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. The study Sponsor 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 their 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 CRF. 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.
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
3
INTRODUCTION
CA045001 is a Phase 3 randomized study of NKTR-214 (bempegaldesleukin) combined with 
nivolumab vs nivolumab monotherapy in participants with unresectable or metastatic melanoma 
that is previously untreated. Bempegaldesleukin consists of interleukin-2 (IL-2; See Appendix 1: 
Abbreviations), which has the same amino acid sequence as aldesleukin, conjugated at a defined 
region within the protein to releasable PEG chains. The six PEG chains render the molecule 
inactive. After administration in vivo, the PEG chains are slowly hydrolyzed to generate active 
cytokine conjugates. The most active IL-2 conjugates are 2-PEG-IL-2 and 1-PEG-IL-2. The 
location of the PEG chains on the active conjugated-IL-2 reduces affinity to the IL-2 receptor alpha 
subunit (IL-2Ra), reducing the activation of the high affinity IL-2 receptor (IL-2Rαβγ) found on 
Tregs. In the tumor, bempegaldesleukin preferentially activates CD8+ T and NK cells over Tregs. 
This Phase 3 study will allow for direct comparison of bempegaldesleukin combined with 
nivolumab vs nivolumab monotherapy as measured by ORR, PFS, OS, and other clinical endpoints 
in treatment naive participants with unresectable or metastatic melanoma.
Per Protocol Amendment 03, participants who are currently receiving bempegaldesleukin plus
nivolumab are required to discontinue bempegaldesleukin and will receive nivolumab 
monotherapy.
3.1
Study Rationale
Activation of programmed cell death protein-1 (PD-1) pathway inhibits CD-28-mediated 
upregulation of cytokines, inhibits T cell activation, and inhibits the expansion of previously 
activated cells. Blockade of the PD-1 pathway has demonstrated clinical activity across multiple 
tumor types including melanoma. An accumulating body of evidence supports that low levels of 
tumor infiltrating lymphocytes (TILs) in pretreatment biopsies predicts for poor clinical response 
to PD-1 pathway blockade.1,2,3 Bempegaldesleukin promotes biased signaling through the IL-2 
intermediate affinity receptor (IL-2Rβγ) as opposed to the high affinity receptor (IL-2Rαβγ) found 
on regulatory T-cells (Tregs). Bempegaldesleukin increases intratumoral CD8+ lymphocytes and 
natural killer cells as well as the number of PD-1+ CD8+ cells in the tumor and peripheral blood. 
The biologic activity of bempegaldesleukin makes it a potentially promising immunotherapy to 
combine with checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway.
The current study aims to demonstrate that treatment with bempegaldesleukin in combination with 
nivolumab will be efficacious in participants with unresectable or metastatic melanoma that is 
previously untreated. Additional objectives of the study include characterization of safety and 
tolerability, as well as 
 potential predictive biomarkers
.
3.1.1
Research Hypothesis
This section is not applicable per Protocol Amendment 03.
Treatment with bempegaldesleukin combined with nivolumab will improve objective response 
rate (ORR), progression-free survival (PFS), and overall survival (OS) when compared with
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
nivolumab monotherapy in participants with unresectable or metastatic melanoma that is 
previously untreated.
3.2
Background
3.2.1
Melanoma Background / Current Therapies
Melanoma is the most serious form of skin cancer and the incidence varies globally. Melanoma
accounts for approximately 3% of all cancer deaths in Australia and 1% and 2% of all cancer 
deaths in Europe and the United States (US).4,5 In 2020, it is estimated that approximately 29,000
patients worldwide will present with unresectable stage III and stage IV melanoma, where the 5-
year survival rate is 18% for late-stage disease.6
Prior to 2011, approved therapies for the treatment of metastatic melanoma were limited and 
included chemotherapy (dacarbazine) and immunotherapy (IL-2). Historically chemotherapy was 
used as palliative therapy for melanoma with modest response rates and responses that were 
usually short lived. Treatment of melanoma patients with high dose IL-2 demonstrated a response 
rate of 10%-15% with approximately 5% of patients developing a complete response and a portion 
of the responders achieved durable long-term responses.7 The use of high dose IL-2 is restricted 
to specialized centers, as the treatment requires hospitalization for drug administration and toxicity 
management by a specially trained team.
Since 2011, agents in 3 new therapeutic classes received approval for the treatment of unresectable 
or metastatic melanoma as monotherapy or in combination. The approved agents include 1) anti-
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibodies, such as ipilimumab; 
2) anti-PD-1 receptor blocking antibodies, which include nivolumab and pembrolizumab; and 3) 
small molecules targeting the intracellular kinase pathways of BRAF and MEK in BRAF V600E 
positive melanoma. BRAF inhibitors (vemurafenib or dabrafenib) and MEK inhibitors 
(cobimetinib or trametinib) either alone or in combination, show improved OS or median PFS 
compared with chemotherapy, but patients often develop resistance to therapy.8,9,10,11 Importantly, 
effective treatment with these agents is limited to patients with BRAF mutation positive tumors 
(approximately 40%-50% of patients).
According to the most recent National Comprehensive Cancer Network (NCCN) Guidelines, 
checkpoint immunotherapy with anti-PD-1 therapies, which are effective regardless of BRAF 
mutation status, is recommended first-line therapy for treatment of unresectable or metastatic 
melanoma. Options in this category include pembrolizumab, nivolumab, or nivolumab/ipilimumab 
combination therapy.1 PD-L1 expression in pretreatment tumor biopsy correlates with clinical 
benefit to anti-PD-1 based treatment;12 however, PD-L1 expression has not been recommended to 
guide melanoma treatment decisions given that low expressers may still have durable 
responses.1,13 Although checkpoint inhibitors significantly improved clinical outcome, a significant 
portion of patients progress and treatment-related toxicities often require patients to discontinue 
therapy.
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
3.2.2
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.14,15,16
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 as well as negative co-stimulatory signals in 
addition to antigen recognition by the TCR.17 Collectively, these signals govern the balance 
between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA-4, ICOS, and BTLA.18 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 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.19 These results suggest that PD-1 blockade has the potential to activate anti-self T-
cell responses, but these responses are variable and dependent upon various host genetic factors. 
Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to self-
antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the MLR. Using a cytomegalovirus (CMV) re-
stimulation assay with human 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/N, and PAN02).20
3.2.3
Bempegaldesleukin Mechanism of Action
Bempegaldesleukin (NKTR-214) 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-
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
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 regulatory T cells (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 Tregs that are activated through the IL-2 receptor alpha beta gamma (IL-
2Rαβγ).21,22,23,24,25 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.24,25 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.26
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 Nivolumab
Nivolumab has demonstrated safety and efficacy as monotherapy in the treatment of advanced 
melanoma in treatment naive patients in two Phase 3 trials. In CheckMate-066 previously 
untreated melanoma patients with advanced melanoma without BRAF mutations were randomized 
treatment with either nivolumab versus dacarbazine. There was a 58% reduction in the risk of 
death with nivolumab treatment group (hazard ratio [HR] for death, 0.42 [99.79% CI, 0.25–0.73]
P < 0.001).27 CheckMate-067 was a double-blind, Phase 3 study to evaluate the efficacy and safety 
of nivolumab monotherapy and nivolumab plus ipilimumab combination therapy compared to 
ipilimumab monotherapy in metastatic or unresectable melanoma regardless of BRAF mutation 
status. Nine hundred forty-five participants were randomized 1:1:1 to receive either 3 mg/kg of 
nivolumab every 2 weeks (plus ipilimumab-matched placebo); 1 mg/kg of nivolumab every 3 
weeks plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by 3 mg/kg of nivolumab 
every 2 weeks; or 3 mg/kg of ipilimumab every 3 weeks for 4 doses (plus nivolumab-matched 
placebo). The overall response rate was 44% in the nivolumab monotherapy arm and 19% in the 
ipilimumab monotherapy arm. The hazard ratio for progression or death was 0.55 (95% CI, 0.45 
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
to 0.66) with nivolumab versus ipilimumab. The rate of OS at 3 years was 52% in the nivolumab 
group, as compared with 34% in the ipilimumab group.13 The median duration of response was 
not reached in the nivolumab monotherapy group and was 19.3 months in the ipilimumab group. 
These data led to FDA and EMA approval of nivolumab monotherapy as frontline treatment in 
patients regardless of BRAF mutation status. 
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Protocol Amendment No.: 03
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
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, IL-2 mediated AEs (eg, flu-like symptoms, rash, pruritus, 
fatigue, hepatic transaminase elevations, and serum creatinine elevations), infusion-related 
reactions/hypersensitivity reactions, thyroid dysfunction, eosinophilia, 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 Investigator’s Brochure 
and will not be repeated herein.
Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
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 adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 6. Most high-grade events were manageable 
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
with the 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 IL-2 mediated AEs (eg, flu-like symptoms, rash, pruritus, fatigue, 
hepatic transaminase elevations, and serum creatinine elevation), infusion related reactions, 
thyroid dysfunction, eosinophilia, 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, and 
some of these cases shared clinical characteristics consistent with immune-mediated AEs 
associated with checkpoint inhibitors.
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 severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the trial, then the 
benefit and risk considerations remain the responsibility of the Investigator.
The final ORR and PFS analyses, and the first OS interim analysis (combined with the second OS 
interim analysis) have been completed using the locked database with a database lock date of 01-
Feb-2022. The addition of bempegaldesleukin to nivolumab did not result in a statistically 
significant improvement in PFS (HR 1.09, 97% CI, 0.88-1.35) or ORR compared to nivolumab 
monotherapy, and the significance threshold for OS was also not crossed at the combined first and 
second OS analyses. Given there was no additional clinical benefit in the doublet therapy arm 
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Bempegaldesleukin (NKTR-214) and Nivolumab
compared to the monotherapy arm for the primary endpoints of PFS and ORR, the Sponsor, in 
consultation with the DMC, decided to unblind the trial and to perform no additional formal 
analyses for the OS endpoint. 
After the Sponsor reviewed the topline results from the ORR and PFS final analysis, additional 
toxicities with no added efficacy were observed in the experimental arm. Therefore participants 
are required to discontinue bempegaldesleukin and may continue nivolumab monotherapy for the 
remainder of the study treatment period. 
4
OBJECTIVES AND ENDPOINTS
Table 4-1 presents the objectives and endpoints of the study. The final ORR and PFS analyses, 
and the first OS interim analysis (combined with the second OS interim analysis) have been 
completed using the locked database with database lock date of 01-Feb-2022. Given there was no
additional clinical benefit in the doublet therapy arm compared to the monotherapy arm for the 
primary endpoints of PFS and ORR, the Sponsor, in consultation with the DMC, has decided to 
unblind the trial. No additional OS formal analyses will be performed. Any further efficacy 
analyses, if conducted, will be descriptive.
Per Protocol Amendment 03, the secondary and exploratory objectives except biomarker 
parameters are no longer applicable. Biomarker sample collection will not be applicable per 
Protocol Amendment 03. However, exploratory analysis of biomarkers on previously collected 
samples as per Section 9.8 may be conducted.
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To 
compare
ORR 
using 
RECIST 
1.1 
for
bempegaldesleukin combined with nivolumab and that 
of nivolumab monotherapy in participants with 
previously untreated unresectable or metastatic 
melanoma
•
ORR by BICR
•
To 
compare 
PFS 
using 
RECIST 
1.1 
of 
bempegaldesleukin combined with nivolumab and that 
of nivolumab monotherapy in participants with 
previously untreated unresectable or metastatic 
melanoma 
•
PFS by BICR
•
To compare OS of bempegaldesleukin combined with 
nivolumab and that of nivolumab monotherapy in 
participants with previously untreated unresectable or 
metastatic melanoma
•
OS
Secondary
•
To evaluate efficacy of bempegaldesleukin combined 
with nivolumab and that of nivolumab monotherapy 
•
CBR, DoR, TTR by BICR per RECIST 1.1
•
ORR, PFS, CBR, DoR, TTR by Investigator per 
RECIST 1.1
•
To evaluate the association between PD-L1 tumor 
expression 
on 
tumor 
cells 
(≥1% 
or 
•
PFS and ORR by BICR and OS in biomarker 
population
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
< 1%/indeterminate) and efficacy measures including 
PFS and ORR by BICR and OS. 
•
To evaluate the safety and tolerability of 
bempegaldesleukin combined with nivolumab and 
that of nivolumab monotherapy 
•
Safety and tolerability
Exploratory
•
To characterize the effect of nivolumab when 
administered as monotherapy and in combination with 
bempegaldesleukin on immune cell populations and 
markers of immune activation. Tumor tissue may also 
be explored for potential biomarkers of immune 
activation.
•
Biomarker parameters
•
To assess efficacy of bempegaldesleukin combined 
with nivolumab and nivolumab monotherapy based on 
tumor mutation burden and blood-based tumor 
mutation burden.
•
PFS, OS, ORR in Biomarker Population.
•
To evaluate PFS after the next line of treatment (PFS2) 
of bempegaldesleukin combined with nivolumab and 
that of nivolumab monotherapy in participants with 
•
PFS2 by Investigator per RECIST 1.1
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
previously untreated unresectable or metastatic 
melanoma
5
STUDY DESIGN
5.1
Overall Design
This is a multicenter, randomized, open-label, Phase 3 study that will evaluate the efficacy and 
safety of bempegaldesleukin in combination with nivolumab compared with nivolumab 
monotherapy in adult and adolescent (≥ 12 years of age) participants with previously untreated 
unresectable or metastatic melanoma. The study is divided into a Screening period, a Treatment 
period, and a Long-Term Follow-up period.
 
 
 
 
 
 
 
Participants will be randomized (1:1) to 1 of 2 treatment arms:
The original treatments in Arm A and Arm B are not applicable per Protocol Amendment 03.
•
Arm A: Bempegaldesleukin 0.006 mg/kg IV Q3W + nivolumab 360 mg IV Q3W (sequential 
dosing)
•
Arm B: Nivolumab 360 mg IV Q3W
•
Note:
•
Bempegaldesleukin dose is based on IL-2 equivalent component.
•
Nivolumab dosing in both arms for participants < 40 kg will be weight-based 4.5 mg/kg IV 
Q3W. 
Randomization will be stratified by:
•
PD-L1 tumor expression status (≥1% vs < 1% or indeterminate) based on the PD-L1 IHC 28-8 
pharmDx assay)
•
BRAF mutation status (V600 mutation positive vs wild type) based on local testing.
•
AJCC 8th edition M stage [M0 / M1any[0] (Stage III any LDH or Stage IV Normal LDH) vs 
M1any[1] (Stage IV Elevated LDH)] based on the screening imaging and laboratory test 
results.
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
This study schematic is not applicable per Protocol Amendment 03. Figure 5.1-1 provides the 
study schematic, and Section 2 outlines the study procedures in the Schedule of Activities.
Figure 5.1-1:
Study Schematic
Per Protocol Amendment 03:
•
Participants who have completed therapy and are currently in survival follow-up should
discontinue from the study immediately if AE reporting requirements have been fulfilled as 
per Section 9.2.3. Documentation of last overall survival should occur upon discontinuation.
•
Participants who have completed therapy and are currently within the 100 days safety follow-
up should discontinue from the study once they complete the safety follow up 100 days after 
the last dose of study treatment if AE reporting requirements have been fulfilled as per Section
9.2.3. Documentation of last overall survival should occur upon discontinuation.
•
Participants in Arm A are required to discontinue bempegaldesleukin and may continue 
nivolumab monotherapy. Participants receiving treatment in Arm A and Arm B will receive
nivolumab monotherapy on study at 480 mg IV Q4W. Participants < 40 kg will be administered 
a body weight adjusted nivolumab dose of 6 mg/kg IV Q4W.
•
All participants will have 100 days safety follow-up or until AE reporting requirements have 
been fulfilled as per Section 9.2.3. Documentation of last overall survival should occur upon
discontinuation. The Sponsor will close the study once the last participant has completed the 
safety follow-up.
5.1.1
Screening Period
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’ 
Population:
• Treatment naïve (1L setting)
• Unresectable stage III or stage IV
Stratification factors:
• PD-L1 ≥ 1% v. PD-L1 < 1 % / 
indeterminate
• BRAF mut v. WT
• M0 / M1 any[0] vs M1any[1] 
Randomization 
1:1
N=764
Screening
Arm A
NKTR-214 0 006 mg/kg IV Q3W
and
Nivolumab 360 mgb IV Q3W
Arm B
Nivolumab 360 mgb IV Q3W
b Nivolumab dosing in both arms for participants < 40 kg will be weight-based 4.5 mg/kg IV Q3W.
c Treatment beyond progression may be permitted if protocol criteria met.
d Maximum treatment duration of 24 months.
e Progression determined by investigator with BICR confirmation.
Treat until 
RECIST 1.1 
progression or 
unacceptable 
toxicity c,d,e
Treat until RECIST 
1.1 progression or 
unacceptable 
toxicity c,d,e
Follow-Up
Treatment
Follow-up for 
safety, RECIST 
1.1 
progression, 
and survival
Endpoints
• Primary
•
ORR by BICR
•
PFS by BICR
•
OS
• Secondary:
•
ORR and PFS by investigator
•
PFS and ORR by BICR in BM 
population
•
OS in BM population
•
Safety/tolerability
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
standard care. After signing the ICF, participants will be evaluated for entry criteria during the 
Screening period before administration of study drug(s). Rescreening after screen failure will be 
allowed. Imaging of the brain with MRI is required of all participants during Screening. CT of the 
brain (without and with contrast) can be performed if MRI is contraindicated
For participants whose BRAF mutation status is unknown, BRAF status must be determined by 
local testing prior to study randomization.
Sufficient, recent tumor tissue submitted should be from an unresectable primary tumor lesion or 
any metastatic site. The tumor tissue should be from a site not previously irradiated and with no 
intervening treatment between time of acquisition and enrollment. Either a formalin-fixed, 
paraffin-embedded (FFPE) tissue block or 20 unstained tumor tissue sections, with an associated 
pathology report, must be submitted to the core laboratory for inclusion. FFPE tissue block and 
unstained slides submitted should be from biopsy obtained within 6 months prior to enrollment. 
Unstained slides should be sectioned within 3 months prior to submission. Tumor tissue should be 
obtained from core biopsy, punch biopsy, excisional or incisional biopsy, or surgical specimen and 
then submitted to the central laboratory. The Medical Monitor (or designee) can be consulted for 
eligibility if subjects have less than 20 unstained slides. The central laboratory must provide IRT 
with PD-L1 results from tumor tissue sample prior to randomization. All research sites will be 
blinded to the results of biomarker (PD-L1) testing. Participants must not have received any 
systemic anticancer therapy after the date that the submitted tumor tissue was obtained.
5.1.2
Treatment Period
The treatment period of the study is divided into multiple treatment cycles with associated 
evaluations and procedures. One cycle of treatment is defined as 3 weeks. Results of the 
assessments must be reviewed and documented before administering the first dose of the next 
cycle. Every effort should be made to schedule visits within the protocol-specified windows. 
Assessments and frequency are described in Section 2. 
 
 
 
 
 
 
Participants will be treated until 
disease progression, death, unacceptable toxicity, symptomatic deterioration, the Investigator’s 
decision to discontinue treatment, the participant’s decision to discontinue treatment or withdraw 
consent, the participant is lost to follow-up, BMS and Nektar Therapeutics decide to terminate the 
study, or for a maximum of 24 months of treatment. In certain circumstances, participants with 
progressive disease per RECIST 1.1, but with otherwise stable or improved performance and 
clinical status, may continue to be treated in the event of a perceived benefit per Investigator; see 
Section 8.1.3 for treatment beyond progression criteria.
Protocol Amendment No.: 03
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Per Protocol Amendment 03, participants who are currently 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 at 480 mg 
IV Q4W. Participants < 40 kg will be administered a body weight adjusted nivolumab dose of 6 
mg/kg IV Q4W.
Investigators have the following options for participants who are still on treatment:
1) Discontinue bempegaldesleukin and continue nivolumab monotherapy if the participant is 
assigned to the experimental arm (bempegaldesleukin plus nivolumab) for the protocol-
specified duration
2) Continue assigned nivolumab monotherapy (i.e. nivolumab) for the protocol-specified 
duration 
3) Discontinue the participant from assigned study treatment 
4) Investigators should inform participants who are still on treatment and those on follow up about 
the study results and counsel them on treatment choices. Decisions regarding treatment options 
should be made jointly by Investigators and participants based on a risk/benefit analysis 
assessed individually for each participant. The counseling and decision should be clearly 
documented in the medical record of participant. All participants must be re-consented.
5.1.3
Long-Term Follow-Up
Long-term follow-up should continue until withdrawal of consent, death, or study termination by 
the Sponsor. The total maximum duration of the study is up to 2 years +100 days from 
randomization of the last participant.
Timing for long-term follow-up will be as follows:
•
Assessments should continue as described in Table 2-3.
•
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 (± 7days) from the last dose of study treatment. Both 
follow-up visits should be conducted in person.
•
Additional assessments may occur when the decision is made to discontinue treatment. 
•
Not applicable per Protocol Amendment 03. 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. 
•
Per clinical judgment, the participant may come in earlier.
•
In case of a clinically significant AE, 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. 
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
5.1.4
Data Monitoring Committee and Other External Committees
A Data Monitoring Committee will be established to provide oversight of safety and efficacy 
considerations in protocol CA045001 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 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.
5.2
Number of Participants
It is expected that approximately 1,020 participants will need to be enrolled in order to randomize 
764 participants, assuming a screen failure rate of approximately 25%. Approximately 
764 participants with previously untreated unresectable or metastatic melanoma will be 
randomized (1:1) to 1 of 2 treatment arms.
5.3
End of Study Definition
The start of the trial is defined as first visit for first participant screened. End of trial is defined as 
the last visit or scheduled procedure shown in the Schedule of Activities for the last participant. 
Study completion is defined as the final date on which data for the primary endpoint was or is 
expected to be collected, if this is not the same.
The first and second OS interim analyses have been completed using the locked database on 01-
Feb-2022, and no additional OS formal analyses will be performed.
This paragraph is not applicable per Protocol Amendment 03. The total duration of the study 
for the OS primary endpoint will be determined by accrual of events and is expected to occur 
approximately 68 months after the date of the first participant to be randomized (See Section 10). 
Additional follow-up for PFS and OS may be conducted up to approximately 5 years after the 
randomization of the last participant.
5.4
Scientific Rationale for Study Design
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 treatment-naive melanoma. In the most recent analysis of the dose escalation part, 
the response rate in this cohort is 69% (11 out of 16 participants) with 1 complete response and 10
partial responses with all responders maintaining their response.27 With 3 years of follow-up, 
nivolumab monotherapy in the CheckMate-067 study demonstrated an ORR of 44%, a 3-year PFS 
of 32% and a 3-year OS of 52%.13 The 3-year analysis of CheckMate-067 reaffirmed that 
responses to checkpoint inhibitors continue to evolve with longer follow-up as the number of 
Protocol Amendment No.: 03
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
participants achieving a complete response to nivolumab increased from 28 to 52 participants out 
of 316 total (9% to 16%) with a median duration of response that has still not been reached. It is 
anticipated that a similar evolution of responses will be seen in the combination of 
bempegaldesleukin and nivolumab as evolution of responses over time has been reported in the 
setting of high dose IL-2.
5.4.2
Rationale for Study Comparator and Study Population
PD-1 blockade is the recommended first-line therapy for treatment of BRAF WT and BRAF 
Mutant unresectable or metastatic melanoma in the NCCN Guidelines. Options in this category 
include pembrolizumab, nivolumab, or nivolumab / ipilimumab combination therapy.12 Three year 
follow-up data from the CheckMate-067 study in which participants received nivolumab or the 
combination of nivolumab and ipilimumab demonstrated PFS rates of 32% and 39% and OS rates 
of 52% and 58%, respectively.13 Although first-line treatment with checkpoint inhibitors 
significantly improved clinical outcome for melanoma patients, a significant portion of patients 
progress or discontinue treatment due to treatment-related toxicities.1 These data support the need 
for combinations such as bempegaldesleukin and nivolumab that may yield greater clinical 
efficacy without adding significant treatment related toxicities. 
5.4.3
Rationale for Inclusion of Adolescent Participants
Adolescent (generally aged 12-17 years) enrollment into clinical trials has been historically lower 
than enrollment of their pediatric counterparts. Lack of participation in pediatric trials may be due 
to differences in tumors observed in adolescent participants vs their pediatric counterparts, as 
tumors in adolescents may mirror those observed more often in adults. For trials in adult 
participants with tumor types that also occur in adolescents, adolescents are often excluded due to 
safety or regulatory concerns. Overall, this has led to a delay in the study of new therapies in 
adolescents, and most problematically, a delay in new efficacious therapies reaching this 
population. It has been recommended, therefore, that adolescents be considered for trials in adult 
populations for tumor types that are observed in adolescents and that share features common to 
those tumors that occur in adults.31,32
Although rare, the incidence of childhood and adolescent melanoma in the US has been increasing 
in the past 35 years. This trend is most prominent in the adolescent age range. A recent genomic 
analysis of pediatric melanoma demonstrates that conventional melanoma in children and 
adolescents shares many of the genomic features that have been described in adult melanoma, 
including BRAF mutations.33 Given the similarities observed in adolescent melanoma compared 
to adult, as well as the overarching need for inclusion of adolescents in clinical trials of potentially 
new efficacious therapies, adolescents will be included in this study where locally permitted.
Individual countries and sites have the option of opting out of adolescent eligibility.
5.4.4
Rationale for Choice of Endpoints
CA045001 will use the primary endpoints of ORR, PFS, and OS. ORR and PFS will be assessed 
per RECIST 1.1 by BICR. ORR will further be described by the durability and depth of responses, 
as those aspects are important characterizations of responses with immune-oncology treatments. 
Protocol Amendment No.: 03
Date: 19-May-2022
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
In the current melanoma clinical environment where multiple approved agents (ipilimumab and 
BRAF inhibitors) are available to treat the patients who progress on nivolumab with or without 
NKTR, PFS will not be confounded by subsequent therapy.
5.4.5
Rationale for Open-Label Design
This section is not applicable per Protocol Amendment 03. Due to the hydration program and 
the special restrictions for withholding anti-hypertensive medications in the bempegaldesleukin
arm, a placebo-controlled, double-blinded study is not appropriate for this study. 
5.4.6
Rationale for Stratification by M Staging, BRAF, and PD-L1
In order to minimize the potential for imbalances across treatment arms, there will be 
3 stratification factors utilized in this trial: American Joint Committee on Cancer (AJCC) 8th 
edition M stage (M0 / M1any[0] (Stage III any LDH or Stage IV Normal LDH) vs M1any[1]
(Stage IV Elevated LDH)), BRAF mutation status (mutation positive vs wild type), and PD-L1 
tumor expression (≥1% tumor cell surface expression [positive] vs < 1% tumor cell surface 
expression [negative]/indeterminate). Prognostic implications of M Staging are well established.34
BRAF mutations have likewise been associated with adverse clinical outcomes in melanoma 
patients, as well as differences in PFS and OS in patients treated with nivolumab.35
Previous clinical studies with nivolumab monotherapy have shown patients with PD-L1 positive 
tumors may have higher response rates than those with negative or indeterminate expression.36
Participants in the current trial will therefore be stratified by PD-L1 tumor expression status, as 
the effect of PD-L1 tumor expression on the response to nivolumab and bempegaldesleukin
combination is not yet known.
5.4.7
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 nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 
2-4 months,37,38,39,40,41,42 and emerging data suggests that benefit can be maintained in the absence 
of continued treatment. A recent analysis in a melanoma study suggests the majority of patients 
who discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the absence 
of further treatment.43 Furthermore, a limited duration of ipilimumab, including only 4 induction 
doses, resulted in long term survival in patients with metastatic melanoma, with a sustained plateau 
in survival starting around 2 years after the start of treatment.44
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously-treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 participants were alive >5 years and remained progression-free without any 
subsequent therapy. In the CA209003 NSCLC cohort, the overall survival (OS) curve begins to 
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.45 These survival 
outcomes are similar to Phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2 year OS rates of 23% and 
29%, and 3 year OS rates of 16%-18% for squamous and non-squamous NSCLC respectively).46
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized Phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in participants with previously treated, PD-L1-positive, advanced 
NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.47
Keynote-006 was a randomized Phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.48
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed 
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
PFS compared to those who were randomized to stop treatment, with median PFS (post-
randomization) not reached vs 10.3 months, respectively; HR = 0.42 (95% CI, 0.25 to 0.71). With 
a median follow-up of 14.9 months post-randomization, there also was a trend for patients on 
continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, the PFS curves 
in both groups plateau approximately 1 year after randomization (ie, 2 years after treatment 
initiation), suggesting that there may be minimal benefit in extending treatment beyond a total of 
2 years.49
Collectively, these data suggest that there is minimal, if any, benefit derived from continuing 
immuno-oncology treatment beyond two years in advanced tumors. However, even though 
immunotherapy is well tolerated, patients will be at risk for additional toxicity with longer term 
Protocol Amendment No.: 03
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
treatment. Therefore, in this study, treatment will be given for a maximum of 24 months from the 
start of study treatment (regardless of number of cycles administered).
This paragraph is not applicable per Protocol Amendment 03. Given the hypothesis that co-
administration of bempegaldesleukin with nivolumab will potentiate the pharmacological effects 
of nivolumab, the duration of bempegaldesleukin therapy will be restricted to 24 months to match 
the duration of nivolumab therapy.
5.5
Justification for Dose
5.5.1
Justification for Dose of Bempegaldesleukin
This section is not applicable per Protocol Amendment 03. The dose for bempegaldesleukin is 
0.006 mg/kg Q3W for participants taking in consideration the clinical safety profile associated 
with the robust immune system activation observed in the PIVOT-02 study. 
 
5.5.2
Justification for Dose of Nivolumab
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, cHL, squamous cell carcinoma of the head and neck (SCCHN), and 
urothelial carcinoma, using body weight normalized dosing (mg/kg), and has been safely 
administered at doses up to 10 mg/kg Q2W. Nivolumab is currently approved for the treatment of 
various tumors, including melanoma, NSCLC, RCC, cHL, SCCHN, and urothelial carcinoma, 
using a regimen of either nivolumab 240 mg Q2W, nivolumab 3 mg/kg Q2W, and 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 predicted 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.
Finally, nivolumab 360 mg Q3W is currently being investigated in combination with a number of 
other agents, including bempegaldesleukin in Study 16-214-02 (PIVOT-02), and platinum-doublet
chemotherapy dosing, with no new or increased safety events observed to date. Per Protocol 
Amendment 03, participants in Arm A should discontinue bempegaldesleukin and may continue 
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
nivolumab monotherapy. Participants in Arm A and Arm B will receive nivolumab monotherapy 
at 480 mg IV Q4W. Participants < 40 kg will be administered a body weight adjusted nivolumab 
dose of 6 mg/kg IV Q4W.
5.5.3
Rationale for Bempegaldesleukin/Nivolumab Combination Dose
This section is not applicable per Protocol Amendment 03. 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 mg/kg to 0.012 mg/kg; a dosing frequency of Q2W
(6 patients) was further explored at 0.006 mg/kg.
Table 5.5.3-1:
*Not applicable per Protocol Amendment 03 Patient Exposure 
supporting combination dose
Bempegaldesleukin
Dosing Frequency
Nivolumab
(Flat Dosea) 
Dosing 
Frequency
Bempegaldesleukin
Dose (mg/kg)
No. Patients 
Examined 
for Safety
Positive 
Biomarker 
Data and/or 
Evidence of 
Clinical 
Activity?
Bempegaldesleukin
Monotherapy
Q3W
n/a
0.003, 0.006,
0.009, 0.012
22
Yes
Q2W
n/a
0.006
6
Yes
Bempegaldesleukin+
Nivolumab
Q3W
Q2W
0.006
4
Yes
Q2W
0.006
3
Yes
Q3W
0.006
25
Yes
Q2W
0.003
3
Yes
Q3W
0.009
3
Yes
a Nivolumab Q2W = 240 mg, Q3W = 360 mg.
Abbreviations: Q2W = every 2 weeks; Q3W = every 3 weeks; n/a = not applicable.
•
The Safety Review Committee reviewed the totality of data and concluded the following for 
all 5 combination dose cohorts with a data cut of 05-Oct-2017:
•
Two patients at the bempegaldesleukin 0.009 mg/kg Q3W + nivolumab 360 mg Q3W dose 
level experienced dose limiting toxicities: Grade 3 hypotension and Grade 4 metabolic 
acidosis, each of which resolved within 5 days and the patients continued on treatment at a 
lower dose of bempegaldesleukin.
•
There were no Grade ≥ 3 treatment-related adverse events (TRAEs) at bempegaldesleukin
0.006 mg/kg Q3W + nivolumab 360 mg Q3W: the recommended Phase 2 dose.
•
TRAEs that occurred in ≥ 50% of the patients included fatigue, flu-like symptoms (combined 
MedDRA preferred terms of influenza-like illness, pyrexia, and chills), rash (combined 
MedDRA preferred terms of rash, rash erythematous, rash macular, rash maculopapular, and 
rash pruritic), and pruritus.
•
TRAEs were consistent across all five dose cohorts.
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
•
Management guidelines implemented in the combination program for hypotension were 
effective to mitigate the risk for Grade ≥ 3 hypotension.
•
No Grade ≥ 3 immune-mediated AEs were observed.
•
Cytokine-related AEs such as fever, chills, pruritus, fatigue, and rash are predictable based on 
the mechanism of action and were generally of mild severity and short duration.
•
The addition of bempegaldesleukin did not exacerbate nivolumab-related AEs that are 
commonly classified as immune-mediated AEs.
•
Bempegaldesleukin alone or in combination with nivolumab did not produce capillary leak 
syndrome, which is commonly observed in patients treated with high-dose IL-2.
At the time of the data cut, tumor response data were available for 34 patients, including 10 with 
metastatic melanoma, 19 with RCC, and 5 with NSCLC. Of these 34 response-evaluable patients, 
24 were treated at 0.006 mg/kg bempegaldesleukin with nivolumab 360 mg flat dose Q3W; 17 
patients had partial or complete responses and 13 had stable disease.
Given the totality of data, including safety/tolerability, reproducible PK, dose-independent 
pharmacodynamic (PD) profile, immune cell activation, and promising efficacy data 
 
, the Safety Review Committee approved 
bempegaldesleukin 0.006 mg/kg Q3W plus nivolumab 360 mg Q3W as the recommended dose to 
be administered in the late phase studies.
5.5.4
Justification for Dose for Adolescents
The PK of drugs and many therapeutics proteins has been shown to be similar between adolescent 
and adults once the effect of body size on PK is taken into consideration. Therefore, in general, 
adult doses would be expected to achieve similar systemic exposures in adolescents. Population 
PK model based simulation has shown that exposures produced by nivolumab 360 mg Q3W were 
well below the exposure range of 10 mg/kg Q2W regimen, a clinically safe dose, over a dose range 
of 34-180 kg in adults. Therefore, a minimum body weight threshold in adolescents (≥ 40 kg) is 
defined to receive the same adult flat dose to prevent exceeding target adult exposures.50,51
Participants ≥ 40 kg will be administered nivolumab 480 mg IV Q4W. Participants < 40 kg body 
weight will be administered a weight-based dose of 6 mg/kg IV Q4W that is equivalent to adult 
dose (typical subject of 80 kg body weight). The remainder of this paragraph is not applicable 
per Protocol Amendment 03. Participants ≥ 40 kg will be administered nivolumab 360 mg Q3W. 
Participants < 40 kg will be administered body weight adjusted nivolumab dose 4.5 mg/kg Q3W.
Additional details on dosing are provided in the nivolumab IB.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
participant 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.
c) For adolescent participants unable to give their written consent, in accordance with local 
regulations, one or both parents, a guardian, or a legally acceptable representative must be 
informed of the study procedures and must document permission by signing the informed 
consent form approved for the study prior to clinical study participation. Each participant 
must be informed about the nature of the study to the extent compatible with his or her 
understanding. Should a participant become capable or reach the age of majority, his or her 
consent should be obtained as soon as possible. The explicit wish of a participant who is a 
minor or unable to give his or her written consent, but who is capable of forming an opinion 
and assessing information to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the investigator. Minors who are judged to be of 
an age of reason as determined by local requirements should also give their assent. The 
assent should be documented based on local requirements. Continued assent should be 
documented when important new information becomes available that is relevant to the 
participant’s assent.
2) Type of Participant and Target Disease Characteristics
a) Participants must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of ≤1 (adults 18 years or older) /Lansky Performance Score ≥ 80% (minors ages 12-
17 only) (for details, see Appendix 5).
b) Histologically confirmed stage III (unresectable) or stage IV melanoma, as per AJCC 
staging system, 8th edition (Note: Mucosal melanomas will be considered M1 for 
stratification).34
c) Treatment-naïve participants (ie, no prior systemic anticancer therapy for unresectable or 
metastatic melanoma) with the exception of prior adjuvant and/or neoadjuvant treatment 
for melanoma with approved agents (eg, BRAF/MEK inhibitors, ipilimumab, nivolumab, 
pembrolizumab or interferon). Participants who have had recurrence within the 6 months 
of completing adjuvant and/or neoadjuvant treatment are not eligible.
d) Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) 
per RECIST 1.1 criteria
e) Not Applicable as of Amendment 02; see 2(l) for updated criterion: All participants must 
have tissue submitted during screening. Either a formalin-fixed, paraffin-embedded 
(FFPE) tissue block or unstained tumor tissue sections, obtained within 3 months prior to 
enrollment, with an associated pathology report, must be submitted to the core laboratory 
for inclusion. Biopsy should be excisional, incisional, punch biopsy, core needle or 
surgical specimen. Fine needle aspiration is unacceptable for submission. Biopsies of bone 
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lesions that do not have a soft tissue component are also unacceptable for submission. 
Central lab must provide IRT with the results of PD-L1 testing prior to randomization.
i)
In order to be randomized, a participant must be classified as PD-L1 positive (≥1% 
tumor cell membrane staining) vs PD-L1 negative (< 1% tumor cell membrane 
staining)/PD-L1 indeterminate (tumor cell membrane scoring hampered by high 
cytoplasmic staining or melanin content) based on the PD-L1 IHC 28-8 pharmDx 
assay. If only an insufficient amount of tumor tissue from an unresectable or metastatic 
site is available from prior to the start of the screening phase, then a fresh biopsy will 
be required during the screening phase for performance of biomarker analyses. 
Non-evaluable participants are not eligible for randomization.
f)
 
 
 
 
If the participant has > 1 measurable lesion, 
the lesion planned for biopsy while on treatment cannot be designated as a target lesion at 
baseline. Additional target lesions should be available for radiographic efficacy 
assessments.(Note: These same lesion criteria apply for patients who consent to the 
optional biopsy in the main study.)
g) Participants must have known BRAF V600 mutation status or consent to BRAF V600 
mutation testing per local institutional standards by approved methodology during the 
Screening period. The site is responsible for entering results of BRAF testing into the IRT 
prior to randomization. Participants with indeterminate or BRAF status not reported prior 
to randomization are not permitted to be randomized to a treatment arm.
h) Prior palliative radiotherapy must be completed at least 2 weeks prior to randomization. 
Participants must have recovered from all radiation-related toxicities. Note: radiated 
lesions cannot be used as measurable lesions unless there is clear evidence of progression.
i)
Participants must be able and willing to comply with the study visit schedule and study 
procedures.
j)
A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram or multigated acquisition (MUGA) scan test.
k) ≥12 weeks life expectancy
l)
All participants must have tissue submitted during screening period to allow for participant 
enrollment into the study. Tissue submitted should be from an unresectable primary tumor 
lesion or any metastatic site. The tumor tissue should be from a site not previously 
irradiated and with no intervening treatment between time of acquisition and enrollment. 
Central lab must provide IRT with the results of PD-L1 testing prior to randomization. 
Either a FFPE tissue block or 20 unstained tumor tissue sections, with an associated 
pathology report, must be submitted to the core laboratory for inclusion. FFPE tissue block 
and unstained slides submitted should be from biopsy obtained within 6 months prior to 
enrollment. Unstained slides should be sectioned within 3 months prior to submission.
Submission of an FFPE block is strongly preferred but unstained slides are also acceptable. 
Tissue may be from a core biopsy, punch biopsy, excisional or incisional biopsy, or surgical 
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specimen; fine needle aspiration and other cytology samples are not acceptable. Biopsies 
of bone lesions that do not have a soft tissue component are also unacceptable for 
submission. The Medical Monitor (or designee) can be consulted for eligibility if subjects 
have less than 20 unstained slides.
i)
In order to be randomized, a participant must be classified as PD-L1 positive (≥1% 
tumor cell membrane staining) vs PD-L1 negative (< 1% tumor cell membrane 
staining) or PD-L1 indeterminate (tumor cell membrane scoring hampered by high 
cytoplasmic staining or melanin content) based on the PD-L1 IHC 28-8 pharmDx 
assay. If only an insufficient amount of tumor tissue from an unresectable or metastatic 
site is available from prior to the start of the screening phase, then a fresh biopsy will 
be required during the screening phase for performance of biomarker analyses. 
Non-evaluable participants are not eligible for randomization,
3) Age and Reproductive Status
a) Males and females, ages 12 years or older, except where local regulations and/or 
institutional policies do not allow for participants < 18 years of age (pediatric population) 
to participate. If adolescents are not allowed to participate then ≥18 years of age, or age of
majority applies.
i)
Adolescents are not eligible for the 
due to the blood sampling 
and biopsy samples.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception 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. NOTE: WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements, and still must undergo 
pregnancy testing as described in this section.
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (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.
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4 which 
have a failure rate of < 1% when used consistently and correctly.
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6.2
Exclusion Criteria
1) Medical Conditions
a) Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if these have been treated and there is no MRI evidence of progression for at 
least 8 weeks after treatment is complete and within 28 days prior to randomization. There 
must also be no requirement for immunosuppressive doses of systemic corticosteroids 
(> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study treatment 
administration. Stable dose of anticonvulsants is allowed. Treatment for CNS metastases 
may include stereotactic radiosurgery (eg, GammaKnife, CyberKnife, or equivalent) or 
neurosurgical resection. Participants with CNS metastases treated by neurosurgical 
resection or brain biopsy performed within 28 days prior to randomization are not eligible.
Participants who received whole brain radiation therapy are not eligible.
b) Uveal melanoma is excluded.
c) 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 
interfere with the interpretation of safety results (eg, a condition associated with diarrhea 
or acute diverticulitis).
d) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
e) 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.
f)
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 
of start of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune 
disease. (Note: Prophylaxis of contrast allergies with a brief course of corticosteroids is 
acceptable. See Section 7.7.5)
g) History of organ transplant or tissue that requires systemic use of immune suppressive 
agents
h) Active infection requiring systemic therapy within 14 days prior to randomization.
i)
Need for > 2 antihypertensive medications (active components/ingredients) for 
management of hypertension (including diuretics). Participants with hypertension must be 
on a stable anti-hypertensive regimen for the 14 days prior to randomization. Note: An 
antihypertensive medication that contains 2 drugs under one formulation is counted as 
2 antihypertensive medications (eg, angiotensin-converting-enzyme [ACE] inhibitor plus 
diuretic, calcium channel blocker plus ACE inhibitor).
j)
Known cardiac history including:
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i)
History of unstable or deteriorating cardiac disease within the previous 12 months prior 
to screening including but not limited to the following:
(1) Unstable angina or myocardial infarction
(2) Transient ischemic attack (TIA)/cerebrovascular accident (CVA)
(3) Congestive heart failure (New York Heart Association [NYHA] Class III or IV)
(4) Uncontrolled clinically significant arrhythmias
k) 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.
l)
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 7.7.4.1 (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.
m) Participants with inadequately treated adrenal insufficiency.
n) Previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks prior to 
screening.
i)
Acute symptoms must have resolved and based on Investigator assessment in 
consultation with the Medical Monitor (or designee), there are no sequelae that would 
place the participant at a higher risk of receiving investigational treatment. 
o) Participants currently in other interventional trials for coronavirus disease 2019 (COVID-
19), including investigational COVID-19 vaccination trials that are not authorized or 
approved by relevant Health Authorities, should not participate in this clinical trial until 
the COVID-19 vaccine washout period is achieved, as defined in that study.
2) Prior/Concomitant Therapy
a) Use of an investigational agent or an investigational device within 28 days before 
administration of first dose of study drug
b) Participants who have received a live/attenuated vaccine within 30 days before first 
treatment. Replication incompetent virus vaccines are not considered live vaccines (live 
vaccines are defined as those that are capable of transmitting infectious viruses).
c) Prior treatment with IL-2 therapy. 
d) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, agents that target IL-2 pathway 
or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways with the exception of treatment with adjuvant and/or 
neoadjuvant intent as described in inclusion 2c.
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e) Participants with history of life-threatening toxicity related to prior immune therapy (eg,
anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways) except those that are 
unlikely to re-occur with standard countermeasures (eg, hormone replacement after adrenal 
crisis)
f)
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. Refer to Section 7.7.1for prohibited therapies.
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100*103/μL
d) Hemoglobin < 9.0 g/dL
NOTE: May not transfuse within 14 days of randomization to meet eligibility criteria 3.a 
through 3.d. 
e) Serum creatinine > 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or 
calculated using the Cockroft-Gault formula)
Female CLcr = (140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CLcr = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
f)
AST/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).
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody
5) 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
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Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
This section is not applicable per Protocol Amendment 03. Please 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 are not 
subsequently randomized. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants, to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and any 
serious AEs.
6.4.1
Retesting During Screening or Lead-In Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has discontinued 
the study as a pre-treatment failure (ie, participant has not been 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 or Lead-in 
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 may be repeated in an 
effort to find all possible well-qualified participants. Consultation with the Medical Monitor (or 
designee) may be needed to identify whether repeat testing of any particular parameter is clinically 
relevant.
Testing for asymptomatic SARS-CoV-2 infection, for example by reverse transcription polymerase 
chain reaction (RT-PCR) or viral antigen is not required. However, some participants may develop 
suspected or confirmed symptomatic SARS-CoV-2 infection, or be discovered to have 
asymptomatic SARS-CoV-2 infection 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 SARS-CoV-2 infection-related sequelae that 
may place the participant at a higher risk of receiving investigational treatment, and 
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•
Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local,
or regional guidelines
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:
•
Not applicable per Protocol Amendment 03. Bempegaldesleukin (NKTR-214) Powder for 
Solution for Injection
•
Nivolumab Solution for Injection
An investigational product, also known as investigational medicinal product in some regions, is 
defined as a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but used 
or assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
Per Protocol Amendment 03, 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 at 480 mg IV Q4W for the 
remainder of the study treatment period. Participants < 40 kg will be administered a body weight 
adjusted nivolumab dose of 6 mg/kg IV Q4W.
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Table 7-1:
Study Treatment for CA045001
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 03
Bempegaldesleukin (NKTR-
214) Powder for Solution for 
Injection
1.0 mg of rhIL-2 (IL-2) 
per vial
IP
Open-label
Vial (one or more vials 
per carton)
Store at -20°C ± 5°C. 
Protect from light, store 
in original packaging 
until use.
Nivolumab Solution for 
Injection
100 mg (10 mg/mL)
IP
Open-label
Vial (multiple 
vials/carton)
Store at 2° - 8° C. Protect 
from light and freezing.
Abbreviations: C = Celsius; IL-2 = interleukin-2; IMP = investigational medicinal product; IP = investigational product; mg = milligrams; mL = milliliter
Note: *Not applicable per Protocol Amendment 03. For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer to the same molecule
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Per Protocol Amendment 03, participants in Arm A are required to discontinue bempegaldesleukin 
and may continue nivolumab monotherapy. Participants in Arm A and Arm B will receive 
nivolumab monotherapy at 480 mg IV Q4W for the remainder of the study treatment period.
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose 
strength(s)/Dosage 
level(s)
Dosage formulation
Frequency of 
Administration
Route of Administration
Nivolumab
480 mg
Q4W
IV
*Not applicable per 
Protocol Amendment 03
Bempegaldesleukin 
(NKTR-214)a
0.006 mg/kg
Q3W
IV
*Not applicable per 
Protocol Amendment 03
Nivolumab
360 mg 
Q3W
IV
a Not applicable per Protocol Amendment 03. Bempegaldesleukin dose is based on IL-2 content.
Abbreviations: IV = intravenous; Q3W = every three weeks.
Not applicable per Protocol Amendment 03. Nivolumab dosing in both arms for participants < 
40 kg will be weight-based 4.5 mg/kg IV Q3W.
Nivolumab dosing in both arms for participants < 40 kg will be weight-based 6 mg/kg IV Q4W.
Study agent(s) should be administered in an area with access to resuscitation equipment.
All participants should begin study treatment within 3 calendar days of randomization.
7.1.1
Bempegaldesleukin Dosing
Per Protocol Amendment 03, participants receiving bempegaldesleukin plus nivolumab are 
required to discontinue bempegaldesleukin and may continue nivolumab. Therefore, this section 
is not applicable per Protocol Amendment 03. 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 previous cycle 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, and will be administered as an IV 
infusion over 30 (± 5) minutes at a starting dose of 0.006 mg/kg Q3W (± 3 days, Cycle 2 and 
beyond). 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 
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administration should start at least 30 minutes from the end of the bempegaldesleukin
administration. Participants may be dosed no less than 18 days from the previous dose. 
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.
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 in water 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 Investigator’s Brochure for details regarding 
preparation, storage, and administration.
7.1.1.1
Hydration Guidelines
This section is not applicable per Protocol Amendment 03. 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). 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 card/handout.
Adult Hydration Guidelines:
For adult 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 
each cycle). For the next 3 days (Days 2-4) after administration of bempegaldesleukin participants 
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are to be instructed to drink at least 2 liters per day of self-administered oral hydration (see Table 
7.1.1.1-1).
Adolescent Hydration Guidelines:
Hydration guidance for adolescent participants is weight-based (see Table 7.1.1.1-1). Adolescents 
who weigh ≥40 kg follow the Adult Hydration Guidelines. For adolescent participants who weigh 
less than 40 kg randomized to Arm A administer 500 mL of IV fluid on bempegaldesleukin dosing 
days (Day 1 of each cycle). For the next 3 days after administration of bempegaldesleukin (Days 
2-4), adolescents < 40 kg are to be instructed to drink at least 1 liter of fluids per day.
Table 7.1.1.1-1:
Hydration guidelines for Adults and Adolescents
*Not applicable per Protocol Amendment 03.
Adults & Adolescents ≥40 kg
Adolescents < 40 kg
Day of infusion (IV)
1000 mL per day
500 mL per day 
Days 2-4 (Oral)
2000 mL per day 
1000 mL per day
Advise patients to refrain from activity 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). 
Following subsequent administration of bempegaldesleukin, 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 if this is deemed to be in the best interest of the 
participant (eg, evidence of fluid overload).
7.1.2
Nivolumab Dosing
Not applicable per Protocol Amendment 03. 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 (±3 days, Cycle 2 and beyond) cycles. Premedications are not recommended for the first 
dose of nivolumab.
Not applicable per Protocol Amendment 03. 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 24 months of treatment, or the study ends, 
whichever occurs first.
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Bempegaldesleukin (NKTR-214) and Nivolumab
Not applicable per Protocol Amendment 03. Participants < 40 kg will be administered body 
weight adjusted nivolumab dose 4.5 mg/kg Q3W as a 30-minute infusion.
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 25 days from the previous dose during Q4W (±3 days, Cycle 2 and beyond) cycles. 
Premedications are not recommended for the first dose of nivolumab. 
Participants should receive nivolumab at a dose of 480 mg Q4W as a 30-minute infusion on Day 
1 of each treatment cycle until progression, unacceptable toxicity, withdrawal of consent, 
completion of 24 months of treatment, or the study ends, whichever occurs first.
Participants < 40 kg should be administered a body weight adjusted nivolumab dose of 6 mg/kg 
Q4W as a 30-minute infusion.
For participants (< 40 kg), dosing calculations for nivolumab should be based on the body weight 
assessed at baseline. It is not necessary to re-calculate subsequent doses if the participant weight 
is within 10% of the weight used to calculate the previous dose. For nivolumab dosing in 
adolescents, all doses should be rounded up or to the nearest milligram per institutional standard. 
At the end of each infusion, flush the line with sufficient quantity of diluent.
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 patients randomized to Arm A in the event that bempegaldesleukin is 
stopped due to toxicities.
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent.
Please refer to the current version of the pharmacy manual for complete preparation, storage, and 
handling information.
Not applicable per Protocol Amendment 03. In the event that bempegaldesleukin is permanently 
discontinued due to toxicities, see Section 8.1.1.
7.2
Method of Treatment Assignment
Before the study is initiated, each user will receive log-in information and directions on how to 
access the IRT. Each participant will be assigned a unique participant number after signing the 
ICF. Participant numbers will be used on all participants’ study information. Participant numbers 
will not be reassigned. An IRT will be employed to manage participant randomization. The 
Investigator or designee will register the participant for enrollment by following the enrollment 
procedures established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained
•
Year of birth
•
Gender at birth
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through the IRT. The following information is required for participant randomization:
•
Participant number 
•
Year of birth 
•
PD-L1 tumor expression status (PD-L1 positive vs PD-L1 negative/indeterminate), analyzed 
by the central laboratory vendor and transferred to the IRT
•
BRAF V600 mutational status; local results to be entered into IRT by site.
•
M Stage at screening (see Appendix 8)
•
Participants meeting all eligibility criteria will be randomized in a 1:1 ratio and stratified by 
PD-L1 tumor expression status, BRAF status, and AJCC M stage as described below:
•
PD-L1 tumor expression status
−
PD-L1 positive (≥1% tumor cell membrane staining in a minimum of 100 evaluable tumor 
cells) vs
−
PD-L1 negative (< 1% tumor cell membrane staining in a minimum of 100 evaluable tumor
cells)/indeterminate (tumor cell membrane scoring hampered by high cytoplasmic staining 
or melanin content)
•
BRAF status
−
BRAF V600 mutation positive vs
−
BRAF V600 wild type
•
AJCC 8th edition M stage at Screening (See Appendix 8)
−
M0 / M1any[0] (Stage III any LDH or Stage IV Normal LDH) vs 
−
M1any[1] (Stage IV Elevated LDH)
Note: All mucosal melanoma will be considered as M1 and the assignment of strata will be based 
on the baseline LDH level (M0 / M1any[0] for mucosal melanomas with normal LDH and 
M1any[1] for mucosal melanomas with elevated LDH).
The randomization procedures will be carried out via permuted blocks within each stratum, defined 
by combination of PD-L1 tumor expression status (positive ≥1%, negative [< 1%]/indeterminate), 
BRAF V600 mutational status (BRAF mutation positive, BRAF wild type), and M Stage 
(M0 / M1any[0], M1any[1]). The exact procedures for using the IRT will be detailed in the IRT 
manual.
7.3
Blinding
Not applicable as this is an open-label study; however, 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.
 
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NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
 
Based on the CA045-001 study results showing lack of efficacy with bempegaldesleukin plus 
nivolumab compared to nivolumab monotherapy in the first line treatment of patients with 
metastatic or unresectable melanoma, treatment assignment will no longer be blinded to the 
Sponsor. Participants in Arm A will discontinue bempegaldesleukin, and may continue nivolumab 
monotherapy. The Sponsor unblinded the study as no further formal efficacy analyses will be 
conducted.
7.4
Dosage Modification
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
If bempegaldesleukin or nivolumab meets the criteria for dose delay which apply for all drug-
related adverse events regardless of whether the event is attributed to nivolumab or 
bempegaldesleukin or both, then administration of both drugs must be delayed if any of the delay 
criteria in Table 7.4.1-1 and Table 7.4.1-2 are met. 
SARS-CoV-2 infection, either confirmed or suspected, requires delay of nivolumab and 
bempegaldesleukin study treatment. 
Delay bempegaldesleukin and nivolumab dosing for any adverse event, laboratory abnormality, or 
intercurrent illness which, in the judgment of the Investigator, warrants delaying the dose of study 
medication until the criteria to resume are met (Section 8.1.2).
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 Section 8.1.1.
AE grading should be based on CTCAE version 5.
7.4.1
Nivolumab and Bempegaldesleukin Dose Delay, Reduction, and 
Discontinuation Criteria
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Nivolumab administration should be delayed for the following:
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, warrants delaying the dose of study medication. AE criteria for delaying, 
reducing, and discontinuing nivolumab and bempegaldesleukin are available in Table 7.4.1-1
and Table 7.4.1-2.
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Bempegaldesleukin (NKTR-214) and Nivolumab
•
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 participant’s 
health or suitability for enrollment, as determined by the Medical Monitor (or designee).
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 03. 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 03. 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 (or designee) consultation is required for 
dose reduction.
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should 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 
doseb
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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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should 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 (or designee) 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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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should 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 
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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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should 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 SJS, TEN, or 
DRESS
Delay dose
Dosing may resume if SJS, TEN, or DRESS is ruled out 
and rash reduces to ≤ 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
-
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
-
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should be discontinued for participants receiving bempegdesleukin plus nivolumab)
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
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
-
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
-
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should be discontinued for participants receiving bempegdesleukin plus nivolumab)
Drug-related AE per CTCAE v5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
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 03)
Grade 2 non-skin AE, except 
fatigue
Nivolumab: Delay 
doseb
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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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuationa of Nivolumab and 
Bempegaldesleukin (if One is Delayed, Both Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
(Note that bempegaldesleukin should 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; CTCAE, Common Terminology Criteria for Adverse Events; 
CVA, cerebrovascular accident; DRESS, drug-reaction with eosinophilia and systemic symptoms; GBS, Guillain-Barre Syndrome; MG, myasthenia gravis; SJS,
Stevens-Johnson syndrome; T.bili, total bilirubin; TEN, toxic epidermal necrolysis; TIA, transient ischemic attack;ULN, upper limit of normal.
a Permanent discontinuation of study drug should meet the criteria (Section 8.1.1).
b Not applicable per Protocol Amendment 03. If dosing of one drug is delayed, then dosing of both drugs is delayed.
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Table 7.4.1-2:
Bempegaldesleukin-specific Adverse Event Criteria for Delay, Resumption, and Discontinuationa of 
Nivolumab and Bempegaldesleukin (if One is Delayed, Both are Delayed)
*Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Bempegaldesleukin-specific Criteria for Delay, Resumption, and Discontinuation
Serum Creatinine Increased
(transient, non-inflammatory)
Grade 2, 3, or 4
Delay doseb
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 doseb
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 
(e.g., cryptogenic CVA) and for suspected TIA without 
clear alternative etiology. See Appendix 7.*
Abbreviations: AE, adverse event; CVA, cerebrovascular accident; MRI, magnetic resonance imaging; TIA, transient ischemic attack.
a Permanent discontinuation of study drug should meet the criteria (Section 8.1.1).
b Not applicable per Protocol Amendment 03. If dosing of one drug is delayed, then dosing of both drugs is delayed.
*Per Protocol Amendment 03, 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 03.
Protocol Amendment No.: 03
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CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
7.4.1.1
Dose Modification Criteria for Bempegaldesleukin and Nivolumab for 
Cycle 1 ALT/AST Elevations
This section is not applicable per Protocol Amendment 03.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 non-inflammatory etiologies. If non-inflammatory cause, treat accordingly and continue 
bempegaldesleukin and nivolumab. Consider imaging for obstruction. 
If during monitoring ALT/AST increases, follow the guidance for the highest levels.
If AST or ALT > 3.0 to ≤ 5 x ULN (Within first cycle of bempegaldesleukin and nivolumab)
•
Increase frequency of 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
If ALT or AST > 5.0 to ≤ 8.0 x ULN (Within first cycle of bempegaldesleukin and 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):
•
Discontinue bempegaldesleukin and 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
If ALT or AST > 8.0 x ULN (follow Hepatic Adverse Event Management Algorithm)
•
Discontinue bempegaldesleukin and 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
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•
If no improvement in > 3-5 days, worsens or rebounds, add non-corticosteroid 
immunosuppressive medication
Please refer to Section 8.1 for discontinuation criteria.
7.4.2
Monitoring and Management of Elevated Hepatic Transaminases
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 
(Day 8), and are often accompanied by IL-2 mediated AEs such as flu-like symptoms, rash or 
pruritus. The transient elevations in hepatic transaminases are usually asymptomatic, mild or 
moderate in severity, not associated with increased total bilirubin and alkaline phosphatase, resolve 
spontaneously without treatment, and predominantly occur in Cycle 1 and Cycle 2. The 
transaminase elevations are considered to occur in the context of IL-2 mediated AEs. 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 and Appendix 6).
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 IB or OPDIVO product 
labeling for appropriate management.
7.4.3
Monitoring and Management of Eosinophilia
7.4.3.1
Bempegaldesleukin-induced Eosinophilia
This section is not applicable per Protocol Amendment 03. Frequent and significant 
eosinophilia has been observed in patients receiving bempegaldesleukin, primarily starting at 
Cycle 2 with levels plateauing after Cycle 3, consistent with the known pharmacodynamic effect 
of IL-2 therapy. The eosinophilia pattern demonstrates a cyclic waxing and waning pattern 
whereby eosinophil levels peak approximately 7 days after each infusion and wane before the 
participant’s next infusion.
Absolute eosinophil count (AEC) should be closely monitored per protocol. If a participant is 
suspected to have eosinophilic disorder (symptoms may involve skin, lungs, digestive tract, heart, 
blood, and nervous systems) with AEC at or above the 5,000/μL (5 × 109/L) level, delaying 
bempegaldesleukin treatment may be considered while evaluating and treating the participant as 
clinically indicated.
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7.4.3.2
Eosinophilic Disorders
This section is not applicable per Protocol Amendment 03. Isolated cases of hypereosinophilic 
syndrome (HES) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been 
reported. If there is clinical concern for an eosinophilic disorder, the Investigator is encouraged to 
contact the Medical Monitor (or designee).
Additional details regarding eosinophilia and eosinophilic disorders are provided in the 
bempegaldesleukin Investigator’s Brochure.
7.4.4
Monitoring and Management of Adrenal Insufficiency and Hypophysitis
Adrenal insufficiency and hypophysitis have been observed in participants receiving nivolumab 
and ipilimumab. Consider prompt evaluation when participants have signs or symptoms of 
hypophysitis or adrenal insufficiency which includes levels of early-morning 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 
 Cytokine-
Release Syndrome
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7.4.5.2
Management Algorithm for Cytokine-Release Syndrome
This section is not applicable per Protocol Amendment 03. Cytokine-release syndrome (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 Investigator is encouraged to contact the Medical Monitor or 
designee. An algorithm for the management of CRS is provided in Appendix 11 (not applicable 
per Protocol Amendment 03).
7.4.6
Treatment of Bempegaldesleukin-Related or Nivolumab-Related Infusion 
Reactions
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
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, myalgia, hypotension, 
hypertension, bronchospasm, or other hypersensitivity/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 mg 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 mg 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 
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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. Subsequent infusions may be 
administered at a reduced rate (eg, 50% of the original infusion rate) (see Section 7.7.4.1 for 
corticosteroid dose equivalents).
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 products are only dispensed to 
study Participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
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documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and the Pharmacy Manual.
7.5.1
Retained Samples for Bioavailability/Bioequivalence/Biocomparability
Not applicable. 
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability as well as 
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 03 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). For subsequent doses, the oral hydration follow-up should be conducted as clinically 
indicated for participants receiving bempegaldesleukin.
7.7
Concomitant Therapy
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.5)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of melanoma)
•
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.
•
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 7.7.4.1).
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7.7.2
Palliative Therapy
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted. If 
radiologic progression per RECIST 1.1 has been identified by the Investigator prior to the start of 
palliative treatment, the criteria for treatment beyond progression (Section 8.1.3) must be met in 
order for study treatment to continue after the completion of palliative treatment.
7.7.3
Prior and Concomitant Medications
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 the follow-up (100 days from the last dose of the study
treatment) 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.
7.7.3.1
COVID-19 Vaccination
A decision to vaccinate individuals is up to the individual and the treating physician unless 
prohibited by the protocol. Of note, COVID-19 vaccine response and safety may have the potential 
to be affected by administration of a particular IP. 
When feasible, the full vaccination series (eg, both doses of a two-dose series) should be completed 
prior to treatment until the vaccine-associated symptoms of the vaccine are stabilized and a delay 
in treatment would not put the study participant at risk. 
If a participant is already in the study, the full vaccination series is allowable. Study dose 
administration must be delayed until the vaccine-associated symptoms of the vaccine are
stabilized. The appropriate information should be captured to assess any potential vaccine-related 
adverse events. 
There does not need to be a minimum duration between the last administration of IP and 
administration of COVID-19 vaccine. If possible, avoid overlap of administration (eg, at least 
2 days, preferably 7 days apart).
COVID-19 vaccines have the potential to impact immunological pharmacodynamic biomarkers.
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7.7.4
Other Restrictions and Precautions
7.7.4.1
Restricted Treatments
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.4.2
Restricted Treatments
The guidance for anticoagulation and antithrombotic 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 03, participants will receive nivolumab monotherapy only. 
Nivolumab monotherapy does not appear to be associated with an increased risk of ICE, and 
anticoagulation therapy will no longer be mandated for participants enrolled on the study. There 
are 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 benefit/risk for each individual participant.
The remainder of this section is not applicable per Protocol Amendment 03. Participants with 
a history of a venous or arterial thromboembolic event must be receiving a stable regimen of 
therapeutic anticoagulation (preferably LMWH or DOAC). Unless there is a new medical 
contraindication observed after Cycle 1 Day 1, a participant with a history of a venous or arterial 
thromboembolic event must be maintained on therapeutic anticoagulation throughout the 
participant’s time on study treatment.
Anticoagulation options include the following:
•
Low molecular weight heparin (LMWH).
•
Oral factor Xa inhibitors (direct oral anti-coagulants [DOAC] such as rivaroxaban, apixaban, 
or edoxaban).
•
Use of warfarin (Coumadin) is permitted; however, therapeutic dosing should target a specific 
INR stable for at least 4 weeks prior to enrollment. Because bempegaldesleukin has the 
potential to down-regulate metabolizing enzymes for warfarin for approximately 1 week after 
administration of each dose of bempegaldesleukin, frequent monitoring of INR and ongoing 
consideration of warfarin dose adjustments are warranted throughout the participant’s 
participation on study.
If anticoagulation is being newly introduced or adjusted, the Investigator may consider consulting 
the Medical Monitor (or designee) for guidance.
7.7.4.3
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 
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regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. 
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate [eGFR] < 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this participant population. In addition, participants are excluded
from MRI if they have tattoos, metallic implants, pacemakers, etc. Gentle hydration before and 
after IV contrast should follow local standard of care. The ultimate decision to perform MRI in an 
individual participant in this study rests with the site radiologist, the Investigator and the standard 
set by the local Ethics Committee.
7.7.4.4
Blood Pressure Precautions
This section is not applicable per Protocol Amendment 03. Consideration should be given to 
discontinuing antihypertensive medications including diuretics, as well as other drugs with 
hypotensive properties (eg, alpha blockers for benign prostatic hypertrophy) prior to each dose of 
bempegaldesleukin, 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.
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.
7.7.5
Permitted Therapy
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable. 
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 of 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.
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 
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or Day 2 after dosing of bempegaldesleukin or nivolumab and may continue through Day 5 or 
longer as needed.
Administration of red blood cell (RBC) transfusions is allowed for participants with anemia.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration in Protocol 
Section 7.1. Study treatment will be provided via an extension of the study, a rollover study 
requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS.
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 nivolumab and 
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 03, 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.
8
DISCONTINUATION AND RESUMPTION 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 and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
•
Disease progression in the absence of clinical benefit as determined by the Investigator.
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•
Clinical disease progression in the absence of radiologically confirmed progression by 
RECIST 1.1
•
See Section 8.1.1 for Nivolumab and Bempegaldesleukin Discontinuation Criteria.
•
Noncompliance of the participant with protocol-mandated procedures based on the judgment 
and agreement of both the Investigator and Sponsor
If a participant has not progressed following discontinuation of study drug(s), every effort should 
be made to continue to obtain radiographic tumor assessments until Investigator confirmed 
progression.
A participant may also be withdrawn from investigational product/study by the Sponsor, 
Regulatory Authorities, or Institutional Review Boards (IRBs)/ Independent Ethics Committees 
(IECs).
Participants may choose to discontinue the study at any time, for any reason, and without prejudice 
to further treatment.
Refer to the Schedule of Activities 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). Refer to 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 03, participants receiving bempegaldesleukin plus nivolumab are 
required to discontinue bempegaldesleukin and will receive nivolumab monotherapy.
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable.
Participants meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s). However, with Medical Monitor (or designee) approval, treatment with 
bempegaldesleukin or nivolumab alone may continue if the toxicities listed below are considered 
related to bempegaldesleukin or to nivolumab only and once the criteria to resume are met (Section 
8.1.2).
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Nivolumab and bempegaldesleukin treatment should be permanently discontinued per criteria in 
Table 7.4.1-1 and Table 7.4.1-2.
Discontinue study treatment for participants receiving bempegaldesleukin in combination with 
nivolumab:
•
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
Criteria to Resume Bempegaldesleukin and/or Nivolumab
Per Protocol Amendment 03, the text below related to bempegaldesleukin is not applicable. 
Participants may resume treatment with study intervention if they have completed AE management 
(ie, corticosteroid taper) or are on ≤ 10 mg prednisone or equivalent, and meet the requirements 
per Table 7.4.1-1 and Table 7.4.1-2.
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following:
1) At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result (eg, RT-PCR or viral antigen),
2) Resolution of acute symptoms (including at least 24 hours has passed since last fever without 
fever-reducing medications),
3) Evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment, and
4) Consultation by the Medical Monitor (or designee). 
For suspected cases, treatment may also resume if SARS-CoV-2 infection is ruled-out and other 
criteria to resume treatment are met.
If the toxicity resolves to ≤Grade 1 or baseline > 8 weeks after the last dose, but the participant 
does not otherwise meet the criteria for permanent discontinuation (see Section 8.1.1), and the 
Investigator believes that the participant is deriving clinical benefit, then the participant may be 
eligible to resume the study drug(s) following the approval of the Medical Monitor (or designee).
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8.1.3
Treatment Beyond Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease.20,52
Participants, regardless of study arm, will be permitted to continue treatment beyond initial 
RECIST 1.1 defined progressive disease or clinical progression, assessed by the Investigator, as 
long as they meet the following criteria: 
•
Investigator-assessed clinical benefit
•
Tolerance of study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional study treatment. All 
other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply.
Radiographic assessment should continue as per schedule (Table 2-2) during treatment beyond 
progression. The assessment of clinical benefit should be balanced by clinical judgment as to 
whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued study treatment.
If the Investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities, Table 2-2.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time 
of initial progressive disease. This includes an increase in the sum of diameters of all target lesions 
and/ or the diameters of new measurable lesions compared to the time of initial progressive disease.
Study treatment should be discontinued permanently upon documentation of further progression.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least
15 mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
8.1.4
Post Study Treatment Study Follow-up
In this study, ORR, PFS, and OS are key endpoints of the study. Please refer to Section 5.1 for 
follow-up details. Per Protocol Amendment 03, the remainder of this paragraph is not 
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applicable. 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 outcome and/or survival follow-
up data as required and in line with Section 5.1.3 until death or the conclusion of the study. The 
total duration of the study is up to 5 years after randomization of the last participant. 
The Sponsor may request that survival data be collected on all treated/randomized participants 
outside of the protocol-defined window (Schedule of Activities, 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 03, this paragraph is not 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.
8.2
Discontinuation from the Study
Participants who request to 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. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information. 
•
Participants should notify the Investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
Investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
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•
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. 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
labs until all study drug-related toxicities resolve, return to baseline, or are deemed irreversible.
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, 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 CRF. 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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9.1
Efficacy Assessments
Per Protocol Amendment 03, BICR assessment of imaging will be discontinued. Response and 
progression will be determined by the Investigator.
9.1.1
Imaging Assessments for the Study
As of Protocol Amendment 03, images will no longer be submitted to an imaging core lab. Sites 
should be qualified prior to scanning the first participant and understand the image acquisition 
guidelines as outlined in the CA045001 Imaging Manual provided by the imaging core lab. 
Screening and follow-up images should be acquired as outlined in Section 2, (Schedule of 
Activities).
Evaluate any additional imaging that may demonstrate tumor response or progression (including 
scans performed at unscheduled time points and/or at an outside institution) for RECIST 1.1 tumor 
assessment. X-Ray and bone scans that clearly demonstrate interval progression of disease, most 
commonly as unequivocal lesions that are unmistakably new since the prior CT/MRI, should be 
included in tumor assessment.
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be included for 
RECIST 1.1 tumor assessment.
9.1.1.1
Methods of Measurement
Contrast-enhanced CT of the chest, abdomen, pelvis, 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 1.1 
criteria.
Should a participant have contraindication for CT intravenous contrast, 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.
Should a participant have contraindication for both MRI and CT intravenous contrasts, 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. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
Use of CT component of a positron emission tomography-computed tomography (PET-CT)
scanner: Combined modality scanning such as with PET-CT is increasingly used in clinical care, 
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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 1.1 measurements. However, if a site can 
document that the CT performed as part of a 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 1.1 measurements. Note, however, that the PET portion of the CT introduces additional 
data which may bias an Investigator if it is not routinely or serially performed.
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain 
non-target organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
MRI of brain without and with contrast should be acquired as outlined in Section 2 (Schedule of 
Activities). CT of the Brain without and with contrast can be performed if MRI is contraindicated.
Bone scans may be collected per local standards, as clinically indicated.
9.1.1.2
Imaging and Clinical Assessment 
Tumor assessments should continue even if dosing is delayed or discontinued. Changes in tumor 
measurements and tumor responses will be assessed by the same Investigator using RECIST 1.1 
criteria. Investigators will report the number and size of new lesions that appear while on study. 
The time point of tumor assessments will be reported on the CRF based on the Investigator’s 
assessment using RECIST 1.1 criteria (See Appendix 9 for specifics of RECIST 1.1 criteria to be 
utilized in this study). Assessments of PR and CR must be confirmed at least 4 weeks (28 days) 
after initial response. A Best Overall Response (BOR) of stable disease (SD) requires a minimum 
of 42 days on study from randomization to the date of the first imaging assessment.
9.1.1.3
BICR Confirmation of Progression
Per Protocol Amendment 03, BICR will be discontinued and all study treatment decisions will be 
based on the Investigator’s assessment of tumor images.
Not applicable per Protocol Amendment 03. Sites should submit all scans to the imaging core 
lab on a rolling basis, throughout the duration of the study. BICR of scans will occur on a rolling 
basis, blinded to treatment arm, clinical data, and Investigator assessment of submitted scans. 
When progression per RECIST 1.1 criteria is assessed by the Investigator, the site will inform the 
imaging core lab, so that the BICR assessment of progression can be performed. The BICR review 
will be completed and the results provided to the site as specified in 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 03. Participants whose progression is not confirmed 
by the BICR will be required to continue tumor assessments (if clinically feasible) according to 
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the protocol-specified schedule, or sooner if clinically indicated. Also, if participants discontinue 
treatment without radiographic progression, tumor assessments will continue according to the 
protocol specified schedule, as noted in Section 2, until progression has been confirmed by BICR.
All study treatment decisions will be based on the Investigator’s assessment of tumor images and 
not on the BICR assessment. The BICR assessment of progression is only relevant for determining 
when tumor assessments for a given participant are no longer required to be submitted to the 
imaging vendor.
9.1.2
Imaging Assessment for the Study
Per Protocol Amendment 03, BICR assessment of imaging will be discontinued and imaging 
assessment will be performed only by the Investigator.
All study treatment decisions will be based on the Investigator’s assessment of tumor images.
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment.
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9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE), per CTCAE version 5, can be found in 
Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs (SAEs and nonserious AEs) associated with confirmed or suspected SARS-CoV-2 
infection and 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.
•
Cerebrovascular accident (CVA; any grade) is considered an adverse event of special interest 
(AESI/AEOSI) and should be assessed as an SAE. All CVAs are required to follow the 
timelines for SAE reporting (eg, 24 hours).
SAEs to be collected after the 100-day safety visit if the SAE is deemed to be related or residual 
toxicities are persisting. 
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF modules.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of updated 
information being available.
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For participants randomized/assigned to treatment and never treated with study drug, SAEs should 
be collected for 30 days from the date of randomization.
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 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgment in 
the context of known adverse events, when appropriate for the program or protocol.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
 
 
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.
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 8.3). 
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs (SAEs and nonserious AEs) associated with confirmed or 
suspected SARS-CoV-2 infection will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the participant is lost to follow-up (as defined in 
Section 8.3). For suspected cases, participants should be followed until SARS-CoV-2 infection is 
ruled out as per institutional policy on SARS-CoV-2.
Further information on follow-up procedures is given in Appendix 3.
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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 adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and Investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the Investigator must immediately notify the BMS 
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 (WOCBP) 
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.
In cases where a study drug can be present in seminal fluid, at exposures sufficient to potentially 
cause fetal toxicity, and 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 
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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.
This paragraph is not applicable per Protocol Amendment 03. 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 (AESI/AEOSI)
Cerebrovascular accident (CVA; any grade) is considered an adverse event of special interest 
(AESI/AEOSI) and should be assessed as an SAE. All CVAs are required to follow the timelines 
for SAE reporting (eg, 24 hours). CVA management guidelines are provided in Appendix 7.
9.2.8
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the non-serious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting Investigator (eg, anemia versus low hemoglobin value).
9.2.9
Potential Drug Induced Liver Injury
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential drug induced liver injury (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).
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Potential drug induced liver injury is defined as: 
1) Treatment-emergent ALT or AST > 3 times ULN,
AND
2) Total bilirubin > 2 times ULN or clinical jaundice, without initial findings of cholestasis 
(elevated serum alkaline phosphatase),
AND
3) 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 non-serious 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 CRF.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
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 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
Electrocardiograms
All participants will have 12-lead electrocardiogram (ECG) done during Screening as specified in 
the Schedule of Activities (Section 2).
9.4.3
Echocardiogram
Standard echocardiogram will be performed to assess cardiac function and LVEF according to the 
Schedule of Events (Section 2). A MUGA scan can be performed to assess cardiac function and 
LVEF if a standard echocardiogram cannot be performed. Participants who are found to have other 
significant abnormalities on echocardiogram should be discussed with the Medical Monitor (or 
designee) prior to randomization.
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9.4.4
Pregnancy Tests
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 within 24 hours
prior to 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. 
Guidelines to be followed in case of pregnancy and reporting requirements are provided in 
Section 9.2.5.
9.4.5
Clinical Safety Laboratory Assessments
A list of the clinical laboratory analyses to be tested is provided in Table 9.4.5-1. 
All clinical safety laboratory assessments will be performed locally per the Schedule of Activities 
(Section 2).
The Investigator or qualified Sub-Investigator will review all 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 9.2.8.
Table 9.4.5-1:
Clinical Safety Laboratory Assessments
Hematology - CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Creatinine clearance (Screening only)
Blood Urea Nitrogen (BUN) or serum UREA
Glucose
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
CK
TSH, free T3 and free T4 - Screening
TSH, with reflexive fT3 and fT4 if TSH is 
abnormal - on treatment 
Lipase and/or amylase
Serology
Hepatitis B/C (HBsAg, HCV antibody or HCV RNA) - Screening only
(Testing for HIV-1 and HIV-2 must be performed where mandated by local requirements)
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Table 9.4.5-1:
Clinical Safety Laboratory Assessments
Other Analyses
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG). Urine or 
serum.
Follicle stimulating hormone (FSH) Screening -only required to confirm menopause in women 
< age 55) 
Urinalysis - Screening only and as clinically indicated. Urine dipstick can be done and if abnormal 
perform microanalysis
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. 
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9.6
Pharmacodynamics
Biomarker sample collection (
 Table 9.8.2-2) will not be applicable per Protocol 
Amendment 03. However, exploratory analysis of biomarkers on previously collected specimens 
as per Section 9.8 may be conducted.
Exploratory analysis of selected biomarkers in relationship with exposure of nivolumab and 
bempegaldesleukin, and with efficacy may be explored with the data permitted. For more details, 
please see Section 9.8, Biomarkers.
9.7
Pharmacogenomics
Not applicable.
9.8
Biomarkers
Various factors that could potentially predict clinical response and inform on the incidence and/or 
etiology of AEs to treatment with nivolumab in combination with bempegaldesleukin will be 
investigated in peripheral blood and in pre-, on-treatment, and upon recurrence tumor specimens 
(Table 9.8.1-1). Data from these investigations will be evaluated for associations with clinical 
efficacy (eg, ORR, PFS, OS) and safety/toxicity (AE) data. All samples collected may also be used 
for exploratory analyses to assess biomarkers associated with melanoma and/or with 
immunotherapy treatment. Complete instructions on the collection, processing, handling, and 
shipment of all samples described herein will be provided in the Laboratory Manual.
Biomarker sample collection in 
 Table 9.8.2-2 are not applicable per 
Protocol Amendment 03. The biomarker sampling schedules are provided 
 
Table 9.8.2-2:
Biomarker 
Sampling 
Schedule: 
All 
Participants after Randomization into 
 is Completed. Further details of 
sample collection, processing, and shipment will be provided in the laboratory procedures manual.
Any remaining tissue collected for this study will be used to further understand and investigate the 
mechanism of action and progression/relapse of disease in participants treated with nivolumab in 
combination with bempegaldesleukin (Section 9.8.3). Also, the samples will support as yet 
undefined research aims that will advance our understanding of disease and options for treatment. 
It may also be used to support health authority requests for analysis, and advancement of 
pharmacodiagnostic development to better target drugs to the right patients. This may also include 
genetic/genomic exploration aimed at exploring disease pathways, progression and response to 
treatment, etc. 
Residual blood (or blood derivatives such as serum, plasma, plasma circulating tumor DNA 
[ctDNA], PBMCs, and extracted RNA/DNA) or tumor tissue (archival or fresh biopsy and 
extracted RNA/DNA) from tumor biopsy and biomarkers collections (Table 9.8.1-1) will also be 
retained for additional research purposes.
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9.8.1
Additional Research Collection
This section is applicable only for samples collected prior to Protocol Amendment 03. This 
protocol will include residual sample storage for additional research (AR).
For All US sites:
Additional research participation is required for all investigational sites in the US.
If the IRB and investigative site agree to the mandatory additional research retention and/or 
collection, then the study participant must agree to the mandatory additional research collection as 
a requirement for participation in the study.
For non-US Sites
Additional research is optional for all study participants, except where retention and/or collection 
is prohibited by local laws or regulations, ethics committees, or institutional requirements. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study Sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
Residual 
 serum,
 and plasma biomarkers, PBMCs, whole blood and extracted 
DNA/RNA, and tumor biopsy collections Table 9.8.1-1 will also be retained for additional 
research purposes.
Samples kept for future research will be stored at the BMS Biorepository 
 or 
an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be subject to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
Further details of sample collection and processing will be provided in Table 9.8.1-1 to the site in 
the procedure manual.
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Table 9.8.1-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time Points for which residual samples will be retained
Serum and Plasma
Biomarkers
All
Plasma ctDNA
All
PBMCs
All
Isolated DNA/RNA 
All
Whole Blood DNA/RNA
All
Tumor Biopsy
All
Stool Microbiome
All
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9.8.2
Biomarker Sampling Schedule
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Table 9.8.2-2:
Biomarker Sampling Schedule: All Participants after Randomization into 
 is 
Completed
*Not applicable per Protocol Amendment 03.
Collection Timinga
Tumor Biopsy
Myeloid Derived 
Suppressor cells 
(US/Canada only)
PBMC (Not collected 
in Brazil)
Flow Cytometry
Absolute Lymphocyte 
Count
Serum
Plasma ctDNA
Plasma Biomarkers 
Whole Blood RNA 
Gene Expression
Whole Blood DNA
Stool Microbiome
(Optional)b
Screening
X
Cycle 1 Day 1 Pretreatment
X
X
X
X
X
X
X
X
X
Xc
Cycle 1 Day 3d
X
X
X
Cycle 1 Day 8
X
X
X
X
X
Cycle 1 Day 21e
X
X
X
X
X
X
Cycle 2 Day 1
X
X
X
X
X
X
X
Cycle 3 Day 1
X
X
Cycle 4 Day 1
X
X
X
X
Cycle 5 Day 1
X
X
X
X
X
X
X
Day 1 of every other cycle starting at Cycle 7, (eg, C7D1, 
C9D1, C11D1, etc) until EOT
X
X
Day 1 of every 3 cycles starting at Cycle 8 for 1 year (eg,
C8D1, C11D1, C14D1, etc); then every 4 cycles until EOT 
(eg, C24D1, C28D1 etc)
X
Upon occurrence of Grade ≥ 3 drug related AE or lab 
abnormality regarded as a drug related AEf
X
X
X
X
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Table 9.8.2-2:
Biomarker Sampling Schedule: All Participants after Randomization into 
 is 
Completed
*Not applicable per Protocol Amendment 03.
Collection Timinga
Tumor Biopsy
Myeloid Derived 
Suppressor cells 
(US/Canada only)
PBMC (Not collected 
in Brazil)
Flow Cytometry
Absolute Lymphocyte 
Count
Serum
Plasma ctDNA
Plasma Biomarkers 
Whole Blood RNA 
Gene Expression
Whole Blood DNA
Stool Microbiome
(Optional)b
Upon occurrence of a radiographically documented CVA or a 
TIA eventg
X
X
Upon Progressionh
X
X
X
X
X
X
X
X
X
Xc
a Biomarker sampling occurs prior to dosing of study drug. From Cycle 2 onward, collections can occur ± 3 days from the scheduled time. During cycle 1, 
biomarker collection timeframes will match 
collections.
b If the baseline stool microbiome is not collected, then the remaining samples are not needed.
c Optional. Stool collections can be done up to 1 week before dosing day/cycle.
d If patients are dosed on a Thursday, Day 3 samples can be collected on Day 2 (Friday). If participants are dosed on a Friday, Day 3 samples can be collected on 
Day 4 (Monday).
e Biopsy is optional. If a biopsy is taken between C1D15 and C1D21, indicated samples should be collected during this visit. If biopsy is not taken, the collection 
of indicated blood samples are not required. 
f For Grade 3 or greater AEs, indicated blood samples should collected within 48 hours of onset of AE, if feasible.
g Collect indicated blood specimens if feasible, and as close to the CVA or TIA event date as possible.
h Sample collection, including tumor biopsy, upon disease progression is optional but highly recommended.
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9.8.3
Tumor Tissue Specimens
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
All participants must have tumor tissue submitted during the screening period to allow for 
participant enrollment into the study. Tissue submitted should be from an unresectable primary 
tumor lesion or any metastatic site. The tumor tissue should be from a site not previously irradiated 
and with no intervening treatment between time of acquisition and enrollment. Central lab must 
provide IRT with the results of PD-L1 testing prior to randomization. Either a FFPE tissue block
or 20 unstained tumor tissue sections, with an associated pathology report, must be submitted to 
the core laboratory for inclusion. FFPE tissue block and unstained slides submitted should be from 
biopsy obtained within 6 months prior to enrollment. Unstained slides should be sectioned within 
3 months prior to submission. Submission of an FFPE block is strongly preferred but unstained 
slides are also acceptable. Tissue may be from a core biopsy, punch biopsy, excisional or incisional 
biopsy, or surgical specimen; fine needle aspiration and other cytology samples are not acceptable. 
Biopsies of bone lesions that do not have a soft tissue component are also unacceptable for 
submission. 
The Medical Monitor (or designee) can be consulted for eligibility if participants have less than 
20 unstained slides.
PD-L1 stained tissue sections will be assessed by a pathologist and membranous PD-L1 expression 
scored in tumor and immune cells if a minimum of a hundred (100) evaluable tumor cells are 
present. Participants with tumor samples containing less than 100 cells per tissue section will not 
be randomized, but participants with positive, negative, or indeterminate (membrane staining is 
obscured by high cytoplasmic staining or melanin content) PD-L1 tumor expression will be 
stratified based on their expression.
In addition, this pre-treatment tumor sample may be used to assess other putative predictive
biomarkers of nivolumab and bempegaldesleukin efficacy and/or to better characterize the
tumor-immune microenvironment.
Various molecular markers with potential predictive value for the treatment of melanoma with
nivolumab, bempegaldesleukin, and other immunotherapies are currently under investigation and
may be assessed in this study. These tumor tissue biomarkers include, but are not limited to
PD-1, PD-L2, TILs or subpopulations of TILs and any immune mRNA expression signature.
These pre-treatment tumor samples may also be used to further characterize the tumor-
immune microenvironment through assessment of markers that may be associated with the
efficacy of nivolumab and bempegaldesleukin, including but not limited to other T cell checkpoint
receptors and ligands (eg, Lag-3, Tim-3), intratumoral immune cell subsets, including
macrophages, natural killer (NK) cells, T cells and B cells and other molecules, ie, cytokines and 
chemokines.
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If the 
participant has > 1 measurable lesion, the lesion planned for biopsy while on treatment cannot be 
designated as a target lesion at baseline. Additional target lesions should be available for 
radiographic efficacy assessments. These same criteria that apply for lesion selection also apply to
patients who consent to the optional biopsy in the main study.
It is also highly recommended that tumor tissue samples be collected on-treatment and upon
recurrence when safe and feasible. These samples may be used for the assessment of markers
implicated in resistance to immunotherapeutic agents, including but not limited to other T cell
checkpoint receptors and ligands (eg, Lag-3, Tim-3) and intratumoral immune cell subsets,
including but not limited to, T regulatory cells and myeloid derived suppressor cells. These
samples may also be used to investigate the effect of nivolumab and bempegaldesleukin on
the expression of potentially relevant predictive and/or prognostic melanoma biomarkers,
including, but not limited to BRAF mutation and PD-L1 tumor expression and other immuno-
oncology-related events such as upregulation/downregulation of chemokines and cytokines. Both
the pre-treatment tumor sample and the sample collected on-treatment and upon recurrence
may be retrospectively assessed for BRAF mutation status, N-RAS mutation status, as well as
for the expression of other immune or melanoma related genes, RNAs and/or proteins, or for the 
presence of immune cell populations using a variety of methodologies inclusive of, but not limited 
to, IHC, qRT-PCR, genomics, genetic mutation, methylation detection and fluorescent in-situ 
hybridization (FISH).
9.8.4
Tumor Gene Expression and Mutation Analyses
Biomarker sample collection will not be applicable per Protocol Amendment 03. However, 
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
Tumor Mutational Burden (TMB) refers to the total number of nonsynonymous somatic mutations 
that exist within a tumor’s genome. A subset of these mutations, termed neo-antigens, may result 
in an expressed protein that is not recognized by the host’s immune system as self, and therefore 
has the potential to be immunogenic, leading to an anti-tumor immune-mediated response. Tumors 
with a high mutation burden may have a higher rate of neo-antigens which, in principle, would be 
expected to be more immunogenic than tumors with comparatively low mutation burden.54
Therefore, high TMB has been hypothesized to correlate with improved efficacy in patients treated 
with immuno-oncology therapies. This hypothesis has been supported in multiple publications 
across immuno-oncology therapies, tumor types, and lines of treatment. The first published study 
of TMB as a biomarker of clinical outcomes was reported by Snyder et al (2014), where high TMB 
was found to be associated with efficacy in metastatic melanoma patients treated with anti-CTLA-
4 therapy.55 Further studies by Rizvi et al reported TMB as a biomarker of pembrolizumab efficacy 
in second-line NSCLC patients.55 Additional studies of pembrolizumab and atezolizumab in 
NSCLC have been generally consistent with these results.56
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Recently, TMB was evaluated in an exploratory post hoc analysis in the BMS-sponsored first-line 
NSCLC study, CheckMate-026, which represents the first Phase 3 study to demonstrate the impact 
of TMB on efficacy of a PD-1/L1 inhibitor.57 This analysis demonstrated that in patients with high 
TMB, ORR was numerically higher in the nivolumab arm versus the chemotherapy arm (47% vs
28%) and median PFS was longer in the nivolumab arm compared to the chemotherapy arm (9.7 
vs 5.8 months, HR 0.62; 95% CI 0.38, 1.00). OS was notable, though similar (18.3 vs 18.8 months
and 1 year OS rates of 64% vs 60%, respectively), between the arms in patients with high TMB, 
although of note, 68% of patients in the chemotherapy arm received subsequent nivolumab.58
Interestingly, the ORR and mPFS rates observed in the high TMB subgroup within 
CheckMate-026 were similar to those reported in the first line NSCLC study of pembrolizumab 
(Keynote-024), where ORR and mPFS were 45% and 10.3 months, respectively, in patients with 
≥50% PD-L1 expression treated with pembrolizumab monotherapy.58
The available data to date suggest that, in addition to PD-L1, TMB is also a biomarker of clinical 
efficacy to immuno-oncology therapy. Therefore, TMB will be included as an exploratory 
biomarker of clinical efficacy of nivolumab with and without bempegaldesleukin combination 
therapy.
To explore the potential association of tumor mutation burden with clinical outcomes, tumor tissue 
will be evaluated by targeted and/or whole exome sequencing.
Exploratory analyses of mRNA (and/or miRNA) will be completed using RNA isolated from 
tumor tissue. Targeted and/or whole transcriptome RNA-seq, microarrays, and/or similar 
methodologies will be used to assess gene expression signatures, such as but not limited to those 
associated with inflammatory processes and/or immune related signaling, for potential association 
with clinical outcomes.
9.8.5
Peripheral Biomarkers
Biomarker sample collection will not be applicable per Protocol Amendment 03. However, 
exploratory analysis of biomarkers on previously collected specimens as detailed below may
be conducted.
A variety of biomarkers that may predict or impact the treatment efficacy with bempegaldesleukin
and nivolumab will be investigated in peripheral blood specimens taken from all participants prior 
to and during treatment. Several analyses will be completed and are described briefly below. 
Additional biomarker assessments may also be performed if samples are available.
9.8.6
Whole Blood for Genetic Analysis
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
Whole blood will be collected from all participants prior to treatment to generate genomic DNA 
and RNA for Single Nucleotide Polymorphism (SNP)/WES and gene expression analyses, 
respectively. These analyses will focus on SNPs within genes associated with PD-1, CTLA-4, and 
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other immunoregulatory signaling pathways to determine if natural variation within those genes is 
associated with response to nivolumab and bempegaldesleukin treatment and/or with AEs. Also, 
whole blood RNA will be collected on-treatment to assess for potential changes in peripheral gene 
expression due to treatment with nivolumab and bempegaldesleukin combinations.
9.8.7
Exploratory Serum and Plasma Biomarkers
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
Blood samples for exploratory serum and plasma biomarker analyses will be drawn at the specified 
time points indicated in the biomarker table. Additionally, serum and plasma samples will be 
collected when clinically safe and feasible, upon occurrence of a Grade 3 drug-related AE that 
results in a dose delay. Separate blood samples will be collected and processed for serum and 
plasma and then put in frozen storage. Serum and plasma samples may be assessed by ELISA, 
seromics, microRNA profiling, ctDNA measurements, metabolomics and/or other relevant 
multiplex-based protein assay methods for immune -related factors that may predict for nivolumab 
and/or bempegaldesleukin benefit or AEs; such factors may include, but are not limited to levels 
of soluble PD-L1, anti-tumor antibodies, cytokines, chemokines, inflammatory factors, NKG2D 
ligands (eg, soluble MICA), circulating tumor DNA, SARS-CoV-2 serologic status, and 
microRNAs (eg, angiopoietin-2 and fibronectin). Serum and plasma may also be assessed for 
additional factors that may inform on the etiology of CVA events; such factors may include, but 
are not limited to those associated with vascular damage (eg, vWF, soluble P-selectin), coagulation 
and platelet activation (D-dimer, prothrombin 1.2, fibrinogen, solCD40L), eosinophil activation 
(eosinophil cationic protein) and inflammatory markers relevant to CVA (eg, CRP, TNFα, IL-6, 
VCAM/ICAM).
9.8.8
Plasma ctDNA
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
Circulating tumor DNA (ctDNA) are small fragments of DNA that are shed from tumor and can 
be found circulating in the peripheral bloodstream. ctDNA derived from malignant cells can be 
isolated and analyzed from blood-derived plasma for genetic features including, but not limited to 
somatic mutations using targeted sequencing-based methods (eg, Next Generation sequencing). 
To complement the planned genomics analyses outlined for tumor assessments, plasma will be 
collected at baseline and on-treatment to isolate ctDNA. Mutational data derived from these 
samples will be compared to those identified directly in the tumor. Baseline and on-treatment 
changes in mutational burden (either global or individual genes) will be evaluated for association 
with treatment outcomes. Correlation between mutational burden in blood and the tumor will be 
explored.
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9.8.9
Serum MicroRNA (miRNA)
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
MicroRNAs (miRNA) are widely-expressed, small RNAs that regulate the abundance of mRNA 
transcripts and their translation into protein. Global miRNA expression profiling has become 
increasingly common in cancer research, and miRNA signatures that are correlated to stage of 
disease or to clinical outcomes are now available for a variety of cancer types. Expression profiling 
of miRNA may be useful also in identifying molecular markers for the prediction of drug responses 
and for prospective stratification. Intriguingly, miRNAs are stable in serum and may represent 
miRNAs over-expressed in tumors and/or reflect immune system activity. Serum taken at baseline 
and during treatment from participants randomized to each treatment arm will be analyzed for 
miRNA content by microarray or similar methodology. The resulting miRNA profiles will be 
evaluated for changes in miRNA abundance that occurs following treatment and for associations 
with response and survival data. Ultimately, the goal will be to determine if unique 
immunerelevant and/or disease-specific miRNA signatures exist and if they are potentially useful 
for identifying participants who are likely (or unlikely) to respond to nivolumab treatment.
9.8.10
Myeloid Derived Suppressor Cells
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
Myeloid derived suppressor cells (MDSCs) are an immune cell population capable of suppressing 
T cell activation and proliferation. Low pre-treatment MDSC levels in peripheral blood may be 
associated with better overall survival in melanoma participants treated with nivolumab
combination. MDSCs will be measured at baseline and on-treatment to assess pharmacodynamic 
changes or associations with outcome.
9.8.11
Peripheral Blood Mononuclear Cells and Whole Blood 
Immunophenotyping
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
Whole-blood samples will be collected for isolation and cryopreservation of peripheral blood 
mononuclear cells (PBMCs) in both arms of the study. These cryopreserved samples may be used 
for functional activation tests, additional immunophenotyping assays, T-cell receptor sequencing, 
and DNA methylation.
Whole blood immunophenotyping by flow cytometry will be used to assess pre-treatment and 
serial on-treatment changes in composition/activation status of peripheral immune cell subsets to 
determine PD changes and/or association with outcome. Cellular subsets evaluated will include, 
but not limited to, T, B, NK, natural killer T cell (NKT), and T-regulatory cells. Cellular subsets 
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may be defined in terms of, but not limited to, memory phenotype, activation, exhaustion, signaling 
markers, and proliferation status before and after treatment. Several markers may be used to assess 
this including, but not limited to, Ki-67, human-leukocyte antigen-antigen D-related, CTLA-4, 
PD-1, ICOS, CD39, etc.
9.8.12
Microbiome Analysis
Biomarker sample collection will not be applicable per Protocol Amendment 03. However,
exploratory analysis of biomarkers on previously collected specimens as detailed below may 
be conducted.
The potential influence of the gut microbiome on melanoma treatment outcome is not known. It is 
known that the microbiome can affect treatment of certain cancer types (ie, colorectal cancer) 
through several mechanisms, including promotion of disease via induction of chronic 
inflammation or catabolism of polyamines on other carcinogenic digestible material. In addition, 
the innate and adaptive immune system activation state and repertoire may be altered based on 
local microbiota leading to differential activity of nivolumab in cancer participants. DNA will be 
extracted from fecal samples taken prior to therapy and on-treatment with nivolumab and 
nivolumab/bempegaldesleukin combination (Table 9.8.2-2). A gene-sequencing approach will be 
utilized to survey microbial species in the gut in order to define microbiota as a function of efficacy 
and safety. Overall changes in the gut microbiota will also be characterized in individual 
participants that receive therapy.
9.9
Medical Resource Utilization and Health Economics
This section is not applicable per Protocol Amendment 03. Healthcare resource utilization data 
will be collected for all randomized participants using an internal CRF developed for use in 
previous trials. The form, which is completed by study staff, records information about hospital 
admissions, including number of days spent in various wards and discharge diagnosis, as well as 
non-protocol specified visits related to study therapy, including date of visit, reason for visit, and 
type of visit. The health care resource utilization data will be used to support subsequent economic 
evaluations.
10
STATISTICAL CONSIDERATIONS
In general, continuous data will be summarized by descriptive statistics, including number of 
participants, mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized by the number and percentage of participants. Unless otherwise specified, data will 
be summarized by treatment arm.
All efficacy evaluations will be analyzed using the intent-to-treat (ITT) population, and all safety 
endpoints will be summarized using the Safety population.
A detailed description of analysis methods will be provided in the statistical analysis plan (SAP).
The final ORR and PFS analyses, and the first OS interim analysis (combined with the second OS 
interim analysis) have been completed using the locked database with database lock date of 01-
Feb-2022. Given there was no additional clinical benefit in the doublet therapy arm compared to 
the monotherapy arm for the primary endpoints of PFS and ORR, the Sponsor, in consultation with 
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the DMC, has decided to unblind the trial, and no additional OS formal analyses will be performed. 
Any further efficacy analyses, if conducted, will be descriptive.
10.1
Sample Size Determination
The sample size of the study accounts for the three primary efficacy endpoints: ORR, PFS and OS. 
The overall alpha for this study is 0.05, which is split with 0.001 to evaluate ORR, 0.03 to evaluate 
PFS and 0.019 to evaluate OS. All alphas are two-sided. ORR will be analyzed when the first 480 
randomized participants have a minimum follow-up of 6 months. PFS will be evaluated for 
treatment effect at an alpha of 0.03 with at least 90% power; no interim analysis of PFS is planned. 
OS will be evaluated for treatment effect at an alpha level of 0.019. 
A fallback approach will be used to test ORR, PFS, and OS. If ORR is significant, the alpha of 
0.001 allocated to ORR will be passed to OS. If PFS is significant, the alpha of 0.03 allocated to 
PFS will pass to OS. That is,
•
If both ORR and PFS are significant, then OS will be tested at 0.05 level
•
If PFS is significant but ORR is not, then OS will be tested at 0.049 level
•
If ORR is significant but PFS is not, then OS will be tested at 0.02 level
•
If neither ORR nor PFS is significant, then OS will remain to be tested at 0.019 level
It is estimated that approximately 764 previously untreated metastatic melanoma subjects will be 
randomized into two arms in a 1:1 ratio. Table 10.1-1 summarizes sample size design parameters 
and schedule of primary endpoint analyses planned in this study.
Table 10.1-1:
Summary of Sample Size Parameters and Schedule of Analyses
Endpoints
ORR
PFS
OS
Sample size
480: 240 vs 240
764: 382 vs 382
764: 382 vs 382
Power
90%
90%
90%
Alpha
0.1% (2-sided)
3% (2-sided)
1.9% (2-sided)
Alternative Hypothesis: 
Experimental vs Control
ORR: 66% vs 45%
PFS rates for 
nivolumab arm:
63% (3 months)
52% (6 months)
46% (9 months)
37% (18 months)
HR=0.7
mOS:
53.7 months vs 37.6 months
HR=0.7
ORR Final
~35.9 months (29.9
months of accrual + 6 
months of follow-up)
--
--
PFS Final Analysis/OS 
Interim #1
--
~39.8 months
375 PFS events
Critical HR: 0.799
~39.8 months
Critical HR corresponds to 
two-sided alpha = 0.0001, 
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Table 10.1-1:
Summary of Sample Size Parameters and Schedule of Analyses
Endpoints
ORR
PFS
OS
and depends on the number 
of OS events observed
OS Interim #2
--
--
~47.9 months
230 OS events (55% of OS 
Information)
Critical HR: 0.646
OS Interim #3
--
--
~59 months
314 OS events (75% of OS 
Information)
Critical HR: 0.729
OS Final Analysis
--
--
~76.3 months
419 OS events
Critical HR: 0.792
Note: Analysis time projections are updated based on updated enrollment projection in February, 2021. If final ORR 
and final PFS analyses occur close enough, they may be combined into one analysis conducted at the final PFS analysis 
time. In this case, the ORR formal analysis will only be conducted for the ORR population.
10.1.1
Sample Size Justification for ORR Estimate
Given a two-sided alpha of 0.001, 480 subjects in nivolumab+bempegaldesleukin and nivolumab 
arms will provide approximately 90% power to detect 21% ORR difference between the 2 
treatment arms, assuming ORRs of 66% and 45%, respectively, using a Chi-square test. If 
observed ORR difference is greater than 14.9%, it will result a statistically significant result. 
This ORR formal comparison will occur when the first 480 randomized participants have a 
minimum follow-up of 6 months. In the original protocol, the ORR formal comparison was 
projected to occur approximately 15.6 months after the first subject's randomization date (9.6 
months of accrual of 480 subjects and 6 months of ORR follow-up). That projection was based on 
the assumption that the accrual duration of the study was approximately 15 months. 
Based on actual enrollment and updated projection in February 2021, where the accrual duration 
of the study is projected to be approximately 38.8 months, the ORR formal comparison is projected 
to occur approximately 35.9 months from the first subject's randomization date (~29.9 months of 
accrual of 480 subjects and 6 months of ORR follow-up). If final ORR and final PFS analyses 
occur close enough, they may be combined into one analysis conducted at the final PFS analysis 
time. In this case, the ORR formal analysis will only be conducted for the ORR population.
10.1.2
Sample Size Justification for PFS Comparison
Based on the PFS results for nivolumab from BMS Study CA209067 (ie, the CheckMate-067 
Study,36 a non-constant PFS hazard was observed. Thus, for the sample size calculation, a 
piecewise exponential distribution was assumed in each treatment arm with a constant HR of 0.7. 
Specifically, in the nivolumab arm we assume PFS rates of 63%, 52%, 46%, and 37% at 3, 6, 9,
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and 18 months, respectively. Under the assumptions of piecewise exponential distribution for each 
arm and a constant HR of 0.7, the calculated median progression-free survival (mPFS) are
6.96 months and 17.8 months for the nivolumab and nivolumab+bempegaldesleukin arms, 
respectively. At a two-sided alpha level of 0.03, a total of 375 PFS events are needed to detect a 
PFS hazard ratio (HR) of 0.7 with 90% power. In the original protocol, under the assumption of 
15 months of enrollment period, 7-months of minimum follow-up, and a 10% annual drop-out rate, 
a total sample size of 764 subjects is required to observe the needed 375 PFS events at 22 months. 
Under updated projection in February 2021, with 764 subjects and 10% annual drop-out rate, the
PFS analysis time, ie, to observe approximately 375 PFS events, is projected to occur at 
approximately 39.8 months from the first subject's randomization date. It is projected that an 
observed HR of 0.799 or less would result in a statistically significant improvement in the final 
analysis of PFS.
10.1.3
Sample Size Justification for OS Comparison
For OS, at a two-sided alpha level of 0.019, a total of 419 events are needed to detect a HR of 0.70 
with 90% power. Assuming a median OS time for the nivolumab arm (Arm B) of 37.6 months, 
with a total sample size of 764, in the original protocol it is projected the total study duration is 59 
months (15 months for accrual and 44 months for follow up), with a critical boundary hazard ratio 
of 0.792. With updated enrollment projection in February 2021, it is projected the total study 
duration (corresponding to the final OS analysis time) is approximately 76.3 months from the first 
subject's randomization date. All projected OS interim analysis times are updated accordingly.
However, all PFS and OS analysis times are driven by the required number of events. The actual 
analysis times depend on actual enrollment speed and events accrual, thus may be different from 
projections.
Three formal interim analyses of OS are planned for this study. The first OS interim analysis is 
planned at the time point of the final PFS analysis, where OS will be tested at 0.0001 level, 
regardless of the outcome of the final PFS analysis. For instance, if 150 OS events are observed at 
the time point of the final PFS analysis, then the critical boundary on hazard ratio for the first OS 
interim is 0.53.
All other formal OS analyses will be conducted when planned number of OS events specified 
below are observed.
The second OS interim analysis is planned when 230 OS events are observed (55% of the targeted 
OS events for final analysis, projected to happen 47.9 months from FPFV), and the third OS 
interim analysis is planned after observing 314 OS events (75% of targeted OS events needed for 
final analysis, projected to happen 59 months from FPFV). Accounting for the alpha = 0.0001 
spent at the first OS interim, the remaining alpha level will be the overall OS alpha level (as 
described below) minus 0.0001 depending on the ORR and PFS results. If neither ORR nor PFS 
is significant, the remaining alpha level of 0.0189 (alpha=0.019-0.0001) will be spent on the rest
of the OS interim analyses and the final OS analysis. The stopping boundaries for the second OS 
interim, the third OS interim, and the final OS analyses will be derived based on the actual number 
of deaths using the O’Brien and Fleming alpha-spending function in software EAST 6.4.1. If the 
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numbers of events are exactly the same as planned, the critical boundary on hazard ratios for the 
second, third OS interim analyses and the final OS analysis are 0.646, 0.729, and 0.792, 
respectively.
If the final ORR analysis is statistically significant, the significance level of 0.001 spent in the 
ORR analysis will be passed on to the OS analysis. Similarly, if the final PFS analysis is 
statistically significant, the significance level of 0.03 spent in the PFS analysis will also be passed 
on to the OS analysis. The alpha spent at the second, third OS interim analyses and the final OS 
analysis will be adjusted accordingly and the overall alpha level for OS is described at the 
beginning of Section 10.1.
If there are at least 230 OS events at the time point of the final PFS analysis, then the first planned 
OS interim analysis and the second planned OS interim analysis (at 230 OS events) will be merged 
into one OS interim analysis, and will occur at the time point of the final PFS analysis. In this case, 
there will be no extra spending of two-sided alpha = 0.0001 for the first OS interim analysis, and 
the stopping boundaries for all OS analyses will be derived based on the actual number of deaths 
using the O’Brien and Fleming alpha-spending function in software EAST 6.4.1.
If the 419th OS event has not occurred 60 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 observed final number of events using all remaining alpha for OS.
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Enrolled Participants
All participants who signed an informed consent form and were registered 
into the IRT.
Intent-to-Treat (ITT) 
Population/All Randomized 
Participants
All participants who were randomized. Participants are grouped within the 
ITT Population by the treatment to which they were randomized. This is the 
primary analysis set for baseline characteristics and all efficacy analyses.
ORR Population
All randomized participants who have at least 6 months of follow-up at the 
time point of the final ORR analysis. A participant’s follow-up time is 
defined here as the time between randomization date and clinical data cut-off 
date regardless of participant disposition (ie, intent-to-treat principle). 
This is the primary analysis set for the final ORR analysis, which will occur 
when approximately the first 480 randomized participants have at least 6 
months of follow-up.
Safety Population/All Treated 
Participants
All participants who receive at least 1 dose (or partial dose) of study drug. 
Participants are grouped within the Safety population according to the 
treatment they actually received. This is the analysis set for all safety 
analyses, as well as, study drug administration.
Biomarker Population
For predictive biomarkers, biomarker population includes all randomized 
participants who have biomarker data available at baseline. For 
pharmacodynamic biomarkers, the biomarker population incudes all 
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Population
Description
randomized participants who have baseline and at least one post-baseline 
biomarker data available.
All PD-L1 evaluable 
participants
All randomized participants with quantifiable PD-L1 expression.
10.3
Statistical Analyses
A description of the participant population will be included in the statistical output reported, including 
subgroups of age, gender and race.
Per Protocol Amendment 03, the secondary and exploratory objectives are not applicable.
However, exploratory analyses of biomarkers on previously collected samples as per Section 9.8
may be conducted. Any analyses of secondary objectives will be descriptive.
10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
ORR
ORR is defined as the proportion of participants with a confirmed best overall response of 
CR or PR in the ITT population by RECIST 1.1 per BICR.
A pre-planned analysis of blinded independent central review (BICR)-assessed ORR (using 
RECIST v 1.1; confirmed at least 4 weeks later) and duration of response is intended for 
both arms to evaluate the clinical activity of bempegaldesleukin in combination with 
nivolumab relative to nivolumab. 
BICR-assessed ORR will be compared using a Cochran-Mantel Haenszel (CMH) two-sided 
test stratified by the three stratification factors (PD-L1 status, BRAF status, and AJCC M 
stage) at 0.001 level to control the overall study type I error. An associated odds ratio and 
95% and 99.9% confidence interval (CI) will be calculated. The ORR difference between 
the two treatment arms with its 95% and 99.9% CI will be reported. The ORR and its 
corresponding 95% exact CI will also be calculated by Clopper-Pearson method for each 
randomized arm.
Primary
Progression-Free 
Survival
Progression-free survival (PFS) is defined as the time between the date of randomization and 
the first date of documented tumor progression using RECIST 1.1 per BICR (see 
Section 9.1.1.3), or death due to any cause, whichever comes first.
A log-rank test stratified by PD-L1 tumor expression status, BRAF mutation status, and M 
stage will be used to compare PFS between the 2 treatment arms in the ITT Population at 
0.03 level. A Cox proportional hazards model with treatment as the single covariate, 
stratified by the above factors, will be used to estimate the hazard ratio and corresponding 
97% CI. The Kaplan-Meier method will be used to further summarize PFS, including PFS 
curves, medians with corresponding 95% CIs. The PFS rates at 6 and 12 months will also 
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Endpoint
Statistical Analysis Methods
be estimated. In addition, to account for potential non-proportional hazard for PFS, 
sensitivity analyses will be conducted to compare PFS per BICR between treatment groups 
using weighted log-rank test. Technical details will be given in the SAP.
Participants who do not progress or die will be censored on the date of their last evaluable 
tumor assessment. Participants who do not have any on-study tumor assessments and do 
not die will be censored on their date of randomization. Participants who started a new 
anticancer treatment regimen prior to disease progression will be censored on the date of 
their last evaluable tumor assessment prior to receiving the new antineoplastic regimen. 
Participants who are lost to follow up will be censored on the date of their last evaluable 
tumor assessment.
Primary
Overall Survival
Overall survival (OS) is defined as the time between the date of randomization and the date 
of death due to any cause. Participants who do not have a date of death will be censored on 
the last date for which a participant was known to be alive. OS will be analyzed using the 
stratified log rank test, Cox proportional hazards model, and Kaplan Meier method, similar 
to PFS. The OS rates at 12 and 24 months will also be estimated. In addition, similar 
sensitivity analyses to account for potential non-proportional hazard for OS will also be 
conducted.
Secondary
Clinical Benefit 
Rate, 
Duration of 
Response, 
Time to 
Response
The clinical benefit rate (CBR), defined as the proportion of participants with CR, PR, or 
SD per RECIST 1.1 by BICR will be summarized similarly to ORR.
Duration of response (DOR) is defined for participants who have a confirmed CR or PR as 
the date from first documented CR or PR per RECIST 1.1 to the date of the documentation 
of disease progression by BICR or death due to any cause, whichever is earlier. Participants 
who do not have disease progression or die will be censored on the date of their last 
evaluable tumor assessment. The median DOR will be estimated using the Kaplan-Meier 
method with corresponding 95% CI and range.
Time to response (TTR) is defined for participants who had a confirmed CR or PR as the 
time from the date of randomization to date of first documented CR or PR per RECIST 1.1 
as assessed by BICR. The median TTR will be estimated using the Kaplan-Meier method 
with corresponding 95% CI and range.
ORR, PFS, CBR, DoR, TTR assessed by Investigator per RECIST 1.1 will be analyzed 
similarly to these endpoints assessed by BICR.
PFS per BICR, ORR per BICR, and OS in biomarker population (by PD-L1 status) will be 
analyzed similarly as stated above.
Exploratory
PFS2
PFS2 is defined as the time from randomization to objectively documented progression
after the next line of therapy, per Investigator assessment, or to death, whichever occurs 
first. Participants who were alive and without progression after the next line of therapy can 
be censored at last known alive date. Details on the PFS2 analysis will be described in the 
SAP.
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10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Secondary
Safety and 
Tolerability
Safety analyses will be performed in all treated participants. Descriptive statistics of safety 
will be presented using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 5 by treatment group. All on-study AEs, treatment-
related AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI 
CTCAE v5 criteria by system organ class and preferred term. On study lab parameters 
including hematology, chemistry, liver function, and renal function will be summarized 
using worst grade NCI CTCAE v5 criteria.
10.3.3
Other Analyses
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10.3.3.3
Missing Data
Statistical considerations and methodology for handling missing data, including sensitivity analyses 
for PFS and ORR, will be detailed in the SAP.
10.3.4
Interim Analyses
Several interim analyses are planned for this study. Table 10.3.4-1 gives an overview of their 
purposes and timing. The final ORR and PFS analyses, and the first OS interim analysis (combined 
with the second OS interim analysis) have been completed using the locked database with a 
database lock date of 01-Feb-2022. Given there was no additional clinical benefit in the doublet 
therapy arm compared to the monotherapy arm for the primary endpoints of PFS and ORR, the 
Sponsor, in consultation with the DMC, has decided to unblind the trial. No additional OS formal 
analyses will be performed. Any further efficacy analyses, if conducted, will be descriptive.
Table 10.3.4-1:
Interim Analyses Schedule
Analysis
Purpose
Analysis Trigger
Final ORR Analysis
Demonstrate significant 
improvement in ORR
Approximately the first 480 
randomized participants have a 
minimum of 6-month of follow-up
Final PFS Analysis, Interim OS 
Analysis #1
Demonstrate significant 
improvement in PFS and OS
~375 PFS events
Interim OS Analysis #2
Demonstrate significant 
improvement in OS
~230 OS events
Interim OS Analysis #3
~314 OS events
aFinal OS Analysis
~419 OS events
a If the 419th OS event has not occurred 60 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 
observed final number of events using all remaining alpha for OS.
The Statistical Analysis Plan will further describe the planned interim analyses.
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11
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25 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.
26 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. 
27 Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without 
BRAF mutation. N Engl J Med 2015;372:320-30.
28 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. J Clin Oncol 
2018;36(15_suppl):3006-3006.
29 Siefker-Radtke AO, Fishman MN, Balar AV, et al. NKTR-214 + nivolumab in first-line 
advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin 
Oncol 2019;37(7_suppl):388-388.
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30 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.
31 Chuk MK, Mulugeta Y, Roth-Cline M, et al. Enrolling adolescents in disease/target 
appropriate adult oncology clinical trials of investigational agents. Clin Cancer Res. 2017;23:9-
12.
32 Beaver JA, Ison G, and Pazdur R. Reevaluating Eligibility Criteria - Balancing Patient 
Protection and Participation in Oncology Trials. N Engl J Med. 2017;376:1504-1505.
33 Lu C, Zhang J, Nagahawatte P, et al. The genomic landscape of childhood and adolescent 
Melanoma. J Invest Dermatol. 2015;135(3):816–823.
34 Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the 
American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 
2017 Nov;67(6):472-492. doi: 10.3322/caac.21409. Epub 2017 Oct 13.
35 Thomas NE, Edmiston SN, Alexander A, Groben PA, Parrish E, Kricker A, et al. Association 
Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients 
with Higher-Risk Primary Melanoma. JAMA Oncol. 2015;1:359-368.
36 Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in 
untreated melanoma. N Engl J Med. 2015;373(13):1270-1.
37 Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without 
BRAF Mutation. N Engl J Med. 2015;372:320-330.
38 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-
cell non–small-cell lung cancer. N Engl J Med. 2015;373:123-135.
39 Borghaei H, Luis Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced 
nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373:1627-1639.
40 Hellmann, MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line 
treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, 
phase 1, multicohort study. The Lancet Oncol. 2017;18(1):31-41.
41 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or 
monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. 
42 Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-
cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.
43 Schadendorf D, Larkin J, Chiarion-Sileni V, et al. Efficacy and quality of life outcomes in patients 
with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) plus 
ipilimumab (IPI) due to toxicity in a phase III trial (CheckMate 067). Presented at the 2016 Annual 
Meeting of the European Association of Dermato-Oncology, August 31-September 3, 2016, 
Vienna, Austria.
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44 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from Phase II 
and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol.
2015;33:1889-1894.
45 Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of 
nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics 
of long-term survivors. Oral presentation presented at: American Association for Cancer 
Research (AACR) Annual Meeting, April 1-5, 2017, Washington, DC.
46 Felip Font E, Gettinger SN, Burgio MA, et al. Three-year follow-up from Checkmate 017/057: 
Nivolumab versus docetaxel in patients with previously treated advanced non-small lung cancer 
(NSCLC). Poster discussion presentation at the European Society of Medical Oncology Annual 
Meeting, September 8-12, 2017, Madrid, Spain.
47 Herbst RS, Garon E, Kim D-W, et al. KEYNOTE-010: Durable clinical benefit in patients with 
previously treated, PD-L1-expressing NSCLC who completed pembrolizumab. Poster presentation 
at the World Conference on Lung Cancer, December 4-7, 2016, Vienna, Austria.
48 Robert C, Long GV, Schachter J, et al. Long-term outcomes in patients with ipilimumab-naive 
advanced melanoma in the Phase 3 KEYNOTE-006 study who completed pembrolizumab 
treatment. J Clin Oncol. 2017 35:(15_suppl):9504-9504.
49 Spigel DR, et al. Randomized results of continuous vs 1-year fixed-duration in patients with 
advanced non-small cell lung cancer. Oral presentation at the European Society of Medical 
Oncology Annual Meeting. 2017 Sep 8-12; Madrid, Spain.
50 Xu Z, Davis HM, Zhou H. Rational development and utilization of antibody-based therapeutic 
proteins in pediatrics. Pharmacol Ther. 2013;137:225-247.
51 Zhang Y, Wei X, Bajaj G, et al. Challenges and considerations for development of therapeutic 
proteins in pediatric patients. J Clin Pharmacol. 2015;55(Suppl 3):S103-15.
52 Nishino M, Tirumani SH, Ramaiya NH, et al. Cancer immunotherapy and immune-related 
response assessment: The role of radiologists in the new arena of cancer treatment. Eur J 
Radiol. 2015 Jul;84(7):1259-68.
54 Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determine sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-
128.
55 Snyder A, Makarov V, Merghoub T et al. Genetic basis for clinical response to CTLA-4 
blockade in melanoma. N Engl J Med. 2014;371(23):2189-2199.
56 Kowanetz M, Zou W, Shames DS, et al. Tumor mutation burden (TMB) is associated with 
improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. Oral presentation at: The 
17th Annual World Conference on Lung Cancer; December 4-7, 2016; Vienna, Austria.
57 Peters S, Creelan B, Hellmann MD, et al. Impact of tumor mutation burden on the efficacy of 
first-line nivolumab in stage IV or recurrent non-small cell lung cancer: an exploratory analysis 
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of CheckMate 026. Oral presentation at the Annual Meeting of the American Association of 
Cancer Research; April 1-5, 2017; Washington, DC, USA.
58 Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for 
PD-L1-positive non-small-cell lung cancer. NEJM. 2016;375:1823-1833. 
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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
AESI/AEOSI
adverse event of special interest
ACLS
advanced cardiac life support
AEC
absolute eosinophil count
AI
accumulation index
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
additional research
AST
aspartate aminotransferase
AT
aminotransaminase
 
 
 
A-V
atrioventricular
β-HCG
beta-human chorionic gonadotrophin
BICR
Blinded independent central review
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
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Term
Definition
BOR
best overall response
BP
blood pressure
BRAF
proto-oncogene B-Raf
BTLA
B and T lymphocyte associated
BUN
blood urea nitrogen
C
Celsius
Ca++
calcium
Cavg
average concentration
CBC
complete blood count
CBR
clinical benefit rate
CD8+
CD8 positive
CD 122
interleukin-2 receptor subunit beta
CD-28
cluster of differentiation 28
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
cHL
classical Hodgkin’s lymphoma
CI
confidence interval
Cl-
chloride
CLcr
creatinine clearance
Cm
centimeter
Cmaxss
steady state peak concentrations
CMH
Cochran-Mantel Haenszel
CMV
cytomegalovirus
CNS
central nervous system
CR
complete response
CRC
colorectal carcinoma
CRF
Case Report Form, paper or electronic
CRS
cytokine-release syndrome
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Term
Definition
CSTD
closed-system transfer device
CT
computed tomography 
CTAg
Clinical Trial Agreement
CTCAE
Common Terminology Criteria for Adverse Events 
CTLA 4
cytotoxic T-lymphocyte–associated antigen 4
CV
coefficient of variation
CVA
cerebrovascular accident 
Cavgss
simulated steady state average concentration
ctDNA
circulating tumor DNA
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
DLT
dose-limiting toxicity
DMC
Data monitoring committee
DNA
deoxyribonucleic acid
DOAC
direct oral anticoagulant
DOR
duration of response
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
DVT
deep vein thrombosis
EA
extent of absorption
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EEG
electroencephalogram
Eg
exempli gratia (for example)
ELISA
enzyme-linked immunosorbent assay
EMA
European Medical Agency
ESR
Expedited Safety Report
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Term
Definition
F
bioavailability
 
FDA
Food and Drug Administration
FFPE
Formalin-Fixed Paraffin-Embedded
FPFV
first participant first visit
FSH
follicle stimulating hormone
G
gram
CAD
coronary artery disease
CBR
clinical benefit rate
COVID-19
coronavirus disease 2019
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CVA
cerebrovascular accident
FDG
fluorodeoxyglucose
GC
gas chromatography
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
H
hour
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
Human Immunodeficiency Virus
H&N
head and neck
HR
hazard ratio
HRT
hormone replacement therapy
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Term
Definition
IA
interim analysis
ICD
International Classification of Diseases
ICE
ischemic cardiovascular events
ICU
intensive care unit
ICH
International Conference on Harmonisation 
ICOS
inducible T-cell costimulator
IDMC
Independent Data Monitoring Committee
Ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IL-2
interleukin-2
IL-2Rα
IL-2 receptor alpha subunit
IL-2Rβ
IL-2-receptor beta subunit
IL-2Rαβγ
high affinity IL-2 receptor
IL-2Rβγ
intermediate affinity IL-2 receptor
IND
Investigational New Drug
IFN-γ
interferon-γ
IP
investigational products
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
IU
International Unit
IV
intravenous
K
slope of the terminal phase of the log concentration-time curve
K+
potassium
Kg
kilogram
L
liter
LAG3
lymphocyte-activation gene 3
LAM
lactation amenorrhea method
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Term
Definition
LC
liquid chromatography
LDH
lactate dehydrogenase
LMWH
low molecular weight heparin
Ln
natural logarithm
LVEF
left ventricular ejection fraction
MEK
mitogen-activated protein
Mg
milligram
Mg++
magnesium
Min
minute
mL
milliliter
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
MR
medical research
MRI
magnetic resonance imaging
MS
mass spectrometry
MTD
maximum tolerated dose
MUGA
multigated acquisition
μg
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
Ng
nanogram
NIMP
non-investigational medicinal products 
NK
natural killer
NKT
natural killer T cell
NKG2D
natural-killer group 2, member D
NKTR
Nektar Therapeutics
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Term
Definition
N-RAS
neuroblastoma RAS viral oncogene homolog
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over the counter
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic
PD-1
programmed cell death protein-1
PD-L1
programmed death ligand 1
PE
pulmonary embolism
PEG
polyethylene glycol
PET
positron emission tomography
PET-CT
positron emission tomography-computed tomography
PFS
progression-free survival
PFS2
PFS time from randomization to progression after the next line of therapy
PK
pharmacokinetics
PPK
population pharmacokinetics
PO
per os (by mouth route of administration)
PR
partial response
QC
quality control
QD, qd
quaque die, once daily
Q3W
every three weeks
Q4W
every four weeks
R2
coefficient of determination
RBC
red blood cell
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended Phase 2 dose
RNA
ribonucleic acid
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Term
Definition
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SAP
statistical analysis plan
SOC
standard of care
SOP
Standard Operating Procedures
T
Temperature
T
Time
T cell
regulatory T cell
TCR
T cell receptor
TIA
Transient ischemic attack
TILs
tumor infiltrating lymphocytes
Tim-3
T cell immunoglobulin and mucin domain 3
TID, tid
ter in die, three times a day
TMB
tumor mutation burden
TME
tumor microenvironment
TRAE
treatment related adverse events
Tregs
regulatory T cells
TSH
thyroid stimulating hormone
TTR
time to response
ULN
upper limit of normal
US
United States of America
W
Washout
WBC
white blood cell
WHO
World Health Organization
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Term
Definition
WOCBP
women of childbearing potential
 
x g
times gravity
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the CRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP),
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to the Sponsor or designee immediately. A 
potential serious breach is defined as a Quality Issue (eg, protocol deviation, etc) that is likely to 
affect, to a significant degree one or more of the following: (1) the physical, safety or mental 
integrity of one or more subjects/participants; (2) the scientific value of the trial (eg, reliability and 
robustness of generated data). Items (1) or (2) can be associated with either GCP Regulation(s) or 
Trial protocol(s).
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the Investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects/participants. The 
Investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling information to be provided to subjects/participants and any updates. 
The Investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The Investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects/participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted, as soon 
as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects/participants currently enrolled in the study if they are affected by the amendment; and (3) 
the new form must be used to obtain consent from new subjects/participants prior to enrollment.
If the revision is done via an administrative letter, Investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects/participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 
In situations where consent cannot be given by subjects/participants, their legally acceptable 
representatives (as per country guidelines) are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which the participant 
volunteers to participate. 
Sponsor or designee will provide the Investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects/participants, prior to the beginning of 
the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The Investigator, or a person designated by the Investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects/participants must be protected, 
respecting the privacy and confidentiality rules applicable to regulatory requirements, the 
subjects’/participants’ signed ICF and, in the US, the subjects’/participants’ signed HIPAA 
Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
For minors, according to local legislation, one or both parents or a legally acceptable representative 
must be informed of the study procedures and must sign the informed consent form approved for 
the study prior to clinical study participation. The explicit wish of a minor, who is capable of 
forming an opinion and assessing this information to refuse participation in, or to be withdrawn 
from, the clinical study at any time should be considered by the Investigator. 
Minors who are judged to be of an age of reason must also give their written assent.
Subjects/participants unable to give their written consent (eg, stroke or subjects/participants with 
or severe dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The participant must also be informed about the nature of the study to the extent 
compatible with his or her understanding, and should this participant become capable, he or she 
should personally sign and date the consent form as soon as possible. The explicit wish of a 
participant who is unable to give his or her written consent, but who is capable of forming an 
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opinion and assessing information to refuse participation in, or to be withdrawn from, the clinical 
study at any time should be considered by the Investigator.
The rights, safety, and well-being of the study subjects/participants are the most important 
considerations and should prevail over interests of science and society.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
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.
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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 (e.g., 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 
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.
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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.
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The Investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to Sponsor or designee.
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RECORDS RETENTION
The Investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
Investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the Investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the Investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another Investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the Investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
Investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the Investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
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•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the Investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the Investigator 
or designee.
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the clinical study report.
For each CSR related to this protocol, the following criteria will be used to select the signatory 
Investigator:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Study Steering Committee chair or their designee
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Involvement in trial design
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
principal Investigator, sub-investigator or any other member of the study staff without the prior 
written consent of the Sponsor.
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Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work.
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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.
In the European Union (EU), the summary of results and summary for laypersons will be submitted 
within 1 year [6 months for studies including pediatric population] of the end of trial in 
EU/European Economic Area and third countries. 
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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 9.2.8 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 9.2.6 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 (eg, 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: 
SAE Facsimile Number: Will be provided by local site monitor.
SAE Telephone Contact (required for SAE and pregnancy reporting): Will be provided by 
local site monitor.
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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 
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.
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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.
•
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. 
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•
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)
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) AND LANSKY (ADOLESCENTS) 
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.
PERFORMANCE STATUS CRITERIA: Lansky
Score
Lansky Description
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Substantial restriction of, and less time spent, in play activity
60
Out of bed, but minimal active play; keeps busy with quiet activities
50
Gets dressed, but inactive much of day; no active play, able to participate in quiet play
40
Mostly in bed; participates in some quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play limited to passive activities
10
No play; does not get out of bed
0
Unresponsive
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APPENDIX 6
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 7
*NOT APPLICABLE PER PROTOCOL AMENDMENT 03
CEREBROVASCULAR ACCIDENT ADVERSE EVENT
MANAGEMENT ALGORITHM FOR THE COMBINATION OF
BEMPEGALDESLEUKIN WITH CHECKPOINT INHIBITORS
Appendix 7 is not applicable per Protocol Amendment 03. The table below provides a 
management algorithm for possible signs/symptoms of CVA for patients treated with the 
combination of bempegaldesleukin with a checkpoint inhibitor. This general guideline constitutes 
guidance to the Investigator and may be supplemented by clinical judgment 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 guidanceª. 
•
Perform neurological imaging with DWI MRI 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:
o
Discontinue study treatment for patients receiving bempegaldesleukin in
combination with a checkpoint inhibitor (ie, nivolumabb).
2
Neurology consultation recommended.
3
Perform pertinent laboratory assessments including coagulation (D-dimer, complete blood 
count with differential, serum blood urea nitrogen, and creatinine) and exploratory 
biomarkers, 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.
b For other treatment combinations, refer to the relevant protocol(s).
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APPENDIX 8
AJCC MELANOMA STAGING (CANCER STAGING MANUAL 
8TH EDITION)
[From AJCC Cancer Staging Manual, 8th Edition. Amin MB, Edge S, Greene F, Byrd DR, 
Brookland RK, Washington MK, et al. editors. Springer International Publishing. 2017 (pages 577 
& 578)]
Definition of Primary Tumor (T)
T Category
Thickness
Ulceration Status
TX: primary tumor thickness cannot be 
assessed (e.g., diagnosis by curettage)
Not applicable
Not applicable
T0: no evidence of primary tumor (e.g., 
unknown primary or completely 
regressed melanoma)
Not applicable
Not applicable
Tis (melanoma in situ)
Not applicable
Not applicable
T1
≤1.0 mm
Unknown or unspecified
T1a
<0.8 mm
Without ulceration
T1b
<0.8 mm
With ulceration
0.8-1.0 mm
With or without ulceration
T2
>1.0-2.0 mm
Unknown or unspecified
T2a
>1.0-2.0 mm
Without ulceration
T2b
>1.0-2.0 mm
With ulceration
T3
>2.0-4.0 mm
Unknown or unspecified
T3a
>2.0-4.0 mm
Without ulceration
T3b
>2.0-4.0 mm
With ulceration
T4
>4.0 mm
Unknown or unspecified
T4a
>4.0 mm
Without ulceration
T4b
>4.0 mm
With ulceration
Definition of Distant Metastasis (M)
M Category
Anatomic site
LDH level
M0
No evidence of distant metastasis
Not applicable
M1
Evidence of distant metastasis
See below
M1a
Distant metastasis to skin, soft tissue 
including muscle, and/or non-regional 
lymph node
Not recorded or unspecified
M1a(0)
Not elevated
M1a(1)
Elevated
M1b
Distant metastasis to lung with or without 
M1a sites of disease
Not recorded or unspecified
M1b(0)
Not elevated
M1b(1)
Elevated
M1c
Distant metastasis to non-CNS visceral 
sites with or without M1a or M1b sites of 
disease
Not recorded or unspecified
M1c(0)
Not elevated
M1c(1)
Elevated
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M Category
Anatomic site
LDH level
M1d
Distant metastasis to CNS with or without 
M1a, M1b, or M1c sites of disease
Not recorded or unspecified
M1d(0)
Not elevated
M1d(1)
Elevated
Suffixes for M category: (0) LDH not elevated; (1) LDH elevated. No suffix is used if LDH is not recorded or is 
unspecified.
Definition of Regional Lymph Node (N)
N 
Category
Number of tumor-involved regional 
lymph nodes
Presence of in-transit, 
satellite, or microsatellite 
metastases
NX
Regional nodes not assessed (e.g., SLN biopsy not 
performed, regional nodes previously removed for another 
reason)
Exception: pathological N category is not required for T1 
melanomas, use cN
No
N0
No regional metastases detected
No
N1
One tumor-involved node or in-transit, satellite, and/or 
microsatellite metastases with no tumor-involved nodes
N1a
One clinically occult (i.e., detected by SLN biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or three tumor-involved nodes or in-transit, satellite, 
and/or microsatellite metastases with one tumor-involved 
node
N2a
Two or three clinically occult (i.e., detected by SLN biopsy)
No
N2b
Two or three, at least one of which was clinically detected
No
N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or in-transit, satellite, or 
microsatellite metastases with two or more tumor-involved 
nodes, or any number of matted nodes with or without in-
transit, satellite, and/or microsatellite metastases
N3a
Four or more clinically occult (i.e., detected by SLN biopsy)
No
N3b
Four or more, at least one of which was clinically detected, 
or presence any number of matted nodes
No
N3c
Two or more clinically occult or clinically detected, and/or 
presence any number of matted nodes
Yes
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AJCC Prognostic Stage Groups
Clinical (cTNM)
Clinical stage includes microstaging of the primary melanoma and clinical/radiologic/biopsy 
evaluation for metastases. By convention, clinical staging should be used after biopsy of the 
primary melanoma, with clinical assessment for regional and distant metastases. Note that 
pathological assessment of the primary melanoma is used for both clinical and pathological 
classification. Diagnostic biopsies to evaluate possible regional and/or distant metastasis also are 
included. Note there is only one stage group for clinical Stage III melanoma.
When T is....
And N is.....
And M is....
The clinical stage is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IB
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
Any T, Tis
≥N1
M0
III
Any T
Any N
M1
IV
PATHOLOGICAL (pTNM)
Pathological staging includes microstaging of the primary melanoma, including any additional 
staging information from the wide excision (surgical) specimen that constitutes primary tumor 
surgical treatment and pathological information about the regional lymph nodes after SLN biopsy 
or therapeutic lymph node dissection for clinically evident regional lymph node disease.
When T is....
And N is.....
And M is....
The pathological 
stage is...
Tis
N0
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IA
T2a
N0
M0
IB
T2b
N0
M0
IIA
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When T is....
And N is.....
And M is....
The pathological 
stage is...
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, N3b or N3c
M0
IIIC
T1a/b-T2a
N1a-N2a
M0
IIIA
T1a/b-T2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N >N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
Ant T, Tis
Any N
M1
IV
Pathological Stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes 
to complete pathological staging; use cN information to assign their pathological stage.
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Mucosal Melanoma of the Head and Neck TNM definitions
Definition of Primary Tumor (T)
T Category
T Criteria
T3
Tumors limited to the mucosa and immediately underlying soft tissue, 
regardless of thickness or greatest dimension: for example, polypoid nasal 
disease, pigmented or nonpigmented lesions of the oral cavity, pharynx or 
larynx. 
T4a
Moderately advanced disease. 
Tumor involving deep soft tissue, cartilage, bone, or overlying skin.
T4b
Very advanced disease. 
Tumor involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), 
masticator space, carotid artery, prevertebral space, or mediastinal structures.
Definition of Regional Lymph Node (N)
N Category
N Criteria
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastases
N1
Regional lymph node metastases present
Definition of Distant Metastasis (M)
AJCC 7 Prognostic Stage Groups for Mucosal Melanoma of the Head and Neck
When T is....
And N is.....
And M is....
The Clinical stage is...
T3
N0
M0
III
T4a
N0
M0
IVA
T3–T4a
N1
M0
IVA
T4b
Any N
M0
IVB
Any T
Any N
M1
IVC
Reference: AJCC Cancer Staging Manual, 7th Edition. Edge SB, Byrd DR, Compton CC, et al. editors. Springer 
International Publishing. 2010; Chapter 9 (page 97)
M Category
M criteria
M0
No distant metastasis
M1
Distant metastasis present
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APPENDIX 9
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) 
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline 
.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.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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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
Abbreviaitons: 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
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
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.
REFERENCES
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 10
COUNTRY SPECIFIC REQUIREMENTS/DIFFERENCES
Argentina, Czech Republic, Germany, Peru and Any Other Countries Where Exclusion of 
HIV Positive Participants Is Locally Mandated
Section
Country-specific language
Section 2 Flow Chart/Time and Events Schedule
Table 2-1: Screening Assessments - Laboratory Tests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion
Criteria, Exclusion criterion 1k
“Known
history
of
testing
positive
for
human
immunodeficiency
virus
(HIV)
or
known
acquired
immunodeficiency syndrome (AIDS)”to be replaced with
“Positive test for HIV”.
Germany, Sweden- Inclusion criteria were modified to 
 
to clarify that no minor participants will be enrolled in the study or participate in 
the 
. Adolescent hydration guidelines 
 
 are not applicable to adolescent participants in Germany and 
Sweden as no adolescents will be enrolled in Germany or Sweden.
Section Number & Title
Country-specific language
Section 6.1 Inclusion Criteria
Inclusion criterion 1c
Inclusion criterion 3a
Inclusion criterion 3a i)
Not applicable to participants in Germany and Sweden as no
minor participants will be enrolled in Germany or Sweden
Note: no minor participant will be enrolled in Germany or 
Sweden 
Note: no participants will be enrolled in the intensive PK and 
Biomarker sub-study in Germany and Sweden
This section is not applicable per Protocol Amendment 
03. Section 7.1.1.1 Hydration Guidelines. Adolescent 
Hydration Guidelines
Note: not applicable to participants in Germany and Sweden
as no adolescents will be enrolled in Germany or Sweden
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Ireland - Hypertension precautions were modified to reinforce blood pressure medication 
guidance
Section
Country-specific language
Section 7.7.4.3 Hypertension Precautions
͆Eligible participants who are on medications with 
antihypertensive effects for treatment of CAD (eg, b-blockers, 
CCBs, nitrates, etc) are those for whom it is considered safe to
temporarily discontinue these drugs prior to initiation of 
treatment. If the Investigator considers temporary 
discontinuation of such medications may have an adverse 
effect on the patient, such patients should not be included in
the trial.” to be replaced with 
͆Participants who are on medications with antihypertensive 
effects for the treatment of CAD (eg, b-blockers, CCBs,
nitrates, etc) are only eligible to enrol if their physician 
considers it safe to temporarily discontinue these drugs prior 
to initiation of treatment. If the Investigator considers 
temporary discontinuation of such medications may have an
adverse effect on the patient, such patients should not be 
included in the trial͇
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APPENDIX 11
*NOT APPLICABLE PER PROTOCOL AMENDMENT 03
CYTOKINE-RELEASE SYNDROME (CRS) MANAGEMENT 
MEASURES/ALGORITHM
Appendix 11 is not applicable per Protocol Amendment 03. 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.
CRS 
Grade 4
• Life-threatening 
consequences
• Pressor or 
ventilatory support 
indicated
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APPENDIX 12
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 02, 26-Aug-2021
The purpose of this protocol amendment is to update the sample size justification for progression-
free survival (PFS) comparison, add sensitivity analyses to account for potential non-proportional 
hazard for PFS and overall survival (OS) in the efficacy analyses, update analysis time projection 
based on updated enrollment projection, and add provisional languages to trigger OS final analysis 
at 60 months of minimum follow-up if the total planned number of OS events are not reached by 
then. Other updates have been made to align with changes to safety assessments including the 
implementation of National Cancer Institute Common Terminology Criteria for Adverse Events
version 5 (CTCAE v5), a revised cerebrovascular accident (CVA) algorithm, and the addition of 
a cytokine-release syndrome (CRS) algorithm. Guidance for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) status and coronavirus disease 2019 (COVID-19) vaccine has also 
been included. Details have been provided to add clarity and consistency about aging of tumor 
biopsy between the inclusion criteria and tumor tissue specimen sections. Modifications to the 
bempegaldesleukin and nivolumab program standards have been addressed and protocol 
inconsistencies corrected. 
Revisions apply to future participants enrolled in the study, and where applicable, to all 
participants currently enrolled.
Administrative Letter 03 and Administrative Letter 04 were incorporated into Amendment 02.
Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
Title Page
Added contact information for 
the Clinical Scientist and new 
Clinical Trial Physician
To provide current contact 
information for the study
Synopsis 
Changes were made to match 
relevant protocol revisions 
below
For consistency throughout the 
protocol
Throughout the protocol
“NKTR-214” changed to 
“bempegaldesleukin”
To update with International 
Nonproprietary Name (INN) 
2 Schedule of Activities
5.1.1 Screening Period
6.1 Inclusion Criteria (2e and 2l)
9.8.3 Tumor Tissue Specimens
Revised tumor tissue 
requirements.
•
Clarified that tissue 
submitted for screening 
should be from an 
unresectable primary tumor 
lesion or any metastatic site
•
Either a FFPE tissue block 
or 20 unstained tumor tissue 
sections, with an associated 
pathology report, must be 
submitted to the core 
To clarify tissue biopsy 
requirement for screening
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
laboratory for inclusion. 
FFPE tissue block and 
unstained slides submitted 
should be from biopsy 
obtained within 6 months 
prior to enrollment. 
Unstained slides should be 
sectioned within 3 months 
prior to submission
2 Schedule of Activities
3.3.3 Bempegaldesleukin and 
Nivolumab Benefit and Risk 
Assessment
6.2 Exclusion Criteria (1n,1o; 
2b) 
6.4.1 Retesting During 
Screening or Lead-In Phase
7.4 Dose Modification
7.7.3.1 COVID-19 Vaccination
8.1.2 Criteria to Resume 
Bempegaldesleukin and/or 
Nivolumab
9.2.1 Time Period and 
Frequency for Collecting AE 
and SAE Information
9.2.3 Follow-up of AEs and 
SAEs
9.8.7 Exploratory Serum and 
Plasma Biomarkers
Added or modified text to 
address SARS-CoV-2 infection 
and vaccination during study 
participation
NOTE: No additional samples 
will be collected. Samples 
already planned for collection 
will be utilized, if needed
Participant safety due to SARS-
CoV-2 infection
3.2.3 Bempegaldesleukin 
Mechanism of Action
Updated references and 
preclinical and clinical data 
Updated references to reflect 
final publications
3.3 Benefit/Risk Assessment 
and related Subsections
Added pooled safety analyses of 
participants who received 
bempegaldesleukin and 
nivolumab and pooled safety 
analyses of CVA events
Added and updated data and 
information to align with 
Bempegaldesleukin 
Investigator’s Brochure (IB 
v9.2)
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
5.4.7 Duration of Treatment 
with 
Nivolumab/Bempegaldesleukin
Added that treatment is for a 
maximum of 24 months, 
“regardless of number of cycles 
administered”
For clarity
6.2 Exclusion Criteria (1i)
Added protocol-specific text for 
stable anti-hypertensive regimen 
and clarified anti-hypertensive 
medications with 2 drugs
Clarified exclusion criterion
7.4 Dose Modification and 
related Subsections
Table 7.4.1-1: Adverse Event 
Criteria for Delay, Resumption, 
and Discontinue of Nivolumab 
and Bempegaldesleukin (if One 
is Delayed, Both Delayed)
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)
8.1.1 Nivolumab and 
Bempegaldesleukin 
Discontinuation Criteria
8.1.2 Criteria to Resume 
Bempegaldesleukin and/or 
Nivolumab
• Clarified text on dose delay 
for nivolumab or 
bempegaldesleukin or both
• Added Table 7.4.1-1 and 
Table 7.4.1-2 for nivolumab 
and bempegaldesleukin AE 
criteria and subsequent delay, 
resumption, and 
discontinuation
• Modified text to align criteria 
for dose delay, resume, and 
discontinuation with new 
Table 7.4.1-1
Updated study treatment dose 
delay, resume, and 
discontinuation criteria to align 
with the current CTCAE version 
(v5) and to align with 
Bempegaldesleukin IB v9.2 and 
Nivolumab IB v19 Addendum 
01
7.4.3 Monitoring and 
Management of Eosinophilia 
and Subsections
Reworded heading title and 
added two new subsections
Updated to align with 
Bempegaldesleukin IB v9.2
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)
8.1.1 Nivolumab and 
Bempegaldesleukin
Discontinuation Criteria
• Added permanent 
discontinuation criteria for 
bempegaldesleukin treatment 
related to CVA and TIA 
• Added that a management 
algorithm for possible signs 
of CVA/TIA and follow-up 
for participants treated with 
bempegaldesleukin in 
combination with nivolumab 
is provided in Appendix 7 
and updated the appendix
To clarify CVA and TIA 
algorithms and to align with 
Bempegaldesleukin IB v9.2,
Appendix 3
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
9.2.1 Time Period and 
Frequency for Collecting AE 
and SAE Information
9.2.7 Adverse Events of Special 
Interest (AESI/AEOSI)
Table 9.8.2-2 Biomarker 
Sampling Schedule: All 
Participants after Randomization 
into 
 is 
Completed
• Clarified that CVA (any 
grade) should be assessed as 
a serious adverse event 
(SAE)
• In Table 9.8.2-2 footnote, 
changed blood specimen 
from “mandatory” to “if 
feasible, and as close to the 
CVA or TIA event date as 
possible”
7.4.5.2 Management Algorithm 
for Cytokine-Release Syndrome
Added management algorithm 
of CRS in new Appendix 11
To align with 
Bempegaldesleukin IB v9.2 on 
the management of this potential 
risk
7.4.6 Treatment of 
Bempegaldesleukin-Related or 
Nivolumab-Related Infusion 
Reactions
• Added myalgia and 
hypersensitivity to list of 
possible symptoms of 
infusion reaction with 
bempegaldesleukin and 
nivolumab
• Added text regarding 
increasing infusion time for 
subsequent infusions for 
participants with previous 
Grade 1 or 2 infusion 
reactions
Participant safety during 
infusions with both medications
7.6 Treatment Compliance
Clarified frequency for 
contacting participant following 
first 2 infusions
To align with 
Bempegaldesleukin IB v9.2
7.7.3 Prior and Concomitant 
Medications
Clarified all medications, 
supplements, and/or herbs will 
be documented and recorded for 
100 days from the last dose of 
study treatment
Updated for clarification
7.7.4.2 Restricted Treatments
Added section on anti-
coagulation guidance
Participant safety during anti-
coagulation treatment
8.1 Discontinuation from Study 
Treatment
• Added discontinuation due to 
clinical disease progression 
in the absence of 
Participant safety 
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Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
8.1.3 Treatment Beyond 
Progression
radiologically confirmed 
progression by RECIST 1.1
• Clarified that documented 
progression is “BICR-
confirmed” progression and 
removed starting alternate 
cancer therapy
• Added that participants with 
clinical progression can 
continue treatment beyond 
progression
Table 9.8.2-2 Biomarker 
Sampling Schedule: All 
Participants after Randomization 
into 
 is 
Completed
• Revised Cycle “5” to “7” for 
serum and plasma 
biomarkers and changed 
collections to every “other” 
cycle
• Clarified that tumor biopsy 
upon disease progression is 
recommended, but optional
To reduce participant and site 
burden and to add clarity
Protocol Amendment No.: 03
Date: 19-May-2022
207
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
• Clarified footnote “e” that if 
biopsy is not taken, then 
other samples are preferred 
but not required
9.8.11 Peripheral Blood 
Mononuclear Cells and Whole 
Blood Immunotyping
Added paragraph with detail on 
whole blood immunotyping
To clarify purpose of flow 
cytometry and provide examples 
of biomarkers interrogated
10.1 Sample Size Determination 
and related Subsections
Table 10.1-1 Summary of 
Sample Size Parameters and 
Schedule of Analyses
10.3.1 Efficacy Analyses
• Updated projection of 
analysis times based on 
updated enrollment 
projection 
• Added provisional language 
for combining ORR and PFS 
final analysis if they occur 
close enough in time
• Added additional information 
on PFS assumptions and 
provided the estimated 
median PFS by arm
• Added provisional language 
for conducting OS final 
analysis at 60 months after 
last participant randomized if 
the planned OS event number 
is not reached by then 
• Added additional sensitivity 
analyses for PFS and OS to 
account for potential non-
proportional hazards
• To provide update of analysis 
time projection 
• To streamline the ORR and 
PFS final analyses if they 
occur close enough in time
• To provide estimation of 
median PFS, and demonstrate 
that magnitude of treatment 
effect targeted for PFS is 
clinically meaningful
• To account for a slowdown 
in the OS events rate 
observed after 60 months in 
historical nivolumab data, 
which could prevent the final 
OS analysis from being 
performed in a reasonable 
time window 
• To help quantify treatment 
effect under potential non-
proportional hazards for PFS 
or OS
Table 10.3.4-1 Interim Analyses 
Schedule
• Clarified that the analysis 
trigger for the final ORR 
analysis is for “randomized” 
participants to have a 
minimum of 6 months 
follow-up
• Added footnote to clarify the 
final overall survival analysis 
will take place if the 419th 
overall survival event has not 
occurred 60 months after 
randomization of the last 
participant
Clarification
Protocol Amendment No.: 03
Date: 19-May-2022
208
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Protocol Amendment 02
Section Number & Title
Description of Change
Brief Rationale
APPENDIX 2 Study 
Governance Considerations
Updated first paragraph in 
Monitoring section to include 
remote monitoring; added new 
subsection on dissemination of 
study data
Clarified expectations
APPENDIX 3 Adverse Events 
and Serious Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow 
Up and Reporting 
Updated SAE contact 
information
To provide current contact 
information for the study
APPENDIX 6 Management 
Algorithms for Studies Under 
CTCAE Version 5.0
Updated the 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 for the 
Combination of 
Bempegaldesleukin with 
Checkpoint Inhibitors
Revised text
To clarify CVA and TIA 
algorithms and to align with 
Bempegaldesleukin IB v9.2
APPENDIX 10 Country 
Specific 
Requirements/Differences
• Revised title for greater 
clarity 
• Removed HIV requirement 
for France and Spain
• Added Germany specific 
changes from CA045001-
revprot00a-de and 
CA045001-revprot0000b-de 
that are not part of current 
global protocol
Added changes to facilitate use 
of CA045001 Protocol 
Amendment 02 as the global 
protocol
APPENDIX 11 Cytokine-
Release Syndrome (CRS) 
Management 
Measures/Algorithm
Added new appendix 
To align with 
Bempegaldesleukin IB v9.2 on 
the management of this potential 
risk
All
Minor formatting and 
typographical corrections
Minor, therefore have not been 
summarized
Protocol Amendment No.: 03
Date: 19-May-2022
209
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Overall Rationale for Revised Protocol 01, 24-Feb 2020
Program updates were added and internal inconsistencies were corrected. Updates as per Admin 
Letters 01 and 02 were also made.
Revisions apply 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
Throughout
In reference to dosing the term 
“adolescents” was changed to 
“participants”.
In the event that an adult has a weight 
of < 40 kg which will meet criteria for 
Nivolumab weight based dosing.
Title Page
The Protocol Number was corrected to 
CA045001/17-214-08.
As per Admin Letter 01
Synopsis, Inclusion 
Criteria
Added “neoadjuvant” treatment to criterion 
‘c’
Clarification was made to criterion ‘e(i)’ 
regarding tumor tissue sample.
Lesion criterion was added to inclusion 
criterion ‘f’
Clarification of treatments.
Test diagnostic provided.
Clarification of lesion criteria.
Synopsis, Exclusion 
Criteria
Text in criterion ‘a’ was updated to include 
that MRI of the brain is now required within 
28 days prior to randomization, and 
participants with CNS metastases treated by 
neurosurgical resection or brain biopsy 
performed within 28 days prior to 
randomization are not eligible.
Clarification to the timing.
Synopsis, Objective and 
Endpoints
Duration of complete response (DoCR) was 
removed.
To simplify the list of endpoints, given 
the presence of the endpoint “Duration 
of Response (DoR)”
Synopsis, Overall 
Design
Clarified evaluable vs enrolled participants 
in the PK and Biomarker subset.
Clarification of AJCC stages.
Format for stratification clarified to 
match IRT categories:
Protocol Amendment No.: 03
Date: 19-May-2022
210
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1.0
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
M0 / M1any[0] (Stage III any LDH or 
Stage IV Normal LDH) vs M1any[1] 
(Stage IV Elevated LDH).
Synopsis, Study 
Treatment
The international nonproprietary name 
(INN) was added to the table.
Potency was updated for 
bempegaldesleukin.
Compound name added.
To align with Program Essential 
Protocol Elements.
Table 2-1, Tumor 
Sample Submission
Lesion criteria was added.
Clarification of lesion criteria.
Table 2-1, Physical 
Exam and Vital Signs 
(new name for row)
Targeted Physical Exam changed to 
Physical Exam and under the ‘Notes’ 
section removed that heart rate, pulse 
oximetry, etc will be recorded at Baseline 
only.
To align with the Program Essential 
Protocol Elements and study 
procedure.
Table 2-1, Assessment 
of Signs and Symptoms
Row was deleted.
To align with the Program Essential 
Protocol Elements
Table 2-1, Prior and 
Concomitant Medication
“Prior and” was added to the line item.
To align with the Program Essential 
Protocol Elements
Table 2-1, 
Echocardiogram or 
MUGA procedure
Added language in notes section; 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.
To align with the Program Essential 
Protocol Elements
Table 2-1, CBC with 
differential, chemistry, 
endocrine, viral, urinalysis
CBC with differential, chemistry, endocrine, 
viral, urinalysis row now called “Clinical 
Laboratory Testing”
To align with Program Essential 
Protocol Elements
Tale 2-1, Pregnancy Test
The ‘Notes’ section, added that pregnancy 
test was done at Screening as well.
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-1, BRAF 
mutation testing
Added in note section: results from 
NRAS/CKIT mutation testing and prior gene 
expression profiles for risk stratification 
should be recorded if available.
Provide more clarifications/guidance 
on results collected in CRFs.
Table 2-1, Brain 
Imaging
Brain imaging is required within 28 days 
prior to randomization.
As per Admin Letter 02.
Table 2-2, Timepoints
Added timepoints of Day 3-5 in Cycle 1 and 
Cycle 2 and added Cycle 3 and beyond.
To align with Program Essential 
Protocol Elements
Protocol Amendment No.: 03
Date: 19-May-2022
211
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Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2, Administer 
Study Drug
Added an administration timepoint at Cycle 
3 and Beyond, Day 1 (± 3 days).
In ‘Notes’ added that study drug 
administration for nivolumab dose should be 
rounded to the nearest mg and for 
bempegaldesleukin to the second decimal 
digit.
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-2, Rows 
Administer Fluids and 
Review Hydration 
Guidelines with 
Participants
Added an administration timepoint at Cycle 
3 and Beyond, Day 1 (± 3 days).
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-2, Oral 
Hydration Follow-up
New row added with follow-up at Cycle 1 
Day 3-5 and Cycle 2 Day 3-5.
To align with Program Essential 
Protocol Elements
Table 2-2, Targeted 
Physical Examination, 
Measurements, Vital
Signs and Performance 
Status
Changed Cycle 1 Day 8 assessments to 
“Vital Signs only”
Clarified that vital signs should be 
monitored within 30 mins of completion of 
nivolumab administration
To align with the Program Essential 
Protocol Elements
Provide clarification/guidance on 
procedures to be followed.
Table 2-2, Concomitant 
Medication Use
Added a timepoint at Cycle 3 and Beyond, 
Day 1 (± 3 days). 
To align with the Program Essential 
Protocol Elements
Table 2-2, Pregnancy 
Test
Added a timepoint at Cycle 3 and Beyond, 
Day 1 (± 3 days).
Added that serum or urine pregnancy test is 
required within 24 hours prior to treatment in 
women of childbearing potential
To align with the Program Essential 
Protocol Elements
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-2, Clinical 
Laboratory Testing (new 
name for row)
In Clinical Laboratory Testing, added 
testing at Day 1 Cycle 2 and Day 1 Cycle 3 
and in ‘Notes’ added language “For the first 
dose visit, labs need not be repeated if they 
were performed within 72 hours and the 
results are available and have been 
reviewed for eligibility.”
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-2, Body Imaging
In Body Imaging it was clarified that tumor 
assessments will occur until BICR 
confirmed disease progression and 
treatment discontinuation.
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-2, Brain 
Imaging
Added that CT of the brain (without and 
with contrast) can be performed if MRI is 
contraindicated.
Provide more clarity.
Table 2-2, Tumor Biopsy
Added in notes section; If clinically 
feasible, the lesion for biopsy during Cycle 
1 would be the same lesion that was 
Provide more clarity of lesion criteria.
Protocol Amendment No.: 03
Date: 19-May-2022
212
Approved
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
biopsied at baseline. Note: If the participant 
has > 1 lesions, the lesion planned for 
biopsy while on treatment cannot be 
designated as a target lesion at baseline. 
Additional target lesions should be available 
for radiographic efficacy assessments. If the 
participant has only one lesion that is 
measurable and amenable to biopsy, the 
lesion must be greater than 2.0 cm and the 
biopsy cannot be excisional. Note: These 
same criteria apply for lesion selection 
applies to patients who consent to the 
optional biopsy in the main study. Please 
refer to Section 9.8.3 for additional 
information.
Table 2-3 overall
To Follow-up Visit 1 and Follow-up Visit 2 
added ± 7 days
To provide a window.
Table 2-3, Vital signs
In ‘Notes’ section provided the vital signs 
that will be recorded
To align with the Program Essential 
Protocol Elements
Table 2-3, Adverse 
Event Assessments 
(Including SAEs):
Updated notes section that SAEs to be 
collected after the 100-day safety visit if the 
SAE is deemed to be related or residual 
toxicities are persisting.
Provide clarity.
Table 2-3, Performance 
Status
Added an assessment at Follow-up Visit 2
To align with the Program Essential 
Protocol Elements
Table 2-3, Review of 
Concomitant Medications 
From ‘Notes’ removed “In Survival Follow-
up, subsequent cancer treatment only.”
To align with the Program Essential 
Protocol Elements 
Table 2-3, Subsequent 
Anti-Cancer Therapy
Added new row; Subsequent Anti-Cancer 
Therapy to be reviewed at Follow-up Visit 1, 
Follow-up Visit 2 and Survival Follow-up.
Added in the notes section; 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 to subsequent anti-cancer 
therapies will be collected.
To align with the Program Essential 
Protocol Elements
Protocol Amendment No.: 03
Date: 19-May-2022
213
Approved
4.0
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-3, Pregnancy 
Test
Added that serum or urine pregnancy test is 
required in women of childbearing potential
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-3, Clinical 
Laboratory Testing
Clinical laboratory testing at Visit 1 was 
done only if toxicities were present.
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-3, Body Imaging
In Body Imaging it was clarified that tumor 
assessments will occur until BICR 
confirmed disease progression and
treatment discontinuation.
Provide more clarifications/guidance 
on procedures to be followed.
Table 2-3, Brain Imaging
Added that CT of the brain (without and 
with contrast) can be performed if MRI is 
contraindicated.
Provide more clarity
Section 3.2.3, NKTR-
214 Mechanism of 
Action
INN was added and text was updated for 
NKTR-214 mechanism of action.
Compound named and data updates as 
per the Program.
Section 3.3.1, NKTR-
214 Safety Profile
Identified risks of NKTR-214 were added.
Data updates
Section 3.3.3, NKTR-
214 and Nivolumab 
Benefit and Risk 
Assessment 
The NKTR-214 and nivolumab benefit/risk 
assessment was updated.
Data updates
Section 4, Objectives 
and Endpoints
DoCR was removed from Table 4-1
To simplify the list of endpoints, given 
the presence of the endpoint “Duration 
of Response (DoR)”
Protocol Amendment No.: 03
Date: 19-May-2022
214
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.1, Overall 
Design
Study schematic was updated.
Format for stratification clarified to 
match IRT categories:
M0 / M1any[0] (Stage III any LDH or 
Stage IV Normal LDH) vs M1any[1] 
(Stage IV Elevated LDH)
Section 5.1.4, Data 
Monitoring Committee 
and Other External 
Committees
Standard text for when a study will have a 
DMC was added.
Template language added.
Section 5.3, End of 
Study Definition
It was clarified that the total duration of the 
study for the OS primary endpoint was 
expected to occur approximately “68” 
months after the date of the first participant 
to be randomized
Clarification of the estimated OS final 
analysis time.
Section 5.4.6, Rationale 
for Stratification by M 
Staging, BRAF, and PD-
L1 
M stage stratification was clarified.
Clarification made.
Section 5.4.7, Duration 
of Treatment with 
Nivolumab/NKTR-214
Wording modification in the last paragraph 
for the duration of NKTR-214 therapy.
Clarification of text.
Section 5.5.1, 
Justification for Dose of 
NKTR-214
NKTR-214 dose based on IL-2 equivalent 
component was removed.
To reflect the Nektar Program 
Essential Protocol Elements
Section 6.1, Inclusion 
Criteria
A ‘Note’ on mucosal melanoma 
stratifications was added to criterion ‘2b’
Clarification was made to criterion ‘2c’ to 
add neoadjuvant
Clarification was made to criterion ‘2e(i)’ 
regarding tumor tissue sample.
Additional text was included in the Note in 
criterion ‘2f’ to state that “If the participant 
has only 1 lesion that is measurable and 
amenable to biopsy, the lesion must be 
greater than 2.0 cm and the biopsy cannot 
be excisional”.
Provide clarifications/guidance and 
program updates.
Protocol Amendment No.: 03
Date: 19-May-2022
215
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
In criterion ‘2j’, MUGA was NOT required 
to be performed within 60 days prior to 
randomization.
Criterion ‘3a(i)’, ‘3d’ and ‘3e’ were 
updated.
Section 6.2, Exclusion 
Criteria
Criterion ‘1a’ was updated to reflect that 
there should be no MRI evidence of 
progression within 28 days prior to 
randomization and participants with CNS 
metastases treated or brain biopsy 
performed within 28 days prior to 
randomization were not eligible.
In criterion ‘1f’, a Note was added 
“Prophylaxis of contrast allergies with a 
brief course of corticosteroids is 
acceptable.”
Criterion ‘1j(i)(4)’ was updated to remove 
arrhythmias requiring medication for rate 
control. 
Criteria ‘1l’ and ‘1m’ were added as per 
program updates.
In criterion ‘2d’, added “agents that target 
IL-2” and “neoadjuvant”.
In criterion ‘5a’, added regarding prisoners 
who were incarcerated, that it was only in 
countries where local regulations permit.
As per Admin Letter 02.
Provide clarifications/guidance and 
program updates.
Section 6.3, Lifestyle 
Restrictions
Added that there were limitations on 
strenuous activities, long hot showers.
Program updates.
Section 7, Treatment
The international nonproprietary name 
(INN) was added and updates were made to 
the ‘Potency’ and ‘Storage Conditions’ for 
NKTR-214 in Table 7-1.
Abbreviation definitions and a clarification 
‘Note’ added below the table.
Compound named and updates made 
to the drug information.
Section 7.1, Treatments 
Administered
The international nonproprietary name 
(INN) and abbreviations were added to 
Table 7.1-1.
Compound named.
Section 7.1.1, NKTR-
214 Dosing
Updates were made to the section based on 
program updates.
Program updates.
Section 7.1.1.1, 
Hydration Guidelines
Updates were made to the section based on 
program updates.
Program updates.
Section 7.1.2, 
Nivolumab Dosing
This section was updated based on program 
updates.
Program updates.
Protocol Amendment No.: 03
Date: 19-May-2022
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.2, Method of 
Treatment Assignment
M stage stratification was updated and a 
‘Note’ was added on mucosal melanoma 
stratifications.
Clarification was made.
Section 7.3, Blinding
Standard template language was added for 
this open label study.
Template language updates.
Section 7.4, Dosage 
Modification
Standard language as per NKTR Program 
Essential Protocol Elements was added
Program updates.
Section 7.4.1, 
Nivolumab and NKTR-
214 Dose Delay and 
Reduction Criteria
Language adapted to match NKTR Program 
Essential Protocol Elements
Program updates.
Section 7.4.1.1, Dose 
Modification Criteria for 
NKTR-214 and 
Nivolumab for Cycle 1 
ALT/AST Elevations
New section added.
Program updates.
Section 7.4.2, 
Monitoring and 
Management of Elevated 
Hepatic Transaminases
New section added as per program 
requirement. As a result, consequent section 
numbering is changed.
Based on Clinical data from PIVOT 
02
Section 7.4.3, 
Monitoring and 
Management of NKTR-
214-induced 
Eosinophilic Disorder
New section added as per program 
requirement.
Program updates.
Section 7.4.4, 
Monitoring and 
Management of Adrenal 
Insufficiency and 
Hypophysitis
New section added as per program 
requirement.
Program updates.
Section 7.4.5, 
Management Algorithms 
for Immuno-Oncology 
Agents
“Myocarditis” was added to the list of 
management algorithms.
Program updates.
Section 7.4.6, Treatment 
of NKTR-214-Related or 
Nivolumab-Related 
Infusion Reactions
Text regarding reporting Grade 3 and 4 
infusion reactions has been removed. 
Bullet point with text regarding Grade ≥ 2 
infusion-related reactions or hypotension 
was removed.
Program updates.
Protocol Amendment No.: 03
Date: 19-May-2022
217
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1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 7.5.1, Retained 
Samples for 
Bioavailability / 
Bioequivalence / 
Biocomparability
Added “Biocomparability” to section 
heading.
Additional information to align with 
model document template.
Section 7.6, Treatment 
Compliance
Language was updated about the monitoring 
of treatment compliance.
Language was added regarding oral 
hydration follow-up.
Program updates.
Section 7.7.1, Prohibited 
and/or Restricted 
Treatments
Added a bullet point that “Low dose 
acetylsalicylic acid (approx 81 mg/day) 
should not be combined with low molecular 
weight heparins (LMWH) or direct oral 
anticoagulants (DOAC) due to an increased 
risk of hemorrhage
Program updates.
Section 7.7.4.1, 
Restricted Treatments
Added language for participants with a 
history of a venous or arterial 
thromboembolic event.
Program updates
Section 7.7.4.3, Blood 
Pressure Precautions
Section name modified and language was 
updated based on program updates
Program updates.
Section 7.7.5, Permitted 
Therapy
Stated that prophylaxis for flu-like 
symptoms and rash/pruritis “should” be 
initiated on Day 1 or Day 2 after NKTR-
214 dosing.
Changed guidance.
Section 8.1, 
Discontinuation from 
Study Treatment
To bullet #4 added language that “only in 
countries where local regulations permit”, a 
participant who has been imprisoned may 
be permitted to continue as a participant.
Text was updated to state that in all cases of 
pregnancy the study treatment will be 
permanently discontinued and the updated 
Pregnancy section (Section 9.2.6) was 
referred to.
Program update.
Protocol Amendment No.: 03
Date: 19-May-2022
218
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v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 8.1.1, 
Nivolumab and NKTR-
214 Discontinuation 
Criteria
Added “except adrenal insufficiency” to the 
drug-related endocrinopathy bullets.
Added a ‘Note’ for Grade ≥ 3 adrenal 
insufficiency or Grade ≥ 4 hypophysitis.
Added language for CVA and transient 
ischemic attack (TIA).
Added “elevation” to the bullet point 
regarding Grade 4 lymphopenia or 
leukopenia or asymptomatic amylase or 
lipase
Added that for “cytokine related ALT/AST 
elevations < 8 x ULN in Cycle 1 only, study 
treatment does not need to be discontinued”.
Program updates.
Based on Clinical data from PIVOT-
02.
Section 8.1.2, Criteria to 
Resume NKTR-214 
and/or Nivolumab
Removed language in the beginning of this 
section.
Added an exception for participants who 
delay study treatment due to Grade ≥ 2 
creatinine increase due to a non-
inflammatory cause.
Added grade 4 hypophysitis and the 
sentence “Hospitalization for diagnostic 
workup of adrenal insufficiency without 
severe symptoms should not require 
discontinuation” to the bullet for drug-
related endocrinopathies.
Redundant guidance covered in other 
sections.
Program updates.
Program updates.
Section 8.1.3, Treatment 
Beyond Progression
Added a statement that activities for the 
duration of the treatment beyond 
progression should be submitted to the 
central imaging vendor.
Additional guidance added.
Section 8.1.4, Post Study 
Treatment Study Follow-
up
Added text for subsequent cancer therapy 
details that will be collected.
Additional guidance added.
Section 9.1.1, Imaging 
Assessments for the 
Study
Added bone scans in addition to X-rays.
Additional guidance added.
Section 9.1.1.2, Imaging 
and Clinical Assessment
Clarified that the BOR of stable disease 
requires a minimum of 42 days.
Changed from 35 to 42 days.
Protocol Amendment No.: 03
Date: 19-May-2022
219
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v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.2.1, Time 
Period and Frequency 
for Collecting AE and 
SAE Information
Added a bullet that CVA (any grade) is 
considered an adverse event of special 
interest.
Updates to the Nektar program.
Section 9.2.5, Pregnancy
Section was updated as per standard 
language.
Program updates.
Section 9.2.7, Adverse 
Events of Special 
Interest (AESI/AEOSI)
New section added.
Program updates.
Section 9.2.9, Potential 
Drug Induced Liver 
Injury
Definitions of DILI were updated as per 
standard program language.
Program updates.
Section 9.3, Overdose
Added a sentence that all instances of 
accidental overdose and/or dosing errors 
should be reported on the Dosage 
Administration Record eCRF.
Template language updates.
Section 9.4.3, 
Echocardiogram
It was clarified that abnormalities on 
echocardiogram should be discussed with 
medical monitor prior to randomization.
Additional guidance.
Section 9.4.4, Pregnancy 
Tests
It was clarified that a serum or urine 
pregnancy test could be done and a negative 
pregnancy test result must be obtained 
within 24 hours prior to the administration 
of the study drug.
Correct section number (Section 9.2.6) was 
referred to for guidelines to be followed in 
case of pregnancy.
Program updates.
Section 9.4.5, Clinical 
Safety Laboratory 
Assessments, Table 
9.4.5-1
Added “Creatinine clearance (at Screening 
only)” to ‘Chemistry’.
Added “Urine or serum” for pregnancy test.
Added the statement “Urine dipstick can be
done and if abnormal perform 
microanalysis” to ‘Urinalysis’.
Additional guidance for lab collection.
Protocol Amendment No.: 03
Date: 19-May-2022
220
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.6, 
Pharmacodynamics
Added a sentence that selected biomarkers 
may be explored with the data permitted.
Added new information about testing.
Section 9.8, Biomarkers
Removed language that “samples may be 
used to expand the translational R&D 
capability at BMS.”
Other minor updates to the text for clarity.
Adding clarification.
Section 9.8.2, Biomarker 
Sampling Schedule
In Tables 
 9.8.2-2 updates and 
sampling changes were made and the 
footnotes were updated.
Provide additional guidance and 
clarity.
Section 9.8.3, Tumor 
Tissue Specimens
Removed the requirement of a “fresh” 
tumor biopsy sample to be provided at 
Screening.
Added language that “Biopsies of bone 
lesions that do not have a soft tissue 
component are also unacceptable for 
submission”
Lesion criteria were added.
It was recommended that on occurrence of a 
Grade 3 drug-related AE that resulted in 
dose delay, if a biopsy of the affected organ 
was performed, a specimen for biomarker 
analysis also be collected.
A new biopsy is not required.
Provide additional guidance and 
clarity.
Section 9.8.4, Tumor 
Gene Expression and 
Mutation Analyses
Section heading modified.
Added language to explore the potential 
association of tumor mutation burden with 
clinical outcomes.
Added new information about testing.
Section 9.8.7, 
Exploratory Serum and 
Plasma Biomarkers
Added text for additional factors for which 
serum and plasma may be assessed.
Added new information about testing.
Protocol Amendment No.: 03
Date: 19-May-2022
221
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.8.8, Plasma 
cfDNA/ctDNA
New section added.
Added new information about testing.
Section 9.8.9, Serum 
MicroRNA (miRNA)
New section added.
Added new information about testing.
Section 10.1, Sample 
Size Determination
Approach used to test ORR, PFS, and OS 
was added.
Table 10.1-1 (Summary of Sample Size 
Parameters and Schedule of Analyses) was 
added.
Updated projection of analysis times based 
on updated enrollment projection.
Provide additional guidance and 
clarity on the fallback testing strategy 
of primary endpoints and schedule of 
analyses.
Provide update of analysis time 
projections
Section 10.1.1, Sample 
Size Justification for 
ORR Estimate
New section heading added.
Updates to text for clarification.
To provide more clarity.
Section 10.1.2, Sample 
Size Justification for 
PFS Comparison
Minor clarifications were made to the text.
Provide editorial clarification.
Section 10.1.3, Sample 
Size Justification for OS 
Comparison
Section was reworded to include changes in
sample size justification for OS comparison
Provide additional guidance and 
clarity of the fallback testing 
procedure on OS. In addition, 
 
 
 a formal OS interim 
analysis is added at the time of final 
PFS analysis.
Section 10.2, 
Populations for Analyses
Table in this section was updated.
Provide additional guidance and 
clarification on populations for 
analyses.
Section 10.3.1, Efficacy 
Analyses
Table in this section was updated:
•
95% confidence interval was corrected 
to 97% CI for primary endpoint of PFS
•
Mention of DoCR was removed from 
secondary endpoints
Language that participants who do not have 
sufficient baseline or on-study tumor 
assessments to evaluate response status will 
be counted as failures and ORR by 
Investigator assessment, was removed
Provide editorial clarification. DoCR 
was removed to simplify the list of 
endpoints, given the presence of the 
endpoint “Duration of Response 
(DoR)”.
To provide clarifications of ORR and 
to consolidate ORR secondary 
analyses by Investigator-assessed 
ORR to the secondary endpoint 
section.
Protocol Amendment No.: 03
Date: 19-May-2022
222
Approved
4.0
v
Approved
1.0
v

Clinical Protocol
CA045001/17-214-08
NKTR-214 / BMS-986321 
Bempegaldesleukin (NKTR-214) and Nivolumab
Summary of Key Changes for Revised Protocol 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.3.4, Interim 
Analyses
Section was updated to include the interim 
analyses for this study. Table 10.3.4-1 
(Interim Analyses Schedule) was also 
added.
Provide clarity on schedules of 
analyses.
Appendix 1
Abbreviation list was updated
Abbreviations no longer used were 
deleted and new abbreviations used 
were added.
Appendix 2
Appendix was modified to include the latest 
updates
Template language updates.
Appendix 3
Appendix was modified to include the latest 
updates
Template language updates.
Appendix 4
Appendix was modified to include latest 
updates
Template language updates.
Appendix 6
Appendix was modified to include the latest 
updates
Template language updates.
Appendix 7
New appendix with Cerebrovascular 
Accident Adverse Event Management 
Algorithm was added. As a result following 
appendices were renumbered.
Program updates.
Appendix 8
Mucosal Melanoma of the Head and Neck 
TNM definitions were added to the 
appendix.
Information added as per AJCC 7th 
Edition.
Appendix 10
Italy was removed from the countries’ list.
Ireland-specific amendment was added.
Not applicable for Italy.
Hypertension Precautions were 
modified to reinforce blood pressure 
medication guidance for Ireland sites.
Protocol Amendment No.: 03
Date: 19-May-2022
223
Approved
4.0
v
Approved
1.0
v