Phase 1/2 Study of Bempegaldesleukin in Combination With Nivolumab in Children, Adolescents, and Young Adults With Recurrent or Refractory Malignancies (PIVOT IO 020)
Phase: PHASE1
Conditions: Ependymoma, Ewing Sarcoma, High-grade Glioma, Leukemia and Lymphoma, Medulloblastoma, Miscellaneous Brain Tumors, Miscellaneous Solid Tumors, Neuroblastoma, Relapsed, Refractory Malignant Neoplasms, Rhabdomyosarcoma
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
Phase 1/2 Study of Bempegaldesleukin in Combination with Nivolumab in Children, 
Adolescents, and Young Adults with Recurrent or Refractory Malignancies (PIVOT IO 020) 
 
PROTOCOL CA045-020 
 
NCT Number: NCT04730349 
  
Document Date (Date in which document was last revised): November 28, 2021 

Page:
1
Protocol Number:
CA045020/19-214-27
Date:
08-Oct-2020
Revised Date:
28-Nov-2021
REGULATORY AGENCY IDENTIFIER NUMBER(S)
IND: 139,237
EudraCT: 2020-000854-85
CLINICAL PROTOCOL CA045020/19-214-27
Phase 1/2 Study of Bempegaldesleukin in Combination with Nivolumab in Children, 
Adolescents, and Young Adults with Recurrent or Refractory Malignancies (PIVOT IO 020)
Short Title:
Bempegaldesleukin + Nivo in Pediatric Malignancies
Protocol Amendment 01
Clinical Trial Physician-Medical Monitor
Clinical Scientist
Bristol-Myers Squibb Company
Bristol-Myers Squibb Company
Phone
Email: 
Phone 
Email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
6-5-1 Nishi-Shinjuku, Shinjuku-ku,
Tokyo, 163-1327, Japan
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
Aproved
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
Protocol Amendment No.: 01
Date: 28-Nov-2021
2
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).
© 2020 Bristol-Myers Squibb Company
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
Protocol Amendment No.: 01
Date: 28-Nov-2021
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol Amendment 
01
28-Nov-2021

Updated flat dosing schema in Part A to include 
weight-based cohorts (A2F-W and A3F-W).  

Modifications made to align with bempegaldesleukin 
and nivolumab Investigator’s Brochure updates.

Added electrocardiogram assessments.

Added Safety Follow-up Visit 3.

Updated Phase 1 flat dosing de-escalation to 
age/weight.

Added stopping rules for Part B Expansion

Added suspension criteria for toxicity during Part B 
Expansion. 

Updated study treatment dose delay, resumption and 
discontinuation, and adverse events management for 
National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5. Added 
permanent discontinuation criteria for 
bempegaldesleukin treatment related to 
cerebrovascular accident (CVA) and transient eschemic 
attack (TIA). Updated CVA management algorithm 
(Appendix 6).

Updated guidance for severe acute respiratory 
syndrome coronavirus 2 status and coronavirus disease 
2019 vaccine.

Added country specific requirements (Appendix 13)

Added cytokine-release syndrome information and 
management/algorithm (Appendix 14).
Original Protocol
08-Oct-2020
Not applicable
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01:
This is a protocol amendment to modify the flat dosing schema in Part A. In Part A, the flat dosing 
group will now include cohorts (A2F-W and A3F-W) of weight-based dosing of nivolumab 
4.5 mg/kg in combination with both bempegaldesleukin 0.006 mg/kg and 0.003 mg/kg, in the 
event dose-limiting toxicities are observed in the A1F-W cohort of nivolumab 360 mg in 
combination with bempegaldesleukin 0.006 mg/kg. Stopping rules for Part B Expansion have also 
been added. Additional revisions have been made to align with nivolumab and bempegaldesleukin 
Investigator’s Brochure (IB) and overall program standards including safety assessments and 
safety management algorithms. France and Germany country-specific requirements have also been 
added. 
This protocol amendment also includes global changes to reduce redundancies, provide 
clarifications, and increase readability. The protocol synopsis has been updated accordingly.
Revisions are applicable to future participants enrolled in the study and, where applicable, to all 
participants currently enrolled.  
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Updated title to “Clinical Trial Physician-
Medical Monitor” and added Clinical 
Scientist title and contact information.
To align with updates to study 
contacts and roles.
Table 2-1: Screening 
Procedural Outline 
(CA045020)
Section 5.1.1: Screening 
Period 
Revised tumor assessment 
:

Moved Cerebrospinal Fluid (CSF) -
Solid Tumors, Bone Marrow - Solid 
Tumors, CSF - Leukemia, Bone Marrow
- Solid Tumors, CSF - Leukemia, and 
Bone Marrow - Leukemia
 
to Tumor 
Assessment row.
To provide clarification.
Protocol Amendment No.: 01
Date: 28-Nov-2021
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CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-2: On-treatment 
Procedural Outline 
(CA045020)
Section: 9.4.3 
Electrocardiograms
Safety Assessments:
Added 12-Lead Electrocardiogram (ECG) 
assessment with the following visits:

Pre-dose Day 1 of all cycles.

Pre-PK blood draw on Cycle 1, Days 3, 
5, and 8. 

Pre-PK blood draw on Cycle 5, Days 3 
and 5.
Efficacy Assessments 

Added PET-MRI for body imaging 
Health Outcomes  

Added clarification regarding time and 
format (electronic) of Patient-reported 
Outcomes (PRO) assessment form. 
To ensure participant safety and 
to provide clarification.
Table 2-3: Long-term 
Follow-up Period
(CA045020)
Section 5.1.4: Long-term 
Follow-up
Section 9.4.3: 
Electrocardiograms 
Added Safety Follow-up Visit 3, which will 
occur approximately 150 days from the last 
dose of study treatment.  
Added row for 12-lead ECG for Safety 
Follow-up Visit 1.
Added PET MRI to body imaging in 
Efficacy Assessment. 
Deleted Health Outcomes Section. 
Added text to footnote “a” for Visit 3 follow-
up visit 3 too occur approximately 150 days 
(± 7 days) from last dose of study drug.
To ensure participant safety and 
to increase participant 
convenience.
Section 2: Schedule of 
Activities 
Added or modified text to address and clarify 
severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) infection and 
vaccination during study participation. 
Participant safety management 
due to COVID-19.
Protocol Amendment No.: 01
Date: 28-Nov-2021
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CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.3.3: 
Bempegaldesleukin and 
Nivolumab Benefit and Risk 
Assessment
Section 5.1.2: Treatment 
Period 
Section 6.2: Exclusion 
Criteria (5d)
Section 7.4.1: Nivolumab 
and Bempegaldesleukin
Dose Delay, Resumption,
and Discontinuation Criteria 
Section: 7.7.3.1: COVID-19 
Vaccination 
Guidance added for COVD-19 infection 
during study for benefit risk and non-live 
COVID-19 vaccines.
Guidance added for investigational COVID-
19 vaccines.
Exclusion criterion 5) d) revised to previous 
SARS-CoV-2 infection, suspected or 
confirmed, within 4 weeks prior to first dose 
of study drug.
Guidance for study drug administration 
during SARS-CoV-2 infection either 
suspected or confirmed.
Guidance for COVID-19 vaccination during 
study participation.
Section 3.2.2: 
Bempegaldesleukin 
Mechanism of Action 
Updated references. 
Updated references to reflect final 
publications. 
Section 3.2.5.1:
Study 15-214-01 (EXCEL; 
Bempegaldesleukin 
Monotherapy)
Updated text with recent participant clinical 
experience data and references. 
To align with most recent 
language for bempegaldesleukin 
program updates and with 
Bempegaldesleukin IB v9. 
Section 3.2.5.2: Study 16-
214-02 (PIVOT-02; 
Bempegaldesleukin and 
Nivolumab Combination 
Therapy)
Updated with recent participant clinical 
experience data. 
To align with most recent 
language for bempegaldesleukin 
program updates and with 
Bempegaldesleukin IB v9
Section 3.2.5.3:
Pooled Safety Analysis of 
Participants with 
Bempegaldesleukin and 
Nivolumab Exposure 
Newly added section of pooled safety 
analysis of participants who received 
bempegaldesleukin and nivolumab. 
To align with most recent 
language for bempegaldesleukin 
program updates and with 
Bempegaldesleukin IB v9. 
Section 3.2.5.4:
Observed Events of 
Cerebrovascular Accident
Section 3.2.5.4.2: Updated 
Analysis of Cerebrovascular 
Accident Events Observed 
with Bempegaldesleukin
Modified into subsections and updated 
analysis of cardiovascular accident (CVA)
events.  
To align with most recent 
language for bempegaldesleukin 
program updates and with 
Bempegaldesleukin IB v9.
Protocol Amendment No.: 01
Date: 28-Nov-2021
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.3.1: 
Bempegaldesleukin Safety 
Profile
Updated bempegaldesleukin safety profile.
Updated to align with 
Bempegaldesleukin IB v9.
Section 3.3.3:
Bempegaldesleukin and 
Nivolumab Benefit and Risk 
Assessment 
Modified text associated with immune-
mediated AE’s. 
To align with most recent 
language for bempegaldesleukin 
program updates.
Table 4-1: Objectives and 
Endpoints 
Secondary-Part B Expansion
Expanded endpoint to include incidence of 
toxicity. 
To support incorporation of 
stopping criteria rules. 
Section 5: Study Design
Section 5.1: Overall Design
Figure 5.1-2
Section 5.1.2: Treatment 
Period 
Section 5.2: Number of 
Participants
Section 7.1 Treatments 
Administered
Modified flat dosing schema in Part A, 
which will now include cohorts (A2F-W and 
A3F-W) of nivolumab weight-based dosing 
4.5 mg/kg in combination with 
bempegaldesleukin (0.006 mg/kg and 0.003 
mg/kg). 
Modified to allow for the 
assessment of appropriate dosing 
combination in those ≥ 12 years 
and weighing ≥ 40 kg if safety 
findings are observed using flat 
nivolumab dosing.
Section 5.1.3: Dose-limiting 
Toxicities 
Section 9.2: Adverse Events
Section 5.1.3.3 Hematologic 
Dose-limiting Toxicity
Section 5.1.3.4: 
Dermatologic Dose-limiting 
Toxicity
Section 5.1.3.5: Other Dose-
limiting Toxicities
Removed text pertaining to the management 
algorithms for nivolumab and 
bempegaldesleukin using CTCAE v4 
definitions of AE grading. 
Added clarification that  “study drug-related”
events will be considered a dose-limiting 
toxicity (DLT).
To align with nivolumab IB v19 
addendum 01.
To provide clarity and alignment 
on the definition of DLT.
Section 5.1.3.6:
Stopping Rules for Part B 
Added stopping rules for Part B Expansion 
and Tables 5.1.3.6-1 (Suspension Criteria for 
Toxicity) and 5.1.3.6-2 (Suspension 
Probabilities for Toxicity). 
To ensure participant safety.
Section 5.2: Number of 
Participants 
Updated the total sample size number of 
participants from “between approximately 8 
To align with updated study 
design.
Protocol Amendment No.: 01
Date: 28-Nov-2021
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
and 228” to “between approximately 10 and 
234”. 
Section 5.1.5: Data 
Monitoring Committee and 
Other External Committees
Section 10.3.4: Interim 
Analyses
Removed reference to Study Steering 
Committee(SSC).
Removed for clarification.
Section 5.5.2: Justification 
for Dose of Nivolumab
Flat dosing cohort in Part A has been 
modified to allow for changing to weight-
based dosing with nivolumab.
To support the assessment of 
appropriate dosing combination in 
those ≥ 12 years and weighing ≥ 
40 kg if safety findings are 
observed using flat nivolumab 
dosing.
Section 6.1:
Inclusion Criteria 
Added text to clarify the following criteria: 
2) f) “prior to first dose of study drug”. 
2) g) clarified for participants with CNS 
tumors dexamethasone doses should be 
stable for a minimum of a week. 
2) i) “all Grade 2 or higher” for clinically 
relevant radiation-related toxicities. 
Information was rearranged within section. 
Modified:
3) a) i) and 3) b) i) “less than 30 years old”. 
Updated male contraception requirements 
from 7 months to 3 months: 
No longer applicable: 3) b) iii), iv), v), and 
vi)
Added 3) b) viii), ix), x), and xi)
To provide clarification and to 
update contraception 
requirements for 
bempegaldesleukin. 
Section 6.2:
Exclusion Criteria 
Added:

1) d) protocol-specific text for stable anti-
hypertensive 
regimen 
and 
clarified 
antihypertensive medications with 2 
drugs. 

1) 
e) 
clarified 
the 
cardiovascular 
exclusion

1) i) excluding CNS tumors 

2) a) clarified on replication incompetent 
virus vaccines

3) b) No longer applicable as per this 
amendment. 
To provide clarification.
Protocol Amendment No.: 01
Date: 28-Nov-2021
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale

3) 
i) 
“Neutrophils 
< 
1000/uL 
(participants with leukemia or bone 
marrow infiltration are exempt)”. 
Table 7-1 Treatments 
Administered
Modified table 7.1-1 to include 
bempegaldesleukin.
To align with most recent 
language for bempegaldesleukin 
program updates and.
bempegaldesleukin IB v9.
Section 7.1.1:
Bempegaldesleukin Dosing 
Section 7.6: Treatment
Compliance
Added text regarding hydration guidelines.
Added “at least once” to the frequency that 
site personnel must contact the participant to 
remind them of hydration guidelines.
To provide clarification.
Section 7.1.2: 
Nivolumab Dosing 
Added text on weight-based dosing 
calculation. 
To align with most recent 
language for nivolumab program 
updates and nivolumab IB v19.
Section 7.4: Dosage 
Modification and related 
subsections
Section 7.4.1: Nivolumab 
and Bempegaldesleukin 
Dose Delay, Resumption,
and Discontinuation Criteria 
Table 7.4.1-1: Adverse 
Event Criteria for Delay, 
Resumption and 
Discontinuation of 
Nivolumab and 
Bempegaldesleukin (if one 
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)
Updated study treatment dose delay, resume, 
and discontinuation criteria to align with the 
current CTCAE version (v5). 
Added Table 7.4.1-1 and Table 7.4.1-2 for 
nivolumab and bempegaldesleukin AE 
criteria and subsequent delay, resume, and 
discontinuation.
To align with nivolumab IB v19 
addendum 01.
Section 7.4.3: Monitoring 
and Management of 
Eosinophilia 
Modified the heading and added subsections:

7.4.3.1
Bempegaldesleukin-induced 
Eosinophilia 

7.4.3.2 Eosinophilic Disorders 
To align with most recent 
language for bempegaldesleukin 
program updates and with 
Bempegaldesleukin IBv9.
Section 7.4.5: Management 
Algorithms for Immune-
mediated Adverse Events 
and Cytokine-release 
Syndrome
Section and heading title changed  previously
was: Management Algorithms for Immuno-
Oncology Agents (moved to section 7.4.1) 
To align with most recent 
language for bempegaldesleukin 
program updates and with 
Bempegaldesleukin IBv9.
Protocol Amendment No.: 01
Date: 28-Nov-2021
9
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale

Updated Subsection 7.4.5.1 Management 
Algorithms 
for 
Immune-Mediated 
Adverse 
Events 
Associated 
with 
Immuno-Oncology Agents

Added 
new 
subsection 
7.4.5.2 
Management Algorithm for Cytokine-
Release Syndrome.
Section 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 subsequent infusions may be 
administered at a reduced rate.
To provide guidance and to align 
with most recent language for 
bempegaldesleukin program 
updates and with 
Bempegaldesleukin IBv9.
Section 7.7.1: Prohibited 
and/or Restricted 
Treatments 
Updated the number of days to “150” post 
last dose for any live/attenuated vaccine 
during treatment. 
To ensure participant safety.
Section 7.7.3.2: Effect of 
Bempegaldesleukin on 
Pharmacokinetics of 
Concomitant Medications
Added text about decreased tolerability to 
concomitant medication and to reduce the 
dosage during each cycle of 
bempegaldesleukin. 
To clarify effect of 
bempegaldesleukin on PK of 
concomitant medications and to 
ensure participant safety.
Section 7.7.4.1: Restricted 
Treatments
Added anticoagulation guidance.
To align with most recent 
language for bempegaldesleukin 
program updates.
Section 7.7.4.4: Volume of 
Blood
Newly added section referring to pediatric 
guidelines manual to meet maximum daily 
and monthly blood draw limits. 
To ensure participant safety.
Section 8.1.1: Nivolumab 
and Bempegaldesleukin 
Discontinuation Criteria
Section 8.1.2: Treatment 
Beyond Progression
Discontinuation From Study 
Treatment 

Removed redundant criteria now listed in 
Table 7.4.1-1. 

Added 
discontinuation 
beyond 
progression should be balanced by 
clinical judgment.  
Revised to align with Nivolumab 
IB 19 Addendum 01 and 
Bempegaldesleukin IB 9. Also to 
provide flexibility for 
discontinuing treatment.
Section 9.1.2.3: Non-
Hodgkin Lymphoma 
Added PET-MRI
To provide clarification and 
flexibility for imaging modality.
Section 9.1.2.5: Leukemia
Clarified instructions for samples of CSF and 
bone marrow aspirate with buccal swab 
where feasible will be provided in  separate 
laboratory manual. Added: “Response 
assessment will be assessed using Modified 
NCCN Criteria for acute lymphoblastic 
leukemia or Modified Cheson et al 
International Working Group criteria for 
acute myeloid leukemia (see Appendix 12)”
For clarification.
Protocol Amendment No.: 01
Date: 28-Nov-2021
10
Aproved
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v

Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.1.4: Patient-
reported Outcomes

Added that a Caregiver for a child < 7 
years, or older participants with a 
cognitive impairment will complete the 
Patient Reported Outcomes (PRO). 

Added the age-related version of the 
PRO-CTCAE completed at the start of 
the trial should be used throughout the 
treatment period. 

Added alternate administration methods 
may be required if there are exceptional 
circumstances. 
To increase participant and site 
convenience.
Section 9.2.1: Time Period 
and Frequency for 
Collecting AE and SAE 
Information 
Updated the minimum days from “100” to 
“150” days following discontinuation of drug 
for collection of all SAEs and non-serious 
AEs, including confirmed or suspected 
SARS-CoV-2 infection. 
To ensure participant safety.
Section 9.2.6: Immune-
mediated Adverse Events 
Clarified additional information may also be 
collected on Immune-mediated adverse 
events (IMAEs).
To provide clarification.
Section 9.2.7: Additional 
Information Collected for 
Adverse Events Primarily 
Related to 
Bempegaldesleukin
New section created, which includes 
cytokine-release syndrome. 
To align with most recent 
language for bempegaldesleukin 
program updates and 
Bempegaldesleukin IB 9.
Section 9.5.1: 
Pharmacokinetics and 
Immunogenicity 
Assessments 
Table 9.5.1-1: 
Pharmacokinetic and 
Immunogenicity Sampling-
Bempegaldesleukin 
Combined with Nivolumab 
(Parts A and B)

Added draw blood samples from a site 
other than the infusion sites on days of 
infusion. 

Updated immunogenicity sample and 
testing information. 

Added Parts A and B to the table header. 

Added “Part A and B” to the table title 
and updated table with times to collect 
samples throughout the study. 

Added table footnote “c” predose 
samples should be collected within 24 
hours before dose infusion.

Updated table footnote “f” to provide 
instruction for doses administered on 
Friday.

Clarified table footnote “h” that Day 8 
samples can be collected on Day 7. 
To provide clarification on PK 
and immunogenicity sampling.
Protocol Amendment No.: 01
Date: 28-Nov-2021
11
Aproved
2.0
v
Approved
1.0
v

Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Protocol Amendment No.: 01
Date: 28-Nov-2021
12
Aproved
2.0
v
Approved
1.0
v

Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 1:
Abbreviations and 
Trademarks
Updated abbreviations 
Abbreviations were updated for 
clarity and completeness. 
Appendix 2:
Study Governance 
Considerations
Updated first paragraph in
Monitoring section to include remote
monitoring; added new subsection on 
dissemination of study data. 
To clarify expectations for 
monitoring and provide details on 
how clinical study information 
will be made available.
Appendix 5: 
Management Algorithms for 
Studies Under CTCAE 
Version 5.0
Updated management algorithms.
Revised to align with current  
safety management algorithms 
per CTCAE v5.0.
Appendix 6:
Cerebrovascular Accident 
Adverse Event Management 
Algorithm for the 
Combination of 
Bempegaldesleukin with 
Checkpoint Inhibitors 
Appendix was modified to include the latest 
updates.
To clarify CVA and TIA 
algorithms and to align with 
Bempegaldesleukin IB addendum 
v9.2.
Appendix 13:
Country Specific 
Amendments
Updated countries with exclusion of HIV 
positive participants and amended text. 
Added country specific 
requirements/differences for France and 
Germany.
France:

Treatment discontinuation for Grade 4 
hyper and hypothyroidism.

Maximum blood volume specifications 
Germany: 

“All SAEs will be recorded and reported 
to Sponsor or designee immediately, 
without undue delay.”
Updated and added country 
specific requirements for France 
and Germany to facilitate use of 
CA045-020 Protocol Amendment 
01 as the global protocol.
Appendix 14:Cytokine 
Release Syndrome -
Pediatric Adapted 
Management Algorithm
Added new Appendix with cytokine-release 
syndrome  management algorithm.  
Added new Appendix to align 
with Bempegaldesleukin IB v9.
Protocol Amendment No.: 01
Date: 28-Nov-2021
13
Aproved
2.0
v
Approved
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TABLE OF CONTENTS
TITLE PAGE................................................................................................................
DOCUMENT HISTORY..............................................................................................
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 01:............................
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 01................
TABLE OF CONTENTS..............................................................................................
1 SYNOPSIS.................................................................................................................
2 SCHEDULE OF ACTIVITIES..................................................................................
3 INTRODUCTION .....................................................................................................
3.1 Study Rationale.................................................................................................
3.1.1 Research Hypothesis................................................................................
3.2 Background.......................................................................................................
3.2.1 Overview of Malignant Neoplasms in the Pediatric Population .............
3.2.1.1 Pediatric Tumors of the Central Nervous System...........................
3.2.1.2 Pediatric Hematologic Malignancies .............................................
3.2.1.3 Overview of Melanoma in the Pediatric Population ......................
3.2.2 Bempegaldesleukin Mechanism of Action ...............................................
3.2.3 Nivolumab Mechanism of Action.............................................................
3.2.4 Clinical Experience with Nivolumab .......................................................
3.2.4.1 Study ADVL1412 (Nivolumab Monotherapy).................................
3.2.5 Clinical Experience with Bempegaldesleukin..........................................
3.2.5.1 Study 15-214-01 (EXCEL; Bempegaldesleukin Monotherapy)......
3.2.5.2 Study 16-214-02 (PIVOT-02; Bempegaldesleukin and Nivolumab 
Combination Therapy)..........................................................................
3.2.5.3 Pooled Safety Analysis of Participants with Bempegaldesleukin and 
Nivolumab Exposure.............................................................................
3.2.5.4 Observed Events of Cerebrovascular Accident ..............................
3.3 Benefit/Risk Assessment ..................................................................................
3.3.1 Bempegaldesleukin Safety Profile............................................................
3.3.2 Nivolumab Safety Profile.........................................................................
3.3.3 Bempegaldesleukin and Nivolumab Benefit and Risk Assessment ..........
4 OBJECTIVES AND ENDPOINTS...........................................................................
5 STUDY DESIGN.......................................................................................................
5.1 Overall Design ..................................................................................................
5.1.1 Screening Period......................................................................................
5.1.2 Treatment Period .....................................................................................
5.1.3 Dose-limiting Toxicities...........................................................................
5.1.3.1 Gastrointestinal Dose-limiting Toxicities.......................................
5.1.3.2 Hepatic Dose-limiting Toxicity.......................................................
5.1.3.3 Hematologic Dose-limiting Toxicity...............................................
5.1.3.4 Dermatologic Dose-limiting Toxicity .............................................
5.1.3.5 Other Dose-limiting Toxicities........................................................
5.1.3.6 Stopping Rules for Part B ...............................................................
5.1.4 Long-term Follow-up...............................................................................
5.1.5 Data Monitoring Committee and Other External Committees................
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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 Permitting Treatment Beyond Suspected Progression ......
5.4.4 Rationale for Choice of Endpoints...........................................................
5.4.5 Rationale for Open-label Design.............................................................
5.4.6 Rationale for Stratification ......................................................................
5.4.7 Duration of Treatment with Nivolumab/Bempegaldesleukin...................
5.5 Justification for Starting Dose ..........................................................................
5.5.1 Justification for Dose of Bempegaldesleukin...........................................
5.5.2 Justification for Dose of Nivolumab ........................................................
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, Resumption, and 
Discontinuation Criteria.............................................................................
7.4.1.1 Dose Modification Criteria for Bempegaldesleukin and Nivolumab 
for Cycle 1 AST/ALT Elevations ...........................................................
7.4.2 Monitoring and Management of Elevated Hepatic Transaminases ........
7.4.3 Monitoring and Management of 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 Immune-mediated Adverse Events and 
Cytokine-Release Syndrome........................................................................
7.4.5.1 Management Algorithms for Immune-mediated Adverse Events 
Associated with Immuno-oncology Agents ...........................................
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..................................................
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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...................................................................
7.7.3.2 Effect of Bempegaldesleukin on Pharmacokinetics of Concomitant
Medications...........................................................................................
7.7.4 Other Restrictions and Precautions.........................................................
7.7.4.1 Restricted Treatments .....................................................................
7.7.4.2 Imaging Restriction and Precautions .............................................
7.7.4.3 Blood Pressure Precautions ...........................................................
7.7.4.4 Volume of Blood..............................................................................
7.7.5 Permitted Therapy ...................................................................................
7.8 Treatment After the End of the Study...............................................................
8 DISCONTINUATION CRITERIA ...........................................................................
8.1 Discontinuation From Study Treatment............................................................
8.1.1 Nivolumab and Bempegaldesleukin Discontinuation Criteria ................
8.1.2 Treatment Beyond Progression................................................................
8.1.3 Post-study Treatment Study Follow-up....................................................
8.2 Discontinuation From the Study.......................................................................
8.3 Lost to Follow-up..............................................................................................
9 STUDY ASSESSMENTS AND PROCEDURES.....................................................
9.1 Efficacy Assessments........................................................................................
9.1.1 Imaging Assessment for the Study............................................................
9.1.2 Method of Measurement ..........................................................................
9.1.2.1 Ewing Sarcoma, Rhabdomyosarcoma, and Other Solid Tumors ...
9.1.2.2 Neuroblastoma................................................................................
9.1.2.3 Non-Hodgkin Lymphoma................................................................
9.1.2.4 Glioma, Medulloblastoma, Ependymoma, and Other CNS Tumors
...............................................................................................................
9.1.2.5 Leukemia.........................................................................................
9.1.3 Imaging and Clinical Assessment............................................................
9.1.4 Patient-reported Outcomes......................................................................
9.2 Adverse Events .................................................................................................
9.2.1 Time Period and Frequency for Collecting AE and SAE Information ....
9.2.2 Method of Detecting AEs and SAEs.........................................................
9.2.3 Follow-up of AEs and SAEs.....................................................................
9.2.4 Regulatory Reporting Requirements for SAEs.........................................
9.2.5 Pregnancy ................................................................................................
9.2.6 Immune-mediated Adverse Events...........................................................
9.2.7 Additional Information Collected for Adverse Events Primarily Related 
to Bempegaldesleukin .................................................................................
9.2.8 Adverse Events of Special Interest...........................................................
9.2.9 Laboratory Test Result Abnormalities.....................................................
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9.2.10 Potential Drug-induced Liver Injury .....................................................
9.2.11 Other Safety Considerations..................................................................
9.3 Overdose ...........................................................................................................
9.4 Safety ................................................................................................................
9.4.1 Physical Examinations.............................................................................
9.4.2 Vital Signs and Oxygen Saturation..........................................................
9.4.3 Electrocardiograms .................................................................................
9.4.4 Echocardiogram ......................................................................................
9.4.5 Pregnancy Tests.......................................................................................
9.4.6 Clinical Safety Laboratory Assessments..................................................
9.4.7 Imaging Safety Assessment ......................................................................
9.5 Pharmacokinetics..............................................................................................
9.5.1 Pharmacokinetics and Immunogenicity Assessments..............................
9.7 Pharmacogenomics ...........................................................................................
9.9 Medical Resource Utilization and Health Economics ......................................
10 STATISTICAL CONSIDERATIONS ....................................................................
10.1 Sample Size Determination.............................................................................
10.2 Populations for Analyses ................................................................................
10.3 Statistical Analyses.........................................................................................
10.3.1 Efficacy Analyses ...................................................................................
10.3.2 Safety Analyses.......................................................................................
10.3.3 Other Analyses.......................................................................................
10.3.3.1 Pharmacokinetics..........................................................................
10.3.3.2 Immunogenicity Analyses..............................................................
10.3.3.3 Other Exploratory Analyses..........................................................
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.....................................................................
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APPENDIX 5 MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0 .........................................................................................................
APPENDIX 6 CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM FOR THE COMBINATION OF
BEMPEGALDESLEUKIN WITH CHECKPOINT INHIBITORS.......................
APPENDIX 7 KARNOFSKY AND LANSKY CRITERIA........................................
APPENDIX 8 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................
APPENDIX 9 REVISED INTERNATIONAL NEUROBLASTOMA RESPONSE 
CRITERIA..............................................................................................................
APPENDIX 10 INTERNATIONAL PEDIATRIC NON-HODGKIN LYMPHOMA 
RESPONSE CRITERIA.........................................................................................
APPENDIX 11 RESPONSE ASSESSMENT IN NEURO-
ONCOLOGY(RANO)/PEDIATRIC NEURO-ONCOLOGY (RAPNO) ..............
APPENDIX 12 RESPONSE TO THERAPY FOR HEMATOLOGICAL 
MALIGNANCIES..................................................................................................
APPENDIX 13 COUNTRY SPECIFIC AMENDMENTS..........................................
APPENDIX 14 CYTOKINE RELEASE SYNDROME - PEDIATRIC ADAPTED 
MANAGEMENT ALGORITHM...........................................................................
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
1
SYNOPSIS
Protocol Title: Phase 1/2 Study of Bempegaldesleukin in Combination with Nivolumab in 
Children, Adolescents, and Young Adults with Recurrent or Refractory Malignancies (PIVOT IO 
020)
Short Title: Bempegaldesleukin + Nivo in Pediatric Malignancies
Study Phase:
Phase 1/Phase 2 
Rationale:
Over the past several decades, survival of pediatric oncology patients has generally improved, 
largely due to the increased use of multimodality approaches and intensive multi-agent 
chemotherapy regimens. In contrast, despite the dramatic improvement in survival observed in the 
past 3 to 4 decades due to the multidisciplinary approach applied overall to pediatric malignancies, 
the outcomes in patients with relapsed or refractory tumors remain poor. Immuno-oncology (I-O) 
therapies aimed at enhancing the patient’s immune response against the tumor represent an 
important new treatment option for improving outcomes in children with refractory or recurrent 
malignancies. The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) 
pathway has been implicated in several pediatric solid tumor types. A number of pediatric clinical 
programs with PD-1 and PD-L1 inhibitors are currently underway in these and other pediatric 
tumors. To date, the use of single-agent I-O therapy in children has not provided sufficient
evidence of activity to support a comprehensive development program in pediatrics. 
Bempegaldesleukin is an interleukin (IL)-2 pathway agonist that mobilizes, activates, and 
proliferates lymphocytes to the tumor microenvironment and is expected to increase PD-L1 
expression on tumors due to secretion of interferon-gamma and other cytokines by increased 
numbers of tumor-infiltrating lymphocytes. Bempegaldesleukin in combination with the anti-PD-1 
antibody nivolumab demonstrated clinical responses in the adult PIVOT-02 study. These 
observations, along with prior experience with the use of IL-2 (aldesleukin) in pediatric cancer 
patients, implies that bempegaldesleukin in combination with nivolumab may potentially benefit 
pediatric cancer patients.
Study Population:

Females and males, ages less than 18 years old at the time of enrollment for Part A and Part B. 
For Part B, Cohorts B2, B3, and B4 participants less than 30 years old may be enrolled. 

Part A (safety lead in) will include pediatric participants with malignant neoplasms that are 
refractory, relapsed, or participants for whom curative treatments are lacking. Part B (cohort 
expansion) will include pediatric and young adult participants with neuroblastoma, Ewing 
sarcoma, rhabdomyosarcoma, miscellaneous solid tumors, non-Hodgkin lymphoma
(NHL)/leukemia, high-grade glioma, medulloblastoma and central nervous system (CNS)
embryonal tumors, ependymoma, and miscellaneous CNS tumors.
Protocol Amendment No.: 01
Date: 28-Nov-2021
19
Aproved
2.0
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Approved
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
Key Inclusion Criteria

Participants must have received standard-of-care-therapy, and there must be no potentially 
curative treatment available.

A histologically confirmed malignant neoplasm that is refractory, relapsed, or patients for 
whom curative treatments are lacking, including poor prognosis newly diagnosed high-grade 
glioma.

Participants must have measurable or evaluable disease based on Response Evaluation Criteria 
in Solid Tumors v1.1 for solid tumors, Response Assessment in Neuro-Oncology/Response 
Assessment in Pediatric Neuro-Oncology for CNS tumors, International Pediatric Non-
Hodgkin Lymphoma Response Criteria for NHL, revised International Neuroblastoma 
Response Criteria for neuroblastoma, modified National Comprehensive Cancer Network 
Criteria for acute lymphoblastic leukemia, and modified Cheson et al International Working 
Group criteria for acute myeloid leukemia.

Lansky play score for age ≤ 16 years or Karnofsky performance score for age > 16 years 
assessed within 2 weeks of enrollment must be ≥ 60. Participants who are unable to walk 
because of neurologic deficits but who are in a wheelchair will be considered ambulatory for
the purpose of assessing the performance score.

Substantial recovery (ie, no ongoing safety issues) from prior therapy.

An interval of 4 weeks or 5 half-lives, whichever is longer, after the last administration of any 
anti-cancer therapy or any other treatment for malignancies (6 weeks for nitrosoureas), prior 
to first dose of study drug. The interval from most recent biological agent must be 7 days or 5 
half-lives, whichever is longer, prior to first dose of study drug.

Participants with CNS tumors must not receive more than 0.05 mg/kg dexamethasone (or 
equivalent) per day and the dose should be stable for a minimum of a week.

Participants who have received high-dose chemotherapy with autologous hematopoietic cell 
transplantation must be at least 6 months post-hematopoietic cell transplantation and they must 
have a CD4 count of at least 200.

Prior palliative radiotherapy must be completed at least 2 weeks prior to first dose of study 
drug. Participants must have recovered from all Grade 2 or higher clinically relevant radiation-
related toxicities. Participants with newly diagnosed malignant gliomas who may have 
received focal radiation or radiation and temozolomide are eligible. Note: Radiated lesions 
cannot be used as measurable lesions unless they have a new baseline scan after radiation or 
there is clear evidence of progression. 

Documented left ventricular ejection fraction >45% using standard echocardiogram or 
multigated acquisition scan test.
Key Exclusion Criteria

Participants with osteosarcoma, T-cell/natural killer-cell leukemia/lymphoma, and Hodgkin’s 
lymphoma.

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 
Protocol Amendment No.: 01
Date: 28-Nov-2021
20
Aproved
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Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
with the interpretation of safety results (eg, a condition associated with diarrhea or acute 
diverticulitis).

Active infection requiring systemic therapy within 14 days prior to first dose.

Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics). Participants with hypertension must be on a stable anti-hypertensive regimen for the 
14 days prior to treatment assignment. Note: An antihypertensive medication that contains 2 
drugs in 1 formulation is counted as 2 antihypertensive medications (eg, angiotensin-
converting enzyme [ACE] inhibitor plus diuretic, calcium channel blocker plus ACE inhibitor).

Unstable or deteriorating cardiovascular disease, within the previous 12 months prior to 
screening, including, but not limited to, the following:

Unstable angina or myocardial infarction

Transient ischemic attack (TIA)/cerebrovascular accident (CVA)

Congestive heart failure (New York Heart Association Class III or IV)

Uncontrolled clinically significant arrhythmias

History of pulmonary embolism, deep vein thrombosis, or prior clinically significant venous 
or non-CVA/TIA arterial thromboembolic event (eg, internal jugular vein thrombosis) within 
3 months prior to treatment assignment.

Participants with a history of a venous or arterial thromboembolic event must be 
asymptomatic for at least 2 weeks prior to treatment assignment and must be receiving a 
stable regimen of therapeutic anticoagulation (low-molecular-weight heparin or direct oral 
anticoagulation). 

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.

Participants with inadequately treated adrenal insufficiency.

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.

Participants with a condition (excluding CNS tumors) requiring systemic treatment with either
corticosteroids (> 0.12 mg/kg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days of start of study treatment. Inhaled or topical steroids and adrenal 
replacement steroid doses > 0.12 mg/kg daily prednisone equivalent are permitted in the 
absence of active autoimmune disease.

Known human immunodeficiency virus (HIV) positive with an Acquired Immune Deficiency 
Syndrome (AIDS)-defining opportunistic infection within the last year, or a current CD4 count 
< 350 cells/uL. (Participants with known HIV who are enrolled should receive ART therapy 
as clinically indicated and be monitored for CD4 counts and viral load per standard of care by 
a local health care provider.) NOTE: Testing for HIV must be performed at sites where 
mandated locally. HIV positive participants must be excluded where mandated locally.
Protocol Amendment No.: 01
Date: 28-Nov-2021
21
Aproved
2.0
v
Approved
1.0
v

Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab

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. 

Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, agents that target IL-2 pathway or 
anti-cytotoxic T-lymphocyte-associated protein 4 antibody, or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways.

Participants having had a prior allogeneic stem cell transplant.

Participants currently in other interventional trials, including those for COVID-19, may not 
participate in BMS clinical trials until the protocol specific washout period is achieved. If a 
study participant has received an investigational COVID-19 vaccine or other investigational 
product designed to treat or prevent COVID-19 prior to screening, enrollment must be delayed 
until the biologic impact of the vaccine or investigational product is stabilized, as determined 
by discussion between the investigator and the Medical Monitor.

Previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks prior to first 
dose of study drug. Acute symptoms must have resolved and based on investigator assessment 
in consultation with the medical monitor, there are no sequelae that would place the participant 
at a higher risk of receiving investigational treatment.
Objectives and Endpoints:
Objectives
Endpoints
Primary - Part A Safety Lead-in

Safety Lead-in: To estimate the safety and 
tolerability of study treatment in pediatric 
participants with malignant neoplasms that are 
refractory, relapsed, or participants for whom 
curative treatments are lacking.

Incidence of dose-limiting toxicities (DLTs), adverse 
events (AEs), serious AEs (SAEs), drug-related AEs, 
AEs leading to discontinuation, and death.

To characterize the pharmacokinetics (PK) of 
bempegaldesleukin and nivolumab in pediatric 
participants with malignant neoplasms that are 
refractory, relapsed, or participants for whom 
curative treatments are lacking. 

PK parameters that are characterized by population 
PK models.
Primary - Part B Expansion

To estimate the preliminary efficacy (eg, ORR of 
study treatment separately in the following disease 
cohorts):

B1: Neuroblastoma

B2: Ewing sarcoma

B3: Rhabdomyosarcoma

B4: Miscellaneous solid tumors

B5: Non-Hodgkin lymphoma 
(NHL)/leukemia

B6: High-grade glioma

B7: Medulloblastoma and embryonal tumors

Investigator-assessed objective response rate by: 

B1: Revised International Neuroblastoma 
Response Criteria

B2 to B4: Response Evaluation Criteria in 
Solid Tumors v1.1

B5: International Pediatric Non-Hodgkin 
Lymphoma Response Criteria for NHL

B5: Modified National Comprehensive Cancer 
Network Criteria for acute lymphoblastic 
leukemia
Protocol Amendment No.: 01
Date: 28-Nov-2021
22
Aproved
2.0
v
Approved
1.0
v

Clinical Protocol
CA045020/19-214-27
BMS-986321
Bempegaldesleukin (NKTR-214) and nivolumab
Objectives
Endpoints

B8: Ependymoma

B9: Miscellaneous central nervous system 
(CNS) tumors

B5: Modified Cheson et al International 
Working Group criteria for acute myeloid 
leukemia.

B6 to B9: Response Assessment in Neuro-
Oncology/Response Assessment in Pediatric 
Neuro-Oncology 
Secondary - Part B Expansion

To estimate the safety of study therapy in pediatric 
participants.

Incidence of AEs, SAEs, toxicities, drug-related 
AEs, AEs leading to discontinuation, and death.

Incidence of laboratory abnormalities.

To estimate the progression-free survival (PFS) 
and overall survival (OS) of study therapy in 
pediatric participants.

PFS, OS
Abbreviations: AE = adverse event; CNS = central nervous system; DLT = dose-limiting toxicity; DOR = duration of 
response; NHL = non-Hodgkin lymphoma; NKTR-214 = bempegaldesleukin; ORR = objective response rate; OS = 
overall survival; PFS = progression-free survival; PK = pharmacokinetic; SAE = serious adverse event.
Overall Design:
CA045-020 is an open-label, sequential-arm Phase 1b/2 clinical trial of bempegaldesleukin in 
combination with nivolumab in pediatric participants with malignant neoplasms that are refractory, 
relapsed, or participants for whom curative treatments are lacking.
Because pediatric participants vary in age and weight, the starting doses of nivolumab will be 
determined separately based on age or weight. Participants aged < 12 years or weighing < 40 kg 
will be given a weight-based dose of nivolumab (Figure 1-1), and participants aged 12 years and 
weighing 40 kg will be given a flat dose of nivolumab (Figure 1-2).
Number of Participants: 
The total sample size of the study is estimated to be between approximately 10 and 234 participants 
depending on dose de-escalation contingencies in Part A and cohort expansions in Part B. The 
sample size of Part A is not based on statistical considerations, and it depends on the number of 
observed dose-limiting toxicities (DLTs). Accrual estimates for the expansion phase are based on 
the modified Simon 3-stage variant design, except for miscellaneous solid and CNS tumor cohorts 
(Cohorts B4 and B9). Participants in Part A treated at the dosing schema used in Part B can be 
counted in the accrual goals for Part B.
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Treatment Arms and Duration:
Study Treatment: 
Study Treatments for CA045020
Product Description/
Class and Dosage Form
Content
IP/Non-IMP
Investigational product: 
Bempegaldesleukin (NKTR-214)
Powder for Solution for Injection 
1.0 mg of rhIL-2 per viala
IP
Commercial product:
Bempegaldesleukin (NKTR-214) 
Powder for Solution for Injection 
0.3 mg of rhIL-2 per viala
IP
Commercial product:
Bempegaldesleukin (NKTR-214) 
Powder for Solution for Injection 
0.5 mg of rhIL-2 per viala
IP
Nivolumab Solution for Injection
100 mg (10 mg/mL)
IP
Abbreviations: IL-2=interleukin-2; IMP = Investigational Medicinal Product; IP = Investigational Product; 
mg=milligrams, mL= milliliters; rhIL-2 = recombinant human interleukin-2.
a For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer to the same molecule.
Figure 1-1:
Phase 1b (Part A) Dose-finding Study Design for Age- and Weight-
based Dosing of Participants Aged < 12 Years or Weighing < 40 kg for 
Bempegaldesleukin in Combination with Nivolumab*
*For nivolumab 4.5 mg/kg in dosing schema A1W and A2W, up to 360 mg equivalent is the maximum dose.
Abbreviations: DLT = dose-limiting toxicity; IV = intravenous; pts = participants; Q3W = every 3 weeks; W = weight.
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Figure 1-2:
Phase 1b (Part A) Dose-finding Study Design for Flat to Weight-based 
Dosing of Participants Aged ≥ 12 Years and Weighing ≥ 40 kg for 
Bempegaldesleukin in Combination with Nivolumab*
*For nivolumab 4.5 mg/kg in dosing schema A2F-W and A3F-W, up to 360 mg equivalent is the maximum dose.
Abbreviations: DLT = dose-limiting toxicity; F = flat; F-W = flat to weight-based; IV = intravenous; pts = participant; 
Q3W = every 3 weeks.
Phase 1b consists of Part A. In Part A, a maximum of 30 participants (ie, up to 2 cohorts of 6 
participants in the weight/age-based dosing schema and up to 3 cohorts of 6 participants in the flat 
to weight-based dosing schema) will be treated with both nivolumab and bempegaldesleukin 
intravenous every 3 weeks to determine the recommended dose of bempegaldesleukin to take into 
Part B and to determine if nivolumab flat or weight-based dosing will be used for those ≥ 12 years 
and weighing ≥ 40 kg. Assessments for the weight/age-based and for the flat to weight-based 
dosing schemas will run concurrently and are independent of each other.
Figure 1-3:
Phase 2 (Part B) Study Design Schematic
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Abbreviations: CNS = central nervous system; ET = embryonal tumor; NHL = non-Hodgkin lymphoma; RMS = 
rhabdomyosarcoma.
Phase 2 (Part B) will use a modified Simon 3-stage variant design to enroll at least 9 participants 
into 7 individual cohorts (B1 to B3 and B5 to B8) based on tumor type to be treated. For the 
miscellaneous solid tumor and miscellaneous CNS tumor cohorts, the Simon 3-stage variant design 
will not be applied and can accrue up to the maximum of 24 participants. All 9 cohorts will be 
treated with the selected dosing schema(s) from Part A of the study. The Phase 2 cohorts are 
disease and histology specific as presented in Figure 1-3.
The study consists of a screening, treatment, and long-term follow-up period. 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 
conclude(s) the study, or for a maximum of 2 years of treatment. The total duration of the study is 
up to 5 years from first study treatment of the last participant or until the time of primary OS 
analysis, whichever occurs later.
If bempegaldesleukin or nivolumab meet the criteria for dose delay, then administration of both 
drugs must be delayed until the criteria to resume are met. Dose reductions are permitted for 
bempegaldesleukin but not nivolumab. Nivolumab treatment can continue in the event that 
bempegaldesleukin is permanently discontinued if the toxicities are considered related to 
bempegaldesleukin only and once the criteria to resume are met.
Data Monitoring Committee: 
A data monitoring committee (DMC) will be utilized in this study. In Part A, any dosing level in 
which 2 participants’ experience 1 or more DLTs are identified during the DLT period will be 
reviewed by the DMC before accrual into the dose reduced schema proceeds for weight/age-based 
or flat to weight-based dosing, respectively, as outlined in Figure 1-1 (A2W; weight/age-based 
dosing) and Figure 1-2 (A2F-W; A3F-W; flat to weight-based dosing). Since the weight/age-based 
dosing schemas (A1W/A2W) and the flat to weight-based dosing schemas (A1F-W/A2F-W/A3F-
W) are independent from each other, they will be evaluated for DLTs separately.
The selection of the optimal dosing schema for Part B will be made at the completion of Part A 
and can occur separately for the 2 dosing schemas (weight/age-based and flat to weight-based 
dosing, respectively) in conjunction with the DMC.
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2
SCHEDULE OF ACTIVITIES
An overview of the schedule of major assessments in this study are provided in Table 2-1
(Screening), Table 2-2 (On Treatment), and Table 2-3 (Long-term Follow-up).
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Table 2-1:
Screening Procedural Outline (CA045020)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Register in Interactive Response Technology (IRT) system to obtain participant number. The 
participant or legally authorized representative should sign the informed consent prior to any 
study-related assessment is performed.
Study allows for re-enrollment of a participant that is a pre-treatment failure and was not 
previously treated. If re-enrolled, the participant must be re-consented and assigned a new 
participant number from IRT.
Inclusion/Exclusion Criteria
X
Must be confirmed prior to treatment.
See Sections 6.1 and 6.2.
Medical History
X
All relevant medical history including smoking history, and prior anti-cancer therapies.
Safety Assessments
Physical Examination 
X
Include vital signs (blood pressure, heart rate, and temperature) plus height, weight, and pulse 
oximetry within 14 days prior to treatment.
Performance Status
X
Within 14 days prior to treatment, collect Lansky play score for ≤16 years or Karnofsky 
performance score for > 16 years of age (Appendix 7).
Prior and Concomitant Medication 
Use
X
Must be collected within 14 days prior to treatment.
Vaccine use within 30 days prior to treatment must be collected.
Serious Adverse Events (SAE) 
Assessment
X
SAEs collected and reported from time of consent.
All AEs (SAEs or non-serious AEs) related to severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection collected from time of consent. 
Laboratory Tests
Clinical Laboratory Testing
X
All laboratory assessments to be performed within 14 days prior to treatment, except for viral 
testing, which, if clinically indicated, is to be completed within 28 days prior to treatment (see 
Section 9.4.6 for a list of laboratory tests to conduct).
Electrocardiogram
X
Within 14 days prior to treatment (see Section 9.4.3).
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Table 2-1:
Screening Procedural Outline (CA045020)
Procedure
Screening
Visita
Notes
Echocardiogram or Multigated 
Acquisition Scan (MUGA)
X
Left ventricular ejection fraction > 45% within 60 days is required prior to treatment assignment.
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.
Pregnancy Test 
X
Women of childbearing potential only. Serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of human chorionic gonadotropin) to be done at screening visit and 
within 24 hours of first dose of study therapy.
Tumor Assessment
Body Imaging
X

Imaging to be performed within 28 days prior to treatment. See Section 9.1.1 for further 
details. 

Not applicable to participants with leukemia.

Skull base to mid-thigh [18F]fluorodeoxyglucose (FDG) positron emission tomography-
computed tomography (PET-CT) or PET-magnetic resonance imaging (PET-MRI); additional 
anatomy to include all sites of disease) for FDG-avid non-Hodgkin lymphoma.

Contrast-enhanced CT of the chest, contrast-enhanced CT/magnetic resonance imaging (MRI)
of the abdomen, pelvis, and all other known and/or suspected sites of disease.

Participants with metaiodobenzylguanidine (MIBG)-avid neuroblastoma must also undergo 
MIBG scintigraphy in addition to CT/MRI as above.
Brain Imaging
X
MRI of the brain without and with contrast is required for participants at baseline in participants 
with a history of brain metastasis or symptoms. Except for glioma, medulloblastoma, 
ependymoma, and other central nervous system tumors in which an MRI is required, CT of the 
brain (without and with contrast) can be performed if MRI is contraindicated. Brain imaging must 
be done within 28 days prior to treatment. See Section 9.1.1 for further details.
Cerebrospinal Fluid (CSF) - Solid 
Tumors
X
CSF cytopathology should be obtained in any participant with a suspicion or high likelihood of 
CSF dissemination up to 7 days prior to treatment. This sample can be used as the Cycle 1 Day 1 
sample. If initially positive, CSF cytopathology should be followed as part of response assessment. 
See Section 9.1.
 
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Table 2-1:
Screening Procedural Outline (CA045020)
Procedure
Screening
Visita
Notes
Bone Marrow and Buccal Swab -
Solid Tumors
X
For participants with suspected bone marrow disease, bone marrow aspirate obtained where 
clinically indicated should be submitted along with buccal swab up to 28 days prior to treatment. If 
initially positive, bone marrow should be evaluated as part of response assessment. See Section
9.1.
 
CSF - Leukemia
X
Screening sample collected up to 7 days prior to treatment initiation can be used as Cycle 1 Day 1 
pretreatment sample. See Section 9.1.2.5.
 
Bone Marrow and Buccal Swab -
Leukemia
X
Bone marrow aspirate collected at screening and submitted along with buccal swab up to 28 days 
prior to treatment initiation can be used as Cycle 1 Day 1 pre-treatment sample. See Section
9.1.2.5.
 
Abbreviations: CSF = cerebrospinal fluid; CT = computed tomography; FDG = [18F]fluorodeoxyglucose; 
IRT = Interactive Response Technology; MIBG = metaiodobenzylguanidine; MRI = magnetic resonance imaging; MUGA = multigated acquisition; PET = positron 
emission tomography; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
a Some of the assessments referred to in this section may not be captured as data in the electronic case report form. They are intended to be used as safety 
monitoring by the treating physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
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Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Safety Assessments
Targeted Physical 
Examination, Vital 
Signs, and 
Performance Status
X
X*
X
Vital signs (blood pressure, heart rate, and 
temperature), weight, Lansky play score for ≤16 
years or Karnofsky performance score for > 16 
years of age (Appendix 7).
Monitor and record vital signs at predose and 
within 30 minutes after administration of 
nivolumab.
*At Day 8 visits collect vital signs only.
12-lead 
Electrocardiogram 
(ECG)
X
X
X
X
X
X (Cycle 
5 only)
Pre-dose Day 1 of all cycles
Pre-PK blood draw on Cycle 1, Days 3,5, and 8
Pre-PK blood draw on Cycle 5, Days 3 and 5
ECG should be performed within 30 minutes prior 
to PK blood draw.
Participant should rest for 5 minutes prior to each 
ECG
Adverse Events 
Assessment 
(including Serious 
Adverse Events)
Continuously
Adverse events (AEs) will be graded according to 
the National Cancer Institute Common 
Terminology Criteria for AEs (NCI-CTCAE) 
version 5.
Record at each visit. All AEs (SAEs or non-
serious AEs), including those associated with 
SARS-CoV-2 infection, must be collected 
continuously throughout the treatment period and 
for a minimum of 150 days after last dose of study 
treatment (Appendix 3).
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Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Concomitant 
Medication Use
Continuously
Record at each visit.
Laboratory Tests
Clinical Laboratory 
Testing
X
X
X
Hematology and chemistry assessments scheduled 
for the day of study drugs dosing must be 
available and assessed before dosing. Hematology 
and chemistry assessments can be drawn within 
72 hours prior to treatment, though renal function 
(ie, serum creatinine) must be assessed within 24 
hours prior to dosing with bempegaldesleukin or 
as soon as locally feasible.
Refer to Section 9.4.6 for a list of laboratory tests 
to conduct.
Pregnancy Test
X
X
Serum or urine pregnancy test (minimum 
sensitivity units 25 IU/L or equivalent units of 
human chorionic gonadotropin) is required within 
24 hours prior to treatment in women of 
childbearing potential. 
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Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Efficacy Assessments
Body Imaging

Imaging should occur every 9 weeks (± 7 days) from start of 
treatment for the first 54 weeks, then every 12 weeks (± 7 days) 
until disease progression or treatment discontinuation 
(including treatment beyond progression), whichever occurs 
later. Tumor assessment schedule should be maintained 
regardless of dose delays. Use same imaging method as was 
used at screening.

Not applicable to participants with leukemia.

Skull base to mid-thigh [18F]fluorodeoxyglucose (FDG) 
positron emission tomography-computed tomography (PET-
CT) or PET-magnetic resonance imaging (PET-MRI); 
additional anatomy to include all sites of disease) for FDG-avid 
non-Hodgkin lymphoma.

Contrast-enhanced CT of the chest, contrast-enhanced 
CT/magnetic resonance imaging (MRI) of the abdomen, pelvis, 
and all other known and/or suspected sites of disease.

Participants with metaiodobenzylguanidine (MIBG)-avid 
neuroblastoma must also undergo MIBG scintigraphy in 
addition to CT/MRI as above.
All study treatment decisions will be based on the 
investigator’s assessment of tumor images.
See Section 9.1.1 for additional details and to 
Section 8.1.2 for tumor assessment associated with 
treatment beyond progression.
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CA045020/19-214-27
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Bempegaldesleukin (NKTR-214) and nivolumab
Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Brain Imaging

Participants in brain tumor-related cohorts and those with a 
history of brain metastasis or symptoms should undergo MRI 
of the brain without and with contrast every 9 weeks (± 7 days) 
from start of treatment up to 54 weeks, and then approximately 
every 12 weeks (± 7 days), or sooner if clinically indicated. 
Tumor assessment schedule should be maintained regardless of 
dose delays. Cerebrospinal fluid (CSF), if clinically indicated, 
should be followed as per Response Assessment in Pediatric 
Neuro-Oncology guidelines.
Except for glioma, medulloblastoma, 
ependymoma and other central nervous system 
tumors in which an MRI is required, CT of the 
brain (without and with contrast) can be performed 
if MRI is contraindicated.
See Section 9.1.1 for further details.
CSF - Solid tumors
Performed at time of imaging assessments for disease response 
as clinically indicated.
CSF cytopathology should be obtained in any 
participant with a previously positive CSF as part 
of response assessment (see Section 9.1). 
 
 
Bone Marrow-
Solid tumors
Performed at time of imaging assessments for disease response as 
clinically indicated.
Bone marrow biopsy/aspirate should be obtained 
in any participant with a previously positive bone 
marrow aspirate as part of response assessment
(see Section 9.1).
 
CSF - Leukemia
Performed as clinically indicated.
CSF cytopathology should be obtained in any 
participant with a previously positive CSF as part 
of response assessment (see Section 9.1.2.5). 
 
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Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Bone Marrow -
Leukemia
Performed as clinically indicated.
Bone marrow biopsy/aspirate should be obtained 
in any participant with a previously positive bone 
marrow aspirate as part of response assessment. 
 
Pharmacokinetic (PK)/Immunogenicity Assessmentse
Bempegaldesleukin 
PK Plasma 
Samples
See Section 9.5.1 for further details.
Nivolumab PK 
Serum Samples
See Section 9.5.1 for further details.
Immunogenicity 
Samples
See Section 9.5.1 for further details.
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Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Health Outcomes
Patient-reported 
Outcomes (PRO) 
Version of the 
CTCAE
See Notes
Questionnaire to be administered electronically in 
Part B only, on a weekly basis during the first 3
cycles of treatment, every cycle from Cycles 4 
through 8, and then every other cycle (starting at 
Cycle 10) while on treatment until end of
treatment.
PRO-CTCAE™ for adults ≥18 years.
Pediatric (Ped-PRO-CTCAE) for children ≥7 to 
<18 years.
Ped-PRO-CTCAE [Caregiver] for children <7 
years.
Study Drug
Determine Dosing 
Schema
X
See Figure 5.1-1, Figure 5.1-2 and Figure 5.1-3.
Administer 
Intravenous Fluids
X
X
May be withheld if deemed by the investigator to 
be in the best interest of the participant. Refer to 
Section 7.1.1.1 for additional information.
Administer 
Bempegaldesleukin 
+ Nivolumab 
(Parts A and B)
X
X
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Table 2-2:
On-treatment Procedural Outline (CA045020)
Procedure
Cycle 1 Onlya,b
Cycle = 3 wks
Cycle 2 and 
Beyonda,b,c
Each cycle = 3 wks
Notes
Day 1
Day 3
(1 day)d
Day 5
(1 day)
Day 8
(- 1 day)
Day 1
Day 3-5
Review Hydration 
Guidelines with 
Participants
X
X
See Section 7.1.1.1.
Oral Hydration 
Follow-up
X
(Day 3-5)
X
For the first 2 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.
Abbreviations: AE = adverse event; CSF = cerebrospinal fluid; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events
version 5; ECG = electrocardiogram; FDG = [18F]fluorodeoxyglucose; 
 MIBG = metaiodobenzylguanidine; MRI = magnetic resonance 
imaging; NCI = National Cancer Institute; Ped = pediatric; PET = positron emission tomography; PK = pharmacokinetic; PRO = patient-reported outcome; SARS-
CoV-2 = severe acute respiratory syndrome coronavirus 2.
a Some of the assessments referred to in this section may not be captured as data in the electronic case report form. They are intended to be used as safety 
monitoring by the treating physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
b If a dose is delayed, the procedures scheduled for that same time point, with the exception of the body/brain imaging, should also be delayed to coincide with 
when the time point’s dosing actually occurs.
c For Cycle 5 only, participants will return for additional sample collection at Days 3 and 5. Refer to Section 9.5.1 (Table 9.5.1-1) for all details, including allowed 
windows.
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d Samples can be collected ± 3 hours. If participants are dosed on a Thursday, Day 3 samples may be collected on Day 2. If dosed on a Friday, Day 3 sample can 
be collected on Day 4. 
e For participants who require blood draw volume modifications, blood collection volumes will be reduced per guidelines outlined in the laboratory manual.
Omitted blood collection will likely be for 
 pharmacokinetic assessments, since all required safety assessments must be performed.
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Table 2-3:
Long-term Follow-up Period (CA045020)
Procedure
Safety 
Follow-up 
Visit 1a
Safety 
Follow-up 
Visit 2a
Safety
Follow-up 
Visit 3a
Survival Follow-up
Every 3 Months
(14 Days)b
Notesc
Safety Assessments
Vital Signs
X
X
X
Blood pressure, heart rate, temperature.
Performance Status
X
X
Lansky play score for ≤16 years or Karnofsky 
performance score for > 16 years of age (Appendix 
7).
12-lead ECG
X
Participant should rest for 5 minutes prior to each 
ECG.
Adverse Events and 
Serious Adverse Events 
(SAE) Assessment 
X
X
X
See Notes
All SAEs and non-serious AEs should be collected 
continuously during the treatment period and for a 
minimum of 150 days following discontinuation of 
study treatment.
Participants will be followed for all SAEs, non-
serious AEs of special interest (as defined in Section 
9.2.8) and all AEs (SAEs and non-serious AEs) 
associated with confirmed or suspected SARS-CoV-
2 infection until resolution, the condition stabilizes, 
the event is otherwise explained, the event is deemed 
irreversible, the participant is lost to follow-up (as 
defined in Section 8.3), or for suspected cases, until 
SARS-CoV-2 infection is ruled-out.
Subsequent Medications
X
X
X
Review of Subsequent 
Anti-cancer Therapy
X
X
X
X
Additional subsequent cancer therapy details such as 
regimen, setting of the regimen, line of therapy, start 
and end date of each regimen, best response to the 
regimen, and date of progression to subsequent anti-
cancer therapies will be collected.
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Table 2-3:
Long-term Follow-up Period (CA045020)
Procedure
Safety 
Follow-up 
Visit 1a
Safety 
Follow-up 
Visit 2a
Safety
Follow-up 
Visit 3a
Survival Follow-up
Every 3 Months
(14 Days)b
Notesc
Laboratory Tests
Laboratory Tests (includes 
blood and urine samples)
X
If toxicities 
are present.
If toxicities 
are present
See Section 9.4.6 for the list of laboratory tests.
Pregnancy Test
X
X
X
Women of childbearing potential only. Serum or 
urine pregnancy test (minimum sensitivity equivalent 
units 25 IU/L or equivalent units of human chorionic 
gonadotropin) is required.
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Table 2-3:
Long-term Follow-up Period (CA045020)
Procedure
Safety 
Follow-up 
Visit 1a
Safety 
Follow-up 
Visit 2a
Safety
Follow-up 
Visit 3a
Survival Follow-up
Every 3 Months
(14 Days)b
Notesc
Efficacy Assessments
Body Imaging

Imaging should occur every 9 weeks (± 7 days) from start of 
treatment for the first 54 weeks, then every 12 weeks (± 7 days) 
until disease progression (including treatment beyond 
progression) or end of study, whichever occurs later. Use same 
imaging method as was used at screening. After completion of 
study therapy for participants without progression, results of 
additional imaging (including bone marrow and CSF, if 
applicable) are requested for the duration of the study.

Not applicable to participants with leukemia.

Skull base to mid-thigh [18F]fluorodeoxyglucose (FDG) 
positron emission tomography-computed tomography (PET-CT)  
or PET-magnetic resonance imaging (PET-MRI); additional 
anatomy to include all sites of disease for FDG-avid non-
Hodgkin lymphoma.

Contrast-enhanced CT of the chest, contrast-enhanced 
CT/magnetic resonance imaging (MRI) of the abdomen, pelvis, 
and all other known and/or suspected sites of disease.

Participants with metaiodobenzylguanidine (MIBG)-avid 
neuroblastoma must also undergo MIBG scintigraphy in 
addition to CT/MRI as above.
See Section 9.1.1 for further details.
Brain Imaging

Participants in brain tumor-related cohorts and those with a 
history of brain metastasis or symptoms should undergo MRI of 
the brain without and with contrast every 9 weeks (± 7 days) 
from start of treatment up to 54 weeks, and then approximately 
every 12 weeks (± 7 days), or sooner if clinically indicated until 
disease progression (including treatment beyond progression) or 
end of study, whichever occurs later. Cerebrospinal fluid (CSF), 
if clinically indicated, should be followed as per Response 
Assessment in Pediatric Neuro-Oncology guidelines.
Except for glioma, medulloblastoma, ependymoma, 
and other central nervous system tumors in which an 
MRI is required, CT of the brain without and with 
contrast can be performed if MRI is contraindicated.
See Section 9.1.1 for further details.
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Table 2-3:
Long-term Follow-up Period (CA045020)
Procedure
Safety 
Follow-up 
Visit 1a
Safety 
Follow-up 
Visit 2a
Safety
Follow-up 
Visit 3a
Survival Follow-up
Every 3 Months
(14 Days)b
Notesc
CSF - solid tumors and 
leukemia
As clinically indicated.
CSF cytopathology should be obtained in any 
participant with a previously positive CSF as part of 
response assessment. See Section 9.1
Bone marrow aspirate -
solid tumors and leukemia
As clinically indicated
Bone marrow aspirate should be obtained in any 
participant with a previously positive bone marrow 
aspirate as part of response assessment. See Section
9.1.
Survival Status
X
X
X
X
During safety follow-up and every 3 months (clinic 
visit or by telephone) thereafter and during survival 
phase. Include documentation of subsequent 
chemotherapy. See Section 5.1.4.
Pharmacokinetics (PK)/Immunogenicity Assessment
PK Samples
See Section 9.5.1 for further details.
Immunogenicity Samples
See Section 9.5.1 for further details.
Abbreviations: CSF = cerebrospinal fluid; CT = computed tomography; ECG = electrocardiogram; FDG = [18F]fluorodeoxyglucose; 
 
MIBG = metaiodobenzylguanidine; MRI = magnetic resonance imaging; PET = positron emission tomography; SAE = serious adverse event; SARS-CoV-2 = 
severe acute respiratory syndrome coronavirus 2.
a Participants must be followed for at least 150 days after last dose of study treatment. Follow-up Visit 1 should occur 30 days from the last dose (7) days or 
can be performed on the date of discontinuation if that date is greater than 42 days from last dose. Follow-up Visit 2 occurs approximately 100 days (7 days) 
from last dose of study drug. Follow-up Visit 3 occurs approximately 150 days (± 7 days) from last dose of study drug. All 3 follow-up visits should be conducted 
in person.
b Survival follow-up visits to occur every 3 months subsequent to Follow-up Visit 3. Survival visits may be conducted in person or by telephone. Bristol-Myers 
Squibb may request that survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant 
will be contacted to determine their survival status unless the participant has withdrawn consent for all contact.
c Some of the assessments referred to in this section may not be captured as data in the electronic case report form. 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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3
INTRODUCTION
3.1
Study Rationale
Over the past several decades, survival of pediatric oncology patients has generally improved, 
largely due to the increased use of multimodality approaches and intensive multi-agent 
chemotherapy regimens. In contrast, despite the dramatic improvement in survival observed in the 
past 3 to 4 decades due to the multidisciplinary approach applied overall to pediatric malignancies, 
the outcomes in patients with relapsed or refractory tumors remain poor. Immuno-oncology (I-O) 
therapies aimed at enhancing the patient’s immune response against the tumor represent an 
important new treatment option for improving outcomes in children with refractory or recurrent 
malignancies. The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)
pathway has been implicated in several pediatric solid tumor types. A number of pediatric clinical 
programs with PD-1 and PD-L1 inhibitors are currently underway in these and other pediatric 
tumors. To date, the use of single-agent I-O therapy in children has not provided sufficient 
evidence of activity to support a comprehensive development program in pediatrics. 1 , 2 , 3
Bempegaldesleukin is an interleukin (IL)-2 pathway agonist that mobilizes, activates, and 
proliferates lymphocytes to the tumor microenvironment and is expected to increase PD-L1 
expression on tumors due to secretion of interferon-gamma (IFN-γ) and other cytokines by 
increased numbers of tumor-infiltrating lymphocytes (TILs). Bempegaldesleukin in combination 
with the anti-PD-1 antibody nivolumab demonstrated clinical responses in the adult PIVOT-02 
study (Section 3.2.5.2). These observations, along with prior experience with the use of IL-2 
(aldesleukin) in pediatric cancer patients, implies that bempegaldesleukin in combination with 
nivolumab may potentially benefit pediatric cancer patients.
3.1.1
Research Hypothesis 
Treatment with bempegaldesleukin in combination with nivolumab will be safe and have clinical 
activity in pediatric participants with malignant neoplasms that are refractory, relapsed, or 
participants for whom curative treatments are lacking.
3.2
Background
3.2.1
Overview of Malignant Neoplasms in the Pediatric Population
Although pediatric cancer is rare, it is the leading cause of death by disease past infancy among 
children in the United States (US). In 2017, it is estimated that 15,270 children and adolescents 
between the ages of 0 to 19 years will be diagnosed with cancer and 1,790 will die of the disease 
in the US.4 Significant advances have been made in the treatment of children and adolescent 
patients diagnosed with cancer over the past 5 decades. In spite of these advances, an unacceptable 
proportion of children are not cured up front with existing treatment modalities, and those with 
relapsed or metastatic disease still have a dismal outcome. Those who survive often have 
significant lifelong morbidity from toxicities associated with surgery, radiation,
and 
chemotherapy. A significant increase in the incidence of childhood cancer has been observed over 
the past 3 decades. The overall incidence of cancer increased by 1.0% per year in children due to 
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an increased incidence of most tumor types, and by 1.5% in adolescents (15 to 19 years) mainly 
because of the increased incidence of leukemias/lymphomas, epithelial tumors, and melanoma.5,6
Improvement in the outcomes of pediatric patients with cancer has not been uniformly spread 
across all tumor types. Based on data from 54 population-based cancer registries over the period 
from 1988 to 1997,7 the greatest reduction (greater than 50%) in 5-year mortality was observed 
for leukemia (all groups, and acute lymphocytic leukemia [ALL] in particular), lymphomas (all 
groups, and non-Hodgkin lymphoma [NHL] in particular), retinoblastoma, hepatic tumors, and 
germ cell tumors. The use of multidisciplinary approaches and intensive multi-agent chemotherapy 
regimens has substantially improved the outcomes of patients with leukemia, which is most 
commonly diagnosed in the first years of life. Five-year survival of children with neuroblastoma 
has also remarkably increased, ranging from 84% in infancy, which is also the age of highest 
incidence, to 47% for children aged 1 to 4 years, and 38% for those aged 10 to 14 years.8 However, 
for medulloblastoma, osteosarcoma, and Ewing sarcoma, little change was noted in survival,9 and 
broadly, the lowest reduction in mortality from 1988 to 1997 was observed in soft tissue sarcomas 
and central nervous system (CNS) tumors as compared with other pediatric solid tumors.7 One of 
the major advances in pediatric oncology has been the acknowledgement that pediatric tumors are 
fundamentally different from those of adults, with the notable exceptions of Ewing sarcoma,10
many osteosarcomas,11 Hodgkin lymphoma (HL),12 certain subtypes of medulloblastoma,13 and 
melanoma.14
Pediatric Non-Melanoma Solid Tumors: The incidence of solid tumors in pediatric patients is 
rare. The incidence in people aged 14 and younger ranges from 3.9 per 100,000 to 10.2 per 100,000 
(Krebsregister Saarland Cancer Registry 15 ; North Rhine-Westphalia Cancer Registry 16 ; 
Niedersachen Cancer Registry, 17 Cancer Registration Statistics England, 18 Cancer Registry 
France,19 Cancer Registry Slovenia,20 Majaslapa Onkologija,21 Lithuanian Cancer Registry,22
Netherlands Cancer Registry,23 Surveillance, Epidemiology, and End Results Program [SEER] 
version 8.2.12124). The incidence of solid tumors is higher among those aged 0 to 4 years than 
those aged 5 to 14 years and increases with each subsequent 5-year age group, up to over 
3,000 cases per 100,000 in people aged 80 or older (Cancer Registration Statistics England).18
Based on the incidence rates of all solid tumors, there are approximately 6,600 children younger 
than 15 years diagnosed per year in the European Union’s (EU’s) 28 countries. Using the survival 
data from SEER from the US and incidence data from the EU, the prevalence estimate of children 
younger than 15 years at the end of 2017 with a solid tumor diagnosis and still alive is estimated 
to be approximately 73,000 across the US and EU. The age of diagnosis and prevalence of each 
solid tumor, however, varies depending on the underlying histology. For example, neuroblastoma 
is the most common pediatric solid tumor, particularly in children younger than 1 year. 
Osteosarcoma and Ewing sarcoma, however, are traditionally adolescent/young adult tumor types
(for example, Ewing sarcoma has a median age at diagnosis of 15 years). Although all of the tumor 
types have low incidences in the US (below 1 per 100,000 among those aged 1 to 14 years [SEER 
version 8.2.1]), there is also variability within this, with the respective incidence rates per 100,000 
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for patients aged 0 to 14 years being 0.3, 0.8, 0.5, and 0.4 for Ewing sarcoma, neuroblastoma, 
rhabdomyosarcoma (RMS), and osteosarcoma, respectively. Using the US survival and incidence 
data from SEER, the prevalence of children younger than 15 years at the end of 2017 with a 
diagnosis of Ewing sarcoma, osteosarcoma, neuroblastoma, or RMS and still alive is estimated to 
be approximately 16,000.
Common types of solid tumors in children, including brain tumors, neuroblastoma, RMS, Wilms’
tumor, osteosarcoma, and retinoblastoma, have seen significant improvement in survival rates with 
localized disease; however, improvement in survival with metastatic disease has been more 
limited.25,26 Although the introduction of chemotherapeutic drugs into treatment regimens that 
were previously reliant on surgery and radiotherapy marked a major advancement in treatment, 
more still needs to be done because malignant neoplasms remain a leading cause of non-accidental 
death in children aged 5 to 14 years in the US.27
Neuroblastoma: Neuroblastoma is the most common extracranial solid tumor of infancy that 
arises from the sympathetic nervous system. Neuroblastomas are a clinically heterogeneous tumor 
with variable outcomes ranging from spontaneous regression, maturation to a benign 
ganglioneuroma, or aggressive disease with metastatic dissemination leading to death. The 
definition of neuroblastoma risk among various cooperative groups has been inconsistent due to 
the broad spectrum of clinical behavior exhibited by different tumors (eg, spontaneous regression 
or maturation despite multimodality treatment). Consequently, neuroblastomas are now staged 
using the International Neuroblastoma Risk Group Staging System, which was originally
developed as part of an international collaboration to define risk based on image-defined risk
factors.28 However, treatment is based on the Children’s Oncology Group (COG) neuroblastoma 
risk strata. Patients are classified into low-, intermediate-, and high-risk categories based on certain 
characteristics at the time of diagnosis, including age, disease stage, tumor histology, presence or 
absence of amplification of the MYCN oncogene, and quantitative deoxyribonucleic acid (DNA)
content of the tumor (DNA index or ploidy). For patients with low-risk disease, multi-agent low-
or moderate-intensity chemotherapy is reserved for unresectable tumors or for patients who have 
symptoms of spinal cord compression or respiratory or bowel compromise. Frequently used agents 
include combinations of cyclophosphamide, carboplatin or cisplatin, etoposide or teniposide, and 
doxorubicin.
Moderately 
intensive 
multi-agent 
chemotherapy 
(eg, 
with 
doxorubicin 
cyclophosphamide, a platinum drug, and etoposide) is recommended for children with 
intermediate-risk neuroblastoma and is often applied before attempted resection.29 Patients at the 
highest risk for disease progression and mortality are those who are older than 18 months and have 
disseminated disease or localized disease with unfavorable markers such as MYCN amplification. 
An aggressive multimodality approach including high-dose chemotherapy, surgical resection, 
hematopoietic stem cell rescue, and radiation therapy is used. The combination of IL-2, anti-GD2 
monoclonal antibody (ch14.18, dinutuximab), and granulocyte-macrophage colony-stimulating 
factor (GM-CSF) with cis-retinoic acid was evaluated in a Phase 3 trial vs cis-retinoic acid alone 
(standard therapy) in participants with high-risk neuroblastoma in remission after stem cell 
transplant.30,31 This study found improved rates of event-free survival (EFS) (66% vs 46% at 
2 years, P = 0.01) and overall survival (OS) (86% vs 75% at 2 years, P = 0.02) compared with
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standard therapy. However, the contribution of IL-2 in this combination is unclear. Subsequent 
trials performed by the Société Internationale d’Oncologie Pédiatrique (SIOP)-Europe have 
suggested that co-treatment with IL-2 is not beneficial. In this trial, high-risk neuroblastoma 
participants were randomized to receive either ch14.18 alone or in combination with subcutaneous 
IL-2.32 All participants also received 6 cycles of cis-retinoic acid. The 3-year EFS and OS rates in 
participants who did not receive IL-2 were 60% and 66%, respectively, whereas the 3-year EFS 
and OS rates in those who received IL-2 was 57% and 65%, respectively. The differences in both 
EFS and OS between the arms were not significant. Direct comparisons between these 2 trials is 
difficult given the different routes and doses of IL-2 used and the addition of GM-CSF in the latter 
trial. Dinutuximab was approved, in combination with GM-CSF, IL-2, and cis-retinoic acid, for 
the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial
response (PR) to prior first-line multi-agent, multimodality therapy by the US Food and Drug
Administration (FDA) in Mar-2015. Despite intensive multimodality therapy, only approximately 
40% of children remain disease free long-term, and the most common outcome of high-risk 
neuroblastoma is recurrence of disease followed by death. Improving survival in this group of 
children is a priority in international cooperative groups.
Rhabdomyosarcoma: RMS is a common pediatric malignant tumor of the muscle that accounts 
for 40% of all soft tissue sarcomas. These tumors can occur almost anywhere in the body, and 
symptoms are usually dependent on the location of the primary or metastatic lesions.33 The current 
World Health Organization (WHO) classification recognizes 4 distinct histological RMS types: 
embryonal, alveolar, pleomorphic (which occurs most commonly in adults), and spindle 
cell/sclerosing. 34 Due to its diverse morphologies, integrated diagnostic methods, including
immunohistochemical and molecular methods, are necessary to diagnose RMS type. Whereas 
embryonal RMS has no putative genomic markers, the majority of alveolar RMSs are 
characterized by a fusion between the PAX3 or PAX7 genes and FOXO1 gene.35 The prognosis 
varies significantly, from 70% survival for nonmetastatic disease to less than 20% survival for 
metastatic disease. Embryonal RMS and its variants, along with spindle cell RMS, are accepted as
favorable pathologies, whereas alveolar RMS with its solid variant is accepted as an unfavorable 
pathology. This classification is significant for the evaluation of the clinical stage. The risk-
stratification system currently used by the COG incorporates both pretreatment staging (based on 
anatomic site and tumor/node/metastasis status) and clinical group assignment (based on extent of 
disease following pretreatment surgical procedure).33 Patients with recurrent disease have a very 
poor survival independent of treatment modality. The treatment of RMS requires multimodality 
therapy consisting of systemic chemotherapy, with either surgery, radiation therapy, or both 
surgery and radiation therapy to maximize local tumor control. When possible, surgery is 
performed prior to systemic chemotherapy. 36 , 37 , 38 The management and overall treatment 
philosophy for RMS differs between the Soft-tissue Sarcoma Committee of the COG (COG-STS), 
the Intergroup Rhabdomyosarcoma Study (IRS) Group, the US and Canadian precursor to COG, 
and the SIOP Malignant Mesenchymal Tumor (MMT) Group. The main COG-STS objective has 
been the use of local therapies soon after the initial operation or biopsy (except in patients with 
metastatic disease), using radiation therapy for patients with residual disease. The primary intent 
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of the COG-STS approach is avoiding relapse and subsequent salvage therapy. The main objective 
of the MMT Group has been to reduce the use of local therapies by using initial front-line 
chemotherapy followed by second-line therapy only in the presence of poor response. Surgery is 
preferred, and radiation therapy is used only after incomplete resection, regional lymph node 
involvement, or poor clinical response to chemotherapy. The intent of this approach is to avoid the 
risks associated with major surgical procedures and long-term morbidity from radiation therapy.
Survival for most RMS patient subsets is improved with the use of early local therapy, including 
radiotherapy. OS rate with the MMT Group approach was 71%, compared with an OS rate of 84% 
in the IRS-IV study.36 EFS rates at 5 years were 57% in the MMT89 study vs 78% in the IRS-IV 
study. Participants with extremity and head and neck nonparameningeal tumors experienced the 
greatest differences in outcome. Participants with bladder/prostate primary tumors who did not 
receive radiation therapy during initial therapy had lower failure-free survival, but there was no 
difference in OS between the MMT Group and IRS-IV approaches for these participants.39
Although patients with recurrent or progressive RMS sometimes achieve complete remission with 
secondary therapy, the long-term prognosis is usually poor with treatment options of surgery 
and/or radiation therapy and chemotherapy.40,41
Ewing Sarcoma: Ewing sarcoma is the second most common primary malignant bone cancer in 
children and adolescents after osteosarcoma.42 Ewing sarcoma occurs primarily in bones, with rare
occurrences in soft tissues. The median age at diagnosis is 15 years, with a Caucasian male
predilection, and occurs well into early adulthood. Ewing sarcoma has an average incidence of 
2.93 cases/1,000,000 reported annually between 1973 and 2004 that has not increased appreciably 
over the past 30 years.43 Prognostic factors for treatment stratification of Ewing sarcoma are 
metastases at diagnosis, primary site, and age.44 However, there is no widely accepted formal 
staging system, with most studies in Ewing sarcoma being stratified by the presence or absence of 
metastatic disease. The current chemotherapy protocols used to treat Ewing sarcoma include 
various combinations of the following 6 drugs: doxorubicin, cyclophosphamide, vincristine, 
actinomycin-D, ifosfamide, and etoposide. Localized Ewing sarcoma is usually treated via surgical 
excision or radiotherapy, or a combination of both. In cases in which surgical excision is not 
possible due to the large size of the tumor, its anatomical location, or the fact that the acquired 
surgical margin is not sufficient to achieve local control, pre- or postoperative radiotherapy is 
usually selected. The current 5-year OS rate for patients with localized disease is 65% to 75%. 
Patients with metastases have a 5-year OS of 30%, except for those with isolated pulmonary 
metastasis (approximately 50%). Patients with recurrence have a dismal prognosis.45
Wilms’ Tumor: Wilms’ tumor is the most common pediatric kidney tumor of childhood and often 
arises secondary to molecular aberrations in normal renal development, which explains the rarity 
of this tumor in adults. It is often associated with a number of different genetic syndromes and has 
a strong hereditary component for which screening is available.46 Since the late 1960s and early 
1970s, 2 different approaches for the treatment of Wilms’ tumor have been studied extensively by 
the COG and the SIOP. The COG established the standard treatment for Wilms’ tumor in North 
America, consisting of primary surgery when possible except in certain circumstances such as 
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extensive, inoperable tumors at presentation or synchronous bilateral disease, followed by 
chemotherapy and, in high-risk patients, radiation therapy.47,48,49,50 This approach allows for early 
and accurate histologic diagnosis and staging. In contrast, the SIOP established the standard 
treatment in Europe, consisting of initial front-line combination chemotherapy (vincristine and 
dactinomycin) in children with localized tumors, and additional doxorubicin in those presenting 
with metastases, followed by surgery, which results in fewer tumor ruptures during surgery and
lower postoperative staging.51,52 Due to excellent clinical outcomes seen with both the COG and 
the SIOP approaches, OS for patients with Wilms’ tumor in high-income countries is greater than 
90% for localized disease and 75% for metastatic disease.53 Approximately 15% of patients with 
favorable-histology Wilms’ tumor and 50% of patients with anaplastic Wilms’ tumor experience 
recurrence.54 The most common site of relapse is lung, followed by abdomen/flank and liver. As 
a result of modern treatment combinations, the outcome after recurrence has improved up to an 
approximately 60% 5-year survival rate.55,56
Retinoblastoma: Retinoblastoma is primarily a pediatric malignancy and is the most common 
primary intraocular malignancy of childhood, accounting for 10% to 15% of cancers that occur 
within the first year of life. Retinoblastoma occurs in approximately 1 in 15,000 to 1 in 16,600 live 
births in the US and Northern Europe. Between 2005 and 2009, the annual incidence of 
retinoblastoma in the US among children younger than 15 years was 4.1 per million. 57
Retinoblastoma presents unilaterally in approximately 60% to 70% of cases and bilaterally in the 
remaining 30% to 40%. Unilateral retinoblastoma is typically associated with sporadic mutations 
in RB1 tumor suppressor gene, with heritable mutations of RB1 occurring in approximately 10% 
of patients, and a subset of unilateral non-heritable retinoblastoma have high MYCN oncogene 
amplification without RB1 mutation. 58 Bilateral retinoblastoma is frequently associated with 
germline mutations in RB1. First-line therapeutic options for retinoblastoma include local and 
systemic chemotherapy,
cryotherapy, laser photoablation, radioactive plaques (I-125 
brachytherapy), and enucleation. Retinoblastoma is a chemotherapy-sensitive malignancy. The 
agents used most commonly for ophthalmic artery chemosurgery include melphalan, carboplatin, 
and topotecan; various regimens are used for systemic therapy, most typically including 
carboplatin, vincristine, etoposide, and topotecan.59 The overall 5-year survival rate for children 
with retinoblastoma in the US is over 95%. Patients who develop metastatic disease usually do so 
within 1 year of diagnosis; a child who remains recurrence free for 5 years after diagnosis is 
considered cured.60
3.2.1.1
Pediatric Tumors of the Central Nervous System
Brain and other tumors of the CNS are the second most frequent childhood cancer and the most
common solid tumor in children, accounting for nearly 22% of all tumors diagnosed under the age 
of 15 years.15, 61 An estimated 4,620 new cases were diagnosed in 2015, 62 and more than 
28,000 children are estimated to be living with this diagnosis in the US.63 The most common 
primary CNS tumors are gliomas, medulloblastoma, and ependymoma, with high-grade gliomas 
(HGGs) accounting for about 20% of all childhood brain tumors. Whereas some types, such as
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medulloblastoma, ependymoma, and germ-cell tumors, are associated with a reasonably good
prognosis at diagnosis, others such as diffuse intrinsic pontine glioma (DIPG) and high-grade
astrocytoma currently do not have any curative treatment options. The median life expectancy of
children diagnosed with DIPG is less than 1 year, and pediatric patients with high-grade
astrocytoma also suffer from an extremely poor prognosis.
High-grade Glioma: Pediatric HGGs are malignant, diffusely infiltrative, rapidly progressive 
tumors and are managed with surgical resection, adjuvant postoperative radiation, and 
chemotherapy; however, outcome remains dismal, a prognosis that has been unchanged for 
decades, and most patients eventually relapse and die of disease. Although pediatric HGGs 
resemble their adult counterparts histologically, the molecular abnormalities driving these tumors 
are dramatically different. The majority of malignant pediatric HGGs have somatic mutations in 
histone genes and genomic hypomethylation, whereas adult HGGs more frequently have 
abnormalities in signal transduction pathways. 64 The classification of HGGs has undergone 
significant changes in the past few years, which were highlighted by the recent amendments to the 
WHO classification of these tumors. Although this category comprises multiple subtypes of 
tumors, the standard treatment approaches are relatively uniform and are comprised of maximal 
safe surgical resection followed by focal radiation therapy. Although transient responses with this 
approach are observed, the majority of patients will succumb to their disease. The addition of 
chemotherapy, typically temozolomide, may provide a small benefit. For example, the COG trial 
ACNS0126 of surgery, radiation, and temozolomide achieved a 3-year EFS rate for anaplastic 
astrocytoma and glioblastoma multiforme of 13% and 7%, respectively. The 2-year EFS rate was 
17% among participants without O6-methylguanylmethyltransferase (MGMT) overexpression 
and 5% among those with MGMT overexpression (P = 0.045).65 For patients with DIPG, surgery 
is limited to small biopsies; focal radiation therapy is standard; and chemotherapy, including 
temozolomide, has not shown an advantage. The mean OS remains at 9 to 12 months, and most 
patients had died by 2 years from diagnosis.
Medulloblastoma, Atypical Teratoid/Rhabdoid Tumors, Pineoblastoma, and Other Rare 
Embryonal CNS Tumors: Medulloblastoma are small, round, blue-cell tumors of the posterior 
fossa now divided into multiple molecular subtypes based on the molecular pathway affected in 
the tumor.13 Although the majority of subtypes are predominantly identified in children, the sonic 
hedgehog (SHH) subtype is identified in both children and adults and is thought to have similar 
biology.66 Although outcome depends significantly on the tumor subtype, treatment approaches 
are relatively uniform, and almost all patients continue to receive maximal safe surgical resection, 
risk-adapted craniospinal radiotherapy, and multi-agent chemotherapy, typically consisting of 
vincristine,
cisplatin, 1-(2-chloroethyl)-3-cyclohexyl-nitrosourea (lomustine/CCNU),
and/or 
cyclophosphamide. Cure rates are excellent for certain molecular subtypes (eg, windgless > 90%) 
and poor for others (eg, Group 3 MYC amplified < 50%).66, 67 Although the outcome for 
medulloblastoma has improved with traditional therapies, for those with Group 3 tumors, as well 
as those with relapsed disease, the prognosis remains poor. Additionally, therapy can cause 
delayed complications,
including neurocognitive impairment, hearing loss,
endocrine 
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abnormalities, cerebrovascular disease, and second malignancies, with profound effect on quality 
of life in survivors.
Atypical teratoid rhabdoid tumors (AT/RTs), pineoblastoma, and other rare embryonal CNS
tumors are predominantly pediatric malignancies of the CNS and are biologically distinct
molecular subtypes of pediatric brain tumors, although morphologically they resemble
medulloblastoma and are treated with similar approaches. AT/RTs arise mostly in children
younger than 3 years and are associated primarily with loss of SMARCB1 or SMARCA4 gene
expression. Treatment with conventional postoperative chemotherapy alone results in less than
20% survival, whereas treatment with multimodal regimens designed specifically for AT/RTs
containing radiation therapy, intrathecal chemotherapy, and/or high-dose chemotherapy with stem 
cell rescue have achieved 2- or 3-year survival rates ranging between 20% to 50% depending on 
the treatment protocol.68
Pineoblastomas are highly malignant WHO Grade IV69 tumors located in the pineal region that 
usually present with obstructive hydrocephalus. Treatment with the combination of surgery, 
radiation, and chemotherapy is similar to that used for high-risk medulloblastoma and results in 5-
year survival rates of about 60%. Embryonal tumors outside the posterior fossa or pineal region 
are treated similar to pineoblastoma and medulloblastoma, although the long-term survival of this 
group of patients is less than 50%. A complicating factor for many of these patients, including 
those with medulloblastoma, is young age at the time of diagnosis. Due to severe effects of 
radiation therapy on the developing brain, radiation sparing approaches are used. Although slightly 
less effective than the combined surgery, radiation, and chemotherapy approaches mentioned 
above for older children, patients who receive maximal surgery, multi-agent chemotherapy, and 
high-dose chemotherapy with stem cell rescue have a better cognitive outcome. Despite 
improvement in the cure rates of pediatric brain tumors during the past 2 decades of the 20th 
century, which was largely a result of technologic advances in imaging, neurosurgery, radiation 
oncology, and the introduction of combination chemotherapy, outcomes have remained static for 
all of these tumors except medulloblastoma and low-grade gliomas. Developing effective, as well 
as less toxic, treatments for pediatric CNS tumors arguably represents one of the major remaining 
unmet medical needs in pediatric oncology.
Ependymomas: Ependymomas are the third most common brain tumors in the pediatric 
population, comprising 5% to 10% of all brain tumors. Pediatric ependymomas typically arise 
intracranially, in the supratentorial compartment, and within the posterior fossa, and are 
biologically different from spinal cord ependymomas, which typically occur in adults.70 Four 
pediatric subtypes have been further identified through genome methylation profiling.71 The initial 
treatment for ependymoma in the brain consists of maximal safe resection and adjuvant radiation 
therapy. About half the cases of malignant pediatric ependymoma relapse, mostly local recurrences 
that can sometimes be completely surgically resected. However, long-term prognosis for patients 
with recurrent disease is poor, and most will eventually die from relapse. Like many of the other 
primary CNS tumors, ependymomas have seen a significant evolution in their molecular 
categorization and classification. Unfortunately, the molecular pathways identified in these tumors 
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have not lent themselves to treatment with targeted drugs. As such, the standard treatment for 
ependymoma has not changed significantly over the past 2 decades and is comprised of maximal 
safe surgical resection and focal radiation therapy. Although the 5-year EFS and OS of those with 
complete resection is approximately 80%, there are increasing data that this may continue to drop 
to 50% or less over time. For those with incompletely resected ependymoma, the 5-year EFS is 
much lower and less than 20% of patients will survive long term. Although the addition of 
chemotherapy can induce transient responses, it is typically used for patients with bulk residual 
disease and is still being evaluated for its role in improving outcome. At the time of recurrence, 
especially in patients who have already received focal radiation therapy, the long-term prognosis 
of these patients is very poor.
3.2.1.2
Pediatric Hematologic Malignancies
Non-Hodgkin Lymphoma: Lymphomas rank third in the list of most common childhood 
malignancies, constituting 10% to 12% of cancers in children. Nearly two-thirds of the lymphomas 
diagnosed in children are NHL.72 Although the outcome for NHL at diagnosis is excellent using 
treatment strategies that are tailored to the specific patient and disease subtype, those with recurrent 
or refractory disease do poorly and are in need of novel approaches. In children, NHL is distinct 
from the common lymphomas observed in adults and is almost always high grade at presentation. 
Approximately 70% of children with NHL present with advanced disease and/or have metastatic 
involvement, including bone marrow, CNS, and/or bone,73 as opposed to NHL in adults, which 
tends to present as low or intermediate grade. NHL of childhood and adolescence falls into 3 main 
histological categories: mature B-cell (Burkitt and Burkitt-like lymphomas [30%] and diffuse large 
B-cell lymphoma [DLBCL; 10 to 20%]), lymphoblastic lymphoma (20%), and anaplastic large 
cell lymphoma (10%). Other types of lymphoma, including T-cell lymphoma, cutaneous 
lymphomas, and indolent B-cell lymphomas such as follicular lymphoma (FL), are more 
commonly seen in adults and only rarely diagnosed in children.74 NHL accounts for approximately 
7% of cancers in children younger than 20 years. Childhood NHL occurs most commonly in the 
second decade of life and occurs infrequently in children younger than 3 years. In children, NHL 
consists predominantly of mature, aggressive B-cell lymphomas, with Burkitt lymphoma being 
most common in 5- to 14-year-olds and DLBCL predominating in 15- to 19-year-olds. Both have 
superior outcomes relative to adults, with OS rates greater than 90%.74,75 ,76 ,77 Using gene 
expression profiling (GEP), DLBCL has been further differentiated into the germinal center B-
cell-like (GCB) and activated B-cell-like (ABC) subtypes, both of which are biologically and 
clinically diverse entities.78 Adult patients with the GCB subtype have a significantly better OS 
compared with those with the ABC subtype.78,79 , 80 , 81 Compared with adults, children and 
adolescents with DLBCL have a better OS. One explanation may be the difference in biology, 
because pediatric DLBCL shares more features with Burkitt lymphoma, including high 
proliferation, increased MYC expression, decreased BCL2 expression, higher incidence of MYC
translocation, and germinal center phenotype (75%).82,83 In addition, using GEP to distinguish the 
GCB and ABC subtypes of DLBCL, Deffenbacher et al81 more recently reported a 3:1 
predominance of the GCB subtype vs ABC subtype in pediatric DLBCL. Although there was a 
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homogeneity between the pediatric and adult GCB sinusoidal large B-cell lymphoma subtype, 
some subtle differences in gene expression and genetic alterations suggested underlying 
differences in tumor biology between childhood and adult cases. Of the other histological subtypes 
most commonly diagnosed in children and adolescents, lymphoblastic lymphomas (20% of 
childhood NHL) are usually positive for terminal deoxynucleotidyl transferase, with more than 
75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.84
Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma. 
Anaplastic large cell lymphoma accounts for approximately 10% of childhood NHL.85 Although 
the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell 
disease (ie, no T-cell, B-cell, or natural killer [NK]-cell surface antigen expression) does occur. 
All anaplastic large cell lymphoma cases are CD30-positive, and more than 90% of pediatric 
anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. 
About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the 
expression of the NPM-ALK fusion protein; the other 15% of cases are comprised of variant ALK
translocations. Although FL is the second most common lymphoma worldwide, it mainly affects 
adults and rarely occurs in the pediatric population and young adult patients.86 In addition, the 
other types of lymphoma, such as peripheral T-cell lymphoma, T-cell/NK-cell lymphomas, and 
cutaneous lymphomas, more commonly seen in adults, also occur rarely in children. According to 
the National Cancer Institute (NCI) SEER database, from 2007 to 2011, the incidence of NHL 
(except Burkitt lymphoma) increased steadily with age, from 4.5 cases per million individuals in 
the 1- to 4-year-old age group to 14.1 cases per million individuals in the 15- to 19-year-old age 
group. The incidence of NHL was nearly twice as high in males as compared with females, with 
an age-adjusted incidence of 1.5 cases per 100,000 males vs 0.8 cases per 100,000 females.87 Risk 
factors for development of pediatric NHL include congenital and acquired immunodeficiencies 
such as human immunodeficiency virus (HIV) or immunodeficiency after solid organ 
transplantation. Most cases of NHL in the immunocompromised population are associated with 
Epstein-Barr virus (EBV). In endemic Africa, 85% of Burkitt lymphoma is associated with EBV,
whereas EBV is only associated with 15% of cases of Burkitt lymphoma in Europe and the US.74
The primary therapy for childhood NHL is multi-agent chemotherapy, and the intensity and length 
of therapy are usually determined by the subtype and stage of disease. The prognosis for children 
with NHL, both limited- and advanced-stage disease, has improved significantly over the past 
2 decades. The OS for NHL in children across all age groups has continued to steadily improve, 
with a 5-year survival from 2004 to 2010 of 86.5%. Children with limited-stage NHL have an 
excellent prognosis with an estimated 5-year EFS of 90 to 95%.88,89 The prognosis for advanced-
stage disease has also improved and varies based on subtype (60% to 90% 5-year EFS).89,90,91,92,93
The following are known prognostic factors in pediatric NHL: age, site of disease, chromosomal
abnormalities, tumor burden, and early response to therapy (Burkitt lymphoma).85 In children with 
relapsed or refractory NHL, the prognosis is not as promising, and the best treatment approach for 
this poor-risk group continues to be a challenge.94,95 There is little consistency in therapeutic 
approaches, and there is no formal recommendation on the best approach for this poor prognostic 
subgroup; new treatment options are needed.
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Pediatric Leukemias: Leukemias are the most common cancer observed in children and have 
seen a dramatic improvement in outcome over the past 50 years. Although significant differences 
in the upfront treatment exist between the different subtypes of ALL and acute myeloid leukemia 
(AML), those with recurrent disease, especially AML, do poorly and are difficult to salvage or, in
the case of ALL, require intensive treatment (eg, stem cell transplant) associated with significant
long-term morbidity, although 30% to 50% overall with relapsed ALL can be cured. ALL accounts 
for 25% of new cancer diagnoses, or approximately 3,100 new cases in the US per year under the 
age of 20, the majority of which occur in early childhood (younger than 8 years).96 The incidence 
is significantly higher in Hispanic and White children compared with Black children (Section 29 
of the SEER Cancer Statistics Review).97 ALL is divided into T- and B-cell subsets. There are a 
number of genetic syndromes that predispose patients to ALL, the most common of which is Down 
syndrome. Based on new molecular analyses, the B-cell subtypes are categorized based on their 
dominant molecular translocation98 and are major components of prognostic determination and 
treatment intensity. With current approaches, overall cure rates for children with ALL hover 
around 85% to 90% using risk-adapted multi-agent chemotherapy. Risk-based stratification has 
become a central component of treatment for pediatric ALL because it impacts prognosis.99 The 
features that differentiate low-, intermediate-, and high-risk patients vary by group; however, age 
and white blood cell (WBC) count at presentation are thought to be especially important, and age 
younger than 1 year or older than 10 years and WBC > 50,000 at presentation are regarded as high-
risk features.100 Patients on steroids are also considered high-risk because this agent, which has 
potent anti-leukemia cell effects, can artificially reduce the diagnostic WBC count. Another
important variable for high-risk disease is the presence of disease in sanctuary sites (sites where
chemotherapy penetration is thought to be more difficult) and includes the CNS and testes. 
Immunophenotyping has become an important component of ALL categorization. Although in 
general those with pre-B-cell phenotype are most likely to be cured, more aggressive therapy for 
the T-cell phenotypes (except early T-precursor ALL) has improved the outcome for both 
groups.101 Approximately 5% of leukemias have mixed or undifferentiated lineages, and these 
patients tend to have a very poor outcome.102 More recently, cytogenetic profiles of pediatric 
leukemias have further refined the prognostic classification of this disease. For example, 
hyperdiploidy (51-65 chromosomes per cell) and the ETV6/RUNX1 translocation both have 
favorable outcomes and are seen in approximately 25% of cases of pre-B-cell ALL.100 In contrast 
to hyperdiploidy, hypodiploidy (< 44 chromosomes) is a poor prognostic indicator. Finally, 
response to initial induction therapy is also an important predictor of outcome in pediatric ALL.103
Although initial responses based on residual blasts in the bone marrow at end of induction are 
commonly used, the sensitivity of polymerase chain reaction can detect the molecular signature of 
residual blasts to less than 1 cell per 100,000.104 Treatment for ALL typically consists of intensive 
induction with multi-agent chemotherapy (vincristine, corticosteroids, and asparaginase and an 
anthracycline) lasting 4 to 6 weeks and results in remission in 95% of patients. This is followed 
by consolidation, and the duration and drugs used vary between studies. In general, this phase lasts 
6 to 9 months and often adds mercaptopurine, thioguanine, methotrexate, cyclophosphamide, 
etoposide, and/or cytarabine. During these first 2 phases, CNS treatment or prophylaxis are added 
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and can include intrathecal chemotherapy, systemic chemotherapy that can penetrate the blood-
brain barrier, or cranial radiation. Treatment is completed with maintenance chemotherapy, which 
typically lasts a few
years and tends to be antimetabolite based (methotrexate and 
mercaptopurine).100 For patients with high-risk disease (infants, elevated WBC at diagnosis, T-
cell disease, and those with MLL gene rearrangements), the therapy (especially induction and 
consolidation) is intensified but follows the same general principles as discussed previously. After 
induction failure or relapse, high-dose chemotherapy with stem cell rescue has proved to be an 
important salvage strategy that can result in cure in up to 40% of children.105 The reinduction 
regimens are similar to those used at the time of initial diagnosis and can result in initial remission 
in the majority of patients.106 The subsequent choice of therapy is dependent on a number of 
factors but usually includes high-dose chemotherapy and stem cell rescue. A number of new and 
exciting treatment options are now being developed for relapsed ALL, many of which focus on 
harnessing the power of the immune system to identify and kill tumor cells. Chimeric antigen-
receptor T-cells use the patient’s own T-cells genetically modified to express a receptor for a 
leukemia cell target (such as CD19)107 and have been approved for patients with relapsed disease. 
Bispecific (dual specificity) antibodies against CD19 and CD3 108 or antibodies fused with 
toxins109 have also demonstrated exciting results in subsets of patients.
Although advances for AML have paralleled those for ALL, current cure rates hover around 
65%.110 These leukemias account for approximately one-fifth of all leukemias and are thought to 
arise from bone marrow-derived stem or progenitor cells. These are differentiated from chronic 
leukemia by blast counts greater than 20% in the marrow at the time of diagnosis. Like ALL, there 
are a number of associated genetic and environmental factors that can predispose to AML,
including Down syndrome. The treatment of AML, like that for ALL, is risk adapted and 
chemotherapy based. Pediatric patients with AML are typically treated using 2 main elements:
1) Induction is made up of daunorubicin (daunomycin), cytarabine (ara-C) etoposide, and/or 6-
thioguanine and is usually more compressed and thus with greater toxicity. This therapy 
continues until morphologic remission in the blood and bone marrow is achieved (typically 
2 to 3 cycles and successful in 85% to 90%). Concurrent intrathecal chemotherapy similar to 
that used in ALL is typically added to prevent CNS relapse.
2) Consolidation, sometimes referred to as intensification, is designed to kill the residual tumor 
cells that survived induction.
For many patients with a human leukocyte antigen-matched sibling, an allogeneic transplant is 
often the next step, especially in AML patients with poor prognostic markers. Therapy is generally 
much more intense than that used for ALL and does not typically include a maintenance phase. At 
the time of recurrence or for those patients who do not achieve induction remission, attempts at 
salvage with repeat intensive chemotherapy, especially if the interval between initial diagnosis and 
relapse is many years, can be considered. Unfortunately, the overall outcome for relapsed AML 
remains poor, and the majority of patients will succumb to their tumor.
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3.2.1.3
Overview of Melanoma in the Pediatric Population
Advanced melanoma is generally regarded as a similar disease in adolescents and adults and is
treated similarly. Metastatic melanoma does not commonly occur in the pediatric population from 
age 0 to less than 12 years.14 The incidence reported in the US population for the age groups of
1 to 5 years, 5 to 9 years, and 10 to 14 years is 0.10, 0.16, and 0.37 per 100,000, respectively. The
incidence in the US is higher in adolescents: 1.72/100,000 (15 to 19 years) (The SEER Carcinoma 
Statistics Review).24 In the European Cooperative Study Group for Pediatric Rare Tumors 
(EXPeRT) study of melanoma incidence in Italy, Poland, Germany, and France, incidence of 
cutaneous melanoma was reported as 0.7 to 0.8 per million per year for ages 0 to 10 years and 
10 per million per year for ages 15 to 19 years.111 Overall, the pediatric incidence rates (5.4 per 
1 million children and adolescents in the US)112 are dramatically lower than the adult incidence 
and add to the difficulty of evaluating adolescent melanoma in clinical trials. The diagnosis of 
pediatric melanoma is complicated by histologic uncertainty and disease characteristics. 
Melanoma can be confused with Spitz nevi, dysplastic nevi, traumatized nevi, halo nevi, and some 
congenital melanocytic nevi.113 The key primary tumor characteristics, such as the site of the 
primary tumor, stage at diagnosis, tumor thickness, and level of invasion, are comparable between 
adolescent and adult melanoma patients. In contrast, prepubescent patients appear to have different 
characteristics (eg, with thicker tumor lesions) compared with adult melanoma patients. In an 
analysis of 1,255 children (age younger than 20 years), the 10 to 19-year-old age group had similar 
baseline characteristics compared with the 20- to 24-year-old age group.114 There were significant 
differences in baseline characteristics of young children (younger than 10 years) compared with 
adolescents and young adults. Young children were more likely to be non-White and to have 
metastases; nodular or other histology; head, face, or neck primaries; thicker lesions; and history 
of cancer. There are limited clinical studies evaluating treatment outcomes in pediatric and 
adolescent participants with melanoma. Despite the small number of participants, results of these 
studies showed that safety profiles and treatment effects (such as tumor shrinkage or 
pharmacodynamic effects of immunotherapy) in pediatric participants are comparable with adult 
participants. The surgical treatment of the primary tumor in children is not different from that in 
adult participants.115,116,117,118,119 Similar to adult patients, surgical resection, if feasible, for 
limited metastatic disease is recommended for pediatric patients. The National Comprehensive 
Cancer Network (NCCN) outlined the surgical management of melanoma based on stages.120 As 
in adults, there is no chemotherapy with proven efficacy for the small subset of pediatric patients 
with metastatic melanoma. Radiotherapy is rarely indicated in the management of primary 
pediatric melanoma. However, it can be considered in patients with head and neck melanomas at 
high risk for parotid or cervical metastases, and in those who develop brain metastases. Brain 
metastases have been reported to occur during the course of the disease in up to 18% of children 
with melanoma.121 Clinical studies with radiotherapy and chemotherapy in pediatric participants 
with melanoma showed a comparable safety profile to adult participants. Tumor shrinkages in 
individual participants and small studies were reported. However, the study design and the small 
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number of adolescent melanoma participants enrolled (n = 4 to 10) do not allow for a conclusive 
comparison of efficacy to adult studies.122,123,124
Immunotherapy in Melanoma: The FDA approved the expanded indication of ipilimumab 
(YERVOY®) for the treatment of unresectable or metastatic melanoma in pediatric patients aged 
12 years and older.125 In the EU, Yervoy as monotherapy is indicated for the treatment of advanced 
(unresectable or metastatic) melanoma in adults and adolescents aged 12 years and older.126
Nivolumab monotherapy is approved in multiple regions, including the US and EU, for
unresectable or metastatic melanoma and adjuvant treatment of melanoma. Nivolumab 
monotherapy has demonstrated durable response exceeding 6 months and statistically significant 
improvement in OS vs the standard of care (SOC) for adult melanoma participants.127
Anticancer Therapy in Pediatric Oncology: Almost all children with cancer undergo treatment 
in the framework of clinical studies. 128 There are no guidelines providing specific 
recommendations for off-label use of anticancer medications in children.
Summary: The majority of pediatric malignancies are different molecularly and histologically 
from common adult malignancies, with the exception of melanoma, Ewing sarcoma, some
osteosarcomas, SHH medulloblastoma, and HL. Although the large array of pediatric malignancies 
are different from each other, at the time of recurrence or progression they all share an equally 
poor prognosis. Because there are no known mechanisms common to these tumor types, immune-
based therapies may provide an approach to control disease progression by enhancing the immune
system and preventing immune evasion. Based on the potential benefit and expected safety profile 
of treatment of malignant tumors with bempegaldesleukin in combination with nivolumab 
described hereafter, a Phase 1b/2 study to evaluate safety, PK, and anti-tumor activity of 
bempegaldesleukin and nivolumab will be undertaken. This study will enroll participants younger 
than 18 years with refractory/relapsed malignant tumors, including advanced and metastatic 
melanoma, or those who have malignancies of poor prognosis, including newly diagnosed
HGG/DIPG after initial radiation. Signals for anti-tumor activity from the proposed Phase 1b/2
study will help inform the choice of target tumor types for a subsequent therapeutic confirmatory
study in subjects with non-melanoma tumor types.
3.2.2
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 IL-2 receptor and subsequent activation of 
effector T cells. As a PEGylated human recombinant IL-2 molecule of aldesleukin with an average 
of 6 releasable polyethylene glycol (PEG) chains, bempegaldesleukin can be administered 
conveniently in the outpatient setting using an antibody-like dosing regimen. The polymer 
conjugation renders the cytokine initially inactive. Upon intravenous (IV) administration, the PEG 
chains slowly release to generate the active cytokine species (mainly 2-PEG-IL-2 and 1-PEG-IL-
2) that have a peak plasma concentration of 24 to 48 hours after infusion. The slow generation of 
the 2-PEG-IL-2 and 1-PEG-IL-2 significantly mitigates the rapid-onset, systemic cytokine-related 
toxicities associated with high-dose IL-2.
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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 NK 
cells within the tumor microenvironment (TME) over expansion of unwanted intratumoral Tregs 
that are activated through the IL-2 receptor alpha beta gamma (IL-2Rαβγ).129,130,131,132,133
Consistent with this mechanism of action, recent nonclinical studies demonstrate strong synergy 
of bempegaldesleukin with adoptive T-cell therapy, with PD-1 checkpoint blockade, and with 
tumor antigen-specific vaccination, in a variety of mouse models.131,132 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 PD-L1 on tumor cells.134, 135
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 
complementary combination partner with checkpoint inhibitors.
3.2.3
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.136,137,138
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 T-cell receptor.139 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, 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), inducible T-cell co-stimulator (ICOS), 
and B- and T-lymphocyte attenuator (BTLA).140 PD-1 signaling has been shown to inhibit CD28-
mediated upregulation of IL-2, IL-10, IL-13, IFN-γ, and Bcl-xL. PD-1 expression has also been 
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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.141 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 (half maximal effective 
concentration, 0.39 to 2.62 nM) and inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 
(half maximal inhibitory concentration ± 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) restimulation 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, PAN02).142
3.2.4
Clinical Experience with Nivolumab
3.2.4.1
Study ADVL1412 (Nivolumab Monotherapy)
Study ADVL1412 (NCT02304458) is the first study to demonstrate safety and assess anti-tumor 
activity of nivolumab monotherapy in children and young adults with relapsed or refractory solid 
tumors or lymphoma. Part A was a dose confirmation phase where children aged 1 to 18 years 
with recurrent or refractory solid tumors received nivolumab 3 mg/kg IV monotherapy on Days 1 
and 15 of a 28-day cycle. Twelve out of 13 participants were evaluable in Part A (embryonal RMS
[n=1], epithelioid sarcoma [n=2], Ewing sarcoma [n=1], neuroblastoma [n=4], osteosarcoma 
[n=3], undifferentiated sarcoma [n=1], and unspecified sarcoma [n=1]). Nivolumab 3 mg/kg was 
well tolerated and was confirmed as the pediatric recommended Phase 2 dose (RP2D); no dose de-
escalation was required, and no dose-limiting toxicities (DLTs) were observed.1
Part B was a dose-expansion phase in children and young adults aged 1 to 30 years to test the 
safety and anti-tumor activity of the RP2D from Part A in participants with RMS, Ewing sarcoma, 
osteosarcoma, neuroblastoma, HL, and NHL. Participants with nonmeasurable neuroblastoma 
detected only by metaiodobenzylguanidine (MIBG) scintigraphy and participants younger than 
18 years with recurrent, measurable melanoma were also enrolled. In Part B, 72 participants were 
enrolled and 63 were evaluable for toxicity; 5 participants experienced DLTs (Grade 3 elevated 
lipase for more than 7 days [n=1], Grade 4 neutropenia [n=1], Grade 3 pain at tumor site [n=1], 
Grade 3 upper gastrointestinal hemorrhage [n=1], and Grade 2 enterocolitis infection [n=1]), 
2 participants required dose modifications (Grade 2 wheezing and Grade 2 transaminitis), and 
7 discontinued due to adverse events (AEs; prolonged elevation of liver enzymes [n=2], prolonged 
elevated lipase [n=1], prolonged fever [n=1], gastrointestinal bleeding [n=1], infection [n=1], and 
autoimmune disorder, including thyroiditis, elevated creatine kinase, elevated creatinine [n=1]). 
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Anti-tumor activity was observed in 10 HL participants (1 complete response [CR], 2 PR, 5 stable 
disease [SD], and 2 mixed response [MR]) and in 1 participant with NHL (PR), but single-agent 
activity was not observed for the common, non-lymphoma, non-CNS pediatric solid tumors 
studied.1
The most common toxicities attributable to therapy among all participants evaluable for toxicity 
(n = 75) were hematological: anemia (47%), decreased WBCs (32%), decreased lymphocytes 
(29%), and decreased platelets (19%). The most common nonhematological toxicity was fatigue 
(37%). The most common immune-related AE was hepatic toxicity (aspartate aminotransferase
[AST] increase in 29% and alanine aminotransferase [ALT] increase in 24% of participants).
Thirty-seven participants died on study or during follow-up, but none were attributable to study 
therapy.1
The data show that nivolumab is well tolerated in the pediatric age group. Additional details on 
the clinical experience with nivolumab in adults are provided in the nivolumab Investigator 
Brochure (IB).127
3.2.5
Clinical Experience with Bempegaldesleukin
3.2.5.1
Study 15-214-01 (EXCEL; Bempegaldesleukin Monotherapy)
The bempegaldesleukin clinical development program started with the monotherapy study EXCEL 
(Study 15-214-01 [NCT02869295]: A Phase 1/2, Open-label, Multicenter, Dose-Escalation and 
Dose Expansion Study of NKTR-214 in Subjects with Locally Advanced or Metastatic Solid 
Tumor Malignancies). The first part of the study was a dose-escalation phase, designed to evaluate 
the safety and tolerability and define the maximum tolerated dose (MTD) or RP2D of 
bempegaldesleukin. The second part of the study was an expansion phase following identification 
of the RP2D, designed to evaluate the safety and tolerability as well as the efficacy of 
bempegaldesleukin in specific tumor types. Bempegaldesleukin at a dose of 0.009 mg/kg 
administered once every 3 weeks (Q3W) was deemed the MTD by predefined DLT criteria. The 
RP2D was determined to be 0.006 mg/kg Q3W. Enrollment was closed after 28 participants were 
exposed to bempegaldesleukin in the dose-escalation phase, and the dose expansion phase was not 
initiated.
The safety of single-agent bempegaldesleukin has been assessed in 28 participants across 5 dose 
cohorts administered bempegaldesleukin Q3W at doses ranging from 0.003 mg/kg to 0.012 mg/kg,
and a dosing frequency of every 2 weeks (Q2W) was explored at 0.006 mg/kg. For the Q3W dosing 
frequency, doses up to 0.009 mg/kg were well tolerated. One participant dosed at 0.012 mg/kg 
experienced cytokine-release syndrome (CRS) and the DLTs of hypotension and syncope; this 
participant received 2 additional cycles of bempegaldesleukin at a lower dose of 0.006 mg/kg and 
tolerated treatment well. The bempegaldesleukin dose of 0.009 mg/kg was determined to be the 
MTD.
As of the final database lock date of 29-March-2018, the most common AEs considered by the 
investigator to be related to bempegaldesleukin were fatigue (71.4%), flu-like symptoms (67.9%), 
pruritus (64.3%), hypotension (57.1%), rash (50.0%), decreased appetite (46.4%), and arthralgia 
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or cough (32.1% each). Such treatment-related AEs as flu-like symptoms, rash, and pruritus were 
generally mild or moderate in severity, predictable, manageable, and short-lived. These IL-2-
mediated AEs generally occurred 3 to 4 days after dosing and corresponded to the time of peak 
plasma concentration of the active cytokines. The flu-like symptoms were managed with 
acetaminophen and nonsteroidal anti-inflammatory drugs, and the cases of rash/pruritus were 
either self-limiting or treated with antihistamines (steroids were administered for occasional 
participants who had severe rash/pruritus).
Six of 28 participants reported Grade 3 treatment-related AEs, which included hypotension, 
abdominal pain, infusion-related reaction, headache, and syncope. The cases of Grade 3 
hypotension were rapidly reversed with IV fluids, and a hydration-management guideline was 
implemented during the study which mitigated the hypotension severity. One participant, who had 
a prior history of an infusion reaction to a previously administered immunotherapy, discontinued 
treatment due to an infusion-related reaction following the first dose of bempegaldesleukin 
0.009 mg/kg. With the exception of 1 event of hypothyroidism, no other immune-mediated AEs
(IMAEs) consistent with checkpoint inhibitors were reported. No participant experienced capillary 
leak syndrome, and no Grade 4 treatment-related AEs or treatment-related deaths were reported 
on the study.
Fifteen participants (53.6%) reported 31 serious AEs (SAEs) in monotherapy Study 15-214-01. 
Eleven SAEs reported among 7 (25.0%) participants were considered related to treatment. The 
only treatment-related SAE reported for more than 1 participant was hypotension (5 participants, 
17.9%; 4 of 5 were Grade 3 in severity). 
In the 28 participants evaluable for efficacy in Study 15-214-01, best overall response (BOR)
included SD in 14 participants (50%), progressive disease in 12 participants (42.9%), and not 
evaluable for 2 participants (7.1%). Although no objective responses were observed in Study 15-
214-01, 9 participants experienced tumor shrinkage between 1% and 30%, and 2 participants, after 
progressing on multiple prior therapies, had durable SD over 1 year. One participant with 
metastatic melanoma, who was previously treated with ipilimumab and a BRAF inhibitor, received 
25 cycles of bempegaldesleukin and had durable SD for 18 months. A second participant with 
metastatic renal cell carcinoma (RCC), who had progressed on high-dose IL-2 and was refractory 
to single-agent OX40 (ie, an antibody targeting the tumor necrosis factor receptor superfamily 
member 4) and nivolumab, was treated with 19 cycles of bempegaldesleukin and had durable SD
for 14 months. Given the biological properties of bempegaldesleukin and nivolumab, these 
observations further supported the rationale for combining these two agents.
3.2.5.2
Study 16-214-02 (PIVOT-02; Bempegaldesleukin and Nivolumab 
Combination Therapy)
The PIVOT-02 trial (NCT02983045) is an ongoing Phase 1/2 open-label, multicenter, dose-
escalation, and dose-expansion study of bempegaldesleukin in combination with nivolumab and 
other anticancer therapies in participants with locally advanced or metastatic solid tumors. Part 1 
of the study was a dose-escalation phase to evaluate the safety and tolerability and define the MTD 
or RP2D of bempegaldesleukin in combination with nivolumab. Following determination of the 
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RP2D (0.006 mg/kg bempegaldesleukin Q3W plus 360 mg nivolumab Q3W), Part 2 of the study 
is evaluating the safety and tolerability as well as the efficacy of the combination by assessing the 
objective response rate (ORR) at the RP2D. The indications studied in Part 2 include melanoma, 
RCC, non-small cell lung cancer (NSCLC), urothelial carcinoma, breast cancer, gastric cancer, 
colorectal carcinoma (CRC), and small cell lung cancer. Parts 3 and 4 are schedule-finding and 
dose-expansion for the triplet, studying the safety and tolerability of bempegaldesleukin in 
combination with nivolumab and ipilimumab in participants with metastatic RCC, urothelial 
carcinoma, melanoma, or NSCLC who are treatment naïve.
The bempegaldesleukin plus nivolumab dose-escalation portion of PIVOT-02 has been completed, 
with the safety results of bempegaldesleukin at 0.006 mg/kg in combination with nivolumab 
360 mg Q3W indicating no DLTs and no Grade ≥ 3 treatment-related AEs at the time of 
completion. Bempegaldesleukin 0.006 mg/kg in combination with nivolumab 360 mg Q3W was 
the recommended dose regimen to be taken forward into expansion cohorts in Part 2.
As of 28-Oct-2020, a total of 557 participants had been treated with bempegaldesleukin in 
combination with nivolumab (503 participants with doublet [bempegaldesleukin and nivolumab],
43 participants with triplet [bempegaldesleukin, nivolumab, and ipilimumab], and 11 participants 
with doublet [bempegaldesleukin and nivolumab] plus other anticancer study drug). Of the 557 
participants, most have NSCLC (184 patients [33%]), RCC (139 [25%]), or melanoma (102 
[18%]), followed by urothelial carcinoma (61 [11%]), breast cancer (47 [8%]), and CRC (22 [4%]), 
and gastric cancer (2 [< 1%]). The median duration of exposure was 106.0 days (doublet, 101.0; 
triplet, 179.0; doublet plus other anticancer drug, 113.0) (range, 1 to 817 days). 
As of 28-October-2020, among the 503 patients who received the doublet:

94.6% (476 of 503) of participants reported treatment-related AEs; the most frequent were 
fatigue (47.1%), pyrexia (44.7%), pruritus (36.0%), nausea (31.4%), influenza-like illness 
(26.8%), decreased appetite (26.6%), rash (26.0%), and chills (25.8%).

24.9% (125 of 503) of participants reported treatment-related Grade ≥ 3 AEs; the most frequent
were syncope (2.8%), hypotension (2.6%), and lipase increased (2.2%). 

16.3% (82 of 503) of participants reported treatment-related SAEs; the most frequent were 
pyrexia (3.0%), hypotension (2.0%), and pneumonitis (1.0%).
Tumor response data are available for 37 of the dose-escalation participants, including 11 with 
metastatic melanoma, 21 with RCC, and 5 with NSCLC. Of these 37 response-evaluable 
participants, 25 were treated at 0.006 mg/kg bempegaldesleukin combined with nivolumab 360 
mg flat dose Q3W. As of 18-January-2019, 22 of 37 evaluable participants (59.5%) achieved an 
investigator-assessed response (complete or partial response) by Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST v1.1). 135
For select tumors, additional efficacy data have been presented. PIVOT-02 has a 2-stage design,
and data for either the Stage 1 (N1) population alone or in combination with the Stage 2 (N2; 
expansion) population were presented depending on data maturity. Data presented for the 
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efficacy-evaluable population (defined as having received 1 dose of study treatment and having 
undergone at least 1 scan) were as follows:

In first-line RCC participants, a 46% (12 of 26 participants) ORR was observed (N = 48 
enrolled; N = 26 in the N1 + N2 population; 29-May-2018 cutoff).143  

In first-line melanoma participants, a 53% (20 of 38 participants) ORR via blinded independent 
central review (BICR) was observed (N = 41 enrolled; N = 38 included in the N1 + N2 
population; 01-Sep-2020 data cutoff). 144

In first-line metastatic urothelial carcinoma participants, a 48% (13 of 27 participants) ORR 
was observed (N = 41 enrolled; N = 27 in the efficacy evaluable population; 03-Dec-2018 data 
cutoff).145

In metastatic triple-negative breast cancer (TNBC) participants, a 13% (5 of 38 participants) 
ORR was observed (N = 43 enrolled; N = 38 in the efficacy evaluable population; 01-Jul-2019 
data cutoff).146
To date, there have been no clinical studies in pediatric participants with bempegaldesleukin.
Additional details on the clinical experience with bempegaldesleukin are provided in the 
bempegaldesleukin IB.147
3.2.5.3
Pooled Safety Analysis of Participants with Bempegaldesleukin and 
Nivolumab Exposure
A pooled safety analysis (28-Oct-2020 data cutoff) is available of patients who received the 
bempegaldesleukin and nivolumab doublet from the ongoing combination Phase 1/2 studies 
(16-214-02 and 16-214-05), the ongoing combination Phase 2 study (18-214-10), and the 
completed Phase 1 study (CA045-010). Of the 696 patients who received the bempegaldesleukin 
and nivolumab doublet:

93.0% (647 of 696) of patients reported treatment-related AEs; the most frequent were pyrexia 
(42.1%), fatigue (39.9%), pruritis (37.6%), nausea (27.9%), rash (24.6%), decreased appetite 
(23.7%), influenza-like illness (22.4%), and chills (22.1%). 

24.6% (171 of 696) of patients reported treatment-related Grade ≥ 3 AEs; the most frequent 
were hypotension (2.6%), fatigue (2.0%), arthralgia (1.1%), diarrhea (0.9%), and pyrexia 
(1.1%).

15.8% (110 of 696) of patients reported treatment-related SAEs; the most frequent were 
pyrexia (2.6%), hypotension (1.7%), dehydration (0.9%), pneumonitis (0.7%), acute kidney 
injury, and atrial fibrillation, and myocarditis (0.6% each).
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3.2.5.4
Observed Events of Cerebrovascular Accident
3.2.5.4.1 Initial Analysis of Cerebrovascular Accident Events in PIVOT-02 (16-214-
02) Study
Serious events of cerebrovascular accident (CVA), including 1 fatal event, have been observed in 
participants who have received bempegaldesleukin in the triplet combination with nivolumab and 
ipilimumab, in the doublet combination with nivolumab, and in the combination of 
bempegaldesleukin, nivolumab, and other anti-cancer therapy. As of 28-Oct-2019, 3 of 43 
participants (7.0%) who received triplet therapy in Study 16-214-02 (PIVOT-02) had CVA events, 
including 1 fatal event, all of which were considered by the investigator to be related to treatment 
with bempegaldesleukin, nivolumab, and ipilimumab. Additionally, 9 of 488 participants (1.8%) 
who received doublet therapy (bempegaldesleukin and nivolumab) had 10 CVA events, which 
were considered by the investigator to be related to at least 1 of the study treatments in 4 
participants (3 related to the doublet therapy and 1 related to nivolumab only); and 1 of 10 (10.0%) 
participants who received combined bempegaldesleukin, nivolumab, and other anti-cancer therapy 
(platinum-based chemotherapy) had a CVA event, which was considered by the investigator to be 
unrelated to study treatment.
3.2.5.4.2 Updated Analysis of Cerebrovascular Accident Events Observed with 
Bempegaldesleukin
A cumulative search of the bempegaldesleukin global safety database was conducted on 
28-October-2020, which included 1345 patients who received bempegaldesleukin in triplet 
combinations with nivolumab plus ipilimumab or with nivolumab plus NKTR-262 (a toll-like 
receptor agonist 7/8); in doublet combinations with checkpoint inhibitors; in a doublet combination 
with nivolumab plus chemotherapy, and in combination with NKTR-262 from the following 
studies: 15-214-01, 16-214-02, 16-214-05, 17-214-09, 18-214-10, 20-214-29, CA045-001 (17-
214-08), CA045-009 (18-214-03), CA043-010 (18-214-14), SP-IND, and 17-262-01.
Overall, 1.9% (26 of 1345) of patients exposed to bempegaldesleukin reported CVA events. Of 
the 26 patients, 13 patients experienced Grade 3 or 4 events and 4 patients had a fatal outcome. 
The mean time to first CVA event was 218.7 days (range, 4 to 727 days; median, 158 days). 
Twenty of the 26 patients with CVA events received a doublet combination with a checkpoint 
inhibitor, which included 1.7% (19 of 1116) of patients who received nivolumab, 1.3% (1 of 76) 
who received pembrolizumab, and 0% (0 of 23) who received atezolizumab.
Based on these events, CVA was escalated to an AE of special interest (AESI) and mitigations 
were put in place to reduce the risk of CVA. These mitigations include implementation of a CVA 
AE management algorithm (Appendix 6) and updates to the exclusion criteria, renal function and 
hydration assessment, hydration guidelines, concomitant and prohibited medications, dose 
modification guidelines, and discontinuation criteria. Additional information on the clinical safety 
and risk of CVA is found in the bempegaldesleukin IB.147
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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 IB.147
3.3.2
Nivolumab Safety Profile
Extensive details on the safety profile of nivolumab are available in the IB and will not be repeated 
herein.127
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical trials, with no MTD reached at any dose tested up to 
10 mg/kg. Most AEs were low grade (Grade 1 to 2), with relatively few drug-related high-grade 
(Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or causality of AEs with 
respect to nivolumab dose level.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 5. Most high-grade events were manageable with the 
use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed in these 
algorithms. 
Nivolumab monotherapy has been studied in a Phase 1/2 trial in children and young adults with 
relapsed or refractory solid tumors or lymphoma. Nivolumab was considered to be safe and well 
tolerated. The study established a favorable safety profile for nivolumab in children and young 
adults (see Section 3.2.4).1
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.127
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.  
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Hypotension has been identified as a clinically significant AE 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 participants 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 
participants to PD-L1-positive participants suggests that the addition of bempegaldesleukin to a 
checkpoint inhibitor (nivolumab) may change the tumor microenvironment in PD-L1-negative 
participants such that the combination may contribute to antitumor activity with an acceptable 
safety profile.
While significant improvement in the outcome of children diagnosed with cancer has been 
achieved over the last 5 decades, in patients with recurrent or refractory disease as well as those 
with newly diagnosed malignant glioma, the over prognosis remains dismal and the majority will 
succumb to their disease. Based on the mechanism of action of bempegaldesleukin and nivolumab, 
this combination offers an opportunity to activate an immune response that has the potential to 
provide benefit to these children. While all treatments have associated risk, nivolumab1 and other 
PD-1/PD-L1 inhibitors2,3 have been well tolerated in pediatric patients at the same doses and 
schedules proposed in this study. Soluble IL-2 is a cytokine that has been extensively evaluated in 
both adult and pediatric patients and is currently approved for use in children with neuroblastoma. 
Based on the adult toxicity profile of bempegaldesleukin, which due to its unique properties, has 
a significantly improved adverse event profile compared to the approved soluble formulation of 
IL-2, it is anticipated that the risk associated with the administration in pediatric participants will 
be less than the currently approved formulation.
In conclusion, the currently available safety data demonstrate that bempegaldesleukin and 
nivolumab is a well-tolerated I-O combination therapy. Given the encouraging clinical activity and 
manageable and generally nonoverlapping toxicity profile, the potential for direct benefit in 
participants 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 has coronavirus disease 2019 (COVID-19) during the trial, then the benefit and risk 
considerations remain the responsibility of the investigator. Non-live COVID-19 vaccination is 
considered a standard concomitant medication within the study. However, the efficacy and safety 
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of non-live vaccines (including non-live COVID-19 vaccines) in participants receiving nivolumab 
and bempegaldesleukin is not fully known.
4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary - Part A Safety Lead-in

Safety Lead-in: To estimate the safety and 
tolerability of study treatment in pediatric 
participants with malignant neoplasms that are 
refractory, relapsed, or participants for whom 
curative treatments are lacking.

Incidence of dose-limiting toxicities (DLTs), 
adverse events (AEs), serious AEs (SAEs), drug-
related AEs, AEs leading to discontinuation, and 
death.

To characterize the pharmacokinetics (PK) of 
bempegaldesleukin and nivolumab in pediatric 
participants with malignant neoplasms that are 
refractory, relapsed, or participants for whom 
curative treatments are lacking. 

PK parameters that are characterized by population 
PK models.
Primary - Part B Expansion

To estimate the preliminary efficacy (eg, ORR of 
study treatment separately in the following disease 
cohorts):

B1: Neuroblastoma

B2: Ewing sarcoma

B3: Rhabdomyosarcoma

B4: Miscellaneous solid tumors

B5: Non-Hodgkin lymphoma (NHL)/leukemia

B6: High-grade glioma

B7: Medulloblastoma and embryonal tumors

B8: Ependymoma

B9: Miscellaneous central nervous system 
(CNS) tumors

Investigator-assessed objective response rate by:

B1: Revised International Neuroblastoma Response 
Criteria

B2 to B4: Response Evaluation Criteria in Solid 
Tumors v1.1

B5: 
International 
Pediatric 
Non-Hodgkin 
Lymphoma Response Criteria for NHL

B5: Modified National Comprehensive Cancer 
Network Criteria for acute lymphoblastic leukemia

B5: Modified Cheson et al International Working 
Group criteria for acute myeloid leukemia.

B6 to B9: Response Assessment in Neuro-
Oncology/Response 
Assessment 
in 
Pediatric 
Neuro-Oncology
Secondary - Part B Expansion

To estimate the safety of study therapy in pediatric 
participants.

Incidence of AEs, SAEs, toxicities, drug-related 
AEs, AEs leading to discontinuation, and death.

Incidence of laboratory abnormalities.

To estimate the progression-free survival (PFS) and 
overall survival (OS) of study therapy in pediatric 
participants.

PFS, OS
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Tertiary/Exploratory - Part A and Part B

To investigate the objective response rate (ORR; 
Part A), PFS (Part A), and duration of response 
(DOR) in participants with measurable disease at 
baseline.

ORR, PFS, DOR

To 
characterize 
the 
PK
in 
Part 
B
of 
bempegaldesleukin and nivolumab in pediatric 
participants with malignant neoplasms that are 
refractory, relapsed, or participants for whom 
curative treatments are lacking. 

PK parameters that are characterized by population 
PK models.

To 
characterize 
the 
immunogenicity 
of 
bempegaldesleukin and nivolumab.

Anti-NKTR-214, anti-interleukin-2, and anti-
polyethylene glycol antibodies and anti-nivolumab 
antibody and their relationship with select PK 
measures, safety, and efficacy, if appropriate.

To evaluate changes in patient-reported tolerability 
(Part B only).

Proportion of patients with score >3 during 
treatment and proportion of patients reporting 
improvement/worsening 
during 
treatment 
in 
selected items from the Patient-Reported Outcome 
– Common Terminology Criteria for Adverse 
Events (PRO-CTCAE).
Abbreviations: AE = adverse event; CNS = central nervous system; DLT = dose-limiting toxicity; DOR = duration of 
response; Ig = immunoglobulin; NHL = non-Hodgkin lymphoma; NKTR-214 = bempegaldesleukin; ORR = objective 
response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; PRO-CTCAE = Patient 
Reported Outcome-Common Terminology Criteria for Adverse Events; SAE = serious adverse event.
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5
STUDY DESIGN
5.1
Overall Design
CA045-020 is an open-label, sequential-arm Phase 1b/2 clinical trial of bempegaldesleukin in 
combination with nivolumab in pediatric participants with malignant neoplasms that are refractory, 
relapsed, or participants for whom curative treatments are lacking.
Because pediatric participants vary in age and weight, the starting doses of nivolumab will be 
determined separately based on age or weight. Participants aged < 12 years or weighing < 40 kg 
will be given a weight-based dose of nivolumab (see Figure 5.1-1), and participants aged 12 
years and weighing 40 kg will be given a flat dose of nivolumab (see Figure 5.1-2).
Phase 1b consists of Part A. In Part A, a maximum of 30 participants (ie, up to 2 cohorts of 
6 participants in the weight/age-based dosing schema and up to 3 cohorts of 6 participants in the 
flat to weight-based dosing schema) will be treated with both nivolumab and bempegaldesleukin
IV Q3W to determine the recommended dose of bempegaldesleukin to take into Part B and to 
determine if nivolumab flat or weight-based dosing will be used for those ≥ 12 years and weighing 
≥ 40 kg. 
The study design schematic is presented for Part A in Figure 5.1-1 and Figure 5.1-2 and for Part 
B in Figure 5.1-3.
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Figure 5.1-1:
Phase 1b (Part A) Dose-finding Study Design for Age- and Weight-based Dosing of Participants Aged 
< 12 Years or Weighing < 40 kg for Bempegaldesleukin in Combination with Nivolumab*
*for nivolumab 4.5 mg/kg in dosing schema A1W and A2W, up to 360 mg equivalent is the maximum dose
Abbreviations: DLT = dose-limiting toxicity; IV = intravenous; pts = participant; Q3W = every 3 weeks; W=weight/age-based dose.
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Figure 5.1-2:
Phase 1b (Part A) Dose-finding Study Design for Flat to Weight-based Dosing of Participants Aged ≥12 
Years and Weighing ≥ 40 kg for Bempegaldesleukin in Combination with Nivolumab*
*for nivolumab 4.5 mg/kg in dosing schema A2F-W and A3F-W, up to 360 mg equivalent is the maximum dose
Abbreviations: DLT = dose-limiting toxicity; F=flat dose; IV = intravenous; pts = participant; Q3W = every 3 weeks.
Dosing Schema A2F-W
Bempegaldesleukin
0.006 mg/kg IV Q3W + 
nivolumab 4.5 mg/kg 
IV Q3W*
Dosing Schema A1F-W
Bempegaldesleukin
0.006 mg/kg IV Q3W + 
nivolumab 360 mg IV 
Q3W
Dosing Schema A3F-W
Bempegaldesleukin
0.003 mg/kg IV Q3W + 
nivolumab 4.5 mg/kg 
IV Q3W*
< 1 of 6 pts experience 
DLT
< 1 of 6 pts experience 
DLT
< 1 of 6 pts experience 
DLT
Dosing Schema A1F-W 
will be used for Part B
Dosing Schema A2F-W 
will be used for Part B
Dosing Schema A3F-W 
will be used for Part B
> 2 of 6 pts 
experience 
DLT
> 2 of 6 pts 
experience 
DLT
> 2 of 6 pts 
experience 
DLT
Flat to 
Weight-
based 
Dosing Stops
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Phase 2 (Part B) will use a modified Simon 3-stage variant design148 (Section 10.1) to enroll at 
least 9 participants into 7 individual cohorts (B1 to B3 and B5 to B8) based on tumor type to be 
treated. For the miscellaneous solid tumor and miscellaneous CNS tumor cohorts, the Simon 3-
stage variant design will not be applied and can accrue up to the maximum of 24 participants. All 
9 cohorts will be treated with the selected dosing schema(s) from Part A of the study. The Part B
cohorts are disease and histology specific, as presented in Figure 5.1-3. Further details on the 
progression of enrollment can be found in Section 5.1.2.
Figure 5.1-3:
Phase 2 (Part B) Study Design Schematic
Abbreviations: CNS = central nervous system; ET = embryonal tumor; NHL = non-Hodgkin lymphoma; RMS = 
rhabdomyosarcoma.
The total duration of the study is up to 5 years from start of study treatment of the last participant,
or until the time of primary OS analysis, whichever occurs later.
5.1.1
Screening Period
Written informed consent (and assent where appropriate) must be obtained before starting any 
protocol-specified procedures or evaluations not considered to be part of the participants’ standard 
care. Once informed consent/assent is received, participants will be evaluated for entry criteria 
during the Screening period prior to the administration of the study drug.
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Palliative radiation to non-target lesions is permitted. Participants receiving palliative radiation to 
target lesions require reimaging post radiation and prior to initiation of drug therapy.
5.1.2
Treatment Period
Phase 1b - Part A
For Part A, up to 6 participants will be enrolled in each dosing schema (total maximum of 30 
participants) starting with dosing schemas A1W (weight/age-based dosing) and A1F-W (flat to 
weight-based dosing) for 1 cycle (each cycle is 21 days). Assessments for the weight/age-based
and for the flat to weight-based dosing schemas will run concurrently and are independent of each 
other. Any dosing level in which ≥2 participants experience 1 or more DLTs identified during the 
DLT period will be reviewed by the data monitoring committee (DMC; Section 5.1.5) before 
accrual into the dose-reduced schema proceeds for weight/age-based or flat to weight-based 
dosing, respectively, as outlined in Figure 5.1-1 (A2W; weight/age-based dosing) and Figure 5.1-
2 (A2F-W; flat to weight-based dosing).
Since the weight/age-based dosing schemas (A1W/A2W) and the flat to weight-based dosing 
schemas (A1F-W/A2F-W/A3F-W) are independent from each other, they will be evaluated for 
DLTs separately. If dosing in one schema must be reduced or stopped due to DLTs, the other 
schema will continue as outlined. For participants in any tolerated dosing schemas, participants 
will continue treatment 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, Bristol-Myers 
Squibb (BMS) and Nektar Therapeutics conclude(s) the study, or for a maximum of 2 years of 
study treatment.
Participants in Part A treated at the dosing schema used in Part B can be counted in the accrual 
goals for Part B. The selection of the optimal dosing schema for Part B will be made at the 
completion of Part A and can occur separately for the 2 dosing schemas (weight/age-based and 
flat to weight-based dosing, respectively) in conjunction with the DMC. 
Phase 2 - Part B
For Part B, 9 participants will be enrolled into each of the following tumor-specific cohorts using 
the optimal dosing schemas identified in Part A:

B1: Neuroblastoma

B2: Ewing sarcoma

B3: RMS

B5: NHL/leukemia

B6: High-grade glioma

B7: Medulloblastoma and CNS embryonal tumors 

B8: Ependymoma
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For each of the cohorts above, if 1 of 9 participants shows a response, an additional 7 participants 
will be enrolled. If 2 of 16 participants shows a response, an additional 8 participants will be 
enrolled for a maximum of 24 participants per cohort.
For the following tumor types, the study will enroll up to a maximum of 24 participants per cohort 
regardless of response:

B4: Miscellaneous solid tumors

B9: Miscellaneous CNS tumors
Participants from Part A treated at the same dose as in Part B (for both dosing cohorts) can be 
included in the accrual numbers for Part B. Participants in Part B will be treated at the appropriate 
dose defined in Part A for each stratum and will therefore be a mixture of participants from the 
weight/age-based and flat to weight-based dosing groups. Participants who initiate therapy in 1
group (weight/age-based or flat to weight-based dosing) will not switch over during the study,
even if there is a change in age or weight while on therapy.
For this study, response will be assessed by institutional review using RECIST v1.1 for solid 
tumors, Response Assessment in Neuro-Oncology (RANO)/Response Assessment in Pediatric 
Neuro-Oncology (RAPNO) for CNS tumors, International Pediatric Non-Hodgkin Lymphoma 
Response Criteria for NHL, revised International Neuroblastoma Response Criteria (INRC) for 
neuroblastoma, modified NCCN Criteria for acute lymphoblastic leukemia, and modified Cheson 
et al International Working Group criteria for acute myeloid leukemia.
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 conclude(s) the study, or for a maximum of 2 years of treatment. 
In certain circumstances, participants with progressive disease using disease-specific criteria, but 
with otherwise stable or improved performance and clinical status, may continue to be treated for 
a total of 2 years from Cycle 1 Day 1, in the event of a perceived benefit per Investigator; see 
Section 8.1.2 for treatment beyond progression criteria.
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 Investigator.
5.1.3
Dose-limiting Toxicities
For the purpose of guiding decisions regarding dose de-escalation in Parts A and B, DLTs will be 
defined based on the incidence, intensity, and duration of AEs for which no clear alternative cause 
is identified. The DLT period will start on Cycle 1 Day 1 and end at Day 42 (therefore, 6 weeks). 
The severity of AEs will be graded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events version 5 (CTCAE v5). In addition to DLTs, the Sponsor 
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will evaluate the overall tolerability of the dose determination in Part A before deciding if Part B 
will be evaluated in this participant population.
For the purpose of participant management, DLTs that occur at any time will result in study drug 
being delayed pending evaluation of the event in relation to study drug, in accordance with 
Section 7.4. A participant is considered DLT evaluable after receiving 1 dose of any study drug. 
Participants who withdraw from the study during the 6-week DLT evaluation period for reasons 
other than a DLT may be replaced with a new participant at the same dose level. The incidence of 
DLT(s) during the 6-week DLT evaluation period will be used to help guide de-escalation 
decisions and to define the MTD/RP2D. AEs occurring after the 6-week DLT period will be 
considered for the purposes of defining the RP2D upon agreement between the Sponsor and 
Investigators. Participants experiencing a DLT will be evaluated to determine if they are eligible 
to continue study drug at modified dosing (Section 7.4.1) or if they should discontinue from the 
study. 
5.1.3.1
Gastrointestinal Dose-limiting Toxicities
Any one of the following study drug-related events will be considered a gastrointestinal DLT:

Grade 2 colitis that lasts longer than 7 days, despite best supportive treatment.

Grade 3 colitis that lasts more than 5 days.

Grade 4 colitis or diarrhea.

Grade 3 diarrhea that lasts longer than 72 hours with adequate supportive treatment.
5.1.3.2
Hepatic Dose-limiting Toxicity
Any 1 of the following study drug-related events will be considered a hepatic DLT: 

Grade 2 elevations in AST or ALT with symptomatic liver inflammation (eg, right upper 
quadrant tenderness, jaundice, and pruritus). 

Grade 3 or above elevation of AST and/or ALT, as below

≥ 8 times ULN 

>5.0 - < 8 times ULN persisting for > 7 days

Grade 4 elevations in AST, ALT, ALP, or total bilirubin.

Grade 4 elevations in AST, ALT, ALP, or total bilirubin in the absence of cholestasis.

AST or ALT > 3 × ULN and concurrent total bilirubin > 2 × ULN without initial findings of 
cholestasis (elevated ALP; eg, findings consistent with Hy’s law or FDA definition of potential 
drug-induced liver injury [pDILI]). Note that this specific category of DLT uses ULN rather 
than CTCAE grade for definition.

For participants with hepatic metastases, AST or ALT > 8 × ULN or AST or ALT > 5 × ULN 
for 14 days.
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5.1.3.3
Hematologic Dose-limiting Toxicity
Any of the following study drug-related events will be considered a DLT:

Febrile neutropenia.

Grade 3 hemolysis (ie, requiring transfusion or medical intervention such as steroids).

Grade 3 thrombocytopenia with clinically significant bleeding, or any requirement for platelet 
transfusion.

Grade 4 neutropenia > 7 days in duration.

Grade 4 thrombocytopenia.

Grade 4 anemia not explained by underlying disease.
5.1.3.4
Dermatologic Dose-limiting Toxicity
Any of the following study drug-related events will be considered a DLT: 

Grade 3 rash if no improvement (ie, resolution to < Grade 1) after a 1- to 2-week infusion 
delay. Topical steroid treatment is allowed for symptom control.

Grade 4 rash.
5.1.3.5
Other Dose-limiting Toxicities
Any of the following study drug-related events will be considered a DLT: 

Any AE that requires discontinuation of nivolumab per the local labeling information

Any grade immune-related encephalitis.

Any incidence of Grade 3 prolongation of QT interval corrected using Fridericia’s correction 
formula (QTcF) on electrocardiograms (ECGs).

Any death not clearly due to the underlying disease or extraneous causes.

Grade 2 drug-related uveitis, episcleritis, iritis, eye pain, or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within 2 weeks/until the following 
dose OR requires systemic treatment. 

Grade 2 pneumonitis that does not respond to dose delay and systemic steroids within 14 days.

Grade 3 fatigue lasting 1 week.

Grade 3 drug-related uveitis, episcleritis, iritis, pneumonitis, bronchospasm, or neurologic 
toxicity.

Grade 3 myocarditis.

Grade 3 electrolyte abnormality associated with clinical symptoms.

Grade 3 electrolyte abnormality that lasts > 72 hours.

Grade 4 hypersensitivity/infusion reaction, or Grade 3 that does not resolve to Grade 1 in 
< 6 hours. 
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Other ≥Grade 3 study drug-related toxicities will be considered DLTs, except those clearly and 
incontrovertibly due to disease progression and extraneous causes. However, the following Grade 
3 or 4 events will NOT be considered DLTs: 

Isolated Grade 3 or 4 electrolyte imbalances/abnormalities not associated with clinical 
symptoms and either resolve spontaneously or are corrected with supplementation/appropriate 
management within 72 hours of their onset. Confirmatory laboratory test is required within 
72 hours.

Grade 3 nausea or vomiting that lasts less than 48 hours and either resolves spontaneously or 
responds to conventional medical intervention.

Grade 3 or Grade 4 elevation of amylase or lipase not associated with symptoms or clinical or 
radiographic evidence of pancreatitis.

Grade 3 fever not associated with hemodynamic compromise or neutropenia (eg, hypotension, 
clinical or laboratory evidence of impaired end-organ perfusion).

Grade 3 endocrinopathy that is well controlled by hormone replacement.

Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to sites of known or 
suspected tumor).

Grade 3 fatigue.

Grade 3 infusion reaction that returns to Grade 1 in < 6 hours.

Grade > 3 AE resulting from non-compliance with oral hydration guidelines.
5.1.3.6
Stopping Rules for Part B
During Part B, monitoring of toxicity events (as specified in Section 5.1.3) will be performed in 
each cohort. The monitoring function for toxicity is defined as the posterior probability of the 
toxicity rate > 30% given cumulative data >0.90. This criterion implies that the given cohort may 
be stopped for enrollment if there is a greater than 90% probability that the toxicity rate will 
be > 30%. The monitoring process will be applied first when at least 5 toxicity-evaluable 
participants are treated in a cohort and for every 5 additional toxicity-evaluable participants 
thereafter.
This monitoring process is based on a Bayesian sequential monitoring design149 where one 
assumes a beta (0.6, 1.4) prior distribution for the toxicity rate, which has a mean of 0.3 
corresponding to a 30% approximate target toxicity rate in Part A. The posterior distribution at 
any time point is beta (0.6 + n, 1.4 + [m-n]), where n is the number of participants observed with 
toxicity and m is the total number of toxicity-evaluable participants in the cohort.
The resulting boundaries are presented in Table 5.1.3.6-1 and Table 5.1.3.6-2. Table 5.1.3.6-2 also 
summarizes the probability to cross those boundaries as well as average sample size reached at 
suspension in a cohort for different toxicity rates.
If the boundary in a cohort is met at any time during Part B, the accrual will be suspended for that 
cohort and the DMC will meet to review the safety data, taking into account all available safety 
information across all cohorts before making a final recommendation to the Sponsor.
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Table 5.1.3.6-1:
Suspension Criteria for Toxicity During Part B Expansion
Number of Toxicity-Evaluable Participants in the 
Cohort (Cumulative)a
Suspend Accrual if ≥ Number of Participants with 
Toxicity
4
Not applicable
5
4
10
6
15
8
20
9
a Assuming cohort can enroll up to 24 participants.
Table 5.1.3.6-2:
Suspension Probabilities for Toxicity During Part B Expansion
Toxicity Rate
Average Number of Accrual 
Reached at Suspensiona
Probability of Suspending 
Accrual
10%
24
0.00
20%
24
0.02
30%
23
0.14
40%
19
0.44
50%
15
0.77
60%
11
0.95
70%
8
1
80%
6
1
a Assuming cohort can enroll up to 24 participants.
5.1.4
Long-term Follow-up
Long-term follow-up should continue until withdrawal of consent, death, or study termination by 
the Sponsor. The total duration of the study is up to 5 years from first study treatment 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 150 days after the last dose of study treatment. The 
first 3 follow-up visits should be conducted in person.

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. 

Follow-up Visit 3 occurs approximately 150 days (± 7 days) from the last dose of study 
treatment.
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
Additional assessments may occur when the decision is made to discontinue treatment. 

Subsequent to Follow-up Visit 3, 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. Additional assessments described in Section 2 will also be 
collected. After completion of study therapy for participants without progression results of 
additional imaging, including bone marrow and CSF, if applicable, are requested for the 
duration of the study.

Per clinical judgment, the participant may come in earlier to all follow-up visits.

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. Tumor scans will also continue as described in Section 2.
5.1.5
Data Monitoring Committee and Other External Committees
A DMC will be established to provide oversight of safety and to provide advice to the Sponsor 
regarding actions the committee deems necessary for the continuing protection of participants. 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. The DMC 
will meet at least every 6 months or more frequently as needed on an ad-hoc basis. Information 
regarding DMC membership, responsibilities, and procedures are detailed in the DMC charter. 
The DMC will be informed should a safety signal emerge and may convene an ad-hoc meeting on 
its own initiative. 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. The DMC will review all available data (safety and efficacy) at each meeting. At 
the conclusion of each DMC meeting, the committee will provide the Sponsor with a 
recommendation to continue, modify, or terminate the study protocol based upon their review. 
Ultimately, decisions regarding the study protocol will be made by the Sponsor in conjunction 
with feedback from Investigators and the DMC.
5.2
Number of Participants
The total sample size of the study is estimated to be between approximately 10 and 234 participants
depending on dose de-escalation contingencies in Part A and cohort expansions in Part B. A 
complete description of the sample size is provided in Section 10.1. Accrual estimates for the 
expansion phase are based on the modified Simon 3-stage variant design and are provided in 
Figure 5.1-3.
In Part A, if ≥2 participants in the weight/aged-based cohort experience DLTs (A1W/A2W; n = 
2), then the weight/aged-based group would drop to the lower dose of bempegaldesleukin. If ≥2 
participants in the flat to weight-based dosing schema experience DLTs (A1F-W; n=2), then the 
flat to weight-based dosing group would maintain the bempegaldesleukin dose and change to 
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weight-based dosing of nivolumab (A2F-W; n=2). If ≥2 participants in the flat to weight-based 
dosing schema had DLTs in the A2F-W cohort, then the flat to weight-based dosing group would
drop to the lower dose of bempegaldesleukin and maintain the weight-based dosing of nivolumab 
(A3F-W; n=2). If ≥2 participants in each of the weight/aged-based or flat to weight-based dosing 
schemas at the lowest doses again had DLTs (A1W/A2W; n = 4/A1F-W/A2F-W/A3F-W; n = 6), 
the trial would close. Therefore, the actual minimal accrual is 10 participants.
In Part A, if 6 participants are treated in each of the weight/aged-based or flat to weight-based
dosing schemas (A1W/A1F-W; n =12) and there is a need to dose reduce in both cases due to 
DLTs, another 6 participants would be enrolled in the lower dose levels (A2W/A2F-W/A3F-W; n 
= 18). If this lower dose was tolerated, then Part B will start using the lower dose level (see Figure 
5.1-1 and Figure 5.1-2). 
Part B allows up to a maximum of 24 participants in each of the 9 cohorts (n = 216). Since the 
participants in Part A treated at the RP2D could be counted in the accrual Part B, 12 of the 30
participants in Part A would be accounted for, leaving only 18 more to be added to the total. As 
such, the maximum number of participants would be 234.
5.3
End of Study Definition
This study will consist of 3 periods: screening, treatment, and follow-up. The start of the trial is 
defined as the first visit for the first screened participant. End of trial is defined as the last scheduled 
procedure shown in the Schedule of Activities in Section 2 for the last participant. Study 
completion is defined as the final date on which data for the primary endpoint were or are expected 
to be collected, if it is not the same. Follow-up for a minimum of 3 years (from study entry) is 
planned, if applicable, but no more than 5 years.
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for the Combination of Bempegaldesleukin and Immune 
Checkpoint Inhibitors 
This study is designed to evaluate the safety and efficacy of study therapy in pediatric malignant
tumors, including leukemias, NHL, neuroblastoma, RMS, Ewing sarcoma, high-grade glioma, 
medulloblastoma, ependymoma, and miscellaneous solid and CNS tumors. These tumor subtypes 
have quite different molecular genetics, natural disease histories, survival outcomes, and responses
to current therapies that preclude use of 1 endpoint for all groups and require analysis in distinct 
cohorts, recognizing that there is important heterogeneity even within these cohorts.
Single agent PD-1 and PD-L1 inhibition has had very limited activity to date in pediatric solid and 
central nervous system tumors.1,2,3 It is likely that some of this is related to the low mutational 
burden characteristic of most pediatric malignancies that limit the stimulatory response needed to 
activate T cells. Bempegaldesleukin, an IL-2 derivative that induces T cell activation and 
proliferation may overcome this problem and in conjunction with a checkpoint inhibitor, allow for 
both the activation of the T cell response while providing the needed dis-inhibition to allow it 
function.
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5.4.2
Rationale for Study Comparator and Study Population
Pediatric patients with cancer are in need of new therapies and this combination has the potential 
to activate an anti-tumor response while inhibiting the checkpoint molecules that could suppress a 
response. As per the new FDA guidelines, assessment of new agents in pediatrics is based on the 
MOA of the agent(s) being tested.
5.4.3
Rationale for Permitting Treatment Beyond Suspected Progression
Accumulating 
clinical 
evidence 
indicates 
some 
participants 
treated 
with 
immune 
system-stimulating agents may develop progression of disease (by conventional response criteria) 
before demonstrating clinical objective responses and/or SD. This phenomenon was observed in 
approximately 10% of participants in the Phase 1 study of nivolumab. Two hypotheses have been 
put forth to explain this phenomenon. First, enhanced inflammation within tumors could lead to
an increase in tumor size, which would appear as enlarged index lesions and as newly visible small 
non-index lesions. Over time, both the malignant and inflammatory portions of the mass may then 
decrease leading to overt signs of clinical improvement. Alternatively, in some individuals, the 
kinetics of tumor growth may initially outpace antitumor immune activity. With sufficient time, 
the antitumor activity will dominate and become clinically apparent. Therefore, participants 
initially meeting radiologic criteria for disease progression (see Section 9.1) will be allowed to 
continue study therapy until a second radiologic confirmation of progression as long as the 
following criteria are met: (1) the participant experiences investigator-assessed clinical benefit and 
(2) the participant is tolerating the study treatment.
5.4.4
Rationale for Choice of Endpoints
Part B of this trial is designed as a signal-seeking study and includes a large number of different 
tumor types with heterogeneous biology and outcomes. Although radiographic or other disease-
appropriate defined measures of response may not always directly correlate with improved 
participant outcome, ORR remains the best and most reliable measure of treatment effect.
ORR will be used to evaluate for potential signals of activity of the study treatment. Trials of 
nivolumab are either recently completed in pediatric participants with solid tumors, including 
lymphoma (CA209-070; NCT02304458),1 or nearing completion for CNS tumors (CA209-908; 
NCT03130959) and will provide important comparators to this study with the addition of 
bempegaldesleukin (see Section 3.2.4).
5.4.5
Rationale for Open-label Design
This trial seeks to identify the toxicity and appropriate dose of the combination under study in 
addition to an assessment of an early efficacy signal. A placebo-controlled, double-blinded trial 
would not be appropriate at this stage of pediatric development. Additionally, due to the hydration 
program and the special restrictions for withholding antihypertensive in the bempegaldesleukin 
arm, a placebo-controlled, double-blinded study is not appropriate for this study.
5.4.6
Rationale for Stratification 
Part B of this trial is designed as a signal-seeking study and includes a large number of different 
tumor types with heterogeneous biology and outcomes. In order to maximize the chances of 
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observing an efficacy signal, participants in Part B will be assessed in 9 different disease cohorts 
(see Figure 5.1-3).
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 development program indicate that 
most of the responses occur early, with a median time to response of 2 to 4 months, and emerging 
data suggest that benefit can be maintained in the absence of continued treatment. A recent analysis 
in a melanoma study suggests that the majority of participants who discontinue nivolumab for 
toxicity maintain disease control in the absence of further treatment.150
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 adult participants with previously treated advanced solid 
tumors (including 129 subjects 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 OS curve begins to plateau after 2 years, 
with an OS rate of 25% at 2 years and 18% at 3 years.151 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
to 18% for squamous and non-squamous NSCLC, respectively).152
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 
Q3W) vs docetaxel in participants with previously treated, PD-L1-positive, advanced NSCLC that 
specified a maximum treatment duration of 2 years for pembrolizumab. OS was significantly 
longer with both pembrolizumab 2 mg/kg (hazard ratio [HR]: 0.72; P = 0.00017) and 
pembrolizumab 10 mg/kg (HR: 0.60; P < 0.00001) compared with docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 participants who received 
pembrolizumab, 47 participants completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2participants 
(4%) having confirmed progression after stopping at 2 years.153
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 treatment of only 1 year was associated with increased 
risk of progression in previously treated participants with NSCLC, suggesting that treatment 
beyond 1 year is likely needed. In CA209153, participants 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 participants still on 
treatment at 1 year and without progression, those who were randomized to continue nivolumab 
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had significant improvement in progression-free survival (PFS) compared with those who were 
randomized to stop treatment, with median PFS (post-randomization) not reached vs 10.3 months, 
respectively (HR: 0.42 [95% confidence interval (CI): 0.25 to 0.71]). With a median follow-up of 
14.9 months post-randomization, there also was a trend for participants 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.154
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond 2 years in advanced tumors. However, although immunotherapy is well 
tolerated, participants will be at risk for additional toxicity with longer-term treatment. Therefore, 
in this study, treatment will be given for a maximum of 2 years from the start of study treatment.
Given the hypothesis that co-administration of bempegaldesleukin with nivolumab will potentiate 
the pharmacological effects of nivolumab, the duration of bempegaldesleukin therapy will also be 
restricted to 2 years to match the duration of nivolumab therapy.
5.5
Justification for Starting Dose
5.5.1
Justification for Dose of Bempegaldesleukin
The dose for bempegaldesleukin is 0.006 mg/kg Q3W taking in consideration the clinical safety 
profile associated with the robust immune system activation observed in the PIVOT-02 study. 
Please refer to Section 3.2.5.2 for additional details on PIVOT-02.
5.5.2
Justification for Dose of Nivolumab
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, RCC, classical HL, 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, classical HL, SCCHN, and urothelial 
carcinoma, using a regimen of either nivolumab 240 mg Q2W, nivolumab 3 mg/kg Q2W, or 
nivolumab 480 mg every 4 weeks.
Nivolumab has been shown to be safe and well tolerated up to a dose level of nivolumab 10 mg/kg 
Q2W. Population pharmacokinetics (PPK) analyses have shown that the pharmacokinetics (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 is expected to be 
similar to those following administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W 
administered to participants weighing 80 kg, the approximate median weight of participants with 
NSCLC, melanoma, and RCC used in the PPK analyses. Given that the Cavgss estimates for 
nivolumab 360 mg Q3W are predicted to be similar to those for nivolumab 240 mg Q2W and 
nivolumab 3 mg/kg Q2W, the efficacy is predicted to be similar for these regimens. It should be 
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noted that the maximum concentration at steady state (Cmaxss) following nivolumab 360 mg Q3W 
is predicted to be less than that 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.127
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. This study will 
therefore initiate treatment at the same dose level of bempegaldesleukin and nivolumab that will 
include flat dosing with nivolumab 360 mg Q3W for participants aged 12 years and older and 
weighing at least 40 kg or the weight-based equivalent (nivolumab 4.5 mg/kg Q3W) for 
participants younger than age 12 years or weighing less than 40 kg.
In Protocol Amendment 01, the flat dosing cohort in Part A has been modified to allow for
changing to weight-based dosing with nivolumab. This update is based on a recent population 
pharmacokinetic modeling analysis of nivolumab concentration data that included data from 
pediatric subjects (NCI# NCT02304458) in Nivolumab IBv20. It is predicted that adolescents aged 
> 12 years and weighing > 40 kg and < 80 kg receiving a flat dose of nivolumab (ie, 360 mg Q3W) 
may be exposed to higher levels of nivolumab in the blood than adults receiving the same flat 
dosing regimen. This is based on the estimate of lower clearance of nivolumab in pediatric patients,
including adolescents in the modeling analysis. It is not known whether the predicted increased 
exposure to nivolumab may be associated with an increased risk of side effects. This prediction is 
based on modeling, as there are no available data for pediatric or adolescent patients treated with 
the flat dosing. Although the reason for the estimated lower clearance of nivolumab is not 
definitely known, it may be due to differences in physiological disease states between pediatric 
and adult tumors. It should be noted that nivolumab exposure in adolescent subjects receiving the 
flat dose was predicted to be below the exposure observed in adults receiving the well-tolerated 
nivolumab monotherapy regimen of 10 mg/kg Q2W. In Part A, should any DLTs be observed with 
the flat dosing of nivolumab, the addition of weight-based dosing will allow for the evaluation of 
weight-based nivolumab with bempegaldesleukin in those ≥ 12 years and weighing ≥ 40 kg.
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Prior to study participation, written informed consent from participants, or in the case of 
minors, written permission (informed consent) from parents (both, if required by local law), 
guardians, or legally acceptable representatives must be obtained according to local laws 
and regulations.
b) Assent from minor participants, where appropriate, should be obtained per local laws and 
regulations and should be documented in accordance with local requirements.
c) Written informed consent and Health Insurance Portability and Accountability Act 
(HIPAA) authorization (applies to covered entities in the US only) must be obtained from 
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the participant/legal representative prior to performing any protocol-related procedures, 
including screening evaluations (that are not part of normal participant care).
d) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study, including disease assessment. 
Participants with glioma, medulloblastoma, ependymoma, and other CNS tumors must be 
able to undergo magnetic resonance imaging (MRI) with and without contrast because 
computed tomography (CT) scan is not permitted for these tumor types.
2) Type of Participant and Target Disease Characteristics
a) Participants must have received SOC therapy, and there must be no potentially curative 
treatment available.
b) Histologically confirmed malignant neoplasms that are refractory, relapsed, or participants 
for whom curative treatments are lacking, including newly diagnosed high-grade glioma.
c) Participants must have measurable or evaluable disease based on RECIST v1.1 for solid 
tumors, RANO/RAPNO for CNS tumors, International Pediatric Non-Hodgkin Lymphoma 
Response Criteria for NHL, revised INRC for neuroblastoma, modified NCCN Criteria for 
acute lymphoblastic leukemia, and modified Cheson et al International Working Group 
criteria for acute myeloid leukemia.
d) Lansky play score for age ≤ 16 years or Karnofsky performance score for age > 16 years 
assessed within 2 weeks of enrollment must be ≥ 60. Participants who are unable to walk 
because of neurologic deficits but who are in a wheelchair will be considered ambulatory 
for the purpose of assessing the performance score (Appendix 7).
e) Substantial recovery (ie, no ongoing safety issues) from prior therapy.
f)
An interval of 4 weeks or 5 half-lives, whichever is longer, after the last administration of 
any anti-cancer therapy or any other treatment for malignancies (6 weeks for nitrosoureas), 
prior to first dose of study drug. The interval from most recent biological agent must be 7 
days or 5 half-lives, whichever is longer, prior to first dose of study drug.
g) Participants with CNS tumors must not receive more than 0.05 mg/kg dexamethasone (or 
equivalent) per day and the dose should be stable for a minimum of a week.
h) Participants who have received high-dose chemotherapy with autologous hematopoietic 
cell transplantation must be at least 6 months post-hematopoietic cell transplantation and 
they must have a CD4 count of at least 200.
i)
Prior palliative radiotherapy must be completed at least 2 weeks prior to first dose of study 
drug. Participants must have recovered from all Grade 2 or higher clinically relevant
radiation-related toxicities. Participants with newly diagnosed malignant gliomas who may 
have received focal radiation or radiation and temozolomide are eligible. Note: Radiated 
lesions cannot be used as measurable lesions unless they have a new baseline scan after 
radiation or there is clear evidence of progression.
j)
Documented left ventricular ejection fraction (LVEF) >45% using standard 
echocardiogram or multigated acquisition (MUGA) scan test.
k) Participant re-enrollment: This study permits the re-enrollment of a participant who has 
discontinued the study as a pretreatment failure (ie, participant has not been treated). If re-
enrolled, the participant must be re-consented (Section 6.4.1).
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3) Age and Reproductive Status
a) Female Participants 
i)
Females, ages less than 18 years old at the time of enrollment for Part A and Part B. 
For Part B, Cohorts B2, B3, and B4, participants less than 30 years old may be enrolled.
ii) Women who are not of childbearing potential are exempt from contraceptive 
requirements.
iii) Women participants must have documented proof that they are not of childbearing 
potential.
iv) WOCBP must have a negative highly sensitive serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 
within 24 hours prior to the start of study treatment.
(1) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
v) Additional requirements for pregnancy testing during and after study intervention are 
located in Section 2, Schedule of Activities.
vi) The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
vii)WOCBP must agree to follow instructions for method(s) of contraception defined in 
Appendix 4 and as described below and included in the informed consent form (ICF).
viii)
WOCBP are permitted to use hormonal contraception methods (as described in 
Appendix 4).
ix) A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies:
(1) Is not a WOCBP 
OR
(2) Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of < 1% per year) with low user dependency (as described in 
Appendix 4) during the intervention period and for at least 5 months post-treatment 
completion and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction for the same time period.
b) Male Participants 
i)
Males, ages less than 18 years old at the time of enrollment for Part A and Part B. For 
Part B, Cohorts B2, B3, and B4, participants less than 30 years old may be enrolled.
ii) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception defined in Appendix 4 and as described below.
iii) Not applicable as of Amendment 01; see 3) b) viii) for updated criterion: 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 
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breastfeeding. Males should continue to use a condom during the intervention period 
and for at least 7 months post-treatment completion. 
iv) Not applicable as of Amendment 01; see 3) b) ix) for updated criterion: Female 
partners of males participating in the study should be advised to use highly effective 
methods of contraception during the intervention period and for at least 7 months post-
treatment completion in the male participant.
v) Not applicable as of Amendment 01; see 3) b) x) for updated criterion: Male 
participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, 
oral), even if the participants have undergone a successful vasectomy, during the 
intervention period and for at least 7 months post-treatment completion.
vi) Not applicable as of Amendment 01; see 3b(xi) for updated criterion: Male 
participants must refrain from donating sperm during the intervention period and for at 
least 7 months post-treatment completion.
vii)Breastfeeding partners should be advised to consult their health care providers about 
using appropriate highly effective contraception during the time the participant is 
required to use condoms.
viii)
Male participants will be required to always use a latex or other synthetic condom 
during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the 
participants have undergone a successful vasectomy or if their partner is already 
pregnant or breastfeeding. Males should continue to use a condom during the 
intervention period and for at least 3 months post-treatment completion. 
ix) Female partners of males participating in the study should be advised to use highly 
effective methods of contraception during the intervention period and for at least 3 
months post-treatment completion in the male participant.
x) Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from sexual activity or use a male condom during any sexual activity 
(eg, vaginal, anal, oral), even if the participants have undergone a successful 
vasectomy, during the intervention period and for at least 3 months post-treatment 
completion.
xi) Male participants must refrain from donating sperm during the intervention period and 
for at least 3 months post-treatment completion.
Investigators shall counsel women of childbearing potential (WOCBP), and male participants who 
are sexually active with WOCBP, on the importance of pregnancy prevention, the implications of 
an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study 
drug, present in seminal fluid, to a developing fetus, even if the participant has undergone a 
successful vasectomy or if the partner is pregnant.

The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.

Local laws and regulations may require the use of alternative and/or additional contraception 
methods.
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6.2
Exclusion Criteria
1) Medical Conditions
a) Participants with osteosarcoma, T-cell/NK-cell leukemia/lymphoma, and HL.
b) 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).
c) Active infection requiring systemic therapy within 14 days prior to first dose.
d) Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics). Participants with hypertension must be on a stable antihypertensive regimen for 
the 14 days prior to treatment assignment. Note: An antihypertensive medication that 
contains 2 drugs in 1 formulation is counted as 2 antihypertensive medications (e.g., 
angiotensin-converting-enzyme [ACE] inhibitor plus diuretic, calcium channel blocker 
plus ACE inhibitor).
e) Unstable or deteriorating cardiovascular 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)/CVA
(3) Congestive heart failure (New York Heart Association Class III or IV)
(4) Uncontrolled clinically significant arrhythmias
f)
History of pulmonary embolism, deep vein thrombosis, or prior clinically significant 
venous or non-CVA/TIA arterial thromboembolic event (eg, internal jugular vein 
thrombosis) within 3 months prior to treatment assignment.
(1) Participants with a history of a venous or arterial thromboembolic event must be 
asymptomatic for at least 2 weeks prior to treatment assignment 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.
(2) 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.
g) Participants with inadequately treated adrenal insufficiency.
h) 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.
i)
Participants with a condition (excluding CNS tumors) requiring systemic treatment with 
either 
corticosteroids 
(> 0.12 
mg/kg
daily 
prednisone 
equivalent) 
or 
other 
immunosuppressive medications within 14 days of start of study treatment. Inhaled or 
topical steroids and adrenal replacement steroid doses > 0.12 mg/kg daily prednisone 
equivalent are permitted in the absence of active autoimmune disease.
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j)
Known human immunodeficiency virus (HIV) positive with an Acquired Immune
Deficiency Syndrome (AIDS)-defining opportunistic infection within the last year, or a
current CD4 count < 350 cells/uL. (Participants with known HIV who are enrolled should 
receive ART therapy as clinically indicated and be monitored for CD4 counts and viral 
load per standard of care by a local health care provider.) NOTE: Testing for HIV must be 
performed at sites where mandated locally. HIV positive participants must be excluded 
where mandated locally (see Appendix 13).
k) 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. 
l)
Participants with serious or uncontrolled medical disorders.
2) Prior/Concomitant Therapy
a) Participants who have received a live/attenuated vaccine within 30 days before first 
treatment (see Section 7.7.3.1). Replication-incompetent virus vaccines are not considered 
live vaccines (live vaccines are defined as those that are capable of transmitting infectious 
viruses). 
b) 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.
c) 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 treatment. Refer to Section 7.7.1 for prohibited therapies. 
d) Participants having had a prior allogeneic stem cell transplant.
e) Participants currently in other interventional trials, including those for COVID-19, may not 
participate in BMS clinical trials until the protocol specific washout period is achieved. If 
a study participant has received an investigational COVID-19 vaccine or other 
investigational product designed to treat or prevent COVID-19 prior to screening, 
enrollment must be delayed until the biologic impact of the vaccine or investigational 
product is stabilized, as determined by discussion between the investigator and the Medical 
Monitor.
3) Physical and Laboratory Test Findings
a) WBC < 2000/μL (participants with leukemia or bone marrow infiltration are exempt)
b) Not applicable as of Amendment 01; see 3) i)
for updated criterion:
Neutrophils < 1500/μL (participants with leukemia or bone marrow infiltration are exempt)
c) Platelets < 100 x 103/μL (participants with leukemia or bone marrow infiltration are
exempt)
d) Hemoglobin < 9.0 g/dL (can be transfused; there is no limit on the number of transfusions)
e) Serum creatinine > 1.5 × ULN for age, unless creatinine clearance (CrCl) ≥ 40 mL/min 
(measured or calculated using the Cockcroft-Gault formula or as per institutional practice)
i)
Female CrCl = (140 - age in years) × weight in kg × 0.85
                               72 × serum creatinine in mg/dL
ii) Male CrCl = (140 - age in years) × weight in kg × 1.00
                            72 × serum creatinine in mg/dL
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f)
AST/ALT: > 3.0 × ULN
g) Total bilirubin > 1.5 × ULN (except participants with Gilbert’s syndrome, who must have 
a total bilirubin level of < 3.0 × 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).
i)
Neutrophils < 1000/μL (participants with leukemia or bone marrow infiltration are exempt)
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
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 BMS approval is required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
c) Inability to comply with restrictions as listed in Section 6.3 (Lifestyle Restrictions).
d) Previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks prior to first 
dose of study drug. Acute symptoms must have resolved and based on investigator 
assessment in consultation with the Medical Monitor, there are no sequelae that would 
place the participant at a higher risk of receiving investigational treatment.
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
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 who 
are not subsequently entered in the study/included in the analysis population. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, as 
applicable, and to respond to queries from regulatory authorities. Minimal information includes 
date of consent, demography, screen failure details, eligibility criteria, and any serious AEs.
6.4.1
Retesting During Screening or Lead-in Period
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been treated). If re-
enrolled, the participant must be re-consented.
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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 first study treatment is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline, may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
Testing for asymptomatic SARS-CoV-2 infection, for example by 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 reverse transcription polymerase chain reaction (RT-PCR) or viral antigen test 
result, and

At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and

Acute symptoms (eg, cough, shortness of breath) have resolved and

In the opinion of the investigator, there are no COVID-19-related sequelae that may place the 
participant at a higher risk of receiving investigational treatment, and 

Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local,
or regional guidelines.
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 
Noninvestigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:

Nivolumab Solution for Injection

Bempegaldesleukin (NKTR-214) Powder for Solution for Injection
An IP, also known as IMP in some regions, is defined a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a clinical study, including products already with 
a marketing authorization but used or assembled (formulated or packaged) differently than the 
authorized form, or used for an unauthorized indication, or when used to gain further information 
about the authorized form.
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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the SOC for a given diagnosis, may be considered as non-IPs.
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Table 7-1:
Study Treatments for CA045020
Product 
Description/Class
and Dosage Form
Content
IP/Non-IMP
Blinded or Open 
Label
Packaging/
Appearance
Storage Conditions
(per label)
Investigational product:
Bempegaldesleukin 
(NKTR-214) Powder 
for Solution for 
Injection
1.0 mg of rhIL-2 per 
viala
IP
Open-label
Vial (one or more vials 
per carton)
Refer to the label on
container and/or
pharmacy manual
Commercial product:
Bempegaldesleukin 
(NKTR-214) Powder 
for Solution for 
Injection
0.3 mg 
of rhIL-2 per viala,
IP
Open-label
Vial (one or more vials 
per carton)
Refer to the label on 
container and/or 
pharmacy manual
Commercial product:
Bempegaldesleukin 
(NKTR-214) Powder 
for Solution for 
Injection
0.5 mg 
of rhIL-2 per viala,
IP
Open-label
Vial (one or more vials 
per carton)
Refer to the label on 
container and/or 
pharmacy manual
Nivolumab Solution for 
Injection
100 mg (10 mg/mL)
IP
Open-label
Vial (multiple vials per 
carton)
Refer to the label on 
container and/or 
pharmacy manual
Abbreviations: IL-2 = interleukin-2; IMP = Investigational Medicinal Product; IP = Investigational Product; mg = milligrams; mL = milliliters; rhIL-2 = 
recombinant human IL-2.
a For bempegaldesleukin (NKTR-214), IL-2 and rhIL-2 refer to the same molecule.
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7.1
Treatments Administered
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
Bempegaldesleukin 
(NKTR-214)a
0.003 mg/kg and 0.006 mg/kg
Q3W
IV
Nivolumab
360 mg or 4.5 mg/kg
Q3W
IV
Abbreviations: IV = intravenous; mg = milligrams; Q3W = every 3 weeks.
a Bempegaldesleukin dose is based on IL-2 content.
Study agent(s) should be administered in an area with access to resuscitation equipment. Dosing
calculations should be based on the actual body weight assessed at baseline. It is not necessary to 
recalculate subsequent doses if the participant’s weight is within 10% of the weight used to 
calculate the previous dose. All doses should be rounded up to the nearest milligram or per 
institutional standard. 
After participants are assigned to an initial nivolumab regimen (either weight/age-based or flat to 
weight-based dosing), participants should remain on that regimen for the duration of the study.
Participants should be carefully monitored for infusion reactions during study treatment 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.6. 
Doses of study treatment may be interrupted during infusion (see Section 7.4.6), delayed (see 
Section 7.4.1), or discontinued (see Section 8.1) depending on how the participant tolerates 
treatment. Dosing visits (cycles) are not skipped or omitted, but they may be delayed. Within a 
specified dosing schema, there will be no dose escalations or reductions of nivolumab allowed. 
Premedications are not recommended for the first dose of study therapy. Study therapy may be 
administered within 3 days before or after the scheduled dose. 
7.1.1
Bempegaldesleukin Dosing
Each participant’s bempegaldesleukin dose will be determined by the participant’s weight in 
kilograms, which will be determined before the start of each cycle. If the participant’s weight is 
within 10% of the Cycle 1 Day 1 weight, the study drug doses do not need to be recalculated 
depending on institutional guidelines/preference.
Bempegaldesleukin will be administered IV via infusion or syringe pump. Bempegaldesleukin will 
be administered first before nivolumab. Bempegaldesleukin will be administered as an IV infusion 
over approximately 30 minutes (exclusive of the flush time) at a starting dose of 0.006 mg/kg Q3W
(± 3 days). After the bempegaldesleukin IV infusion is administered, flush the intravenous line 
with an appropriate amount of diluent (e.g, 0.9% Sodium Chloride or 5% Dextrose in Water) to 
ensure that the complete dose is administered. However, if a syringe pump is used, no flush is 
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permitted unless otherwise permitted by institutional procedures. Nivolumab administration 
should start at least 30 minutes from the end of the bempegaldesleukin administration.
Participants should be carefully monitored for infusion reactions during bempegaldesleukin 
administration. If an acute infusion reaction is noted, participants should be managed according to
Section 7.4.6. If the participant experiences a Grade 2 infusion-related reaction or hypotension 
during the days after bempegaldesleukin dosing, the participant may be monitored overnight at the 
discretion of the Investigator; longer periods of monitoring may be implemented at the discretion 
of the Investigator.
Treatment with bempegaldesleukin may be delayed or reduced as described in Section 7.4.1. In 
the event that nivolumab is permanently discontinued due to toxicities, see Section 8.1.1.
Bempegaldesleukin treatment can continue for participants in the event that nivolumab is 
permanently discontinued due to toxicities (see Section 8.1.1).
Please refer to the Pharmacy Manual/current IB for details regarding preparation, storage, and 
administration.147
7.1.1.1
Hydration Guidelines
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 assigned to bempegaldesleukin, 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 are to be instructed to drink at least 2 liters per 
day of self-administered oral hydration (see Table 2-2).
Pediatric Hydration Guidelines:
Hydration guidance for pediatric participants is weight and age based. Participants who weigh 
40 kg and are aged 12 years will follow the Adult Hydration Guidelines. 
For pediatric participants who weigh < 40 kg but are 10 kg, 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), pediatric participants < 
40 kg but 10 kg are to be instructed to drink at least 1 liter of fluids per day.
For pediatric participants who weigh < 10 kg, administer 250 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), participants < 10 kg are to be instructed to drink at least 500 mL of fluids per day.
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Table 7.1.1.1-1:
Hydration Guidelines for Adult and Pediatric Participants
Adult & Pediatric
≥ 40 kg and Aged ≥ 12 Years
Pediatric
≥10 kg to < 40 kg
Pediatric
< 10 kg
Day of infusion (IV)
1000 mL 
500 mL 
250 mL
Days 2-4 (oral)
2000 mL per day 
1000 mL per day
500 mL per day
Abbreviation: IV = intravenous; kg = kilograms; mL = milliliters.
Advise participants to refrain from activities that may contribute to dehydration (including, but not 
limited to, strenuous activity, long hot showers, and saunas) for Days 1 to 4 of each cycle of 
treatment with bempegaldesleukin. Advise participants with orthostatic symptoms to call their 
treating oncologist and consider increasing oral hydration. 
Between Days 3 and 5, inclusive, following administration of the first 2 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
Within a specified dosing schema, 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) cycles. Premedications are not recommended for the first dose of nivolumab. In the 
event that bempegaldesleukin is permanently discontinued due to toxicities, see Section 8.1.1.
Participants should receive nivolumab as an approximately 30-minute (± 5 minutes) infusion on 
Day 1 of each treatment cycle Q3W (3 days) until progression, unacceptable toxicity, withdrawal 
of consent, completion of 2 years of treatment, or the study ends, whichever occurs first.
Participants should begin study treatment within 3 calendar days of treatment assignment.
For weight-based dosing, use body weight for dosing calculations. It is not necessary to re-
calculate subsequent doses if the participant weight is within 10% of the baseline weight or the 
weight used to calculate the previous dose. Round all doses to the nearest milligram per 
institutional standard.
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.
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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. In the event that 
bempegaldesleukin is permanently discontinued due to toxicities, see Section 8.1.1.
Nivolumab injection, 100 mg/10 mL (10 mg/mL) and 40 mg/4 mL (10 mg/mL), is to be 
administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, low-protein binding 
in-line filter at the protocol-specified doses. It is not to be administered as an IV push or bolus 
injection. When the dose is based on participant weight (ie, mg/kg), nivolumab injection can be 
infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, United States 
Pharmacopeia (USP), or 5% Dextrose Injection, USP, to protein concentrations as low as 
0.35 mg/mL. When the dose is fixed (eg, 360 mg flat dose), nivolumab injection can be infused 
undiluted or diluted so as not to exceed a total infusion volume of 120 mL. Nivolumab infusion 
must be promptly followed by a flush of diluent to clear the line. Instructions for dilution and 
infusion of nivolumab injection may be provided in the clinical protocol, pharmacy binder, or 
pharmacy reference sheet. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent.
Nivolumab infusions are compatible with polyvinyl chloride or polyolefin containers and infusion 
sets and glass bottles.
When bempegaldesleukin
and
nivolumab are to be administered on the same day, 
bempegaldesleukin should be administered first, followed by nivolumab. 
7.2
Method of Treatment Assignment
Before the study is initiated at an investigative site, each user will receive login information and 
directions on how to access the Interactive Response Technology (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 dosing (either age/weight-based or flat to weight-based dosing). 
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
7.3
Blinding
Not applicable because this is an open-label study; however, the specific treatment to be taken by 
a participant will be assigned using an IRT. Treatment assignments will be released to the 
bioanalytical laboratory in order to minimize unnecessary analysis of samples. 
7.4
Dosage Modification
If bempegaldesleukin or nivolumab meet the criteria for dose delay, then administration of both 
drugs must be delayed until the criteria to resume are met (see Table 7.4.1-1 for AE Criteria for 
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Delay, Resumption, and Discontinuation of both drugs and Table 7.4.1-2 for bempegaldesleukin-
specific criteria).
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. I-O 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 I-O agent in this protocol. Early recognition 
and management of AEs associated with I-O agents may mitigate severe toxicity.
Discontinuation criteria for nivolumab and bempegaldesleukin are found in Section 8.1.1.
7.4.1
Nivolumab and Bempegaldesleukin Dose Delay, Resumption, and 
Discontinuation Criteria
In Oct-2020, the nivolumab AE grading criteria and algorithms were updated to CTCAE v5, and 
the AE criteria for delaying, resuming, and discontinuation of nivolumab and bempegaldesleukin 
are available in Table 7.4.1-1.

SARS-CoV-2 infection either confirmed or suspected, requires delay of nivolumab and 
bempegaldesleukin study treatment. 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. For suspected cases, treatment may also resume if 
SARS-CoV-2 infection is ruled-out and other criteria to resume treatment are met.
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.
All study treatment must be delayed at the same time. Because of the potential for clinically 
meaningful nivolumab-related AEs requiring early recognition and prompt intervention, 
management algorithms have been developed for suspected pulmonary toxicity, gastrointestinal, 
hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity,
renal toxicity, and 
myocarditis. The algorithms recommended for use are included in Appendix 5.
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.
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Bempegaldesleukin dosing may resume at the same bempegaldesleukin dose or at a lower 
bempegaldesleukin dose level when toxicity resolves to Grade 1 or returns to baseline, except for 
instances where the potential recurrence of the event poses an undue risk for the participant. 
Medical Monitor consultation is required for dose reduction.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
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 dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
Grade 4 
Permanently 
discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after pneumonitis has resolved to 
Grade ≤1.
Grade 3 or 4 
Permanently 
discontinue
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
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).
Concurrent AST or ALT > 3× 
ULN and T.bili > 2× ULN, 
regardless of baseline value
Permanently 
discontinue 
Endocrinopathy
Adrenal Insufficiency
Grade 2 adrenal insufficiency
Delay dose
Dosing may resume after adequately controlled with 
hormone replacement.
Grade 3 or 4 adrenal 
insufficiency or adrenal crisis
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming nivolumab or 
bempegaldesleukin therapy. If adrenal insufficiency 
resolves or is adequately controlled with physiologic 
hormone replacement, participant may not require
discontinuation of nivolumab or bempegaldesleukin.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
Drug-related AE per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Hyperglycemia
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3)
Delay dose
Dosing may resume if hyperglycemia resolves to 
Grade ≤1 or baseline value or is adequately controlled 
with glucose-controlling agents.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming therapy. If 
hyperglycemia resolves or is adequately controlled with 
glucose-controlling agents, participant may not require 
discontinuation of nivolumab or bempegaldesleukin.
Hypophysitis/Hypopituitarism
Symptomatic Grade 1-3 that is 
also associated with 
corresponding abnormal lab 
and/or pituitary scan
Delay dose 
Dosing may resume if endocrinopathy resolves to be 
asymptomatic or is adequately controlled with only 
physiologic hormone replacement.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming nivolumab or 
bempegaldesleukin therapy. If endocrinopathy resolves or 
is adequately controlled with physiologic hormone 
replacement, participant may not require discontinuation 
of nivolumab or bempegaldesleukin.
Hyperthyroidism or 
Hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if endocrinopathy resolves to be 
asymptomatic or is adequately controlled with only 
physiologic hormone replacement or other medical 
management.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with and approval from the Medical 
Monitor needed prior to resuming nivolumab or 
bempegaldesleukin therapy. If endocrinopathy resolves or 
is adequately controlled with physiologic hormone 
replacement or other medical management, participant 
may not require discontinuation of nivolumab or 
bempegaldesleukin.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
Drug-related AE per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
Skin
Rash
Grade 2 rash covering > 30% 
body surface area or Grade 3 
rash 
Delay dose 
Dosing may resume when rash reduces to ≤ 10% body 
surface area. 
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN),
or drug reaction with 
eosinophilia and systemic 
symptoms (DRESS)
Delay dose
Dosing may resume if SJS, TEN, or DRESS is ruled out 
and rash reduces to  ≤ 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
Grade 2
Delay dose
Dosing may resume when AE resolves to baseline. 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
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 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
Other Drug-related AE 
(not listed above, see 
Grade 2 non-skin AE, except 
fatigue
Nivolumab: Delay dose
Dosing may resume when AE resolves to Grade ≤ 1 or 
baseline value.
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
Drug-related AE per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
bempegaldesleukin-specific criteria 
in Table 7.4.1-2 for further 
guidance)
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
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 
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Table 7.4.1-1:
Adverse Event Criteria for Delay, Resumption, and Discontinuation of Nivolumab and 
Bempegaldesleukin (if one delayed, both delayed)
Drug-related AE per CTCAE V5
Severity 
Action Taken
Clarifications, Exceptions, and Resume Criteria
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; MS = myasthenia 
gravis; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; T.bili = total billirubin; TIA = transient ischemic attack; ULN = upper limit of normal.
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Table 7.4.1-2:
Bempegaldesleukin-specific Adverse Event Criteria for Delay, Resumption, and Discontinuation of 
Nivolumab and Bempegaldesleukin (if one is delayed, both are delayed)
Bempegaldesleukin-specific Drug-
related AE per CTCAE V5
Severity
Action Taken
Clarifications, Exceptions, and 
Resume Criteria
Serum Creatinine Increased
(transient, non-inflammatory)
Grade 2, 3, or 4
Delay dose*
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 5) 
Other Drug-related AE (not listed in 
Table 7.4.1-1)
Persistent Grade 2 toxicity except 
fatigue and asthenia
Delay dose*
Dose delay at the discretion of the 
Investigator. Note: Persistent Grade 2 
is defined as a Grade 2 AE lasting ≥ 
3 weeks and ongoing at the time of 
subsequent dosing that is attributed 
as either “possibly related” or 
“related” to bempegaldesleukin
TIA/CVA
All grades
Permanently discontinue both drugs
Any new CVA event confirmed by 
MRI with diffusion-weighted 
imaging, regardless of neurological 
symptoms (eg, cryptogenic CVA) 
and for suspected TIA without clear 
alternative etiology. See Appendix 5.
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; CVA = cerebrovascular accident; MRI = magnetic resonance 
imaging; TIA = transient ischemic attack
*If dosing of one drug is delayed, then dosing of both drugs is delayed.
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7.4.1.1
Dose Modification Criteria for Bempegaldesleukin and Nivolumab for 
Cycle 1 AST/ALT Elevations
These recommendations are for Cycle 1 only and are not intended to serve as rigid guidelines or 
to replace clinical judgment. Subsequent cycles should follow standard Hepatic Adverse Event 
Management Algorithm (Appendix 5).
Rule out alternative etiologies. Consider imaging if obstruction is suspected. If there is a 
noninflammatory etiology, treat accordingly and continue bempegaldesleukin and nivolumab. 
If ALT/AST increases during monitoring, follow the guidance for the highest levels.
AST or ALT > 3.0 to ≤ 5 × ULN (within first cycle of bempegaldesleukin + nivolumab)
Increase frequency of liver function test monitoring to approximately every 3 days and delay 
treatment until lab abnormalities resolve to Grade 1 or baseline.
If no improvement within 7 days, treat with 0.5-1 mg/kg/day prednisone equivalents and taper 
steroids over at least 1 month before resuming treatment.
ALT or AST > 5.0 to ≤ 8.0 × ULN (within first cycle of bempegaldesleukin + nivolumab)
Increase frequency of monitoring to approximately every 3 days until lab abnormalities resolve to 
Grade 1 or baseline.
Treatment must be delayed until lab abnormalities resolve to Grade 1 or baseline.
If no improvement within 7 days (follow Hepatic Adverse Event Management Algorithm
[Appendix 5]):
Discontinue bempegaldesleukin + nivolumab
1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month
Consult gastroenterologist
Consider adding noncorticosteroid immunosuppressive medication if no improvement in 
> 3-5 days, worsens or rebounds while on steroids
ALT or AST > 8.0 × ULN (follow Hepatic Adverse Event Management Algorithm
[Appendix 5])
Discontinue bempegaldesleukin + nivolumab
Increase frequency of monitoring to approximately 1-2 days

1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month

Consult gastroenterologist

If no improvement in > 3–5 days, worsens or rebounds, add noncorticosteroid 
immunosuppressive medication
Please refer to Section 8.1 for discontinuation criteria.
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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 
(Days 4-8) and are often accompanied by other 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).
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 product labeling 
for appropriate management.127
7.4.3
Monitoring and Management of Eosinophilia
7.4.3.1
Bempegaldesleukin-induced Eosinophilia
Frequent and significant eosinophilia has been observed in participants 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 the study 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 5000/µL (5 × 109/L) level, delaying 
bempegaldesleukin treatment may be considered while evaluating and treating the participant as 
clinically indicated.
7.4.3.2
Eosinophilic Disorders
Isolated cases of hypereosinophilic syndrome 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.
Additional details regarding eosinophilia and eosinophilic disorders are provided in the 
Bempegaldesleukin Investigator’s Brochure.
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7.4.4
Monitoring and Management of Adrenal Insufficiency and Hypophysitis
Adrenal insufficiency and hypophysitis have been observed in participants receiving nivolumab. 
Consider prompt evaluation when participants have signs or symptoms of hypophysitis or adrenal 
insufficiency, which includes levels of early-morning adrenocorticotropic hormone, cortisol, 
thyroid-stimulating hormone (TSH), and free thyroxine (fT4). Co-management with an 
endocrinologist is recommended for participants with preexisting adrenal insufficiency.
7.4.5
Management Algorithms for Immune-mediated Adverse Events and 
Cytokine-Release Syndrome
7.4.5.1
Management Algorithms for Immune-mediated Adverse Events 
Associated with Immuno-oncology Agents
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 I-O
agents in this protocol. Early recognition and management of AEs associated with I-O agents may 
mitigate severe toxicity. Management algorithms (see the nivolumab IB) have been developed to 
assist Investigators in assessing and managing the following groups of AEs:

Gastrointestinal

Renal

Pulmonary

Hepatic

Endocrinopathy

Skin

Neurological

Myocarditis

CVA
A management algorithm for possible signs and symptoms of CVA and cytokine-release syndrome 
for participants treated with bempegaldesleukin in combination with a checkpoint inhibitor is 
provided in Appendix 6 and Appendix 14, respectively.
Management algorithms for AEs associated with I-O agents are presented in Appendix 5.
For pediatric participants, dosages should be provided by kg or in accordance with 
institutional standards.
7.4.5.2
Management Algorithm for Cytokine-Release Syndrome
Cytokine-release syndrome 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 
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macrophage activation syndrome. For suspected CRS of Grade 3 or above, the Investigator is 
encouraged to contact the Sponsor. An algorithm for the management of CRS is provided in 
Appendix 14.
7.4.6
Treatment of Bempegaldesleukin-related or Nivolumab-related Infusion 
Reactions
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, arthralgia, 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):

For pediatric participants, dosages should be provided by kg or in accordance with institutional 
standards.

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 pediatric dose equivalent (or equivalent drug class) and/or 
acetaminophen/paracetamol 325 to 1000 mg (or pediatric dose equivalent) at least 30 minutes 
before subsequent infusions. Subsequent infusions may be administered at a reduced rate (ie, 
50% of the original 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):

For pediatric participants, dosages should be provided by kg or in accordance with 
institutional standards.

Stop the bempegaldesleukin or nivolumab infusion, begin an IV infusion of normal saline, and 
treat the participant with diphenhydramine 50 mg IV or pediatric dose equivalent (or equivalent
drug class) and/or acetaminophen/paracetamol 325 to 1000 mg (or pediatric dose equivalent); 
remain at the bedside and monitor the participant until resolution of symptoms. Corticosteroid 
and/or bronchodilator therapy may also be administered as appropriate. If the infusion is 
interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve. If symptoms recur after restarting the bempegaldesleukin or nivolumab infusion, then 
no further bempegaldesleukin or nivolumab will be administered at that visit. Administer 
diphenhydramine 50 mg IV (or pediatric dose equivalent), 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 pediatric dose equivalent (or equivalent drug class) and/or 
acetaminophen/paracetamol 325 to 1000 mg (or pediatric dose equivalent) should be 
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administered at least 30 minutes before the infusion. If necessary, corticosteroids (up to 25 mg 
of methylprednisolone or pediatric dose equivalent [or equivalent drug class]) may be used.
Subsequent infusions may be administered at a reduced rate (ie, 50% of the original infusion 
rate). 
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):

For pediatric participants, dosages should be provided by kg or in accordance with 
institutional standards.

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 (or pediatric equivalent) for IM administration or 0.1 to 0.25 
mg of a 1:10,000 solution (or pediatric equivalent) injected slowly for IV administration, 
and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV or pediatric dose 
equivalent (or equivalent drug class), 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 IP should be stored in a secure area according to local regulations. It is the responsibility of 
the investigator to ensure that IP is only dispensed to study participants. The IP 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.
IP documentation (whether supplied by BMS or not) must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (eg, required diluents, administration sets).
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Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
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 the 
participant’s medical records and electronic case report form (eCRF). Study drug will be 
administered in the clinic by trained personnel. Drug accountability should be reviewed by the site 
study staff at each visit.
The date and time of start and end of infusion and the exact amount given at each infusion will be 
recorded. In case the treatment has to be interrupted during an infusion and the dosing is not 
resumed, the medical personnel should evaluate the percentage of dose received by the participant 
and document it in the participant record.
At least once between Days 3 and 5 (inclusive) following the first 2 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.
Any reason for noncompliance should also be documented.
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 
AE):

Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella) during treatment and until 150 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).

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, nonpalliative radiation therapy, or standard or investigational agents for treatment 
of the tumor). Participants may receive focal radiation therapy for palliation.

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.
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7.7.2
Palliative Therapy
Palliative (limited-field) radiation therapy and palliative surgical resection are permitted and must 
be clearly documented in the study record. Participants receiving palliative radiation to target 
lesions require reimaging post radiation and prior to initiation of drug therapy.
7.7.3
Prior and Concomitant Medications
Recording of prior medications should include prior cancer treatments: previous immunotherapy, 
chemotherapy, targeted therapy, radiation, over-the-counter (OTC) medications, herbs, and dietary 
supplements. 
All medications (prescription and OTC), vitamin and mineral supplements, and/or herbs taken by 
the participant from Screening through End of Treatment phase will be documented and recorded, 
including start and stop date, dose and route of administration, frequency, and indication. 
Medications taken for a procedure (eg, biopsy) should also be included.
Premedications should not be administered prior to the initial administration of bempegaldesleukin
or nivolumab, but if a participant reports symptoms (such as nausea and/or vomiting), prophylactic 
use of antiemetics may be used.
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 first dose of treatment until the biologic impact of the vaccine is 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 may be delayed until the biologic impact of the vaccine is stabilized, as determined 
by the Investigator. 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; however, if possible, overlap of administration should be 
avoided (A 2-day gap is recommended, but a 7-day gap is preferable).
7.7.3.2
Effect of Bempegaldesleukin on Pharmacokinetics of Concomitant 
Medications
Bempegaldesleukin causes transient increases in circulating cytokines lasting for about 1 week 
after bempegaldesleukin dosing in the Q3W dosing schedule. Several of these cytokines (IFN-γ, 
IL-6, IL-10) have the potential to decrease the activity of multiple drug-metabolizing enzymes and 
drug transporters. Consequently, treatment with bempegaldesleukin may lead to a temporary 
decrease in clearance of drugs that are substrates of these Phase I and Phase II drug metabolizing 
enzymes, or drug transporters. Where indicated based on decreased tolerability or the occurrence 
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of AEs related to a concomitant drug, reduce the dosage of the concomitant drug during Days 3 to 
8 of each cycle of bempegaldesleukin.
7.7.4
Other Restrictions and Precautions
7.7.4.1
Restricted Treatments
Participants with a condition requiring systemic treatment with either corticosteroids (> 0.12 
mg/kg daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
treatment assignment are excluded. Inhaled or topical steroids and adrenal replacement steroid 
doses > 0.12 mg/kg daily prednisone equivalent are permitted in the absence of active autoimmune 
disease.
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

Oral factor Xa inhibitors (direct oral anticoagulants such as rivaroxaban, apixaban, or 
edoxaban).

Use of warfarin (Coumadin) is permitted; however, therapeutic dosing should target a specific 
international normalized ratio (INR) stable for at least 4 weeks prior to enrollment. Because 
bempegaldesleukin has the potential to downregulate metabolizing enzymes for warfarin for 
approximately 1 week after administration of each dose of bempegaldesleukin, frequent 
monitoring of INR and ongoing consideration of 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 for guidance.
7.7.4.2
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history, and renal status), the appropriate imaging modality and contrast 
regimen per imaging study. Imaging contraindications and contrast risks are to be considered in 
this assessment. Participants with renal insufficiency are to be assessed as to whether they should 
receive contrast and, if so, which contrast agent and dose is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis; therefore, MRI 
contrast is contraindicated. In addition, participants may be excluded from MRI if they have 
tattoos, metallic implants, pacemakers, etc. This will be outlined in the image acquisition manual.
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Gentle hydration before and after IV contrast should follow local SOC. The ultimate decision to 
perform MRI in an individual participant in this study rests with the site radiologist, the 
investigator, and standards set by the local Ethics Committee.
7.7.4.3
Blood Pressure Precautions
Consideration should be given to withholding antihypertensive medications, including diuretics, 
as well as other drugs with hypotensive properties (eg, alpha blockers for benign prostatic 
hyperplasia), particularly when therapy involves multiple antihypertensive drugs and classes other 
than thiazide diuretics. If withholding antihypertensive medications, withhold no less than 
12 hours and no more than 48 hours prior to each dose of bempegaldesleukin. Participants who 
are on medications with antihypertensive effects for the treatment of coronary artery disease (eg, 
beta-blockers, calcium 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 stepwise 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.
7.7.4.4
Volume of Blood
Blood sample collection volumes will be appropriately reduced per guidelines outlined in the 
laboratory manual to meet pediatric institutional guidelines for maximum daily and monthly blood 
draw limits. 
7.7.5
Permitted Therapy
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 antihistamines is permitted on study per the Investigator’s 
discretion. Prophylaxis for rash and/or pruritus should be initiated on either Day 1 or Day 2 after 
dosing of bempegaldesleukin or nivolumab and may continue through Day 5 or longer as needed.
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted in the absence of active autoimmune disease. 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.
Direct effects of immune treatment on tumor may produce neurologic AEs, collectively termed 
“tumor flare,” depending on the location and usually associated with radiographic changes (see 
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Section 5.4.2). Treatment with high-dose steroids should be implemented immediately to control 
inflammation and edema in addition to any other indicated therapy. In most cases, improvement 
is fairly rapid; tapering of steroids should be guided by neurologic effects but often may be tapered 
more quickly than advised for immune-mediated effects on normal tissues. Contact with BMS 
Medical Monitor is recommended.
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 specified 
in 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 the combination
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.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation From Study Treatment
Participants MUST discontinue IP (and non-IP 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 AE, laboratory abnormality, or intercurrent illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
participant.

Termination of the study by BMS.

Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply, and 
BMS approval is required.)

Confirmed disease progression or investigator-assessed clinical progression as specified in 
Section 9.1.2 (with exceptions noted in Section 8.1.2).

Toxicity as specified above and in Section 9.2.

Maximal clinical benefit as assessed by investigator.

Pregnancy.
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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 most 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 page.
8.1.1
Nivolumab and Bempegaldesleukin Discontinuation Criteria
Bempegaldesleukin and nivolumab treatment must be permanently discontinued per criteria in 
Table 7.4.1-1 and Table 7.4.1-2. Discontinue nivolumab and bempegaldesleukin for any AE, 
laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, presents 
substantial clinical risk to the participant with continued nivolumab and bempegaldesleukin 
dosing. 
Participants meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s). However, per investigator assessment, treatment with nivolumab or 
bempegaldesleukin 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 7.4.5).

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/or 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 AEs 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 reinitiating 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.
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8.1.2
Treatment Beyond Progression
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of progressive disease.142,155
Participants treated with nivolumab ± bempegaldesleukin will be permitted to continue nivolumab 
bempegaldesleukin treatment beyond initial disease-appropriate defined progressive disease, 
assessed by the investigator, up to a maximum of 2 years from date of first dose 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.
Participants may continue receiving study drug until confirmation of progression. Section 9.1.2
outlines the criteria used to assess tumor response for each tumor type under study. If the follow-
up radiographic and/or histological assessment confirms that progression has occurred, the date of 
progression will be the date at which progression was first determined.
Radiographic and histological assessments/scans should continue in accordance with the Section 2
Schedule of Activities for the duration of the treatment beyond progression and radiographic 
assessments/scans should be submitted to the central imaging vendor. 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.
Radiographic Assessment of Further Progression
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 with the time of initial progressive 
disease.
Study treatment should be discontinued permanently upon documentation of further progression. 
The decision to discontinue treatment beyond progression should be balanced by clinical judgment 
as to whether the participant is clinically deteriorating and unlikely to receive any benefit from 
continued study treatment.
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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 that become measurable, these new lesions must demonstrate an absolute increase of 
at least 5 mm.
8.1.3
Post-study Treatment Study Follow-up
In this study, objective response rate is a key endpoint. 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 until death or the conclusion of the study.
The Sponsor may request that survival data be collected on all treated participants outside of the 
protocol defined window (Section 2). At the time of this request, each participant will be contacted 
to determine their survival status unless the participant has withdrawn consent for all contacts or 
is lost to follow-up.
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 for protocol-specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 

Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.

The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post-treatment study follow-up and entered on the 
appropriate CRF page.

In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.

If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
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8.3
Lost to Follow-up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If, after all attempts, the participant remains lost to follow-up, then the last known alive date 
as determined by the investigator should be reported and documented in the participant’s 
medical records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities. 
•
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 first dose of study treatment. 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 used 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.
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If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary AEs, the participant should be immediately evaluated 
to rule out pulmonary toxicity, according to the suspected pulmonary toxicity management 
algorithm in the BMS-936558 (nivolumab) IB.127
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
9.1.1
Imaging Assessment for the Study
Images will be submitted to a central imaging vendor and may undergo BICR at any time. Prior to 
scanning the first participant, sites should be qualified and understand the image acquisition 
guidelines and submission process as outlined in the CA045-020 Imaging Manual provided by the 
central imaging vendor.
Additional imaging that may demonstrate tumor response or progression (eg, scans performed at 
unscheduled time points and/or at an outside institution, radiographs demonstrating unequivocal 
evidence of disease progression) should be collected for tumor assessments and submitted to the 
central imaging vendor.
9.1.2
Method of Measurement
9.1.2.1
Ewing Sarcoma, Rhabdomyosarcoma, and Other Solid Tumors
Contrast-enhanced CT/MRI of the chest, abdomen, pelvis, and all other known/suspected sites of 
disease should be performed for tumor assessments. Images should be acquired with slice 
thickness of 5 mm or less with no intervening gap (contiguous). Every attempt should be made to 
image each participant using an identical acquisition protocol on the same scanner for all imaging 
time points. Tumor measurements should be made by the same investigator or radiologist for each 
assessment, whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the investigator using the RECIST v1.1 
criteria (see Appendix 8). Assessments of PR and CR must be confirmed at least 4 weeks (28 days) 
after initial response.
If a participant has a contraindication for CT IV contrast, then a contrast-enhanced MRI of the 
chest, abdomen, pelvis, and other known/suspected sites of disease should be obtained.
If a participant has a contraindication for both MRI and CT IV contrasts, then a non-contrast MRI 
of chest, abdomen, pelvis, and other known/suspected sites of disease should be obtained.
If a participant has a contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT IV contrast, then a non-contrast CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease is acceptable.
Use of CT component of a Positron Emission Tomography (PET)-CT scanner: Combined 
modality scanning such as with PET-CT is increasingly used in clinical care and is a 
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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 v1.1 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.
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.
9.1.2.2
Neuroblastoma
Along with imaging described in Section 9.1.2.1, MIBG scintigraphy should be performed for 
participants with MIBG-avid tumors, according to revised INRC.156 Tumor response will be 
assessed by the investigator using the revised INRC (see Appendix 9). Confirmation of response 
after initial assessment of PR and CR is not required.
9.1.2.3
Non-Hodgkin Lymphoma
Participants with [18F] fluorodeoxyglucose (FDG)-avid NHL should be followed with FDG PET-
CT or PET-MRI of the skull base to mid-thigh and other known/suspected sites of disease. 
Participants with FDG non-avid NHL should be followed with contrast-enhanced CT/MRI of the 
chest, abdomen, pelvis, and all other known/suspected sites of disease. 
The International Pediatric Non-Hodgkin Lymphoma Response Criteria (see Appendix 10).157
Confirmation of response after initial assessment of PR and CR is not required.
9.1.2.4
Glioma, Medulloblastoma, Ependymoma, and Other CNS Tumors
Brain MRI without and with gadolinium contrast should be performed as outlined in Section 2
(Schedule of Activities). Participants who are unable (due to existent medical condition, ie, 
pacemaker or implantable cardioverter-defibrillator device) or unwilling to have a contrast-
enhanced MRI of the brain at baseline are excluded from the study. Participants who become 
unable to undergo MRI imaging after the start of participation in the study may continue in the 
study for assessment of OS as long as there is no safety issue that would require monitoring by 
MRI. Assessments of PR and CR must be confirmed at least 4 weeks (28 days) after initial 
response.
For participants with medulloblastoma and miscellaneous seeding CNS tumors, RAPNO criteria 
will be used to assess tumor response and will include cerebrospinal fluid (CSF) analysis where 
clinically indicated (see Appendix 11).158
For participants with glioma, ependymoma, and miscellaneous non-seeding CNS tumors, RANO 
criteria will be used to assess tumor response (See Appendix 11).159
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9.1.2.5
Leukemia
Cerebrospinal fluid and bone marrow aspirate with buccal swab will be collected as clinically 
indicated, along with complete blood counts for platelets and neutrophils as outlined in the 
Schedule of Activities (Section 2), the clinical safety laboratory assessments (Table 9.4.6-1)
 
. A bone marrow biopsy/aspirate should be 
performed as clinically indicated if relapse is suspected. 
 
Response assessment will be assessed using Modified NCCN Criteria for acute lymphoblastic 
leukemia or Modified Cheson et al International Working Group criteria for acute myeloid 
leukemia (see Appendix 12).
9.1.3
Imaging and Clinical Assessment
Tumor assessments should continue even if dosing is delayed or discontinued. Sites should not 
change the schedule of imaging due to a dose delay. Changes in tumor measurements and tumor 
responses should be assessed by the same investigator or designee using the applicable 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 eCRF based on the investigator’s assessment 
using applicable criteria. A BOR of SD requires a minimum of 56 days on study from date of first 
dose to the date of the first imaging assessment.
9.1.4
Patient-reported Outcomes
The evaluation of patient-reported outcomes (PROs) is an increasingly important aspect of clinical 
efficacy in oncology trials. Such data provide an understanding of the impact of treatment from 
the participant’s and/or caregiver’s perspective and offer insights into participant experience that 
may not be captured through physician reporting.
Given the evidence that clinicians underreport symptomatic AEs, selected items from the PRO-
CTCAE (including the pediatric and caregiver version) will be used to enhance the assessment of 
symptomatic AEs in the trial. AEs will be selected based on the known clinical profile of the 
treatments being included in the trial, clinical judgment, and the experience of the study team 
members. Participants will be asked to complete the PROs version of the CTCAE (PRO-CTCAE;
adults aged ≥18 years), Pediatric PRO-CTCAE (Ped-PRO-CTCAE; children aged ≥7 to <18
years), or Caregiver PRO-CTCAE (Ped-PRO-CTCAE [Caregiver]) (children aged <7 years, or 
older participants with a cognitive impairment which would limit their ability to complete a PRO) 
at designated study visits. The age-related version of the PRO-CTCAE completed at the start of 
the trial should be used throughout the treatment period. When possible, participants should 
complete the PRO measures prior to any other assessments or study procedures when they are 
being administered during study visits. If exceptional circumstances preclude the continued 
administration of measures using planned modalities, then alternate administration methods may 
be required, after consultation with Sponsor or Sponsor’s representative. 
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The corresponding age version of the PRO-CTCAE will be provided in the participant’s preferred 
language, if available. This questionnaire may be administered electronically on a weekly basis 
during the first 3 cycles of treatment, every cycle from Cycles 4 through 8, every other cycle 
(starting at Cycle 10) while on treatment, and at end of treatment in Part B only. 
9.2
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
Appendix 1 in the Investigator’s Brochure (IB) represent the Reference Safety Information to 
determine expectedness of serious adverse events for expedited reporting.
All nonserious AEs (not only those deemed to be treatment related), with the exception of 
nonserious AEs related to SARS-CoV-2 infection, should be collected continuously during the 
treatment period and for a minimum of 150 days following discontinuation of study treatment. 
All SAEs must be collected from the time of signing the consent, including those thought to be 
associated with protocol-specified procedures, for a minimum of 150 days of discontinuation of 
dosing. For participants assigned to treatment and never treated with study drug, SAEs should be 
collected for 30 days from the date of treatment assignment.
All SAEs, and all AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-
CoV-2 infection must be collected from the date of the participant’s written consent until 150 days 
following discontinuation of dosing.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure, (eg, a follow-up skin biopsy).

Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the CRF module.

All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 

The investigator will submit any updated SAE data to the sponsor or designee within 24 hours
of updated information being available.

CVA (any grade) is considered an AESI and should be assessed for seriousness using the 
standard seriousness definition. However, all CVAs are required to follow the timelines for 
SAE reporting (eg, 24 hours). CVA management guidelines are provided in Appendix 6.
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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
AEs 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 
AEs, when appropriate for the program or protocol.
Every AE must be assessed by the investigator with regard to whether it is considered immune
mediated. For AEs that are potentially immune mediated, additional information will be collected 
on the participant’s case report form.
9.2.3
Follow-up of AEs and SAEs

Nonserious AEs should be followed to resolution or stabilization or reported as SAEs if they 
become serious (see Appendix 3).

Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment, as appropriate.

All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, non-serious AEs of special interest (as defined in 
Section 9.2.8), and AEs (SAEs and non-serious AEs) associated with confirmed or suspected 
SARS-CoV-2 infection will be followed until resolution, the condition stabilizes, the event is 
otherwise explained, the event is deemed irreversible, the participant is lost to follow-up (as 
defined in Section 8.3) or for suspected cases, until SARS-CoV-2 infection is ruled-out.
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.

An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
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the IB and will notify the Institutional Review Boards/Independent Ethics Committees, if 
appropriate, according to local requirements.
Sponsor or designee will be reporting AEs to regulatory authorities and ethics committees 
according to local applicable laws, including European Directive 2001/20/EC and FDA Code of 
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 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 postmenopausal 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.
If the investigator determines a possible favorable benefit-risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the Investigator and the 
BMS Medical Monitor/designee must occur. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
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 ICF for disclosure of this 
information. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
If any sexual activity (eg, vaginal, anal, oral) has occurred between a male participant and a 
pregnant partner(s) without the use of a condom during and at least for 5 half-lives after study 
product administration, the information should be reported to the Sponsor or designee, even if the 
male participant has undergone a successful vasectomy.
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In order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner(s) must sign an ICF for disclosure of this information. Information on 
the pregnancy will be collected on the Pregnancy Surveillance Form.
9.2.6
Immune-mediated Adverse Events
IMAEs are AEs consistent with an immune-mediated mechanism or immune-mediated component 
for which noninflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
IMAEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. Information supporting the assessment will be collected on the participant’s case 
report form.
Additional information may also be collected on IMAEs. A list of relevant AE terms will be 
maintained by the Medical Surveillance Team/Drug Safety Committee or equivalent. 
9.2.7
Additional Information Collected for Adverse Events Primarily Related 
to Bempegaldesleukin
Additional information may also be collected on select AEs primarily related to 
bempegaldesleukin (eg, capillary leak syndrome and cytokine-release syndrome). A list of relevant 
AE terms will be maintained by the Medical Surveillance Team/Drug Safety Committee or 
equivalent.
9.2.8
Adverse Events of Special Interest
CVA (any grade) is considered an AESI and should be assessed for seriousness using the standard 
seriousness definition. However, all CVA events are required to follow the timelines for SAE 
reporting (eg, 24 hours). CVA management guidelines are provided in Appendix 6.
9.2.9
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning.

Any laboratory test result that is clinically significant or meets the definition of an SAE 

Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted

Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that, wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia vs low hemoglobin value).
9.2.10
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 (pDILI) event. All occurrences 
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of pDILIs, meeting the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 
3 for reporting details).
pDILI 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, preexisting chronic or 
acute liver disease, or the administration of other drug (s) known to be hepatotoxic.
9.2.11
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3). All instances of accidental 
overdose and/or dosing errors should be reported on the Dosage Administration Record eCRF.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2).
9.4.1
Physical Examinations
Refer to Schedule of Activities (Section 2).
9.4.2
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. 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.
Pulse oximetry will also be included at baseline only. 
9.4.3
Electrocardiograms
All participants will have 12-lead ECG done during Screening, Treatment, and in Long-term 
Follow-up as specified in the Schedule of Activities (Section 2).
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9.4.4
Echocardiogram
Standard echocardiogram will be performed to assess cardiac function and LVEF according to the 
Schedule of Activities (Section 2). A MUGA scan can be performed to assess cardiac function and 
LVEF if a standard echocardiogram cannot be performed. 
9.4.5
Pregnancy Tests
Serum or urine pregnancy tests will be performed on WOCBP 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 postmenopausal 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.
9.4.6
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Table 9.4.6-1:
Clinical Safety Laboratory Assessments
Hematology – Complete Blood Count
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
Blood urea nitrogen (BUN) or serum urea
Glucose
Albumin
Sodium
Potassium
Chloride
Calcium
Phosphorus
Creatinine kinase
TSH, free T3, and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is 
abnormal - on treatment 
Lipase and/or amylase
Serology - only if clinically indicated based on medical history and risk factors
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 9.4.6-1:
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. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBC = complete blood count; CK = creatinine kinase; FSH = follicle stimulating 
hormone; fT3 = free triiodothyronine; fT4 = free thyroxine; HBsAG = hepatitis B surface antigen; hCG = human 
chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LDH = lactate 
dehydrogenase; RNA = ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; 
WOCBP = women of childbearing potential.
9.4.7
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.5
Pharmacokinetics
9.5.1
Pharmacokinetics and Immunogenicity Assessments
PK and immunogenicity assessment data will be collected from study participants assigned to the 
nivolumab + bempegaldesleukin arms in both Parts A and B at the time points indicated in Table 
9.5.1-1.
All time points are relative to the start of the first study drug administration. All on-treatment time 
points are intended to align with days on which study drug is administered; if dosing occurs on a 
different day, the PK and immunogenicity sampling should be adjusted accordingly. If it is known 
that a dose is going to be delayed, then the predose sample should be collected just prior to the 
delayed dose. However, if a predose sample is collected but the dose is subsequently delayed, an 
additional predose sample should not be collected. All predose samples should be collected within 
24 hours before the start of any dose infusion. Draw blood samples from a site other than the 
infusion site (ie, contralateral arm) on days of infusion.
Further details of sample collection, processing, and shipment will be provided in the Laboratory 
Manual. For participants < 26 kg or those who require blood draw volume modifications, sample 
collection volumes will be appropriately reduced per guidelines outlined in the laboratory manual 
to meet pediatric institutional guidelines for maximum daily and monthly blood draw limits.
Serum PK samples will be analyzed for nivolumab by a validated ligand-binding assay. Plasma 
PK samples will be analyzed for NKTR-214-RC (bempegaldesleukin-related molecules; mixture 
of compounds containing IL-2 independent of PEG conjugation status) and total PEG (mixture of 
compounds containing PEG independent of conjugation status to IL-2) by validated ligand-binding 
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assays as well as NKTR-214-AC (active bempegaldesleukin-related molecules; mixture of 2-PEG-
IL-2, 1-PEG-IL-2, and free IL-2) by a qualified ligand-binding assay.
Validated methods to detect anti‑nivolumab, anti-NKTR-214, anti-PEG, and anti-IL-2 ADA (anti-
drug antibodies) will be used to analyze the immunogenicity samples. Immunogenicity sample 
testing will be done in tiers per the 2019 FDA guidance.160  Samples will be first tested with 
screening electrochemiluminescence assays (ECLAs). Putative positive samples for anti-
nivolumab, anti-NKTR-214, or anti-IL-2 ADA will then be analyzed in competition ECLA assays 
to confirm positivity. Confirmed anti‑NKTR-214 ADA positive samples will be tested further in 
a PEG immuno-competition assay to determine the antibody specificity of the reactivity to the 
PEG or non-PEG (IL-2, linker) moiety of the NKTR‑214. Confirmed positive samples from anti-
nivolumab, anti‑NKTR‑214, and anti-IL-2 ADA assays will then be tested to obtain a titer. 
Samples confirmed to be positive for anti-nivolumab, anti‑NKTR‑214, and anti-IL-2 ADA will 
also be tested for neutralizing activity for IL-2 and nivolumab using validated cell-based assays. 
Blood samples designated for assessments (eg, immunogenicity, PK
) from the same 
collection time point may be used interchangeably for analyses, if required (eg, insufficient volume 
for complete assessment, to follow-up on suspected immunogenicity-related AE, etc.). For 
pediatric participants, local standards for volumes of blood based on body weight that may be 
drawn within a specific time period should be followed. In order to obtain the samples required 
for safety, PK, 
 evaluations specified at a time point, blood volumes for safety laboratory 
analysis should be minimized through the use of pediatric sample tubes, if possible. In the case
that, despite using these measures, the blood volumes required in the Schedule of Activities for a 
given time point will exceed those recommended in the laboratory manual, the sponsor should be 
contacted for further instructions on which blood tests can be omitted or modified to meet volume 
requirements. These omitted/modified tests will likely be 
 
pharmacokinetic assessments since all required safety assessments must be performed.
Additionally, residual blood samples will be archived and may be used for potential exploratory 
analysis (eg, analysis of drug-ADA immune complexes, exploratory PK) and or for additional 
method purposes (eg, cross-validation, ADA/PK selectivity, cut point, etc.). 
For all PK blood samples, the date and actual time collected must be recorded. For participants 
whose only peripheral access is via a venous access device or peripherally inserted central catheter, 
refer to the Laboratory Manual for the proper technique to ensure undiluted whole blood for PK 
assessments.
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Table 9.5.1-1:
Pharmacokinetic and Immunogenicity Sampling - Bempegaldesleukin Combined with Nivolumab
(Parts A and B)
Study Day of Sample 
Collection
(1 cycle = 3 weeks)a,b
Event
Time (Relative to 
Start of 
Bempegaldesleukin 
Infusion)
Hr:Min
Bempegaldesleukin  
PK Plasma
Sample
Bempegaldesleukin 
IMG Serum
Sample
Nivolumab
PK Serum
Sample
Nivolumab
IMG Serum
Sample
Cycle 1 Day 1
Predosec
00:00
X
X
X
X
EOId
00:30
X
04:00e
X
Cycle 1 Day 3f
48:00f
X
Cycle 1 Day 5g
96:00g
X
Cycle 1 Day 8h
168:00h
X
Cycle 2 Day 1
Predosec
00:00
X
X
X
X
Cycle 5 Day 1
Predosec
00:00
X
X
X
X
EOId
00:30
X
Cycle 5 Day 3f
48:00f
X
Cycle 5 Day 5g
96:00g
X
Cycle 11 Day 1
Predosec
00:00
X
X
X
X
Cycle 17 Day 1
Predosec
00:00
X
X
X
X
Cycle 23 Day 1
Predosec
00:00
X
X
X
X
Cycle 29 Day 1
Predosec
00:00
X
X
X
X
Follow-up Visit 1
X
X
X
Follow-up Visit 2
X
X
X
Abbreviations: EOI = end of infusion; IMG = immunogenicity; IV = intravenous; PK = pharmacokinetic.
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a If a participant permanently discontinues study drug treatment during the sampling period, they will move to sampling at the follow up visits. 
b For participants < 26 kg or those who require blood draw volume modifications, sample collection volumes will be appropriately reduced per guidelines outlined 
in the laboratory manual.
c All predose samples should be collected within 24 hours before the start of any dose infusion. 
d EOI=End of Infusion. This sample should be taken immediately after the completion of the bempegaldesleukin administration and flush. EOI samples may not 
be collected from the same IV access as drug was administered.  If the end of infusion is delayed to beyond the nominal infusion duration, the collection of this 
sample should also be delayed accordingly.
e Sample can be collected ± 1 hour but is preferred as close to 04:00 hours as is clinically feasible.
f Samples can be collected ± 3 hours. If participants are dosed on Thursday, Day 3 sample can be collected on Day 2 (Friday). If participants are dosed on a 
Friday, Day 3 sample can be collected on Day 4 (Monday).
g Day 5 sample can be collected ± 1 day. 
h Day 8 samples can be collected on Day 7.
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9.7
Pharmacogenomics
Not applicable.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.9
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination 
The sample size of Part A (Phase 1 bempegaldesleukin in combination with nivolumab) is not 
based on statistical considerations, and it depends on the number of observed DLTs.
For Part B (Phase 2), the Simon 3-stage variant design will enroll an initial 9 participants per tumor 
cohort, and any cohort in which at least 1 response is observed may enroll up to 7 additional 
participants. If 2 or more responses in the first 16 participants are observed, an additional 
8 participants (total 24) can be accrued to an individual cohort. A cohort in which at least 
3 responses are observed would be considered to warrant further clinical development. This design 
assumes that a true response rate of 5% or less would not be of clinical interest and a true response 
rate of at least 20% would be of clinical interest. If the true response rate is 5%, the rule described
above will identify it of sufficient activity for further study with a probability of 0.08 (type I error), 
and the study will have an average sample size of 12.9 (per tumor cohort using Simon 3-stage 
variant design) with 84% probability of early termination. If the true response rate is 20%, the rule 
described above will identify it of sufficient activity for further study with a probability of 0.77 
(power against the alternative hypothesis ORR = 0.20), and the study will have an average sample 
size of 21.5 per tumor cohort using Simon 3-stage variant design with 20% probability of early 
termination. 
Table 10.1-1:
Dose Expansion Cohorts: Characteristics of the Simon 3-stage 
Variant Design
ORR 
Probability of 
Early Stopping at 
Stage 1
Probability of 
Early Stopping at 
Stage 2
Probability of 
Early Stopping
(Cumulative)
Probability to 
Conclude Efficacy
5%
63%
21%
84%
8%
20%
13%
6%
20%
77%
Abbreviation: ORR = objective response rate.
Inference for ORR will be based on the actual number of participants treated and evaluable in each 
cohort, using adjusted 95% CI based on the Atkinson and Brown method. 163 The design 
parameters are presented in Table 10.1-1. For the miscellaneous solid tumor cohort and the 
miscellaneous CNS tumor cohort, the Simon 3-stage variant design will not be applied and can 
accrue up to the maximum of 24 participants. If a participant with melanoma becomes eligible for 
enrollment after accruing the maximum of 24 participants in the miscellaneous solid tumor cohort, 
then they will be allowed to enroll in the trial.
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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign informed consent. This is the dataset for disposition.
Treated
All enrolled participants who received at least 1 dose of any study drug. This 
is the dataset for safety evaluation.
Response-evaluable participants
All treated participants with measurable disease at a baseline tumor
assessment (source: eCRF).
PK-evaluable participants
All treated participants with at least 1 PK concentration measurement post-
treatment.
Immunogenicity-evaluable
participants
Bempegaldesleukin, nivolumab ADA-evaluable participants: all treated
participants with baseline and at least 1 post-baseline bempegaldesleukin, 
nivolumab immunogenicity assessment.
Abbreviations: ADA = anti-drug antibody; eCRF =electronic case report form; PK = pharmacokinetic.
10.3
Statistical Analyses
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses and procedures for accounting 
for missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary and secondary endpoints. 
A description of the participant population will be included in the clinical study report, including 
subgroups of age, gender, and race.
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10.3.1
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary Endpoint (Part B)/Tertiary (Part A)
ORR is defined as the number of participants whose BOR is 
confirmed CR or PR divided by all participants with the same 
disease. BOR is defined as the best response designation, as 
determined by investigators, recorded between the date of first 
dose and the date of objectively documented progression per 
imaging criteria (or blood and/or bone marrow assessment for 
leukemia) or the date of subsequent therapy, whichever occurs 
first. All available response designations will contribute to the 
BOR assessment.
The following criteria will be used:

RECIST 1.1 for solid tumors

RANO/RAPNO for CNS tumors

International Pediatric Non-Hodgkin Lymphoma 
Response Criteria for NHL

Revised INRC for neuroblastoma

Modified NCCN Criteria for acute lymphoblastic 
leukemia

Modified Cheson et al International Working Group 
criteria for acute myeloid leukemia.
ORR and corresponding 2-sided adjusted 95% 
CI by the Atkinson and Brown method will be 
provided for participants from Part 2 by tumor 
type (if applicable). Response from 
participants from Part 1 will only be listed. 
ORR will be reported first on response-
evaluable participants and repeated on all 
treated participants.
Tertiary Endpoint (Part A and Part B)
DOR is computed for all treated participants with a BOR of CR 
or PR and is defined as the time between the date of first 
response and the date of disease progression or death, whichever 
occurs first. 
Median DOR using the Kaplan-Meier method 
and corresponding 2-sided 95% CI may be 
reported for participants from Part 2 by tumor 
type (if appropriate). 
DOR will be reported first on all response-
evaluable participants and then on all treated 
participants.
Secondary Endpoint (Part B)/Tertiary Endpoint (Part A)
PFS is defined as the time from first dose to the date of the first 
documented tumor progression or death due to any cause. 
Participants who die without a reported prior progression will be 
considered to have progressed on the date of death. Participants 
who did not have disease progression or die will be censored at 
the date of last evaluable tumor assessment. 
PFS rate at 24 weeks is defined as the probability to be alive and 
progression free after 24 weeks.
Median PFS will be estimated using the 
Kaplan-Meier method and corresponding 2-
sided 95% CI using Brookmeyer and Crowley 
methodology (using log-log transformation) 
for treated participants from Part B by tumor 
type (if appropriate).
The PFS rate will be estimated by the Kaplan-
Meier method and corresponding 95% CI will 
be derived based on Greenwood formula for 
treated participants from Part B by tumor type 
(if appropriate).
Analysis will only be conducted if the sample 
size exceeds 15 participants in the cohort.
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Endpoint
Statistical Analysis Methods
Secondary Endpoint (Part B)
OS is defined as the time between the date of first dose and the 
date of death. A participant who has not died will be censored at 
the last known alive date. OS will be followed continuously 
while participants are on study drug and every 3 months via in-
person or phone contact during the survival follow-up phase of 
the study drug.
OS rate at 1, 2, and 3 years is defined as the probability to be
alive after 1, 2, and 3 years.
Median OS will be estimated using the 
Kaplan-Meier method and corresponding 2-
sided 95% CI using Brookmeyer and Crowley 
methodology using log-log transformation) for 
treated participants from Part 2 by tumor type 
(if appropriate).
The OS rate will be estimated by the Kaplan-
Meier method, and corresponding 95% CI will 
be derived based on Greenwood formula for 
treated participants from Part 2 by tumor type 
(if appropriate).
Analysis will only be conducted if the sample 
size exceeds 15 participants in the cohort.
Abbreviations: BOR = best overall response; CI = confidence interval; CR = complete response; DOR = duration of 
response; INRC = International Neuroblastoma Response Criteria; NCCN = National Comprehensive Cancer 
Network; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial 
response; RANO = Response Assessment in Neuro-Oncology; RAPNO = Response Assessment in Pediatric Neuro-
Oncology; RECIST = Response Evaluation Criteria in Solid Tumors.
The primary efficacy analyses will be performed on the response-evaluable population and 
repeated on the treated population for the final analysis. Details on censoring scheme on time-
to-event endpoints such as OS, PFS, and DOR will be described in the SAP. Efficacy analysis
will be performed by each tumor type separately; however, treated participants in the safety
lead-in period (Part A) who meet the inclusion criteria for the corresponding cohort and who 
were treated at the same dose level as Part B will also be included in the tumor cohort analysis.
10.3.2
Safety Analyses
All safety analyses for will be performed on the treated population.
Endpoint 
Statistical Analysis Methods
Primary Endpoint (Part A)/Secondary Endpoint (Part B)
Incidence of DLTs, AEs including IMAEs and 
AESI, SAEs, drug-related AEs, AEs leading to 
discontinuation, and death
AEs will be graded according to CTCAE v5.0
Incidence of laboratory abnormalities
Laboratory values will be graded according to 
CTCAE v5.0
DLT rate by dose level. Frequency distribution of treated 
participants with AE using the worst CTCAE grade. 
Participants will only be counted (1) once at the PT level, (2)
once at the System Organ Class level, and (3) once in the
“Total participant” row at their worst CTCAE grade, regardless
of System Organ Class or PT. By cohort.
Laboratory shift table using the worst CTCAE grade per 
participant by cohort.
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CTCAE = Common Terminology 
Criteria for Adverse Events version 5; DLT = dose-limiting toxicity; IMAE = immune-mediated adverse event; PT = 
Preferred Term; SAE = serious adverse event.
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10.3.3
Other Analyses 
10.3.3.1
Pharmacokinetics 
Endpoint 
Statistical Analysis Methods
Primary Endpoint (Part A)
PK parameters , such as peak, trough, and time-
averaged concentration, CL, and Vd
Characterized by PPK models 
Abbreviations: CL = clearance; PK = pharmacokinetic; PPK = population pharmacokinetics; Vd = volume of 
distribution.
PK data obtained in this study may be combined with data from other studies in the clinical 
development program to develop population PK models. These models may be used to evaluate 
the effects of intrinsic and extrinsic covariates on the PK of bempegaldesleukin and/or nivolumab 
and to determine measures of individual exposure (such as steady state peak, trough, and time-
averaged concentration). Model-predicted exposures may be used for exposure-response analyses 
of selected efficacy and safety endpoints. If the analyses are conducted, the results of population 
PK and exposure-response analyses will be reported separately.
10.3.3.2
Immunogenicity Analyses
Immunogenicity will be reported for positive status of ADA for anti-nivolumab/anti-IL-2/anti-
NKTR-214/anti-PEG (such as persistent positive, other positive, only last sample positive, 
baseline positive) and ADA negative status, relative to baseline. In addition, presence of 
neutralizing antibody may be reported, if applicable. Effect of immunogenicity on safety/efficacy 
and PK may be explored.
10.3.3.3
Other Exploratory Analyses
PK, 
patient-reported outcomes,
 analyses will be 
described in the SAP finalized before database lock. 
10.3.4
Interim Analyses
The SAP will further describe the planned interim analyses. The expansion phase of this study 
employs a 3-stage variant design framework. Therefore, there will be interim analyses planned 
when the required number of response evaluable participants in a cohort have available tumor data 
to take a decision and no later than 6 months after the start of the treatment of the last response 
evaluable participants of the current stage. The interim analyses will be reviewed by the DMC. No 
formal inferences requiring any adjustment to statistical significance level will be performed.
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11
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102 Gerr H, Zimmermann M, Schrappe M, et al. Acute leukaemias of ambiguous lineage in 
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116 Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 
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133 Bentebibel SE, Hurwitz ME, Bernatchez C, et al. A first-in-human study and biomarker 
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135 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;10:1158-1173.
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2003;21:807-39.
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escape. Nat Immunol 2002;3(11):991-8.
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2005;23:515-48.
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novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000;192(7):1027-34.
141 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands 
in regulating autoimmunity and infection. Nat Immunol 2007;8(3):239-45.
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solid tumors: immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20.
143 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. Abstract #3006.
Presented at Annual Meeting of the American Society of Clinical Oncology; 2018 Jun 1-5; 
Chicago, IL.
144 Diab A, Puzanov I, Maio, M. Clinical activity of BEMPEG plus NIVO in previously untreated 
patients with metastatic melanoma: updated results from the Phase 1/2 PIVOT-02 study. Paper 
presented at Annual Meeting of the Society for Immunotherapy of Cancer (SITC); 2019 Nov 
6-10; National Harbor, MD.
145 Siefker-Radtke AO, Fishman M, Balar V, et al. NKTR-214 + nivolumab in first-line 
advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. Presented 
at Annual Meeting of the American Society of Clinical Oncology Genitourinary Cancers 
Symposium; 2019 Feb 14-16; San Francisco, CA.
146 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. 
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Poster presented at the 2019 CRI-CIMT-EATI-AACR International Cancer Immunotherapy 
Conference; 2019 Sep 25-28; Paris, France.
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2020. Document Control No. 
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1997;16(23):2701-11.
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trials with multiple outcomes. Stat Med 1995;14:357–79.
150 Schadendorf D, 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; 2016 Aug 31-Sep 3; Vienna, Austria.
151 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 at the American Association for Cancer Research 
(AACR) Annual Meeting; 2017 Apr 1-5; Washington, DC, USA.
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nivolumab versus docetaxel in patients with previously treated advanced non-small lung cancer 
(NSCLC). Poster 1301PD. Poster discussion presentation at the European Society of Medical 
Oncology Annual Meeting; 2017 Sep 8-12; Madrid, Spain. 
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previously treated, PD-L1-expressing NSCLC who completed pembrolizumab. Poster 
presentation at the World Conference on Lung Cancer; 2016 Dec 4-7; Vienna, Austria.
154 Spigel DR, McLeod M, Hussein MA, et al. Randomized results of fixed-duration (1-yr) vs
continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC). 
Oral presentation at the European Society of Medical Oncology Annual Meeting; 2017 Sep 8-
12; Madrid, Spain.
155 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;84(7):1259-68.
156 Park JR, Bagatell R, Cohn SL, et al. Revisions to the International Neuroblastoma Response 
Criteria: a consensus statement from the National Cancer Institute Clinical Trials Planning 
Meeting. J Clin Oncol 2017;35(22):2580-7.
157 Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma 
response criteria. J Clin Oncol 2015;33(18):2106-11.
158 Warren KE, Vezina G, Poussaint TY, et al. Response assessment in medulloblastoma and 
leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatruc 
Neuro-Oncology committee. Neuro Oncol 2018;20:13-23.
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159 Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-
grade gliomas: Response Assessment in Neuro-Oncology Working Group. Clin Oncol 
2010;28(11):1963-72.
160 US Food and Drug Administration. Immunogenicity Testing of Therapeutic Protein Products 
Developing and Validating Assays for Anti-Drug Antibody Detection Guidance for Industry 
FDA-2009-D-0539. Available from: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/immunogenicity-testing-therapeutic-protein-products-developing-and-
validating-assays-anti-drug. Accessed 9-Sept-2020.
163 Atkinson EN, Brown BW. Confidence limits for probability of response in multistage Phase II 
clinical trials. Biometrics 1985;41(3):741-4.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
ABC
activated B-cell-like
AC
active cytokines
ACE
angiotensin-converting enzyme
ADA
anti-drug antibody
AE
adverse event
AEC
absolute eosinophil count
AESI
adverse event of special interest
AIDS
acquired immunodeficiency syndrome
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase 
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ART
antiretroviral therapy
AST
aspartate aminotransferase
AT/RT
atypical teratoid rhabdoid tumor
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BOR
best overall response
BTLA
B- and T-lymphocyte attenuator
Cavgss
steady state average concentration 
CBC
complete blood count
CI
confidence interval
Cmaxss
maximum concentration at steady state
CMV
cytomegalovirus
CNS
central nervous system
COG
Children’s Oncology Group
COVID-19
coronavirus disease 2019
CR
complete response
CRC
colorectal carcinoma
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Term
Definition
CrCL
creatinine clearance
CRS
Cytokine release syndrome
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4
CVA
cerebrovascular accident
DIPG
diffuse intrinsic pontine glioma
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOAC
direct oral anticoagulation
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECLA
Electrochemiluminescence assay
eCRF
electronic case report form
EFS
event-free survival
EOI
end of infusion
EOT
end of treatment
EPE
Essential Protocol Elements
ET
embryonal CNS tumor
EU
European Union
FDA
Food and Drug Administration
FDG
[18F]fluorodeoxyglucose
FL
follicular lymphoma
FSH
follicle-stimulating hormone
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Term
Definition
fT3
free triiodothyronine
fT4
free thyroxine
GCB
germinal center B cell-like
GEP
gene expression profiling
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBV
hepatitis B virus
hCG
human chorionic gonadotropin 
HCV
hepatitis C virus
HGG
high-grade glioma
HIPAA
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
HR
hazard ratio
IB
Investigator Brochure
ICF
informed consent form
ICOS
inducible T-cell co-stimulator
IFN-γ
interferon gamma
IL
interleukin
IL-2
interleukin-2
IL-2Rαβγ
interleukin-2 receptor alpha beta gamma
IL-2Rβγ
interleukin-2 receptor beta gamma
IMAE
immune-mediated adverse event
IMG
immunogenicity
IMP
Investigational Medicinal Product
INR
international normalized ratio 
INRC
International Neuroblastoma Response Criteria
I-O
immuno-oncology
IP
Investigational Product
IRS
Intergroup Rhabdomyosarcoma Study 
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Term
Definition
IRT
Interactive Response Technology
IV
intravenous
LDH
lactate dehydrogenase
LMWH 
low-molecular-weight heparin
LVEF
left ventricular ejection fraction
MGMT
O6-methylguanylmethyltransferase
MIBG
metaiodobenzylguanidine
MMT
Malignant Mesenchymal Tumor 
MR
mixed response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
NK
natural killer
NKTR-214
bempegaldesleukin
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over the counter
PD-1
programmed cell death protein 1 
pDILI
potential drug-induced liver injury
PD-L1
programmed death-ligand 1
PEDS
pediatric
PEG
polyethylene glycol
PET
positron emission tomography
PFS
progression-free survival
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Term
Definition
PK 
pharmacokinetic
PPK
population pharmacokinetics
PR
partial response
PRO
patient-reported outcome
PT
Preferred Term
Q2W
every 2 weeks
Q3W
every 3 weeks
QTcF
QT interval corrected using Fridericia’s correction formula
RANO
Response Assessment in Neuro-Oncology
RAPNO
Response Assessment in Pediatric Neuro-Oncology
RC
related cytokines
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
rhIL-2
recombinant human IL-2
RMS
rhabdomyosarcoma
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
sAG
surface antigen
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SEER
Surveillance, Epidemiology, and End Results Program
SHH
Sonic hedgehog
SIOP
Société Internationale d’Oncologie Pédiatrique
SOC
standard of care
SSC
study steering committee
STS
Soft-tissue Sarcoma Committee
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Term
Definition
SUSAR
suspected, unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TIA
transient ischemic attack
TIL
tumor-infiltrating lymphocyte
Tim-3
T-cell immunoglobulin mucin 3
TME
tumor microenvironment
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF 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 Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of Good Clinical Practice (GCP) (occurring in 
any country) in connection with that trial or the protocol related to the trial which is likely to affect 
to a significant degree the safety or physical or mental integrity of 1 or more subjects of the trial 
or the scientific value of the trial.
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. 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 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. 
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 
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 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 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, 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, 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 must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ 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 unable to give their written consent (e.g., stroke or subjects 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 opinion and assessing information to 
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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 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, 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.
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 
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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 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. 
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 
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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.

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 
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method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.

Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non-study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants’. BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases. 
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 

External Principal Investigator designated at protocol development

Participant recruitment

Involvement in trial design

Other criteria (as determined by the study team)
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.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 

a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)

elective surgery, planned prior to signing consent

admissions as per protocol for a planned medical/surgical procedure

routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)

medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases

admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)

admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.9 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (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: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 

1 week minimum for vaginal hormonal products (rings, creams, gels)

4 week minimum for transdermal products

8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure

End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
human teratogenicity or fetotoxicity. This should be evaluated in context of safety margins 
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from the no-observed adverse effect level (NOAEL) or the time required for 5 half-lives of the 
IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b 

oral (birth control pills)

intravaginal (vaginal birth control suppositories, rings, creams, gels)

transdermal 

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy

Progestogen-only hormonal contraception associated with inhibition of ovulation (This
method of contraception can only be used by WOCBP participants in studies where 
hormonal contraception is permitted by the study protocol)b 

oral 

injectable 

Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation and/or implantation (This method of contraception can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol) b,c

Bilateral tubal occlusion

Vasectomized partner 
Male participants will be required to always use a latex or other synthetic condom during any sexual 
activity (eg, vaginal, anal, oral) with WOCBP; even if the participants have undergone a successful 
vasectomy or if their partner is already pregnant or breastfeeding.

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. 
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The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.

Continuous abstinence must begin at least 30 days prior to initiation of study therapy

It is not necessary to use any other method of contraception when complete abstinence is 
elected. 

WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 

Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 

Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative 
methods of contraception should be utilized. 
c Intrauterine hormone releasing systems are acceptable methods of contraception in the absence of definitive drug 
interaction studies when hormone exposures from intrauterine devices do not alter contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
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COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 5
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 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 
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 6
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM FOR THE COMBINATION OF 
BEMPEGALDESLEUKIN WITH CHECKPOINT INHIBITORS
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 in combination 
with nivolumab.
For unexplained neurological symptoms (such as hemiparesis, confusion, dysarthria, or visual 
disturbances) that may be associated with CVA:
Recommend following the Advanced Cardiac Life Support (ACLS) Adult Suspected Stroke 
Algorithm that includes time-sensitive assessment and rtPA use guidance.
Perform neurological imaging with diffusion-weighted imaging (DWI) MRI as soon as feasible 
after the initial presentation of symptoms, preferably within 24 hours, or as indicated following 
an acute intervention. DWI MRI is preferred, but if contraindicated, alternative imaging 
modalities may be used. 
If imaging is consistent with a CVA, proceed to the following:
1 For any new CVA event confirmed by imaging (DWI MRI preferred unless 
contraindicated), regardless of neurological symptoms (eg, cryptogenic CVA), and for 
suspected TIA without clear alternative etiology:
Discontinue study treatment for participants receiving bempegaldesleukin in combination 
with a checkpoint inhibitor (ie, nivolumab).a
2
Neurology consultation recommended
3
Perform pertinent laboratory assessments including coagulation (D-dimer, complete blood 
count with differential, serum blood urea nitrogen, and creatinine) 
 
, preferably by central laboratory testing. Local laboratory testing is allowed 
when central laboratory testing is not possible.
4
Consider cardiac echocardiogram (trans-esophageal as appropriate) to evaluate for potential 
source of emboli
Abbreviations: ACLS = Advanced Cardiac Life Support; CVA = cerebrovascular accident; DWI = diffusion-weighted 
imaging; MRI = magnetic resonance imaging; rtPA = recombinant tissue plasminogen activator; TIA = transient 
ischemic attack.
a ACLS-algorithms.com. Adult Stroke Algorithm, (ACLS) Advanced Cardiac Life Support [Internet]; 2021[cited 5 
May 2021]. Available from: https://acls-algorithms.com/adult-stroke-algorithm/. Additional consideration to the 
above CVA management guidelines for adolescent study population: rtPA use is not approved in this age group for 
acute ischemic stroke indication. Follow age-appropriate institutional guidelines for antithrombotic therapies for 
emergency ischemic stroke management.
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APPENDIX 7
KARNOFSKY AND LANSKY CRITERIA
STATUS
STATUS
KARNOFSKY
LANSKY
KARNOFSKY or 
LANSKY
Normal, no complaints
Fully active, normal
100
Able to carry on normal activities; minor signs or 
symptoms of disease
Minor restrictions in 
physically strenuous 
activity
90
Normal activity with effort; some signs or symptoms of 
disease
Active, but tires more 
quickly
80
Cares for self. Unable to carry on normal activity or to do 
active work
Substantial restriction of, 
and less time spent, in play 
activity
70
Requires occasional assistance, but able to care for most of 
his needs
Out of bed, but minimal 
active play; keeps busy 
with quiet activities
60
Requires considerable assistance and frequent medical care
Gets dressed, but inactive 
much of day; no active 
play, able to participate in 
quiet play
50
Disabled. Requires special care and assistance
Mostly in bed; participates 
in some quiet activities
40
Severely disabled. Hospitalization indicated though death 
non imminent
In bed; needs assistance 
even for quiet play
30
Very sick. Hospitalization necessary. Active supportive 
treatment necessary
Often sleeping; play 
limited to passive 
activities
20
Moribund
No play; does not get out 
of bed
10
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APPENDIX 8
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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’).
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.
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
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 
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.
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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: 
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 
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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 
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.
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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
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable.
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
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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
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
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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 = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
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 9
REVISED INTERNATIONAL NEUROBLASTOMA RESPONSE 
CRITERIA
Table 1:
Primary (Soft Tissue) Tumor Responsea
Responseb
Anatomic + MIBG (FDG+PET)c Imaging
CR
< 10 mm residual soft tissue at primary site
AND
Complete resolution of MIBG or FDG-PET uptake (for MIBG-nonavid tumors) at primary site
PR
≥ 30% decrease in longest diameter of primary site
AND
MIBG or FDG-PET uptake at primary site stable, improved, or resolved
PD
> 20% increase in longest diameter taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study)
AND
Minimum absolute increase of 5 mm in longest dimensiond
SD
Neither sufficient shrinkage for PR nor sufficient increase for PD at the primary site
Source: Park JR, Bagatell R, Cohn SL, et al. Revision to the International Neuroblastoma Response Criteria: A 
Consensus Statement from the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 35:2580-2587.
Abbreviations: CR = complete response; FDG = [18F]fluorodeoxyglucose; MIBG = metaiodobenzylguanidine; 
PD = progressive disease; PET = positron emission tomography; PR = partial response; SD = stable disease.
a Not for use in assessment of metastatic sites.
b In participants with bilateral adrenal lesions, response will be based on the sum of the longest dimensions of both 
sites unless biopsy proves one to be ganglioneuroma. In participants with multifocal nonadrenal disease, the largest 
tumor will be considered the primary tumor, and additional lesions will be assessed as metastatic sites unless biopsy 
proven to be ganglioneuroma.
c Used for MIBG-nonavid tumors.
d Mass that does not meet PD measurement criteria but has fluctuating MIBG avidity will not be considered PD.
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Table 2:
Tumor Response at Metastatic Soft Tissue and Bone Sites
Response
Anatomic + MIBG (FDG+PET)a Imaging
CR
Resolution of all sites of disease, defined as:

Nonprimary target and nontarget lesions measure < 10 mm
AND

Lymph nodes identified as target lesions decrease to a short axis < 10 mm
AND

MIBG uptake or FDG-PET uptake (for MIBG-nonavid tumors) of nonprimary lesions 
resolves completely
PR
≥ 30% decrease in sum of diametersb of nonprimary target lesions compared with baseline AND 
all of the following:

Nontarget lesions may be stable or smaller in size
AND

No new lesions
AND

≥ 50% reduction in MIBG absolute bone score (relative MIBG bone score ≥ 0.1 to ≤ 0.5) 
or ≥ 50% reduction in number of FDG-PET–avid bone lesionsc,d
PD
Any of the following:

Any new soft tissue lesion detected by CT/MRI that is also MIBG avid or FDG-PET avid

Any new soft tissue lesion seen on anatomic imaging that is biopsied and confirmed to be 
neuroblastoma or ganglioneuroblastoma

Any new bone site that is MIBG avid

A new bone site that is FDG-PET avid (for MIBG-nonavid tumors) AND has CT/MRI 
findings consistent with tumor OR has been confirmed histologically to be neuroblastoma 
or ganglioneuroblastoma

> 20% increase in longest diameter taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study) AND minimum absolute 
increase of 5 mm in sum of diameters of target soft tissue lesions

Relative MIBG score ≥ 1.2d
SD
Neither sufficient shrinkage for PR nor sufficient increase for PD of nonprimary lesions
Source: Park JR, Bagatell R, Cohn SL, et al. Revision to the International Neuroblastoma Response Criteria: A 
Consensus Statement from the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 35:2580-2587.
Abbreviations: CR = complete response; CT = computed tomography; FDG = [18F]fluorodeoxyglucose; MIBG = 
metaiodobenzylguanidine; MRI = magnetic resonance imaging; PD = progressive disease; PET = positron emission
tomography; PR = partial response; SD = stable disease.
a Used for MIBG-nonavid tumors
b Sum of diameters is defined as the sum of the short axis of discrete lymph nodes (ie, cervical, axillary nodes) added 
to the sum of the longest diameters of non–lymph node soft tissue metastases. Masses of conglomerate nondiscrete
lymph nodes will be measured using longest diameter.
c For participants with soft tissue metastatic disease, resolution of MIBG and/or FDG-PET uptake at the soft tissue 
sites is not required; all size reduction criteria must be fulfilled.
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d Relative MIBG score is the absolute score for bone lesions at time of response assessment divided by the absolute 
score for bone lesions at baseline before therapeutic interventions. The same scoring method (eg, Curie or 
International Society of Pediatric Oncology European Neuroblastoma) must be used at all assessment time points. 
MIBG single-photon emission computed tomography (SPECT) or MIBG-SPECT/CT may be used for scoring 
purposes, but the same imaging methodology should be used for all evaluations.
Table 3:
Bone Marrow Metastasis Responsea
Response
Cytologyb/Histologyc
CR
Bone marrow with no tumor infiltration on reassessment, independent of baseline tumor 
involvement
PD
Any of the following:
•
Bone marrow without tumor infiltration that becomes > 5% tumor infiltration on 
reassessment
OR
•
Bone marrow with tumor infiltration that increases by > 2-fold and has > 20% tumor 
infiltration on reassessment
MD
Any of the following:
•
Bone marrow with ≤ 5% tumor infiltration and remains > 0 to ≤ 5% tumor infiltration on 
reassessment
OR
•
Bone marrow with no tumor infiltration that has ≤ 5% tumor infiltration on reassessment
OR
•
Bone marrow with > 20% tumor infiltration that has > 0 to ≤ 5% tumor infiltration on 
reassessment
SD
Bone marrow with tumor infiltration that remains positive with > 5% tumor infiltration on 
reassessment but does not meet CR, MD, or PD criteria
Source: Park JR, Bagatell R, Cohn SL, et al. Revision to the International Neuroblastoma Response Criteria: A 
Consensus Statement from the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 35:2580-
2587; Burchill SA, Beiske k, Shimada H, et al. Recommendations for the standardization of bone marrow disease 
assessment and reporting in children with neuroblastoma: On behalf of the International Neuroblastoma Response 
Criteria Bone Marrow Working Group. Cancer 2017;123:1095-1105.
Abbreviations: CR = complete response; MD = minimal disease; PD = progressive disease; SD = stable disease.
NOTE. In the case of discrepant results between aspirations or core biopsies from 2 or more sites taken at the same 
time, the highest infiltration result should be reported using the criteria in this table.
a Response will be compared with baseline disease evaluations before enrollment in a clinical trial or, for newly 
diagnosed participants, with baseline at specific times during therapy (ie, at diagnosis and before start of therapy, 
before specific phases of therapy such as induction, high-dose chemotherapy with stem-cell rescue consolidation, 
or postconsolidation immunotherapy).
b Accompanied by immunocytology (recommended, not mandatory).
c Accompanied by immunohistochemistry (IHC); specific recommendations included in Burchill et al: 
IHC of multiple sections (> 3 sections) from all bone marrow biopsies using a minimum of 2 antibodies; to minimize 
cost, 3 sections might be placed on a single slide with each antibody. The quality of any immunohistological 
analysis should be monitored by simultaneous processing of a positive control sample. Relevant controls can be 
sections from multi-tissue blocks including the adrenal gland or other neuroendocrine tissues; an ideal control 
would have areas of positive and negative cells. A bone marrow biopsy is regarded as negative for tumor in the 
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absence of neuroblastoma cell nests detected by hematoxylin and eosin staining and IHC, using a minimum of 2 
antibodies to analyze at least 3 sections. A case should only be confirmed as negative after the assessment of all 
available sections.
Table 4:
Determination of Overall Response
Response
Cytology/Histology
CR
All components meet criteria for CR
PR
PR in at least 1 component and all other components are either CR, MDa (bone marrow), PR (soft 
tissue or bone), or NIb; no component with PD
MR
PR or CR in at least one component but at least one other component with SD; no component with 
PD
SD
SD in one component with no better than SD or NIb in any other component; no component with PD
PR
Any component with PD
Source: Park JR, Bagatell R, Cohn SL, et al. Revision to the International Neuroblastoma Response Criteria: A 
Consensus Statement from the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 35:2580-2587.
Abbreviations: CR = complete response; MD = minimal disease; MR = minor response; NI = not involved; PD = 
progressive disease; PR = partial response; SD = stable disease.
a For bone marrow assessment only.
b Site not involved at study entry and remains uninvolved.
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APPENDIX 10
INTERNATIONAL PEDIATRIC NON-HODGKIN LYMPHOMA 
RESPONSE CRITERIA
Table 1:
International Pediatric NHL Response Criteria
Criterion
Definition
CR

Disappearance of all disease (three designations)
CR

CT or MRI reveals no residual disease or new lesions

Resected residual mass that is pathologically (morphologically) negative for disease 
(detection of disease with more sensitive techniques described as supporting data [Table 2])

BM and CSF morphologically free of disease (detection of disease with more sensitive 
techniques described as supporting data [Table 2])
CRb

Residual mass has no morphologic evidence of disease from limited or core biopsy (detection 
of disease with more sensitive techniques described as supporting data [Table 2]), with no 
new lesions by imaging examination

BM and CSF morphologically free of disease (detection of disease with more sensitive 
techniques described as supporting data [Table 2])

No new and/or progressive disease elsewhere
CRu

Residual mass is negative by FDG-PET; no new lesions by imaging examination

BM and CSF morphologically free of disease (detection of disease with more sensitive 
techniques described as supporting data [Table 2])

No new and/or progressive disease elsewhere
PR

50% decrease in SPD on CT or MRI; FDG-PET may be positive (Deauville score or 4 or 5 
with reduced lesional uptake compared with baseline);

No new lesion and/or no PD;

Morphologic evidence of disease may be present in BM or CSF if present at diagnosis 
(detection of disease with more sensitive techniques described as supporting data [Table 2]);

However, there should be 50% reduction in percentage of lymphoma cells
MR

Decrease in SPD > 25% but < 50% on CT or MRI; no new lesion and/or no PD; 

Morphologic evidence of disease may be present in BM or CSF if present at diagnosis 
(detection of disease with more sensitive techniques described as supporting data [Table 2]);

However, there should be 25% to 50% reduction in percentage of lymphoma cells
NR

For those who do not meet CR, PR, MR, or PD criteria
PD

For those with > 25% increase in SPD on CT or MRI, Deauville score 4 or 5 on FDG-PET 
with increase in lesional uptake from baseline, or development of new morphologic evidence 
of disease in BM or CSF
Source: Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response 
Criteria. J Clin Oncol 2015;33:2106-2111.
Abbreviations: BM = bone marrow; CR = complete response; CRb = complete response biopsy negative; CRu = 
complete response unconfirmed; CT = computed tomography; FDG = [18F]fluorodeoxyglucose; MR = minor 
response; MRI = magnetic resonance imaging; NHL = non-Hodgkin lymphoma; NR = no response; PD = progressive 
disease; PET = positron emission tomography; PR = partial response; SPD = sum of product of greatest perpendicular 
diameters.
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Table 2:
Supporting International Pediatric NHL Response Criteria Data
Criterion
Definition
BM 
involvement
Currently defined by morphologic evidence of lymphoma cells; this applies to any histologic 
subtype; type and degree of BM involvement should be specifieda
BMm
BM positive by morphology (specify percentage of lymphoma cells)
BMi
BM positive by immunophenotypic methods (histochemical or flow cytometric analysis; 
specify percentage of lymphoma cells)
BMc
BM positive by cytogenetic or FISH analysis (specify percentage of lymphoma cells)
BMmol
BM positive by molecular techniques
CNS 
involvement
CSF status
CSF positivity is based on morphologic evidence of lymphoma cells; CSF should be considered 
positive when any number of blasts is detected; CSF may be unknown; as with BM, type of 
CSF involvement should be described whenever possible
CSFm
CSF positive by morphology (specify No. of blasts/μL)
CSFi
CSF positive by immunophenotype methods (histochemical or flow cytometric analysis; 
specify percentage of lymphoma cells)
CSFc
CSF positive by cytogenetic or FISH analysis (specify percentage of lymphoma cells)
CSFmol
CSF positive by molecular techniques
RM
RMm
Tumor detected by standard morphologic evaluation
RMi
Tumor detected by immunophenotypic methods (immunohistochemical or flow cytometric 
analysis)
RMc
Tumor detected by cytogenetic or FISH analysis
RMmol
Tumor detected by molecular techniques
Source: Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response 
Criteria. J Clin Oncol 2015;33:2106-2111.
Abbreviations: BM = bone marrow; FISH = fluorescent in situ hybridization; NHL = non-Hodgkin lymphoma; PB = 
peripheral blood; RM = residual mass.
a Same approach should be used for PB involvement (ie, PBm, PBi, PBc, PBmol).
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APPENDIX 11
RESPONSE ASSESSMENT IN NEURO-ONCOLOGY(RANO)/PEDIATRIC NEURO-ONCOLOGY 
(RAPNO)
Table 1:
Summary of RAPNO Response Criteria In Medulloblastoma and Leptomeningeal Seeding Tumors
Response
CR
PR
SD
PD
Criteria
Must meet ALL criteria
Must meet ALL criteria
Must meet ALL criteria
Must meet ANY criteria
MRI-brain
Complete disappearance of all 
disease (enhancing and non-
enhancing, measurable and 
nonmeasurable) for a minimum 
of 4 weeks; no new lesions
≥50% decrease (compared with 
baseline) in the sum of the 
products of perpendicular
diameters of all (up to 4)
measurable lesions sustained for 
at least 4 weeks; no progression
of nonmeasurable disease
Does not meet criteria for CR,
PR, or PD
≥25% increase (compared with 
smallest measurement at any 
time point) in the sum of the 
products of perpendicular
diameters of all measurable
lesions; significant progression
of nonmeasurable disease not
attributed to prior therapy; any
new tumor (any new lesions 
suspected to be treatment 
related should be confirmed by 
biopsy)
MRI-spine
Complete disappearance of all 
disease (enhancing and non-
enhancing, measurable and 
nonmeasurable) for a minimum 
of 4 weeks; no new lesions
≥50% decrease (compared with 
baseline) in the sum of the 
products of perpendicular
diameters of all measurable
lesions sustained for at least 4 
weeks; no progression of
nonmeasurable disease. If
negative at baseline, must
remain negative
Does not meet criteria for CR,
PR, or PD
≥25% increase (compared with
smallest tumor measurement at
any time point) in the sum of the
products of perpendicular 
diameters of all (up to 4) 
measurable lesions; significant 
progression of nonmeasurable 
disease not attributed to prior 
therapy; any new tumor (any 
new lesions suspected to be 
treatment related should be 
confirmed by biopsy)
CSF cytology
If tumor cells are present at
baseline, must be negative × 2 
(sampling at least 2 weeks
apart)
If absent (negative) at baseline,
must remain absent. If present at 
baseline, can be present or
absent
If absent at baseline, must 
remain absent. If present at 
baseline, can be present or 
absent
Previously absent tumor cells in
CSF now present (positive)
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Table 1:
Summary of RAPNO Response Criteria In Medulloblastoma and Leptomeningeal Seeding Tumors
Response
CR
PR
SD
PD
Criteria
Must meet ALL criteria
Must meet ALL criteria
Must meet ALL criteria
Must meet ANY criteria
Neurologic 
exama
Stable or improving
Stable or improving
Stable or improving
Clinical deterioration not 
attributable to other causes
Steroid use
Off steroids or physiologic
replacement doses only
Stable or less than baseline dose
Stable or less than baseline dose
Extra-CNS 
disease
If positive at any time point,
must be reevaluated and have no 
evidence of disease
No new sites of disease
No new sites of disease
New sites of disease
Serum or CSF 
AFP, βhCG (if 
obtained, eg, 
germ cell 
tumors)
Must be within normal range for 
age
A previously negative (normal) 
assessment becomes positive
Source: Warren KE, Vezina G, Poussaint TY, et al. Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from Response 
Assessment in Pediatric Neuro-Oncology committee. Neuro Oncol 2018;20:13-23.
Abbreviations: AFP, alpha-fetoprotein; βhCG, beta human chorionic gonadotropin; CNS = central nervous system; CR = complete response; CSF = cerebrospinal 
fluid; MRI = magnetic resonance imaging; PD = progressive disease; PR = partial response; SD = stable disease.
a If it is unclear that the participant has disease progression, it may be a reasonable option to keep the participant on study until subsequent assessments (eg, MRI, 
CSF cytology) confirm progression. If subsequent testing confirms progression, the date of progression should be backdated to the onset of neurologic 
deterioration.
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Table 2:
RANO Criteria for Time-point Response Assessment Incorporating 
MRI and Clinical Factors
Response
Criteria
CR
Requires all of the following: complete disappearance of all enhancing measurable and 
nonmeasurable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; 
participants must be off corticosteroids (or on physiologic replacement doses only); and stable or 
improved clinically. Note: Participants with nonmeasurable disease only cannot have a complete 
response; the best response possible is stable disease.
PR
Requires all of the following: 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions; no progression of nonmeasurable 
disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the 
scan evaluation should be no greater than the dose at time of baseline scan; and stable or 
improved clinically. Note: Participants with nonmeasurable disease only cannot have a partial 
response; the best response possible is stable disease.
SD
Requires all of the following: does not qualify for complete response, partial response, or 
progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan. In the event that the corticosteroid dose was increased for new 
symptoms and signs without confirmation of disease progression on neuroimaging, and 
subsequent follow-up imaging shows that this increase in corticosteroids was required because of 
disease progression, the last scan considered to show stable disease will be the scan obtained 
when the corticosteroid dose was equivalent to the baseline dose.
PD
Defined by any of the following: 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained either at 
baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids (Stable
doses of corticosteroids include participants not on corticosteroids); significant increase in 
T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with 
baseline scan or best response after initiation of therapya not caused by comorbid events (eg, 
radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects); any new lesion; clear clinical deterioration not attributable to other 
causes apart from the tumor (eg, seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or changes in corticosteroid dose; failure to return 
for evaluation as a result of death or deteriorating condition; or clear progression of 
nonmeasurable disease.
Source: Wen PY, Macdonald DR, Reardon DA, et al. Updated Response Assessment Criteria for High-Grade 
Gliomas: Response Assessment in Neuro-Oncology Working Group; J Clin Oncol 2010;28:1963-72.
Abbreviations: CR = complete response; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance 
imaging; PD = progressive disease; PR = partial response; SD = stable disease.
a Stable doses of corticosteroids include patients not on corticosteroids.
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Table 3:
RANO Criteria for Determining First Progression Depending on 
Time after Radiotherapy
First Progression
Definition
Progressive disease < 12 
weeks after completion 
of radiotherapy
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 80% 
isodose line) or if there is unequivocal evidence of viable tumor or histopathologic 
sampling (eg, solid tumor areas [ie, > 70% tumor cell nuclei in areas], high or 
progressive increase in MIB-1 proliferation index compared with prior biopsy, or 
evidence for histologic progression or increased anaplasia in tumor). Note: Given the 
difficulty of differentiating true progression from pseudoprogression, clinical decline 
alone, in the absence of radiographic or histologic confirmation of progression, will 
not be sufficient for definition of progressive disease in the first 12 weeks after 
completion of radiotherapy.
Progressive disease 12 
weeks after completion 
of radiotherapy
1. New contrast-enhancing lesion outside of radiation field on decreasing, stable, or 
increasing doses of corticosteroids.
2. Increase by 25% in the sum of the products of perpendicular diameters between 
the first post radiotherapy scan, or a subsequent scan with smaller tumor size, and the 
scan at 12 weeks or later on stable or increasing doses of corticosteroids.
3. Clinical deterioration not attributable to concurrent medication or comorbid 
conditions is sufficient to declare progression on current treatment but not for entry 
onto a clinical trial for recurrence.
4. For participants receiving antiangiogenic therapy, significant increase in T2/FLAIR 
non-enhancing lesion may also be considered progressive disease. The increased 
T2/FLAIR must have occurred with the participant on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of 
therapy and not be a result of comorbid events (eg, effects of radiation therapy, 
demyelination, ischemic injury, infection, seizures, postoperative changes, or other 
treatment effects).
Source: Wen PY, Macdonald DR, Reardon DA, et al. Updated Response Assessment Criteria for High-Grade 
Gliomas: Response Assessment in Neuro-Oncology Working Group; J Clin Oncol 2010;28:1963-72.
Abbreviation: FLAIR = fluid-attenuated inversion recovery.
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Table 4:
RANO Assessment of Best Overall Response
Best Overall Response
Criteria
CR
CR observed in assessments 4 weeks apart per RANO
PR
PR observed in assessments 4 weeks apart per RANO
SD 
Note: To qualify for SD there 
must be a minimum on-
treatment period of 6 weeks.)
SD observed and does not qualify for CR or PR 
or 
Suspected PD followed with histologic results not confirming PD, and no CR, 
PR or SD observed 
Not Evaluable (NE)
Insufficient data to determine disease progression or response
PD
No CR, PR, or SD prior to PD
Source: Wen PY, Macdonald DR, Reardon DA, et al. Updated Response Assessment Criteria for High-Grade 
Gliomas: Response Assessment in Neuro-Oncology Working Group; J Clin Oncol 2010;28:1963-72.
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease.
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APPENDIX 12
RESPONSE TO THERAPY FOR HEMATOLOGICAL 
MALIGNANCIES 
The assessment of the response to therapy in the bone marrow and cerebrospinal fluid (CSF) is 
solely based on cytological criteria.
ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Bone marrow status categories:
M1: Representative bone marrow aspirate with <5% lymphoblasts, satisfactory cellularity and 
signs of regenerating normal hematopoiesis
M2: Bone marrow with ≥5% and < 25% of lymphoblastic leukemic blasts irrespective of the
cellular content
M3: Bone marrow with ≥25% of lymphoblastic leukemic blasts irrespective of the cellular content
These criteria were modified from the National Comprehensive Cancer Network Criteria 
especially with respect to hematopoietic regeneration (platelets 50,000/μL and not 100,000/μL and 
absolute neutrophil count (ANC) > 500/μL and not 1000/μL). Since this mostly affects platelet 
regeneration, we distinguish between complete response without platelet recovery (CRp) and 
complete response with incomplete hematological recovery (CRi), in which respectively platelet 
regeneration or both platelet and ANC regeneration are below the level of recovery required for 
complete respone (CR) designation. Moreover, the categories of partial response (PR) and stable 
disease (SD) were defined.
Table 1:
Response to Therapy for Acute Lymphoblastic Leukemia
Category
Definition
Non-representative bone marrow
Markedly reduced cellularity despite signs of 
regeneration in the peripheral blood and differential 
count of nucleated cells in the marrow largely 
corresponding to that in the peripheral blood. It should 
be repeated particularly when therapeutic decisions are 
taken based on the results.
Complete response (CR)
Attainment of M1 bone marrow status, or <1% by flow 
or molecular testing, with no evidence of circulating 
blasts or extra-medullary disease (No 
lymphadenopathy, splenomegaly, skin/gum 
infiltration/testicular mass/CNS involvement) and with 
recovery of peripheral counts (ANC >0.50 x 109/L 
(500/µL) and platelet count > 50 x 109/L (50,000/µL), 
transfusion independent). The detection of leukemic 
cells below the threshold of cytological detection using 
molecular or flow cytometric methods is compatible 
with the definition of CR. No recurrence for 4 weeks.
Complete response without platelet recovery (CRp)
Meets all criteria for CR except platelet count
(≤50 x 109/L [50,000/µL])
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Table 1:
Response to Therapy for Acute Lymphoblastic Leukemia
Category
Definition
Complete response with incomplete hematological 
recovery (CRi)
Meets all criteria for CR except platelet count or ANC 
(ANC ≤0.50 x 109/L [500/µL]) and/or insufficient 
recovery of platelets (≤50 x 109/L [50,000/µL])
Partial response (PR)
For participants with an M2 marrow already at study 
entry, greater than 50% relative reduction (with a 
minimum of 10% absolute reduction) in the bone 
marrow aspirate leukemic cell count, irrespective of 
recovery of the peripheral blood counts.
Non-response or stable disease (SD)
Stable disease is present when the participant fails to 
qualify for CR, CRp, CRi, PR, or PD.
Treatment Failure
Progressive disease (PD)
Increase of at least 25% in the absolute number of 
circulating or bone marrow blasts or development of 
extra-medullary disease, or other laboratory or clinical 
evidence of PD, with or without recovery of ANC or 
platelets
Refractory disease 
Any participant not achieving CR, CRp or CRi after 1
or 2 cycles and does not meeting criteria for 
progressive disease.
Molecular reappearance
A reconversion after minimal residual disease (MRD) 
negativity to reproducible MRD positivity. A 
reconfirmation is strongly recommended. This finding 
does not fulfill the conditions for the definition of 
subsequent relapse
Relapse
Reappearance of blasts in blood or bone marrow 
(> 5%; M2 or greater) or >1% with previous/supportive 
molecular findings, or in any extramedullary site after a 
CR.
Source (Adapted from): (1) Pediatric Acute Lymphoblastic Leukemia Version 12.2020. NCCN Clinical Practice 
Guidelines in Oncology (NCCN Guidelines). NCCN.org; 25-Nov-2019; (2) Acute Lymphoblastic Leukemia Version 
1.2020. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN.org; 15-Jan-2020.
Abbreviations: ANC = absolute neutrophil count; CNS = central nervous system; CR = complete response; CRi = 
complete response with incomplete hematological recovery; CRp = complete response without platelet recovery; 
MRD = minimal residual disease; PD = progressive disease; PR = partial response; SD = stable disease.
Classification of Central Nervous System (CNS) status:

CNS-1: No lymphoblasts in CSF regardless of white blood cell (WBC) count.

CNS-2: WBC < 5/mcL in CSF with presence of lymphoblasts.

CNS-3: WBC ≥ 5/mcL in CSF with presence of lymphoblasts or, for pediatric participants, the 
clinical symptoms of cranial nerve palsy (if not explained by extracranial tumor), clinical 
spinal cord compression, or isolated intracerebral mass.
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
If the participant has leukemic cells in the peripheral blood and the lumbar puncture is 
traumatic and WBC ≥5/mcL in CSF with blasts, then compare the CSF WBC/red blood cell 
(RBC) ratio to the blood WBC/RBC ratio. If the CSF ratio is at least 2-fold greater than the 
blood ratio, thente classification is CNS-3; if not, then it is CNS-2.
Table 2:
Response Criteria for CNS Disease in Acute Lymphoblastic 
Leukemia
Category
Definition
Remission
Achievement of CNS-1 status in a participant with 
CNS-2 or CNS-3 status at diagnosis
Relapse
New development of CNS-3 status or clinical signs of 
CNS leukemia such as facial nerve palsy, brain/eye 
involvement, or hypothalamic syndrome without 
another explanation.
For pediatric participants, new development of CNS-2 
status on 2 consecutive lumbar punctures (between 2 to 
4 weeks apart) with confirmation by 
immunophenotyping or other molecular testing 
methods.
Source (Adapted from): (1) Pediatric Acute Lymphoblastic Leukemia Version 12.2020. NCCN Clinical Practice 
Guidelines in Oncology (NCCN Guidelines). NCCN.org; 25-Nov-2019; (2) Acute Lymphoblastic Leukemia Version 
1.2020. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN.org; 15-Jan-2020.
Abbreviations: CNS = central nervous system. 
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ACUTE MYELOID LEUKEMIA (AML)
Table 3:
Response to Therapy for Acute Myeloid Leukemia
Category
Definition
Complete remission/response (CR)a
Bone marrow blasts <5%; absence of blasts with Auer 
rods; absence of extramedullary disease; absolute 
neutrophil count > 1 x 109/L (1000/μL); platelet count 
> 80 x 109/L (80,000/μL); independence of 
transfusions for a minimum of 1 week. No duration of 
response is required for CR.
CR with incomplete recovery (CRi)b
All CR criteria except for residual neutropenia (< 1 x 
109/L [1000/µL]) or thrombocytopenia (< 80 x 109/L 
[80,000/µL]). No duration of response is required for 
CR.
Morphologic leukemia-free state
Bone marrow blasts <5%; absence of blasts with Auer 
rods; absence of extra-medullary disease; no 
hematologic recovery required 
Partial remission (PR)
All hematologic criteria of CR; decrease of bone 
marrow blast percentage to 5 to 25%; and decrease of 
pretreatment bone marrow blast percentage by at least 
50%. A value of ≤5% blasts may also be considered a 
PR if Auer rods are present. No duration of response is 
required for PR
Cytogenetic CR (CRc)
Reversion to a normal karyotype at the time of 
morphologic CR (or CRi) in cases with an abnormal 
karyotype at the time of diagnosis; based on the 
evaluation of 20 metaphase cells from bone marrow
Stable Disease (SD)
A subject who has no CR/CRi/PR nor has progressive 
disease for a period of at least 2 months should be 
considered SD 
Treatment Failure
Resistant disease (RD)
Failure to achieve CR or CRi (general practice; Phase 
2/3 trials), or failure to achieve CR, CRi, or PR (phase 
1 trials); only includes participants surviving ≥ 7 days 
after completion of initial treatment, with evidence of 
persistent leukemia by blood and/or bone marrow 
examination (this should be stated by bone marrow 
examination < day 42 and at the end of intensification 
courses)
Progressive disease (PD)
Increase of at least 25% in the absolute number of 
circulating leukemic cells, development of new sites of 
extra-medullary disease, or other laboratory or clinical 
evidence of PD, with or without recovery of ANC or 
platelets
Refractory disease 
Any participant not achieving CR, CRi after one or two 
cycles and not meeting criteria for progressive disease
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Table 3:
Response to Therapy for Acute Myeloid Leukemia
Category
Definition
Molecular reappearance
A reconversion after minimal residual disease (MRD) 
negativity to reproducible MRD positivity. A 
reconfirmation is strongly recommended. This finding 
does not fulfill the conditions for the definition of 
subsequent relapse
Relapsec
Bone marrow blasts ≥5%; or reappearance of blasts in 
the blood; or development of extramedullary disease
Early Death
Death in aplasia
Death occurring ≥ 7 days after completion of initial 
treatment while cytopenic; with an aplastic or 
hypoplastic bone marrow obtained within 7 days of 
death, without evidence of persistent leukemia (< day 
42)
Death from indeterminate cause
Early bleeding/leukostasis
Deaths occurring before completion of therapy, or < 7 
days after its completion; or deaths occurring ≥7 days 
after completion of initial therapy with no blasts in the 
blood, but no bone marrow examination available (<
day 42)
Sources (Adapted from): (1) Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642-4649; (2) 
Creutzig U, Kaspers GJ. Revised recommendations of the International Working Group for diagnosis, standardization 
of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J 
Clin Oncol. 2004;22(16):3432-3433; (3) Creutzig U, van den Heuvel-Eibrink MM, Gibson B, et al. Diagnosis and 
management of acute myeloid leukemia in children and adolescents: recommendation from an international expert 
panel. Blood 2012:120:3187-3205.
Abbreviations: CR = complete response/remission; CRc = cytogenetic response/remission; CRi = complete 
response/remission with incomplete recovery; MRD = minimal residual disease; PD = progressive disease; PR = 
partial remission; RD = resistant disease; SD = stable disease.
Note: Definitions of response criteria are based primarily on those given by Cheson et al. and amended by Creutzig 
and Kaspers.
a All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate 
with spicules; if ambiguous, consider repeating examination after 5-7 days; flow cytometric evaluation may help 
to distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy should be performed 
in cases of dry tap, or if no spicules are obtained; no minimum duration of response required.
b The criterion of CRi is of value in protocols that use intensified induction or double-induction strategies, in which 
hematologic recovery is not awaited but intensive therapy will be continued. In such protocols, CR may even not 
be achieved in the course of the entire treatment plan. In these instances, the overall remission rate should include 
CR and CRi participants. Some participants may not achieve complete hematologic recovery, even with longer 
observation times. As treatment courses should be very condensed (with minimal delay) in pediatric participants, 
treatment is continued, even without complete platelet recovery. Therefore, the recommended cut-off value for 
platelets indicating CR is 80 x 109/L.
c In participants with low blast percentages (5 % to 10 %), a repeat marrow should be performed to confirm relapse. 
Appearance of new dysplastic changes should be closely monitored for emerging relapse. In a participant who has 
been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy effect and recovery of 
hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related MDS/AML.
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APPENDIX 13
COUNTRY SPECIFIC AMENDMENTS
Country/Location 
Requirement
Section
Country-specific language
Any countries 
where exclusion of 
HIV positive 
participants is 
locally mandated
Section 2 Schedule of 
Activities 
Table 2-1: Screen 
Procedural Outline 
(CA045020)
Laboratory Tests
Add “HIV” to the list of laboratory tests
Section 6.2 Exclusion 
Criteria, Exclusion 
criterion 1) j)
Standard language in exclusion criteria add: “Countries where 
exclusion of HIV positive participants is locally mandated.” 
France 
Table 7.4.1-1 Adverse 
Event Criteria for 
Delay, Resumption, and 
Discontinuation of 
Nivolumab and 
Bempegaldesleukin (if 
one delayed, both 
delayed)
In the Event of Grade 4 hyperthyroidism and hypothyroidism 
Section 7.7.4.4 Volume 
of Blood
Based on Ethical considerations for clinical trials on 
medicinal products conducted with minors (Revision 1, 18-
Sep-2017), the volume of each sample must not exceed 1% of 
the total blood volume at any single time and the total volume 
of blood sample must not exceed 3% of the total blood 
volume over a period of 4 weeks.1
Germany 
Section 9.2.1 Time 
Period and Frequency 
for Collecting AE and 
SAE information and 
Appendix 3 
All SAEs will be recorded and reported to Sponsor or 
designee immediately, without undue delay. 
References:
1
Ethical considerations for clinical trials on medicinal products conducted with minors. Revision 1, 18 
September 2017. Available from URL: https://ec.europa.eu/health/sites/default/files/files/eudralex/vo-
10/2017_09_18_ethical_consid_ct_with_monors.pdf. Accessed 03-Jun-2021.
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APPENDIX 14
CYTOKINE RELEASE SYNDROME - PEDIATRIC ADAPTED 
MANAGEMENT ALGORITHM
The following treatment management guidelines are provided for general guidance. These 
guidelines should not be a substitute for a more individualized, tailored approach to managing a 
patient experiencing cytokine release syndrome (CRS).
CRS Management Measures/Algorithm
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:

Grade 1 (Fever with or without constitutional symptoms) supportive care as per institutional guidelines.

Grade 2 (Hypotension responding to fluids, hypoxia responding to < 40% O2). Inpatient monitoring with fluid 
management, oxygen supportive care, and management of isolated symptoms based on institutional practices.

Monitor for persistent or worsening clinical condition after initial treatment of CRS and evaluate for other 
contributing conditions. It is particularly important to reassess the patient for coexisting infections, and cardiac, 
pulmonary, thromboembolic and other complications.
Grading Assessment per CTCAE v.5.0
Treatment Measures Recommended
Grade 3 CRS 
Hypotension managed with 
one pressor

Hypoxia requiring >40% O2

Vasopressor support per institutional guidelines should be 
considered if the hypotension is refractory to 20 ml/kg  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- dexamethasone 0.2 
mg/kg Q 6 hrs or 12 hrs for subjects <50 kg. Dexamethasone 
10 mg Q 6 or 12 hrs for subjects > 50kg.   Alternatively, 
methylprednisolone 1-2 mg/kg/d divided Q6 hrs

For severe CRS cases that require simultaneously aggressive 
management of hypotension, oxygenation and cardiac 
telemetry, consult Intensivist for ICU evaluation. Consider 
anti-IL-6 (tocolizumab)
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