Clinical trial NCT04646044
Conditions: Covid-19 Coronavirus Disease 2019
Keywords: BEMPEG Bempegaldesleukin CD122 CD122-Biased Agonist CD122-Biased Cytokine Coronavirus Disease COVID-19 IL-2 receptor agonist Lymphopenia Mild COVID NKTR-214 SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
Sponsor: Nektar Therapeutics
Start date: 2020-11-13; Completion date: 2021-05-18
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this phase-1b, multicenter, randomized double-blind, placebo-controlled, trial is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bempegaldesleukin (BEMPEG; NKTR-214) in combination with standard of care (SOC) in adult patients with mild COVID-19 (coronavirus disease 2019). The trial will also define the recommended phase 2 dose (RP2D) of bempegaldesleukin in patients with mild COVID-19.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Bempegaldesleukin intervention 2: Standard of Care intervention 3: Placebo
Intervention descriptions: intervention 1: Administered as an intravenous infusion intervention 2: Standard of Care Treatment for COVID-19 Infection intervention 3: Administered as an intravenous infusion

Protocol documents:
Prot_000.pdf: 
Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 1 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
 
Nektar Therapeutics 
CLINICAL PROTOCOL 
 
Protocol Number: 
20-214-34 
Title: 
A Multicenter, Phase 1b, Randomized, Double-Blind, 
Placebo-Controlled Trial of the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of a Single 
Dose of Bempegaldesleukin (NKTR-214) Plus 
Standard of Care versus Placebo Plus Standard of Care 
in Adults with Mild COVID-19 
Version: 
Original 
Date: 
21 September 2020 
US IND No.: 
152960 
Investigational Products: 
bempegaldesleukin (NKTR-214) 
Indication: 
Treatment of SARS-CoV-2 mild infection 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
 
  
 
 
  
 
 
 
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or 
consultant for review by you, your staff, and the applicable Institutional Review 
Board/Independent Ethics Committee and applicable Regulatory Authorities. Your 
acceptance of this document constitutes agreement that you will not disclose the 
information herein to others without written authorization from Nektar Therapeutics 
except to the extent necessary to obtain informed consent from persons who participate as 
patients in this study. 
 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 2 of 114 
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PRINCIPAL INVESTIGATOR COMMITMENT 
 
 
Protocol Number: 20-214-34 
Title: 
A Multicenter, Phase 1b, Randomized, Double-Blind, Placebo-Controlled 
Trial of the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of a Single Dose of Bempegaldesleukin (NKTR-214) 
Plus Standard of Care versus Placebo Plus Standard of Care in Adults with 
Mild COVID-19 
Version: 
 
Date: 
Original 
  
21 September 2020 
 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312) and 
ICH E6 Good Clinical Practice guidelines, as well as with any and all applicable federal, state 
and/or local laws and regulations, and agree to conduct the study in accordance with the protocol 
referenced herein. 
 
 
 
Principal Investigator Signature 
 
Date 
Printed Name: 
 
 
 
Institution: 
 
Address 
 
 
 
 




Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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LIST OF STUDY CONTACTS 
Study Contact 
Name 
Contact Information 
  
 
 
 
 
 
 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 5 of 114 
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TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR COMMITMENT ....................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................8 
LIST OF APPENDICES ...............................................................................................................8 
ABBREVIATIONS ........................................................................................................................9 
1.0 
STUDY SYNOPSIS .........................................................................................................13 
1.1 
Study Schematic.....................................................................................................17 
1.2 
Schedule of Events .................................................................................................19 
2.0 
INTRODUCTION............................................................................................................22 
2.1 
Background ............................................................................................................22 
2.2 
Scientific Rationale for Study Design ....................................................................37 
2.3 
Cohort Review Committee ....................................................................................45 
3.0 
STUDY OBJECTIVES ....................................................................................................46 
3.1 
Primary Objectives .................................................................................................46 
3.2 
Secondary Objectives .............................................................................................46 
4.0 
SELECTION OF STUDY POPULATION ...................................................................48 
4.1 
Inclusion Criteria ...................................................................................................48 
4.2 
Exclusion Criteria ..................................................................................................49 
5.0 
INVESTIGATIONAL PLAN .........................................................................................52 
5.1 
Study Design ..........................................................................................................52 
5.2 
Screening Period ....................................................................................................52 
5.3 
Dose Finding ..........................................................................................................52 
5.4 
Study Stopping Criteria..........................................................................................57 
5.5 
Treatment Period ....................................................................................................57 
5.6 
Monitoring and Management Algorithms .............................................................60 
5.7 
Safety Follow-up ....................................................................................................61 
5.8 
Patient Discontinuation from Study .......................................................................62 
5.9 
End of Study ..........................................................................................................63 
5.10 
Pharmacokinetic and Immunogenicity Measurements ..........................................63 
5.11 
Biomarkers .............................................................................................................64 
5.12 
Prior and Concomitant Medications ......................................................................65 
5.13 
Adverse Events ......................................................................................................67 


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Nektar Therapeutics 
 
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5.14 
Blinding..................................................................................................................67 
5.15 
Method of Assigning Patients to Treatment Groups ..............................................68 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ..............................................70 
6.1 
Bempegaldesleukin (NKTR-214) ..........................................................................70 
6.2 
Placebo: Preparation, Storage, and Packaging .......................................................71 
6.3 
Standard of Care: Preparation, Storage, and Packaging ........................................71 
6.4 
Study Drug Accountability and Reconciliation .....................................................71 
7.0 
ASSESSMENT OF SAFETY ..........................................................................................73 
7.1 
AE Definition and Assessment ..............................................................................73 
7.2 
Monitoring AEs .....................................................................................................73 
7.3 
Grading of AEs ......................................................................................................74 
7.4 
Causality Relationship of AEs ...............................................................................74 
7.5 
AE Reporting and Follow-up .................................................................................75 
7.6 
Serious AE Definition ............................................................................................75 
7.7 
Serious AE Reporting ............................................................................................76 
7.8 
Serious AE Follow-up............................................................................................77 
7.9 
Adverse Events of Special Interest ........................................................................77 
7.10 
Potential Drug-Induced Liver Injury .....................................................................77 
7.11 
Pregnancy Tests/Pregnancy ...................................................................................78 
7.12 
Clinical Laboratory Tests .......................................................................................78 
7.13 
Physical Examinations ...........................................................................................79 
7.14 
Vital Signs ..............................................................................................................79 
7.15 
Electrocardiograms ................................................................................................79 
7.16 
Cohort Review Committee ....................................................................................79 
8.0 
ASSESSMENT OF DISEASE MEASUREMENT .......................................................81 
8.1 
Disease Measurement Assessments .......................................................................81 
8.2 
Other Assessment: Pharmacodynamic Measurement ............................................82 
9.0 
STATISTICAL PLAN .....................................................................................................83 
9.1 
General Considerations ..........................................................................................83 
9.2 
Determination of Sample Size ...............................................................................83 
9.3 
Analysis Sets ..........................................................................................................83 
9.4 
Demographics and Baseline Characteristics ..........................................................83 
9.5 
Safety Analyses ......................................................................................................83 
9.6 
Disease Measurement Analyses .............................................................................84 
9.7 
 
10.0 
STUDY OR STUDY SITE TERMINATION ................................................................85 


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Nektar Therapeutics 
 
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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................86 
11.1 
Changes to the Protocol .........................................................................................86 
11.2 
Monitoring .............................................................................................................86 
11.3 
Direct Access to Source Data/Documents for Audits and Inspections ..................87 
12.0 
ETHICAL CONSIDERATIONS ....................................................................................88 
12.1 
IRB/IEC Approval .................................................................................................88 
12.2 
Written Informed Consent .....................................................................................88 
13.0 
DATA HANDLING AND RECORD KEEPING ..........................................................90 
13.1 
Data Collection Instruments and Source Documents ............................................90 
13.2 
Retention of Essential Documents .........................................................................90 
13.3 
Confidentiality .......................................................................................................91 
13.4 
Security Measures ..................................................................................................91 
14.0 
PUBLICATION PLAN ...................................................................................................92 
15.0 
REFERENCES .................................................................................................................93 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................19 
Table 2: 
Comparison of Aldesleukin to Bempegaldesleukin ...................................23 
Table 3: 
Bempegaldesleukin Increases Absolute Lymphocyte Counts in 
Patients with Cancer ..................................................................................26 
Table 4: 
Treatment-emergent Related Adverse Events by Severity Grade 
Following Bempegaldesleukin 0.003 mg/kg Administration (Study 
15-214-01 [EXCEL]) .................................................................................31 
Table 5: 
Treatment-emergent Related Adverse Events by Severity Grade 
Following Bempegaldesleukin 0.003 mg/kg Administration (Study 
16-214-02 [PIVOT-02]) .............................................................................32 
Table 6: 
Bempegaldesleukin Plasma Exposures and Increases Absolute 
Lymphocyte Counts in Monkeys and Patients with Cancer ......................41 
Table 7: 
Cytokine Determinations in Plasma Samples from Patients Treated 
with Bempegaldesleukin (Study 15-214-01 [EXCEL]) .............................44 
Table 8: 
Dose Finding Scheme ................................................................................53 
Table 9: 
Staggered Dosing Procedures for Each Dose Cohort ................................54 
Table 10: 
Selection and Timing of Dose ....................................................................58 
Table 11: 
Residual Sample Retention for Additional Research Schedule .................65 
Table 12: 
Study Treatments Administered ................................................................70 
Table 13: 
WHO Clinical Progression Scale ...............................................................81 
 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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LIST OF FIGURES 
Figure 1: 
Study Schematic.........................................................................................17 
Figure 2: 
Dose Cohort Schematic..............................................................................18 
Figure 3: 
Release of PEG Groups from Bempegaldesleukin to Form Active 
Cytokines ...................................................................................................24 
Figure 4: 
Bempegaldesleukin Monotherapy Increases Absolute Lymphocyte 
Counts in Patients with Cancer ..................................................................26 
Figure 5: 
Bempegaldesleukin Increases Counts (Top Row) and Proliferation 
(Ki-67+, Bottom Row) in CD4+, CD8+, and NK+ Immune Cells ..............27 
Figure 6: 
Bempegaldesleukin (0.006 mg/kg) Reliably Increases Total 
Lymphocyte Counts in Patients with Cancer Across Age Groups 
(n=456) .......................................................................................................28 
Figure 7: 
C-Reactive Protein Levels after Bempegaldesleukin Administration in 
Female Cynomolgus Monkeys (n=3) ........................................................42 
Figure 8: 
Monocyte and Neutrophil Profiles (Mean + SD) after Administration 
of 0.003 mg/kg Bempegaldesleukin (Study 15-214-01 [EXCEL]) ...........44 
 
LIST OF APPENDICES 
 
Appendix 1: 
Clinical Laboratory Tests ...........................................................................97 
Appendix 2: 
Women Of Childbearing Potential Definitions And Methods Of 
Contracepton ............................................................................................100 
Appendix 3: 
Grading Criteria for Cytokine Release Syndrome ...................................103 
Appendix 4: 
Breakthrough Designation Status: Melanoma .........................................104 
Appendix 5: 
Clinical Studies of Bempegaldesleukin (NKTR-214) .............................105 
 


Protocol No. 20-214-34 
 
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Nektar Therapeutics 
 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
ACE 
angiotensin converting enzyme 
ADA 
anti-drug-antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALC 
absolute lymphocyte count 
ALT (SGPT) 
alanine transaminase (serum glutamic pyruvic transaminase) 
ANC 
absolute neutrophil count 
ARDS 
acute respiratory distress syndrome 
AST (SGOT) 
aspartate transaminase (serum glutamic oxaloacetic transaminase) 
AUC 
area under the concentration-time curve 
Bempeg, BEMPEG 
abbreviation for bempegaldesleukin, the International Nonproprietary Name 
(INN) for NKTR-214 
Bempegaldesleukin 
International Nonproprietary Name (INN) for NKTR-214 
bpm 
beats per minute 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations  
CI 
confidence interval 
Cmax 
maximum concentration 
COVID-19 
coronavirus disease 2019, caused by the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) 
CRC 
Cohort Review Committee 
CRF 
case report form 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
cerebrovascular accident 
DCI 
data collection instrument 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DVT 
deep vein thrombosis 
ECG 
electrocardiogram 
ECLA 
electrochemiluminescence assay 
eCOA 
electronic clinical outcomes assessments 


Protocol No. 20-214-34 
 
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Nektar Therapeutics 
 
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Abbreviation or Term 
Definition 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form  
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate  
EOI 
end of infusion  
FDA 
Food and Drug Administration 
FiO2 
fraction of inspired oxygen 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IFN 
interferon 
IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, 
IL-8, IL-10, IL-18 
interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, 
interleukin-7, interleukin-8, interleukin-10, interleukin-18 
IND 
Investigational New Drug application 
IRB 
institutional review board 
IRT 
Interactive Response Technology  
IV 
intravenous 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantitation 
MCP 
monocyte chemotactic protein 
MDRD 
Modification of Diet Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 


Protocol No. 20-214-34 
 
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Nektar Therapeutics 
 
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Abbreviation or Term 
Definition 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
mg 
milligram 
min 
minute(s) 
MIP 
macrophage inflammatory protein 
mL 
milliliter 
mm Hg 
millimeters of mercury 
MMWR 
Morbidity and Mortality Weekly Report 
msec 
millisecond 
MTD 
maximum tolerated dose  
NaCl  
sodium chloride 
NCI 
National Cancer Institute 
NK 
natural killer 
NKTR-214 
bempegaldesleukin (International Nonproprietary Name) 
NOAEL 
no observed adverse effect level 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non-small cell lung cancer  
NYHA 
New York Heart Association 
OTC 
over-the-counter 
PaO2 
partial pressure of arterial oxygen  
PaO2/FiO2 
ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen 
PARP 
polyadenosine diphosphate ribose polymerase 
PBMC 
peripheral blood mononuclear cell  
PD-L1 
programmed cell death ligand 1 
PE 
pulmonary embolism 
PEG 
polyethylene glycol 
PK 
pharmacokinetic 
q3w 
every 3 weeks 
QTc 
corrected QT interval  
QTcF 
QT interval corrected using Fridericia’s formula 
R 
randomization 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Nektar Therapeutics 
 
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Abbreviation or Term 
Definition 
rhIL-2 
recombinant human interleukin-2 
RT-PCR 
reverse transcription polymerase chain reaction 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SARS 
severe acute respiratory syndrome 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2, the virus causing COVID-19 
SIRS 
systemic inflammatory response syndrome 
SOC 
standard of care 
SOP 
standard operating procedure  
SpO2 
oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
Tmax 
time to maximum concentration 
TNF 
tumor necrosis factor  
Treg 
regulatory T cell 
ULN 
upper limit of normal 
US, USA 
United States of America 
WFI 
Water for Injection 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 


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Nektar Therapeutics 
 
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1.0 
STUDY SYNOPSIS 
Title of Study: 
A Multicenter, Phase 1b, Randomized, Double-Blind, Placebo-Controlled Trial of the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Dose of 
Bempegaldesleukin (NKTR-214) Plus Standard of Care versus Placebo Plus Standard of 
Care in Adults with Mild COVID-19 
Sponsor: 
Nektar Therapeutics 
Name of Finished 
Product(s): 
Bempegaldesleukin (NKTR-214 drug product) 
Name of Active 
Ingredient (s): 
Bempegaldesleukin (NKTR-214) drug substance 
Phase of 
Development: 
Phase 1b 
Objectives: 
The primary objectives are: 
• 
To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
bempegaldesleukin plus standard of care (referred to in this document as 
bempegaldesleukin/SOC) compared with placebo plus standard of care (referred to in 
this document as placebo/SOC) in patients with mild COVID-19 (coronavirus disease 
2019; SARS-CoV-2). 
• 
To evaluate the safety and tolerability of bempegaldesleukin administered as a single 
intravenous (IV) dose and to define the recommended Phase 2 dose (RP2D) of 
bempegaldesleukin in patients with mild COVID-19. 
• 
To assess the effect of bempegaldesleukin on the time course and extent of changes in 
absolute lymphocyte counts. 
Secondary objectives: 
The secondary objectives listed below involve comparison of bempegaldesleukin/SOC 
versus placebo/SOC in patients with mild COVID-19: 
• 
To estimate the incidence of adverse events (AEs). 
• 
To evaluate the frequency of serious AEs (SAEs). 
• 
To determine the percentage of patients who require supplemental oxygen. 
• 
To evaluate clinical status based on the World Health Organization (WHO) Clinical 
Progression Scale. This will be determined once more information is obtained about 
the clinical meaning/interpretation. The scale is as follows: 
Patient state 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory 
mild disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized:  
Moderate 
disease 
Hospitalized, no oxygen therapya 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized:  
Severe 
disease 
Hospitalized; oxygen by non-invasive ventilation or high-flow 
6 
Intubation and mechanical ventilation, PaO2/FiO2 ≥ 150 or 
SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation, PaO2/FiO2 < 150 (SpO2/FiO2 < 200) or 
vasopressors 
8 
 
Mechanical ventilation, PaO2/FiO2 < 150 and vasopressors, dialysis, 
or ECMO 
9 
Dead 
Death 
10 
Abbreviations: ECMO = extracorporeal membrane oxygenation; FiO2  = fraction of inspired oxygen; 
PaO2 = partial pressure of arterial oxygen; SpO2 = oxygen saturation 
a.  If hospitalized for isolation only, record status as for ambulatory patient. 
Source:  WHO 2020 


Protocol No. 20-214-34 
 
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Nektar Therapeutics 
 
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• 
To assess the immunologic effects in blood before and after study drug administration, 
including effects on cytokines, natural killer cells, T-cells, and other serum proteins 
and immune modulators. 
Duration of 
Treatment: 
Patients will be treated with 1 dose of bempegaldesleukin or placebo in combination with 
SOC for COVID-19. 
Study Population: 
Adults aged 18 years and older with mild COVID-19. 
Number of Patients 
(Planned): 
Approximately 30 patients. 
Number of Study 
Sites: 
Up to 10 sites 
Countries: 
United States 
Study Design: 
This is a multicenter, Phase 1b, randomized double-blind, placebo-controlled trial to assess  
the safety, tolerability pharmacokinetics, and pharmacodynamics of 
bempegaldesleukin/SOC in adults with mild COVID-19, as well as to determine the RP2D 
of bempegaldesleukin. 
During the study, patients will receive 1 dose of bempegaldesleukin or placebo and must 
remain in the hospital or be admitted to an in-patient facility for monitoring until at least 
Day 8. 
Patients will be randomized (1:1 ratio) in groups of 10 patients (5 bempegaldesleukin/SOC 
and 5 placebo/SOC) in each cohort to receive one IV infusion of bempegaldesleukin in 
combination with standard of care or one IV infusion of placebo in combination with 
standard of care. 
Eligible patients will be enrolled into 1 of 3 dose cohorts with doses ranging from 
0.00075 mg/kg to 0.003 mg/kg. The first two patients randomized and treated in each dose 
cohort (1 with bempegaldesleukin/SOC and 1 with placebo/SOC) will serve as sentinel 
patients. Enrollment in each cohort will be staggered as follows. A Cohort Review 
Committee (CRC) will monitor blinded safety and tolerability data for the first 72 hours 
after study drug administration from the 2 sentinel patients before additional patients in that 
cohort are treated. If the CRC determines additional patients may be randomized, 2 patients 
will be randomized (1 with bempegaldesleukin/SOC and 1 with placebo/SOC), treated with 
study drug, and observed for 72 hours. For every 2 patients, the Medical Monitor will 
review the blinded safety and tolerability data for the first 72 hours after study drug 
administration to determine if the next 2 patients may be randomized. If it is not possible to 
assess the protocol-defined DLT criteria (see Section 5.3.2.1.1), the Medical Monitor will 
request a review of the safety data by the CRC. After 10 patients have completed a 7-day 
observation period for dose-limiting toxicity (DLT; see Section 5.3.2.1 for additional 
details), the CRC will assess the accumulated, blinded safety and tolerability data, as well 
as any available pharmacokinetic, pharmacodynamic, and disease measurement data, to 
determine whether dose escalation or de-escalation from the tested bempegaldesleukin dose 
level is warranted. This decision will be based on blinded data using pre-defined criteria, 
including the proportion of patients who experience a DLT (see Section 5.3.1). Patients 
who drop out of the study for reasons other than a DLT, before the DLT evaluation period 
(Days 1 to 7) has elapsed, may be replaced. 
The RP2D of bempegaldesleukin in patients with mild COVID-19 will be based on the 
totality of safety, tolerability, pharmacokinetic, pharmacodynamic, and disease 
measurement data. 


Protocol No. 20-214-34 
 
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Nektar Therapeutics 
 
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Key Eligibility 
Criteria:   
The following list contains key eligibility criteria only; a full list of eligibility criteria is 
provided in Section 4.0. 
Key Inclusion Criteria: 
• 
Provide written, informed consent to participate in the study and follow the study 
procedures. 
• 
Male or female patients, age 18 years or older on the day of signing the informed 
consent form. 
• 
Agrees to admission to an in-patient facility for monitoring from Days 1 to 8, inclusive. 
• 
Symptoms of mild illness with COVID-19 (eg, fever, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms) without shortness of breath, 
dyspnea, or clinical signs indicative of more serious COVID-19. 
• 
Confirmed COVID-19 determined by a positive, documented SARS-CoV-2 infection 
determined by a commercial or public health assay in any specimen within 4 days prior 
to the screening visit or during the 7-day screening period. 
• 
Respiratory rate < 20 breaths per minute, heart rate < 90 beats per minute (bpm). 
• 
Oxygen saturation by pulse oximetry > 93% on room air. 
• 
Body mass index < 35 kg/m2. 
• 
Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min. 
• 
Alanine transaminase (ALT) or aspartate transaminase (AST) < 2  upper limit of 
normal (ULN) and total bilirubin < 1.5  ULN. 
• 
Agrees to not participate in another clinical trial for the treatment of COVID-19 while 
on study unless the patient’s condition has worsened and is considered to be moderate, 
severe, or critical by the Investigator. 
Key Exclusion Criteria: 
• 
Shortness of breath, hypoxia (ie, the ratio of the partial pressure of arterial oxygen to 
the fraction of inspired oxygen [PaO2/FiO2] ≤ 300 mm Hg), or signs of serious lower 
airway disease. 
• 
C-reactive protein, lactate dehydrogenase (LDH), or interleukin-6 (IL-6) > 1.5  ULN. 
• 
D-dimer or ferritin > 1.5  ULN. 
• 
Imminently requiring, or currently on, mechanical ventilation or extracorporeal 
membrane oxygenation (ECMO). 
• 
Systolic blood pressure < 90 mm Hg or diastolic blood pressure < 60 mm Hg. 
• 
Evidence of acute respiratory distress syndrome (ARDS) or systemic inflammatory 
response syndrome (SIRS)/shock. 
• 
Known cardiovascular history, including unstable or deteriorating cardiac disease. 
• 
Autoimmune disease. 
• 
History of pulmonary embolism (PE), deep vein thrombosis (DVT), or prior clinically 
significant venous or non-cerebrovascular accident/transient ischemic attack arterial 
thromboembolic event. 
• 
Central nervous system disease or evidence of central nervous system dysfunction. 
• 
History of pulmonary disease, including cystic fibrosis. 
• 
Requirement for > 2 anti-hypertensive medications. 
• 
Unwilling to refrain from alcohol consumption from Day 1 of admission to the 
in-patient facility until discharge from the facility. 
• 
Adrenal insufficiency. 


Protocol No. 20-214-34 
 
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Nektar Therapeutics 
 
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Product Dose and 
Mode of 
Administration for: 
Test Product: The starting dose of bempegaldesleukin will be 0.00075 mg/kg IV. 
Comparator Product: Placebo control will consist of sterile normal saline solution 
administered at the same volume as the active administration. 
 Standard of Care: All patients will receive the standard of care for COVID-19 determined 
by the Investigator or institution, which should follow the approved prescribing guidelines 
in their country and institution. 
Pharmacodynamics 
and Biomarkers: 
Blood samples for analyses of absolute lymphocyte counts, DNA/RNA sequencing, 
SARS-CoV-2 serology, immune cell profiling, including profiling of SARS-CoV-2 specific 
T cells, and cytokines will be collected. Detection of SARS-CoV-2 nucleic acid in 
respiratory specimens will be measured using oropharyngeal swabs and anterior nares or 
nasopharyngeal swabs collected in a manner consistent with the Centers for Disease and 
Control (CDC) specimen collection guidelines (CDC 2020b). Samples will be collected at 
various scheduled sample times from predose to the 30-day follow-up visit (see 
Section 1.2). 
Pharmacokinetic 
and Immunogenicity 
Evaluation: 
Blood samples for pharmacokinetic and immunogenicity will be collected from patients at 
multiple scheduled sampling times during the study. Validated methods will be used to 
measure plasma concentrations of bempegaldesleukin. Pharmacokinetic parameters such as 
maximum concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time 
curve (AUC) will be estimated from plasma concentration-time data where possible. 
Validated methods will be used to measure anti-drug antibodies and their ability to 
neutralize bempegaldesleukin. 
Safety Evaluation: 
Assessment of safety will be determined by an ongoing review of the following: 
• 
AEs, including treatment-emergent AEs, incidence of treatment-related AEs, SAEs, 
and death. 
• 
The AE of special interest, cytokine release syndrome (CRS). 
• 
Clinical laboratory tests (blood and urine sampling). 
• 
Vital signs. 
• 
Physical examination. 
Disease 
Measurement: 
The disease measurements are: 
• 
The percentage of patients who require supplemental oxygen. 
• 
Change from baseline based on the daily collection of the WHO Clinical Progression 
Scale. 
Statistical Methods 
General Considerations: 
In general, continuous data will be summarized by descriptive statistics, including number 
of patients, mean, standard deviation, median, minimum, and maximum. Categorical data 
will be summarized by the number and percentage of patients. 
Safety:  
Safety assessments will include AEs, clinical laboratory tests, and vital signs. All safety 
data will be summarized for the safety population using descriptive statistics. 
Pharmacodynamics: 
The fold change from baseline at each evaluation time and the maximum fold change of 
absolute lymphocyte counts achieved will be summarized by treatment 
(bempegaldesleukin/SOC or placebo/SOC). 
Disease Measurement: 
Disease measurement will be summarized by treatment group for the safety population 
using descriptive statistics. 


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1.1 
Study Schematic 
Figure 1: 
Study Schematic 
 
Abbreviations: bpm = beats per minute; CRC = Cohort Review Committee; COVID-19 = coronavirus disease 2019 (severe acute respiratory syndrome coronavirus 2 
[SARS-CoV-2]); IV =intravenous; R = randomization; RP2D = recommended Phase 2 dose; SOC = standard of care 
a. 
Patients will be evaluated for enrollment during the up to 7-day screening period. The complete list of entry criteria is provided in Section 4.0. 
b. A CRC will review blinded safety, tolerability, pharmacokinetic, pharmacodynamic, and disease measurement data, make decisions about escalating or de-escalating the 
bempegaldesleukin dose, and identify the RP2D (see Section 7.16). 
c. 
If the CRC determines additional patients may be randomized, 2 patients will be randomized (1 with bempegaldesleukin/SOC and 1 with placebo/SOC), treated with study 
drug, and observed for 72 hours. For every 2 patients, the Medical Monitor will review the blinded safety and tolerability data for the first 72 hours after study drug 
administration to determine if the next 2 patients may be randomized (Section 5.3). 
d. The Safety Follow-Up should occur 30 days (± 7 days) after discharge from the hospital or in-patient facility. See Section 5.7 for additional details. 


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Figure 2: 
Dose Cohort Schematic 
 
Note. 
The Safety Follow-Up should occur 30 days (± 7 days) after discharge from the hospital or in-patient facility. See Section 5.7 for additional details. 
a. 
Earliest possible randomization day for the next eligible patients if approved by CRC (see Section 5.3). 
b. Earliest possible randomization day for the next eligible patients if approved by Medical Monitor (see Section 5.3). 






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Laboratory Assessments and Biomarkers: 
f. 
Safety laboratory assessments are categorized in two groups depending on the purpose: 
• 
For local laboratory assessments collected in this study, see Appendix 1A. 
• 
For central laboratory assessments collected throughout the study, see Appendix 1B. 
g. Hematology, serum chemistry, and coagulation assessments should be drawn in the morning. 
h. Predose samples should be collected up to 3 hours before study drug administration. 
i. 
End of infusion samples should be collected within 30 minutes of the end of study drug infusion. 
j. 
If the patient is discharged from the in-patient facility prior to Day 6, a sample will be collected between Days 6 
to 10, inclusive. If the patient is unable to return to the clinic, samples may be collected by research staff or 
designee at an alternate location. 
k. See Section 7.11.1. 
l. 
See Section 5.10.  
m. All biomarker samples should be drawn in the morning. See Section 5.11 for additional details. 
n. Collect oropharyngeal and anterior nares or nasopharyngeal swabs according to the CDC guidelines 
(CDC 2020b). 
Study Drug Administration: 
o. See Sections 5.5.1 and 5.5.2 for additional details. 
p. Patients should receive IV fluid as tolerated on the day of dosing (Day 1) and continue with oral hydration as 
tolerated for the subsequent 3 days. In the event patients cannot adhere to the oral hydration guidelines, IV 
hydration should be administered as clinically indicated. If the patient is prematurely discharged from the 
in-patient facility before Day 4, contact the patient (by telephone or clinic visit) once between Days 2 to 4, 
inclusive, to remind the patient of the oral hydration guidelines and to assess for any symptomatology and 
compliance with the hydration guidelines. Site personnel must document the hydration and the results of the 
discussion. Additionally, advise patients who are discharged from the in-patient facility before Day 8: 
• 
To restrain from activities that may contribute to dehydration (including, but not limited to, strenuous 
activity, long hot showers, and saunas) from Days 1 to 8. 
• 
If experiencing orthostatic symptoms, the patient should contact site personnel and consider increasing oral 
hydration. 
See Section 5.5.4.2 for additional details. 
q. See Section 5.5.3 for additional details. 
r. 
The Safety Follow-Up call should occur 30 days (± 7 days) after discharge from the hospital or in-patient 
facility. If the patient remains at the in-patient facility after Day 8, the Safety Follow-Up call should occur no 
later than 38 days (± 7 days) after Day 1, the day of study drug administration. See Section 5.7 for additional 
details. 
s. 
Samples will be collected 30 days (± 7 days) after hospital or in-patient facility discharge for immunogenicity, 
DNA/RNA sequencing, SARS-CoV-2 serology, immune cell profiling, and detection of SARS-CoV-2 nucleic 
acid. Note: 
• 
If the patient is unable to return to the clinic, samples may be collected by research staff or designee at an 
alternate location. 
• 
If the patient remains at the in-patient facility after Day 8, samples should be collected no later than 38 days 
(± 7 days) after Day 1, the day of study drug administration. 
See Section 5.7 for additional details. 
t. 
If the patient is prematurely discharged from the in-patient facility, site personnel should contact the patient by 
telephone each day until Day 8 for collection of AEs and concomitant medications. 
 


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2.0 
INTRODUCTION 
2.1 
Background 
2.1.1 
COVID-19 
Following the outbreak of severe acute respiratory syndrome (SARS) in 2002, human 
coronaviruses have been reported as pathogens that cause severe symptoms in respiratory tract 
infections. A human coronavirus isolated from the respiratory epithelium of unexplained 
pneumonia patients in Wuhan, China in December 2019, initially named “2019 novel 
coronavirus” (2019-nCoV) and later designated “severe acute respiratory syndrome 
coronavirus 2” (SARS-CoV-2), causes acute lung symptoms, leading to a condition that has been 
named “coronavirus disease 2019” (COVID-19) (Xu 2020). 
2.1.1.1 
Clinical Presentation of Patients with Mild COVID-19 
COVID-19 shows similarities with SARS-CoV and Middle East respiratory syndrome 
coronavirus (MERS-CoV) infections (Gralinski 2020). Most cases of COVID-19 reported to date 
are of mild severity. In China, up to 81% of patients were reported to have mild disease, 
however, this estimate includes a range of disease severity from asymptomatic to mild 
pneumonia (Wu 2020). Among the COVID-19 cases reported to the Centers for Disease and 
Control (CDC) from January 22 to May 30, 2020, 14% of patients were hospitalized, 2% were 
admitted to an intensive care unit, and 5% died. Excluding the 4% of patients who were 
asymptomatic, approximately 75% of patients in the US would be expected to have mild disease 
(Stokes 2020). Symptoms of mild COVID-19 include fever, cough, sore throat, malaise, 
headache, muscle pain, and gastrointestinal symptoms, without shortness of breath or dyspnea 
(FDA 2020). The clinical course may rapidly progress for some patients with mild COVID-19, 
especially for patients with risk factors for severe disease (CDC 2020a; Guan 2020; 
Huang 2020). Worsening of patient clinical status has been observed approximately 5 to 8 days 
after the onset of COVID-19 symptoms (Kujawski 2020; Huang 2020; Guan 2020; Kim 2020). 
In severe cases of COVID-19, the disease can cause pneumonia, severe acute respiratory 
syndrome, multi-organ failure, and death (FDA 2020). 
2.1.2 
Bempegaldesleukin (NKTR-214) for Patients who have Mild COVID-19 
Bempegaldesleukin (NKTR-214) is an engineered interleukin-2 (IL-2) cytokine prodrug that 
provides a controlled and sustained IL-2 signal to T cells and natural killer cells. Upon 
administration to patients with cancer, we observed increased number and proliferation of T cells 
and natural killer cells (see Section 2.1.3.1), and concurrent increases in cytolytic effector 
molecules such as granzyme B in tumor (Bentebibel 2019). To overcome a COVID-19 infection, 
an innate and most importantly adaptive (T cell-mediated) immune response to the virus is 
required, which has been observed in surviving patients (Tan 2020a; Zheng 2020; Zhou 2020; 
Ma 2020 [preprint]). Lymphopenia has been identified as biomarker of COVID-19 disease 
severity (Richardson 2020; Tan 2020a; Ruan 2020; Zhou 2020; Yang 2020a; Thevarajan 2020; 
Chen 2020; Wang 2020). We are conducting this Phase 1b study to evaluate if 


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bempegaldesleukin can be administered safety to patients with mild COVID-19 to maintain 
normal or increase lymphocytes. The ultimate long-term goal of the development program is to 
determine if bempegaldesleukin can overcome lymphopenia in patients hospitalized for 
COVID-19 by correcting both the numerical and functional impairment of lymphocytes to 
improve survival. 
2.1.3 
Bempegaldesleukin (NKTR-214) Polymer Conjugation Design 
Bempegaldesleukin was designed to mitigate the severe toxicities associated with administration 
of IL-2 (aldesleukin, Proleukin®). While aldesleukin is a well-established cytokine therapy first 
approved by the United States Food and Drug Administration (FDA) in 1992 for the treatment of 
metastatic renal cell carcinoma (RCC) and subsequently for the treatment of metastatic 
melanoma, aldesleukin has multiple shortcomings. These challenges include rapid clearance 
(> 95% clearance within 30 minutes), which necessitates frequent administration of high doses 
and resultant increased severe toxicity that led the FDA to issue a black-boxed warning 
(Proleukin 2018). The warning alerts clinicians and patients that aldesleukin administration has 
been associated with capillary leak syndrome, which may result in hypotension and reduced 
organ perfusion that may be severe and can result in death. 
The goal of engineering bempegaldesleukin as a pegylated form of IL-2 was to reduce the 
treatment-limiting toxicities of aldesleukin, prolong the half-life, and ultimately enhance 
efficacy. The differences between aldesleukin and bempegaldesleukin are presented in Table 2. 
Table 2: 
Comparison of Aldesleukin to Bempegaldesleukin 
Parameter 
Aldesleukin (Proleukin)a 
Bempegaldesleukin  
Structure 
Human recombinant IL-2. 
Pegylated human recombinant IL-2. 
Dosing 
IV infusion every 8 hours for 5 consecutive days. 
IV infusion every 2-3 weeks. 
Administration 
Hospital setting. An intensive care facility and 
specialists skilled in cardiopulmonary or intensive 
care medicine must be available. 
Outpatient settingb. 
Half-life 
85 minutes 
20 hours 
Primary 
life-threatening 
AEs requiring 
hospital 
monitoring 
• 
Capillary leak syndrome. 
• 
Cardiac arrhythmias (supraventricular and 
ventricular), angina, myocardial infarction, 
respiratory insufficiency requiring intubation, 
gastrointestinal bleeding or infarction, renal 
insufficiency, edema, and mental status 
changes. 
• 
Impaired neutrophil function and with an 
increased risk of disseminated infection, 
including sepsis and bacterial endocarditis. 
Primary life-threatening toxicities 
associated with aldesleukin have not 
been observed. 
a. 
Proleukin 2018. 
b. Bempegaldesleukin is administered in an outpatient setting when used as an immuno-oncology agent, as safety 
and tolerability have been evaluated in patients with advanced cancers. However, hospitalization or admission to 
an in-patient facility through Day 8 is required in Study 20-214-34 because safety and tolerability have not yet 
been evaluated in patients with COVID-19 (see Section 2.2.3). 


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To date, bempegaldesleukin has been studied as an immunotherapeutic agent in different 
oncology indications in > 600 patients with a well-tolerated safety profile that allows for 
outpatient administration of the compound. The majority of AEs observed have been mild to 
moderate in severity, transient and typically resolve in 2-4 days following study drug 
administration. Bempegaldesleukin has been routinely administered to cancer patients at 
0.006 mg/kg and nivolumab 360 mg q3w. In Study 20-214-34, a single dose of 
bempegaldesleukin will be administered to adults with mild COVID-19 at a starting dose of 
0.00075 mg/kg; this starting dose is one-eighth of the 0.006 mg/kg dose that is commonly used 
in the oncology setting in combination with other agents and is one-twelfth of the maximum 
tolerated dose (MTD) for monotherapy (ie, 0.009 mg/kg; see Section 2.1.4.2.1) in late stage 
cancer. 
2.1.3.1 
Bempegaldesleukin Mechanism of Action, Pharmacokinetics and 
Pharmacodynamics 
Bempegaldesleukin is an immunotherapeutic protein prodrug with unique properties specifically 
designed to activate the immune system by providing a controlled, sustained signal to the IL-2 
receptor pathway. 
Bempegaldesleukin contains aldesleukin conjugated to 3 to 8 polyethylene glycol (PEG) groups, 
with an average of 6 PEG groups per aldesleukin. In this fully pegylated prodrug form, 
bempegaldesleukin is inactive. After administration in vivo, PEG groups release to form various 
PEG-IL-2 species composed of releasable and stable PEG groups. Active cytokines are 
composed of releasable and stable 2-PEG-IL-2, releasable and stable 1-PEG-IL-2, and IL-2 
(Figure 3) that have a peak plasma concentration 26 to 48 hours after infusion. 
Figure 3: 
Release of PEG Groups from Bempegaldesleukin to Form Active 
Cytokines 
 
The slow generation of the 2-PEG-IL-2 and 1 PEG-IL-2 significantly mitigates the rapid-onset of 
systemic cytokine-related toxicities associated with high dose IL-2. In vitro hydrolysis studies 
demonstrate PEG release occurs sequentially, with a half-life of 20 hours for each step in the 
release, supporting the lack of a “burst” IL-2 release (Charych 2016). Therefore, slow release of 


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PEG relative to fast clearance of IL-2 results in predominant exposure to active pegylated IL-2 
conjugates. 
While pegylated IL-2 conjugates are the predominant moieties in plasma following 
bempegaldesleukin dosing, exposure to free IL-2 is very low. In a study of 28 patients receiving 
bempegaldesleukin monotherapy over a dose range of 0.003 to 0.012 mg/kg, due to the slow and 
gradual release of PEG molecules after administration of bempegaldesleukin relative to the fast 
clearance of IL-2, plasma concentrations of free IL-2 were only sporadically detected in 76 of 
425 samples, with free IL-2 concentrations ranging from 0.509 to 4.44 ng/mL (one sample at 
19.4 ng/mL) (Study 15-214-01 [EXCEL]). After administration of 0.003 mg/kg 
bempegaldesleukin, free IL-2 was detected in 4 of 645 samples. IL-2 concentrations in the four 
samples with undetectable levels ranged between 0.6 to 1.3 ng/mL. Hence, exposure to free IL-2 
is low after administration of bempegaldesleukin. In contrast, reported IL-2 levels in patients 
with COVID-19 tended to remain below approximately 35 pg/mL at all stages of the disease 
(Diao 2020; Han 2020; Huang 2020; Liu 2020; Long 2020; Shi 2020; Tan 2020b; Yang 2020b). 
In cancer patients, bempegaldesleukin monotherapy promoted dose-dependent elevations of 
lymphocyte levels over the range of doses tested, 0.003 to 0.012 mg/kg (Figure 4; Table 3). 
Based on pharmacokinetic/pharmacodynamic (PK/PD) modeling, lymphocyte increases are also 
predicted to occur at bempegaldesleukin doses below this range. Lymphocyte kinetics after 
administration of bempegaldesleukin are similar to those described after administration of IL-2 
and include initial activation and relocation to tissue, resulting in a transient decrease in 
lymphocytes on Day 3, followed by a systemic increase with lymphocyte levels reaching 
approximately 2-fold those observed at baseline between Days 8 and 11. Further characterization 
of immune cells on Day 8 confirmed increased numbers of CD4, CD8, and natural killer cells, 
with increased proliferation (Figure 5). Increases in lymphocytes were observed across the 
clinical development program of bempegaldesleukin, independent of patient age, as illustrated 
for patients treated with bempegaldesleukin and nivolumab in Figure 6. 






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Figure 6: 
Bempegaldesleukin (0.006 mg/kg) Reliably Increases Total 
Lymphocyte Counts in Patients with Cancer Across Age Groups 
(n=456) 
 
% Lymphocyte count in Cycle 1 from standard hematology shows bempegaldesleukin at 0.006 mg/kg + nivolumab 
(360 mg) administered q3w increases percentage of lymphocytes in all age groups (<60, [60-80), ≥80 years of 
age). The initial decrease in blood lymphocyte counts is due to lymphocyte activation and extravasation into 
tissues followed by systemic proliferation.  
Source: Study 16-214-02 (PIVOT-02) 
 
In light of its mechanism of action, bempegaldesleukin may provide therapeutic benefit in 
COVID-19 
2.1.4 
Clinical Experience with Bempegaldesleukin 
2.1.4.1 
Studies of Bempegaldesleukin Therapy 
Bempegaldesleukin is currently being studied in multiple clinical trials, and > 600 patients with 
locally advanced or metastatic solid tumors have been treated with bempegaldesleukin to date 
(Appendix 5). The range of doses tested in these oncology trials has been 0.003 to 0.012 mg/kg, 
which is higher than the dose range planned for the current COVID-19 trial, 0.00075 to 
0.003 mg/kg. 
Nektar initiated the bempegaldesleukin oncology development program with Study 15-214-01 
(EXCEL), a Phase 1/2, open-label, multicenter, dose-escalation and dose expansion study of 
bempegaldesleukin monotherapy in patients with locally advanced or metastatic solid tumor 
malignancies. The study provided information on single-agent bempegaldesleukin safety and 
tolerability, pharmacokinetic (PK), the recommended Phase 2 dose (RP2D) in immuno-
oncology, as well as efficacy and pharmacodynamic and immunological changes in blood and 


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tumor samples. The study was closed after 28 patients were enrolled in the dose-escalation 
phase. This allowed the oncology development program for bempegaldesleukin to continue with 
other studies in which bempegaldesleukin is administered in combination with checkpoint 
inhibitors, including nivolumab. 
The combination of bempegaldesleukin with the checkpoint inhibitor nivolumab was initially 
investigated in a Phase 1/2 “basket” study (Study 16-214-02 [PIVOT-02]). This is an ongoing 
trial that includes patients with melanoma, RCC, non-small cell cancer, urothelial carcinoma, 
triple negative breast cancer, and other solid tumors. Results from Study 16-214-02 informed the 
oncology development program for bempegaldesleukin in combination with nivolumab, which 
currently encompasses multiple Phase 2/3 registrational studies, including patients with first-line 
metastatic and adjuvant melanoma, first-line RCC, and patients with metastatic urothelial 
carcinoma who are ineligible for cisplatin treatment. To date, the largest safety data set in 
aggregate has been collected in Study 16-214-02. 
Breakthrough therapy designation was granted on 29 July 2019 for bempegaldesleukin in 
combination with nivolumab for the treatment of patients with untreated unresectable or 
metastatic melanoma based on data from the melanoma cohort in Study 16-214-02 (see 
Appendix 4 for additional details). 
Bempegaldesleukin is administered in combination with nivolumab in several other studies, 
including CA045-010/18-214-14; 18-214-10/CA045-012 (PIVOT-10); CA045-001/17-214-08; 
17-214-09/CA045002 (PIVOT-09). 
In other studies, bempegaldesleukin is administered in combination with the checkpoint inhibitor 
pembrolizumab (Study 16-214-05 [PROPEL]) and the novel pegylated toll-like receptor 
7/8 agonist NKTR-262 (Study 17-262-01 [REVEAL]). Bempegaldesleukin is also being studied 
in combination with avelumab, a human immunoglobulin (Ig)G1 monoclonal antibody directed 
against programmed cell death ligand 1 (PD-L1), with or without 1) talazoparib, a potent, orally 
bioavailable poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, and 
2) enzalutamide, an androgen receptor inhibitor (Study B9991040). In addition, a study is 
underway in which bempegaldesleukin is administered in combination with the VB10.NEO 
vaccine, though no patients have as yet received the combination (Study VB N-01). 
2.1.4.2 
Safety Overview of Bempegaldesleukin 
2.1.4.2.1 
Study 15-214-01 (EXCEL) Bempegaldesleukin Monotherapy 
The first in human trial with bempegaldesleukin was 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 MTD or RP2D of bempegaldesleukin in patients with 
advanced cancers. The starting dose was 0.003 mg/kg and advanced to a maximum of 
0.012 mg/kg. While the higher doses were relevant to explore the anti-cancer properties of the 


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compound, they are not relevant to the efficacy endpoint in this study nor is the safety profile of 
the higher doses representative of the level of risk anticipated for the lower doses used in this 
study. 
In the monotherapy study, 28 patients received bempegaldesleukin and there were no National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 4 
treatment-related adverse events (AEs) or deaths. At the highest dose tested, 0.012 mg/kg 
(or 16-fold the starting dose of this Phase 1b), one patient experienced two DLTs including 
Grade 3 hypotension and grade 3 syncope. The patient’s AEs resolved within 24 hours following 
intravenous (IV) fluid treatment and one dose of tocilizumab. The patient continued to receive 
additional treatment with bempegaldesleukin at 0.006 mg/kg and the subsequent doses were well 
tolerated. Bempegaldesleukin at a dose of 0.009 mg/kg administered once every 3 weeks (q3w) 
was deemed the MTD by pre-defined dose-limiting toxicity criteria. 
The most common treatment-emergent AEs (TEAEs) across the dose levels that were considered 
by the Investigator to be related to bempegaldesleukin were fatigue (71.4%), flu-like symptoms 
(67.9%), pruritus (64.3%), hypotension (57.1%), rash (50.0%), decreased appetite (46.4%), and 
arthralgia or cough (each 32.1%). Such treatment-related TEAEs as flu-like symptoms, rash, and 
pruritus were generally mild or moderate in severity, predictable, manageable, and short-lived. 
These AEs generally occurred approximately 3 to 4 days post-dose, and resolved spontaneously 
or were mitigated by nonprescription oral or topical treatments. The AEs corresponded to the 
pharmacokinetics of the active metabolites of bempegaldesleukin, which peaked at 
approximately 30 hours after dosing. The flu-like symptoms were managed with acetaminophen 
and nonsteroidal anti-inflammatory drugs (NSAIDs) and the cases of rash/pruritus were either 
self-limiting or treated with antihistamines. 
Hypotension can be effectively mitigated by prophylaxis and hydration guidelines, which were 
introduced during Study 16-214-02 (PIVOT-02) and are now included in all studies of 
bempegaldesleukin (see Section 5.5.4). 
The lowest bempegaldesleukin dose administered to date, 0.003 mg/kg, was utilized as 
monotherapy in Study 15-214-01 as part of the dose escalation process and represents the highest 
dose that could be administered in the current study (Study 20-214-34). Among the four patients 
treated at that dose there were no Grade 3 or higher instances of hypotension or any occurrence 
of cytokine release syndrome (see Table 4). 


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Table 4: 
Treatment-emergent Related Adverse Events by Severity Grade 
Following Bempegaldesleukin 0.003 mg/kg Administration (Study 
15-214-01 [EXCEL]) 
Preferred Term 
Bempegaldesleukin 0.003 mg/kg (q3w) 
(N=4) 
All Cycles 
Cycle 1 Only 
Grade 1-2 
n (%) 
Grade 3-5  
n (%) 
Grade 1-2  
n (%) 
Grade 3-5  
n (%) 
Patients with ≥ 1 treatment-
related TEAE 
4 (100.0) 
0 
4 (100.0) 
0 
Flu-like symptomsa 
2 (50) 
0 
1 (25) 
0 
Headache 
2 (50) 
0 
1 (25) 
0 
Hypotension 
2 (50) 
0 
2 (50) 
0 
Pruritus 
2 (50) 
0 
2 (50) 
0 
Rashb 
2 (50) 
0 
2 (50) 
0 
Dizziness 
1 (25) 
0 
1 (25) 
0 
Abdominal pain 
1 (25) 
0 
0 
0 
Chest discomfort 
1 (25) 
0 
1 (25) 
0 
Conjunctivitis 
1 (25) 
0 
1 (25) 
0 
Constipation 
1 (25) 
0 
0 
0 
Depression 
1 (25) 
0 
1 (25) 
0 
Dizziness 
1 (25) 
0 
1 (25) 
0 
Dry skin 
1 (25) 
0 
0 
0 
Dyspnea 
1 (25) 
0 
0 
0 
Hypothyroidism 
1 (25) 
0 
0 
0 
Muscular weakness 
1 (25) 
0 
1 (25) 
0 
Nasal congestion 
1 (25) 
0 
0 
0 
Nausea 
1 (25) 
0 
0 
0 
Orthostatic hypotension 
1 (25) 
0 
1 (25) 
0 
Pancreatitis 
1 (25) 
0 
0 
0 
Rhinitis 
1 (25) 
0 
0 
0 
Abbreviation: TEAE = treatment-emergent adverse event 
a. 
Flu-like symptoms include the following preferred terms: “influenza-like illness”, “influenza”, “pyrexia”, 
“chills” 
b. Rash includes the following preferred terms: “erythema”, “rash”, “rash erythematous”, “rash maculo-papular”, 
“rash papular”, “rash pruritic”, “rash pustular”, “rash vesicular”, “rash generalized”, “rash macular” 
Patients reporting more than one AE within the same preferred term are counted once at the highest severity 
reported 
Data cut off: 29 March 2018. 
Source: t15.10teae_rel_post_v4, t15.12teae_rel_post_c1 
 


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2.1.4.2.2 
Study 16-214-02 (PIVOT-02) Bempegaldesleukin and Nivolumab 
Combination Therapy 
The PIVOT-02 trial (NCT02983045) is an ongoing Phase 1/2 open-label, multicenter, dose 
escalation, and dose expansion study of bempegaldesleukin in combination with nivolumab and 
other anti-cancer therapies in patients with locally advanced or metastatic solid tumors. Part 1 of 
the study was a dose escalation phase that initially evaluated bempegaldesleukin monotherapy in 
22 patients at doses ranging from 0.003 mg/kg to 0.012 mg/kg. 
Among the three patients treated with 0.003 mg/kg of bempegaldesleukin monotherapy in 
Study 16-214-02, there were no Grade 3 or higher instances of hypotension or any occurrence of 
cytokine release syndrome (Table 5). 
Table 5: 
Treatment-emergent Related Adverse Events by Severity Grade 
Following Bempegaldesleukin 0.003 mg/kg Administration (Study 
16-214-02 [PIVOT-02]) 
Preferred Term 
Bempegaldesleukin 0.003 mg/kg (q3w) 
(N=3) 
All Cycles 
Cycle 1 Only 
Grade 1-2 
n (%) 
Grade 3-5  
n (%) 
Grade 1-2  
n (%) 
Grade 3-5  
n (%) 
Patients with ≥ 1 treatment-related TEAE 
3 (100.0) 
0 
3 (100.0) 
0 
Chills 
3 (100.0) 
0 
2 (66.7) 
0 
Nasal congestion 
2 (66.7) 
0 
0 
0 
Pruritus 
2 (66.7) 
0 
1 (33.3) 
0 
Pyrexia 
2 (66.7) 
0 
2 (66.7) 
0 
Rasha 
2 (66.7) 
0 
1 (33.3) 
0 
Abdominal pain 
1 (33.3) 
0 
0 
0 
Anal haemorrhage 
1 (33.3) 
0 
0 
0 
Arthralgia 
1 (33.3) 
0 
0 
0 
Constipation 
1 (33.3) 
0 
0 
0 
Diarrhoea 
1 (33.3) 
0 
0 
0 
Dry skin 
1 (33.3) 
0 
1 (33.3) 
0 
Dyspepsia 
1 (33.3) 
0 
0 
0 
Erythema 
1 (33.3) 
0 
0 
0 
Eye pain 
1 (33.3) 
0 
0 
0 
Face oedema 
1 (33.3) 
0 
0 
0 
Facial paralysis 
1 (33.3) 
0 
1 (33.3) 
0 
Fatigue 
1 (33.3) 
0 
1 (33.3) 
0 
Flushing 
1 (33.3) 
0 
1 (33.3) 
0 
 


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Table 5: 
Treatment-emergent Related Adverse Events by Severity Grade Following 
Bempegaldesleukin 0.003 mg/kg Administration (Study 16-214-02 [PIVOT-02]) 
(Contd) 
Preferred Term 
Bempegaldesleukin 0.003 mg/kg (q3w) 
(N=3) 
All Cycles 
Cycle 1 Only 
Grade 1-2 
n (%) 
Grade 3-5  
n (%) 
Grade 1-2  
n (%) 
Grade 3-5  
n (%) 
Headache 
1 (33.3) 
0 
1 (33.3) 
0 
Hypotension 
1 (33.3) 
0 
1 (33.3) 
0 
Lacrimation increased 
1 (33.3) 
0 
0 
0 
Malaise 
1 (33.3) 
0 
0 
0 
Oedema peripheral 
1 (33.3) 
0 
0 
0 
Periorbital oedema 
1 (33.3) 
0 
0 
0 
Pneumonia 
1 (33.3) 
0 
0 
0 
Rash maculpapular 
1 (33.3) 
0 
1 (33.3) 
0 
Abbreviation: q3w = every 3 weeks; TEAE = treatment-emergent adverse event 
a 
Rash includes the following preferred terms: “erythema”, “rash”, “rash erythematous”, “rash maculo-papular”, 
“rash papular”, “rash pruritic”, “rash pustular”, “rash vesicular”, “rash generalized”, “rash macular” 
Patients reporting more than one AE within the same preferred term are counted once at the highest severity 
reported. 
Data cut off: 28 October 2019. 
Source: Source: t14.9.2taebypt03_tr, t14.9.4taebypt03_g3tr, t14.9.6teabypt03_c1tr, t14.9.8teabypt03_c1g3tr 
 
Information concerning the safety profile of higher doses of bempegaldesleukin used in the 
PIVOT-02 trial is available in the bempegaldesleukin Investigator’s Brochure. 
2.1.4.2.3 
Risk Period for Bempegaldesleukin Active Compounds 
Bempegaldesleukin is a prodrug. The periods when AEs associated with bempegaldesleukin are 
most likely to appear are 1) during or shortly after completion of the IV infusion and 
2) approximately 2-4 days following the infusion. Reactions during or after the infusion period 
typically manifest as transient flushing, chills, itching, rash, and flu-like symptoms. The principal 
period of risk is when the prodrug releases the active moieties. These active forms gradually 
increase after dosing and peak between 24 and 48 hours post-dose. 
2.1.4.2.4 
Cardiac Safety 
Nektar conducted a comprehensive analysis of the cardiovascular safety of bempegaldesleukin 
and potential risk of QT prolongation. Nonclinical cardiovascular safety of bempegaldesleukin 
was evaluated in cynomolgus monkeys with IV administration. Electrocardiographic (ECG) 
changes were monitored following bempegaldesleukin administration throughout the clinical 


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development program. PK/ECG data from Studies 15-214-01 (bempegaldesleukin monotherapy) 
and 16-214-02 (bempegaldesleukin in combination with nivolumab) have served to characterize 
the drug effect on the corrected QT interval (QTc) interval at the proposed therapeutic dose for 
cancer 0.006 mg/kg every 3 weeks. By comparison, the starting dose of bempegaldesleukin in 
this Phase 1b is a single dose of 0.00075 mg/kg or one-eighth the proposed therapeutic dose in 
cancer patients. Dose selection for the study is discussed further in Section 2.2.4. 
Exposure-response analyses of the QTc were conducted using ECG and plasma concentration 
data from Studies 15-214-01 and 16-214-02 (dose escalation part) in accordance with the FDA 
Guidance for Industry. A review of the nonclinical and clinical data indicates that 
bempegaldesleukin has a low risk for cardiac events. 
Nonclinical safety pharmacology studies showed no effect on the QTc interval following a single 
dose of bempegaldesleukin in telemetry-instrumented monkeys or following 3-month repeat 
dosing at exposure > 3.5-fold higher than that at the dose of 0.006 mg/kg/dose that is used in 
ongoing trials in late-stage cancer patients. 
The safety review of clinical data was conducted in a total of 471 cancer patients treated with 
either bempegaldesleukin monotherapy (Study 15-214-01), bempegaldesleukin in combination 
with nivolumab (Study 16-214-02) or bempegaldesleukin in combination with pembrolizumab or 
atezolizumab (Study 16-214-05). Based on the aggregate analysis on the retrieved AE cases from 
bempegaldesleukin studies, no signal indicating a causal relationship between 
bempegaldesleukin administration and QT prolongation or its cardiac complications (torsarde de 
pointes, ventricular tachycardia or sudden cardiac death) has been identified. 
An increase in heart rate related to the hypotensive effect was seen. PK/PD simulated results for 
2000 cancer patients receiving 0.006 mg/kg bempegaldesleukin showed a median baseline heart 
rate of 71 beats per minute (bpm) and a median peak increase of 15 bpm, which occurred at 
2.6 days postdose. The magnitude of the peak was dose-related: following simulated doses of 
0.003 and 0.009 mg/kg, the median peak increases were 11 and 18 bpm, respectively. While 
heart rate increases associated with bempegaldesleukin were well tolerated by the patients in 
Studies 15-214-01 and 16-214-02, similar heart rate increases could be clinically impactful in 
vulnerable patient populations. Hence, patients with decompensated congestive heart failure or 
critical coronary stenosis are excluded from bempegaldesleukin protocols, including 
Study 20-214-34. 
QTc prolongation potential for bempegaldesleukin was evaluated after administration of 
bempegaldesleukin monotherapy (n=28 patients) and also after administration of 
bempegaldesleukin and nivolumab (n=38 patients). Bempegaldesleukin doses in both studies 
exceeded the recommended phase 2 dose of 0.006 mg/kg in late-stage cancer patients. 
Exposure-response analyses evaluated plasma concentrations of the active pegylated IL-2 
conjugates formed after administration of bempegaldesleukin (NKTR-214-AC). Assessment of 
plasma concentration-QTc relationships did not show a correlation for QTc prolongation. Due to 
the increase in heart rate after bempegaldesleukin administration, several heart rate correction 


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methods in addition to the prespecified Fridericia method were used. QTcRMA correction had 
the smallest QTc-RR slope for both studies. Both NKTR-214-AC concentration-dQTcRMA and 
NKTR-214-AC concentration-dQTcF mixed-effects model predicted a decrease in QTc with 
increasing NKTR-214-AC concentrations. The predicted decreases in the corrected QT interval 
(calculated with Fridericia’s formula; QTcF) and in QTcRMA were 17.3 and 11.0 msec, 
respectively, at the geometric mean Cmax of 32.7 ng/mL observed at the 0.009 mg/kg dose of 
bempegaldesleukin. Central tendency analysis of dQTc showed similar results. 
In summary, bempegaldesleukin was associated with a dose-related increase in heart rate and 
concentration-depended decrease in QTc. As the heart rate increases could be clinically 
impactful in vulnerable populations, patients with decompensated congestive heart failure or 
critical coronary stenosis are excluded from Study 20-214-34. 
2.1.4.2.5 
Hypotension and Capillary Leak Syndrome 
No patients in studies of bempegaldesleukin have experienced capillary leak syndrome. 
Hypotension has been characterized as an identified risk of bempegaldesleukin. Instances of 
hypotension appear around 1-4 days following the infusion of bempegaldesleukin, coinciding 
with the peak plasma concentration of the active pegylated IL-2 conjugates formed after 
administration of bempegaldesleukin (NKTR-214-AC). Patients with bempegaldesleukin-
induced hypotension are usually rapidly responsive to fluid administration. 
Importantly, while AEs of hypotension occurred in 2 of the 4 patients who received monotherapy 
with 0.003 mg/kg bempegaldesleukin, the lowest dose administered to date, none were higher 
than Grade 2 severity. By comparison, the starting dose of bempegaldesleukin in the amended 
Study 20-214-34 is 0.00075 mg/kg, ie, one-fourth the dose at which Grade 1 or 2 hypotension 
was observed in 2 patients. Dose selection for this study is discussed further in Section 2.2.4. 
A specific management guideline, including prophylactic fluid administration, was implemented 
in ongoing bempegaldesleukin studies, which has successfully mitigated the risk of hypotension 
(refer to Section 6.2 [Warnings and Precautions] of the bempegaldesleukin Investigator’s 
Brochure). 
2.1.4.2.6 
Flu-like Symptoms and Rash 
Across all studies with bempegaldesleukin, flu-like symptoms including fever, chills/rigors, and 
influenza-like illness, are the most common AEs. In general, these symptoms are mild, transient, 
and consistent with the appearance of active pegylated IL-2 moieties following administration of 
the bempegaldesleukin prodrug. These AEs occur within a predictable time frame, 
approximately 1 to 4 days post-dose, and resolved spontaneously or were mitigated by 
nonprescription oral or topical treatments. The flu-like symptoms, along with rash, are managed 
with NSAIDs, acetaminophen, and antihistamines. These are not anticipated to compromise or 
worsen the respiratory status of COVID-19 patients. 


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Nektar Therapeutics 
 
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2.1.4.2.7 
Cytokine Release Syndrome 
While the safety, tolerability, and PK of bempegaldesleukin have been well described in patients 
with advanced cancers, particularly at 0.006 mg/kg q3w, the possibility cannot be excluded of 
toxicity and PK differences between cancer patients and patients with COVID-19. Consequently, 
the current trial is designed to evaluate bempegaldesleukin, under close monitoring, in a mild 
COVID-19 patient population. This dose-finding study will focus on the safety, tolerability, and 
PK profile of bempegaldesleukin at a starting dose of 0.00075 mg/kg, which is 8 times lower 
than the immuno-oncology dose of 0.006 mg/kg and 12 times lower than the monotherapy MTD 
of 0.009 mg/kg. 
In the bempegaldesleukin Investigator’s Brochure, Edition 8.0, cytokine release syndrome (CRS) 
has been reported in 5 of 605 (0.8%) cancer patients who received bempegaldesleukin as either 
monotherapy or in combination with other therapeutics. Among the 3 patients who received 
bempegaldesleukin monotherapy and experienced cytokine release syndrome, two received a 
dose of 0.009 mg/kg and one received a dose of 0.012 mg/kg. In the combination regimens, two 
cases of cytokine release syndrome were reported in patients who received bempegaldesleukin 
0.006 mg/kg with nivolumab 360 mg. 
All events of cytokine release syndrome for those patients on bempegaldesleukin monotherapy 
were reported as Grade 2 in severity. Both patients receiving bempegaldesleukin with nivolumab 
experienced Grade 3 severity cytokine release syndrome events. 
Following the release of Edition 8.0 of the bempegaldesleukin Investigator’s Brochure, a 
Grade 4 cytokine release syndrome event was reported in a patient from Study 17-262-01 after 
1 cycle of treatment with 0.006 mg/kg bempegaldesleukin followed by 4 cycles of treatment with 
0.003 mg/kg bempegaldesleukin, each combined with 1.92 mg of NKTR-262, an intratumorally 
administered toll-like receptor agonist. 
In this study, the selection of less advanced COVID-19 patients represents a population with 
lower circulating cytokine levels than more advanced patients. Combined with the anticipated 
lack of clinically relevant IL-6 production associated with the proposed starting doses of 
bempegaldesleukin, such patients are expected to be at low risk for exacerbation of the cytokine 
milieu due to the study drug. At the highest planned dose in Study 20-214-34 (0.003 mg/kg), 
IL-6 concentrations were below the limit of quantification in approximately half of the plasma 
samples (additional details are provided in Section 2.2.4.3). 
2.1.4.3 
Summary of Safety 
The currently available safety data demonstrate that bempegaldesleukin is a generally 
well-tolerated immuno-oncology agent when administered to late stage cancer patients as 
monotherapy and in combination with other immunotherapies and chemotherapy. 
Bempegaldesleukin has also been shown to be generally well-tolerated in cancer patients aged 
≥ 60 years. The most common AEs include Grade 1 and 2 flu-like symptoms, including fever, 


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Nektar Therapeutics 
 
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chills/rigors, and influenza-like illness, which occur within a predictable time frame, 
approximately 1 to 4 days post-dose, and typically resolve spontaneously or are mitigated by 
nonprescription oral or topical treatments. These, along with rash, are managed with NSAIDS, 
acetaminophen, and antihistamines. 
Hypotension, a known AE associated with both IL-2 and engineered cytokines, has been 
characterized as an identified risk of bempegaldesleukin. Instances of hypotension coincide with 
the peak plasma concentration of the active pegylated IL-2 conjugates formed after 
administration of bempegaldesleukin (NKTR-214-AC). Hypotension can be mitigated using the 
hydration management guideline, which has successfully reduced the frequency and severity of 
instances of hypotension in ongoing bempegaldesleukin studies and patients with 
bempegaldesleukin-induced hypotension are usually rapidly responsive to fluid administration. 
Given the encouraging clinical activity to increase lymphocytes and the manageable toxicity 
profile, the potential for direct benefit in patients warrants evaluation of bempegaldesleukin with 
standard of care for COVID-19. 
2.2 
Scientific Rationale for Study Design 
This Phase 1b study is designed to identify the RP2D of bempegaldesleukin in patients with mild 
COVID-19 with the long-term aim to advance to future studies evaluating bempegaldesleukin in 
hospitalized patients with moderate COVID-19 who are lymphopenic and at greater risk for 
mortality. 
2.2.1 
Rationale for Placebo Control 
To objectively assess the safety and disease measurement of bempegaldesleukin treatment for 
adults with mild COVID-19, this study will be randomized, double-blind, and placebo 
controlled. 
All patients will also receive the standard of care treatment for mild COVID-19 determined by 
the Investigator or institution, which should follow the approved prescribing guidelines in the 
country. 
2.2.2 
Rationale for Endpoints  
This study is the first evaluation of bempegaldesleukin in patients with mild COVID-19, 
therefore, a primary objective of the study is to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of bempegaldesleukin. 
Another primary objective of the study is to identify the recommended Phase 2 dose (RP2D) of 
bempegaldesleukin in patients with mild COVID-19. 
The final primary objective of the study is to assess the effect of bempegaldesleukin on the time 
course and extent of changes in absolute lymphocyte counts, as decreased levels of lymphocytes 


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have been associated with a fatal outcome in COVID-19 (Tan 2020a), and in Wuhan, China, 
40% to 70% of hospitalized patients for COVID-19 had lymphopenia (Zhou 2020; Huang 2020; 
Tian 2020 [preprint]; Wang 2020). Increased levels of activated CD4+ and CD8+ T lymphocytes 
are observed in recovering patients (Qin 2020) and recovery from COVID-19 is accompanied by 
maintenance of lymphocyte counts and robust T cell activation. In patients with late-stage 
cancer, many who have compromised immune systems, a single IV infusion of 
bempegaldesleukin reliably elevated total lymphocyte counts at least 2-fold within one week 
after treatment in the vast majority of patients, regardless of age. Comparable increases were also 
observed after multiple successive treatment cycles. Hence, evaluating changes in absolute 
lymphocyte counts in patients with mild COVID-19 may be useful to assess the potential 
therapeutic benefit of bempegaldesleukin to improve the recovery time from the disease, shorten 
hospital stays, prevent respiratory decline, and decrease mortality from the infection in patients 
with more moderate COVID-19. 
2.2.3 
Duration of Treatment for Study Drug (Bempegaldesleukin or Placebo) 
Study drug administration will be limited to a single dose administration and monitoring in the 
hospital or in-patient facility will occur for a minimum of 8 days (ie, from Day 1 [day of dosing] 
to at least Day 8). 
Patients will receive study drug in a hospital or in-patient facility setting. 
2.2.4 
Justification for Dose of Bempegaldesleukin 
The starting bempegaldesleukin dose of 0.00075 mg/kg will be administered as a single IV 
infusion over 15 (± 5) minutes in an initial cohort of 10 patients (5 bempegaldesleukin plus 
standard of care [referred to in this document as bempegaldesleukin/SOC] and 5 placebo plus 
standard of care [referred to in this document as placebo/SOC]). The range of doses that may be 
tested, 0.00075 to 0.003 mg/kg, is supported by data demonstrating the potential to be 
pharmacologically active with a low likelihood of the toxicity observed in studies of 
bempegaldesleukin in patients with cancer. This range is specifically supported by extensive 
clinical safety data, toxicology data, and clinical pharmacology data for bempegaldesleukin as 
described in Sections 2.2.4.1, 2.2.4.2, and 2.2.4.3, respectively. 
As an additional measure of caution, the first two patients randomized and treated 
(1 bempegaldesleukin/SOC and 1 placebo/SOC]) in each dose cohort will serve as sentinel 
patients. A Cohort Review Committee (CRC) will monitor the 2 sentinel patients for safety and 
tolerability for the first 72 hours after study drug administration before additional patients are 
dosed within the same cohort. If the CRC determines additional patients may be randomized, 
2 patients will be randomized (1 with bempegaldesleukin/SOC and 1 with placebo/SOC), treated 
with study drug, and observed for 72 hours. For every 2 patients, the Medical Monitor will 
review the blinded safety and tolerability data for the first 72 hours after study drug 
administration to determine if the next 2 patients may be randomized. At the conclusion of each 
dose level cohort, the CRC will assess the accumulated, blinded safety and tolerability data, as 


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Nektar Therapeutics 
 
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well as any available PK, pharmacodynamic, and disease measurement data, to assess the 
benefit/risk profile and determine if dose escalation or de-escalation of bempegaldesleukin at 
dose levels up to 0.003 mg/kg is warranted. 
2.2.4.1 
Summary of Clinical Safety Data 
The clinical experience with bempegaldesleukin administered either as monotherapy or in 
combination with nivolumab in cancer patients has illustrated a predictable safety profile 
manifesting as either acute infusion-related symptoms or related to the early appearance of the 
active cytokines 24-48 hours post-dose. These treatment emergent AEs are typically mild to 
moderate in severity and transient in nature. Hypotension is the most clinically concerning, but 
can be mitigated by maintaining the hydration status of the patient and by appropriate exclusion 
criteria. The starting dose, 12-fold lower than the maximally tolerated dose, and the single dose 
administration utilized in this study, minimize exposure to bempegaldesleukin providing a safety 
margin and allowing careful consideration of the effects of dose escalation or de-escalation. 
Additionally, the enrollment of COVID-19 infected patients with mild disease avoids the 
potential risk of an untoward contribution to the cytokine milieu that complicates the course of 
more advanced patients. 
2.2.4.2 
Summary of Toxicology Data 
Good Laboratory Practice toxicology studies evaluated the safety of bempegaldesleukin 
administered every 14 days to Sprague Dawley rats (0.006 to 0.3 mg/kg) and cynomolgus 
monkeys (0.006, 0.03, and 0.1 mg/kg) for 15 weeks followed by an 8-week recovery period. The 
no observed adverse effect levels (NOAELs) established in the 15-week studies were 0.1 mg/kg 
for the rat and 0.03 mg/kg for the monkey. The monkey was identified as the most sensitive 
species and the starting bempegaldesleukin dose of 0.00075 mg/kg in Study 20-214-34 is 1/40th 
of the monkey NOAEL of 0.03 mg/kg. 
Hypotension is the most clinically significant adverse effect in patients, but similar effects were 
not observed in monkeys. In spite of this difference, monkeys appeared to have similar 
sensitivity to humans in responding to the immunostimulatory effects of bempegaldesleukin. 
Details are provided below. 
Treatment with bempegaldesleukin in the 15-week monkey study resulted in a 
pharmacologically expected, dose-responsive immune stimulation characterized by a cyclic 
pattern of clinical observations and increases in absolute lymphocyte counts following each dose 
administration (Table 6). The clinical observations were of minimal severity at the lowest dose 
tested (0.006 mg/kg), increased with dose level, and were not tolerated at the highest dose tested 
(0.1 mg/kg). 
Bempegaldesleukin-related target organs at the NOAEL dose (0.03 mg/kg) included the 
gastrointestinal (decreased food consumption, liquid feces), immune (increased lymphocytes; 
immune cell infiltration and lymphoid organ enlargement), and skin (dry skin, scabs, rash). 


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Effects in skin and gastrointestinal systems were also noted in clinical trials with 
bempegaldesleukin. The skin changes observed in the monkey were noted following the fourth 
dose and therefore, not relevant to the current protocol for COVID-19 since a single dose 
administration is planned. 
At the terminal sacrifice after 15-weeks of dosing, bempegaldesleukin-related microscopic 
findings at 0.03 mg/kg included minimal to moderate mixed inflammatory cell infiltrates in 
multiple organs (liver, urinary bladder, heart, adrenal medulla, thyroid, and/or kidney, lung, 
esophagus, and/or tongue) and immune organ changes (thymus and spleen) consistent with an 
inflammatory response. All findings were minimal and partially recovered after an 8-week, 
dose-free period. 
Importantly, results from the 15-week monkey study showed that immune stimulation decreased 
with dose. At the lowest dose of bempegaldesleukin evaluated in the 15-week study, 
0.006 mg/kg, minimal inflammatory cell infiltrates were observed and involved fewer tissues 
(liver, kidney, bladder, heart, and adrenal gland). All findings fully recovered after an 8-week, 
dose-free period. 
As shown in Table 6, the fold change in absolute lymphocyte count was similar in the monkeys 
(at 0.006 mg/kg) and humans (at 0.003 mg/kg) when plasma exposures are comparable. 
Therefore, exposure-response for immunological effects was similar in monkeys and humans. A 
comparable degree of immune stimulation is expected in humans and monkeys at doses that 
produce similar plasma exposures. Given this relationship, the degree of immune stimulation 
observed in monkeys at 0.006 mg/kg is expected to be similar to the degree of immune 
stimulation in humans at 0.003 mg/kg. Furthermore, the degree of immune stimulation in 
patients at the starting dose of 0.00075 mg/kg in Study 20-14-34 is expected to be lower than that 
observed in monkeys at 0.006 mg/kg. As 0.006 mg/kg had minimal immunologic effects in the 
15-week monkey study, the exposure-response data indicate a low risk of hyperinflammatory 
responses in patients treated with 0.00075 mg/kg. 


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Table 6: 
Bempegaldesleukin Plasma Exposures and Increases Absolute 
Lymphocyte Counts in Monkeys and Patients with Cancer  
Species 
Dose  
(mg/kg) 
Cmax  
(ng/mL)a 
AUC  
(ng h/mL)a 
AUC Ratio: 
Monkey-to -Human 
Starting Doseb 
ALC Maximum 
Fold Changec 
Monkeys 
0.1 
233 
9940 
54 
5.6 
0.03 
73 
3330 
18 
3.2 
0.006 
15 
794 
4 
2.1 
Humans 
0.009 
43 
2190 
- 
2.6 
0.006 
31 
1460 
- 
2.2 
0.003 
16 
732 
- 
1.8 
0.0015 
8 
366 
- 
1.5 
0.00075 
4 
184 
- 
1.3 
Abbreviation: ALC=absolute lymphocyte count; AUC =area under the concentration-time curve 
a. 
Cmax and AUC are reported for NKTR-214-AC and values for monkeys were measured in Study LS-2017-033 
(Day 1) and for humans were predicted (Table 7).  
b. 
AUC Ratio: Monkey AUC at each dose level divided by human AUC at 0.00075 mg/kg 
c. 
ALC Maximum values reported in monkeys (means; LS-2017-033) and in humans (medians) and are changes from 
baseline after the first dose of bempegaldesleukin. 
Dose-related effects of bempegaldesleukin on C-reactive protein were well described in a 
single-dose toxicity study in monkey. As illustrated in Figure 7, transient increases in C-reactive 
protein were observed in the mid- and high-dose groups (0.03 and 0.1 mg/kg) during the first 
week after administration, with peak concentrations occurring on Days 3-4 (2-3 Days post-dose). 
In the low-dose group, 0.01 mg/kg, changes in C-reactive protein were minimal and only slightly 
higher than in the vehicle control. C-reactive protein was not evaluated in prior clinical studies of 
bempegaldesleukin. As plasma exposures with the 0.03 mg/kg dose in monkeys were more than 
3-times higher than those predicted in patients over the range of doses in Study 20-214-34 
(0.00075 to 0.003 mg/kg), bempegaldesleukin-related increases in C-reactive protein are not 
expected in this clinical study. 


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Figure 7: 
C-Reactive Protein Levels after Bempegaldesleukin Administration in 
Female Cynomolgus Monkeys (n=3) 
 
Note: CRP = C-reactive protein; NKTR-214 = bempegaldesleukin 
Source: A single dose bempegaldesleukin study in the cynomolgus monkey (LS-2012-002) 
In summary, safety margins based on plasma exposures at the NOAEL dose in monkeys indicate 
an 18-fold area under the concentration-time curve (AUC) safety margin for the 0.00075 mg/kg 
starting dose in Study 20-214-34. In addition, the dose-relatedness of immune stimulation in the 
15-week monkey study and calculated monkey-to-human exposure margins support that a low 
(0.00075 mg/kg), single dose of bempegaldesleukin is unlikely to result in a hyperinflammatory 
response in humans. 
2.2.4.3 
Summary of Clinical Pharmacokinetic/Pharmacodynamic Data 
Prior clinical studies evaluated bempegaldesleukin in patients with advanced cancer at doses 
ranging from 0.003 to 0.012 mg/kg. A lower dose range was postulated to result in a favorable 
benefit risk profile in patients with mild COVID-19. Therefore, PK/PD modeling and dose-
response evaluations were used to predict clinical effects at doses ≤ 0.003 mg/kg. 
As bempegaldesleukin is being explored as a possible treatment strategy for increasing 
lymphocyte counts in patients with COVID-19, an endpoint of interest is the change in 
lymphocytes before and after treatment with bempegaldesleukin. This is quantified by measuring 
the fold change from baseline (ie, predose Day 1) absolute lymphocyte count to the maximal 
absolute lymphocyte count between Day 6 and Day 8. A PK/PD model was developed using data 
from Study 15-214-01 (EXCEL) in which bempegaldesleukin monotherapy was administered to 
cancer patients at doses of 0.003 mg/kg (N=4), 0.006 mg/kg (N=11), 0.009 mg/kg (N=5), and 
0.012 mg/kg (N=1). The model predicted median absolute lymphocyte count changes of 
approximately 1.77-, 2.20-, and 2.6-fold for doses of 0.003, 0.006, and 0.009 mg/kg, 
respectively, which well described the observed changes within this dose range (Figure 4 and 
Table 3). The model also predicted median absolute lymphocyte count changes of 


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approximately1.32- and 1.49-fold for doses of 0.00075 and 0.0015 mg/kg, respectively. This 
suggests that the planned doses for Study 20-214-34, 0.00075, 0.0015, and 0.003 mg/kg are 
pharmacologically active. 
Dose-response assessments were performed for 15 inflammatory cytokines to evaluate if 
bempegaldesleukin doses ≤ 0.003 mg/kg could cause hyperinflammation in patients with mild 
COVID-19. Data from cancer patients in Study 15-214-01 (EXCEL; bempegaldesleukin 
monotherapy) were evaluated for each of the cytokines shown in Table 7. Plasma concentrations 
were mostly below the limit of quantification for the following: granulocyte-macrophage 
colony-stimulating factor (GM-CSF), interferon  (IFN-), IL-3, IL-4, IL-7, and tumor necrosis 
factor  (TNF-). Therefore, circulating levels of these 6 cytokines did not appear to be affected 
by bempegaldesleukin from 0.003 to 0.009 mg/kg. The results for the 9 remaining cytokines 
showed that increases in circulating cytokines generally occurred from day 3 to day 7 postdose, 
coinciding with the pharmacokinetic time course of bempegaldesleukin-related active cytokines 
(NKTR-214-AC). The percentage of plasma samples with measurable concentrations tended to 
increase with dose, suggesting dose-response relationships for IL-5, IL-6, IL-8, IL-10, IL-18, 
macrophage inflammatory protein 1 (MIP-1), MIP-1, monocyte chemotactic protein 1 
(MCP-1), and TNF- over the bempegaldesleukin dose range of 0.003 to 0.009 mg/kg. These 
dose-response relationships provide some assurance that any risks associated with 
bempegaldesleukin induced cytokines may be mitigated by using a low range of doses 
(0.00075 to 0.003 mg/kg). 
A final analysis evaluated biomarkers of possible relevance to the risk of hyperinflammation, 
where the magnitude of response was evaluated at the highest planned dose in Study 20-214-34, 
0.003 mg/kg. This analysis included the following biomarkers in plasma: monocytes, 
neutrophils, IL-6, and TNF-. As illustrated in Figure 8, 0.003 mg/kg was not associated with 
meaningful changes in plasma levels of monocytes or neutrophils. As shown in Table 7, IL-6 
concentrations were below the limit of quantification in approximately half of the plasma 
samples from patients treated at 0.003 mg/kg. Based on data from the remaining plasma samples 
from this cohort, levels of IL-6 increased no more than 2-fold in 3 of 4 patients treated with 
bempegaldesleukin at 0.003 mg/kg. In the fourth patient treated at 0.003 mg/kg, IL-6 levels 
showed a 4- to 6-fold increase on Days 2 to 3 postdose. Maximum IL-6 levels after one dose of 
0.003 mg/kg of bempegaldesleukin ranged from < 6.8 to 41 ng/mL. It is difficult to interpret the 
significance of this transient increase in IL-6 because high statistical heterogeneity has been 
encountered comparing IL-6 levels between patients with complicated and non-complicated 
COVID-19 disease (Coomes 2020 [preprint]). Circulating TNF- did not appear to be affected 
by 0.003 mg/kg bempegaldesleukin to a meaningful extent, as plasma concentrations of TNF- 
were quantifiable in only 25% of the plasma samples from patients treated with 0.003 mg/kg 
(Table 7). 
Taken together, the results of PK/PD modeling, dose-response assessments, and evaluation of 
biomarkers at the planned highest dose of 0.003 mg/kg show that bempegaldesleukin doses over 




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2.3 
Cohort Review Committee 
In addition to routine safety monitoring and pharmacovigilance activities, a Cohort Review 
Committee (CRC, see Section 7.16) will be formed to review safety and tolerability data 
throughout the study. Specifically, the CRC will perform the following evaluations: 
1. Monitor the blinded safety and tolerability data for the first 72 hours after study drug 
administration from the first two sentinel patients randomized (1 patient receiving 
bempegaldesleukin/SOC and 1 patient receiving placebo/SOC) and treated to determine if 
additional patients may be enrolled in the dose cohort. If the CRC determines additional 
patients may be randomized, 2 patients will be randomized (1 with bempegaldesleukin/SOC 
and 1 with placebo/SOC), treated with study drug, and observed for 72 hours. For every 
2 patients, the Medical Monitor will review the blinded safety and tolerability data for the 
first 72 hours after study drug administration to determine if the next 2 patients may be 
randomized. If it is not possible to assess the protocol-defined DLT criteria (see 
Section 5.3.2.1.1), the Medical Monitor will request a review of the safety data by the CRC. 
It may be necessary for the CRC to review unblinded data in accordance with Nektar 
Therapeutics internal procedures for unblinding. 
2. Adjudicate reports of Grade 3 dose-limiting toxicities to determine if they meet the 
protocol-defined criteria for a DLT and demonstrate evidence indicating at least a possible 
relationship to study drug in patients confirmed to have received bempegaldesleukin. If it is 
not possible to assess the protocol-defined DLT criteria (see Section 5.3.2.1.1), the CRC may 
review unblinded data in accordance with Nektar Therapeutics internal procedures for 
unblinding. 
3. At the conclusion of each dose level cohort, assess the accumulated, blinded safety and 
tolerability data, as well as any available PK, pharmacodynamic, and disease measurement 
data, to determine if dose escalation or de-escalation is warranted. If it is not possible to 
assess the protocol-defined DLT criteria (see Section 5.3.2.1.1) for the entire cohort to 
determine dose escalation, the CRC may review unblinded data in accordance with Nektar 
Therapeutics internal procedures for unblinding. 
4. The CRC will also establish the RP2D. 
All instances of patient unblinding will be performed in accordance with Nektar Therapeutics’ 
internal procedures for unblinding and associated documentation. 
The CRC will also meet on an ad hoc basis, if needed. 


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives are: 
• To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
bempegaldesleukin/SOC compared with placebo/SOC in patients with mild COVID-19. 
• To evaluate the safety and tolerability of bempegaldesleukin administered as single IV dose 
and to define the RP2D of bempegaldesleukin in patients with mild COVID-19. 
• To assess the effect of bempegaldesleukin on the time course and extent of changes in 
absolute lymphocyte counts. 
3.2 
Secondary Objectives 
The secondary objectives listed below involve comparison of bempegaldesleukin/SOC versus 
placebo/SOC in patients with mild COVID-19: 
• To estimate the incidence of AEs. 
• To evaluate the frequency of serious AEs (SAEs). 
• To determine the percentage of patients who require supplemental oxygen. 
• To evaluate clinical status based on the World Health Organization (WHO) Clinical 
Progression Scale. This will be determined once more information is obtained about the 
clinical meaning/interpretation. The scale is as follows: 
 
Patient state 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild 
disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized:  
Moderate disease 
Hospitalized, no oxygen therapya 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized:  
Severe disease 
Hospitalized; oxygen by non-invasive ventilation or high-flow 
6 
Intubation and mechanical ventilation, PaO2/FiO2 ≥ 150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation, PaO2/FiO2 < 150 (SpO2/FiO2 < 200) or vasopressors 
8 
 
Mechanical ventilation, PaO2/FiO2 < 150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Death 
10 
Abbreviations: ECMO = extracorporeal membrane oxygenation; FiO2 = fraction of inspired oxygen; PaO2 = partial pressure of 
arterial oxygen; SpO2 = oxygen saturation 
a. 
If hospitalized for isolation only, record status as for ambulatory patient. 
Source:  WHO 2020 


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• To assess the immunologic effects in blood before and after study drug administration, 
including effects on cytokines, natural killer cells, T-cells, and other serum proteins and 
immune modulators. 


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4.0 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion Criteria 
Each patient will be entered into this study only if he/she meets all the following criteria: 
1. 
Patient (or legally authorized representative) provides written, informed consent to 
participate in the study and follow the study procedures. The Investigator takes 
responsibility for ensuring that all vulnerable patients are protected and participate 
voluntarily in an environment free from coercion or undue influence. 
2. 
Male or female patients, age 18 years or older on the day of signing the informed consent 
form (ICF). 
3. 
Agrees to admission to an in-patient facility for monitoring from Days 1 to 8, inclusive. 
4. 
Symptoms of mild illness with COVID-19 (eg, fever, cough, sore throat, malaise, 
headache, muscle pain, gastrointestinal symptoms) without shortness of breath, dyspnea, or 
clinical signs indicative of more serious COVID-19. 
5. 
Confirmed COVID-19 determined by a positive, documented SARS-CoV-2 infection 
determined by a commercial or public health assay in any specimen within 4 days prior to 
the screening visit or during the 7-day screening period. 
6. 
Respiratory rate < 20 breaths per minute. 
7. 
Heart rate < 90 bpm. 
8. 
Oxygen saturation by pulse oximetry > 93% on room air. 
9. 
Body mass index < 35 kg/m2. 
10. Demonstrated adequate organ function, as defined below: 
a. Absolute neutrophil count (ANC) ≥ 1500/μL (≥ 1000/μL for patients with known or 
suspected diagnosis of benign ethnic neutropenia)  
b. Platelet count ≥ 100 × 103/μL  
c. Hemoglobin ≥ 12.0 g/dL  
d. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min, where eGFR is estimated by 
the Modification of Diet Renal Disease (MDRD) equation:  
eGFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (age)-0.203 
× (0.742 if female) × (1.212 if black) 
e. Alanine transaminase (ALT) or aspartate transaminase (AST) or < 2 × upper limit of 
normal (ULN) 
f. Total bilirubin < 1.5× ULN 


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11. Reproductive Status 
a. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]) within the 7 days prior to enrollment. 
b. Women must not be breastfeeding. 
c. Women of childbearing potential must agree to follow instructions for method(s) of 
contraception for the duration of study participation or 2 weeks after the last dose of 
study drug, whichever is longer. Women should use an adequate method(s) of 
contraception as indicated in Appendix 2. 
d. Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 2) for the duration of study participation or 
2 weeks after the last dose of study drug, whichever is longer. In addition, male patients 
must refrain from sperm donation during this time. 
e. Investigators shall counsel WOCBP, and male patients who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy. Investigators shall advise on the use of highly effective methods 
of contraception (Appendix 2), which have a failure rate of < 1% when used 
consistently and correctly. 
12. Patients must be able and willing to comply with the study procedures. 
13. Agrees to not participate in another clinical trial for the treatment of COVID-19 while on 
study unless the patient’s condition has worsened and is considered to be moderate, severe, 
or critical by the Investigator. 
4.2 
Exclusion Criteria 
A patient will be excluded from this study if he/she meets any of the following criteria: 
1. 
Shortness of breath, hypoxia (defined as the ratio of the partial pressure of arterial oxygen 
to the fraction of inspired oxygen [PaO2/FiO2] ≤ 300 mm Hg), or signs of serious lower 
airway disease. 
2. 
C-reactive protein, lactate dehydrogenase (LDH), or IL-6 > 1.5  ULN. 
3. 
D-dimer or ferritin > 1.5  ULN. 
4. 
Imminently requiring, or currently on, mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO) for respiratory support for COVID-19. 


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5. 
Systolic blood pressure < 90 mm Hg or diastolic blood pressure < 60 mm Hg. 
6. 
Patients with any evidence of acute respiratory distress syndrome (ARDS) or systemic 
inflammatory response syndrome (SIRS)/shock. 
7. 
Known cardiovascular history including unstable or deteriorating cardiac disease including 
but not limited to the following: 
a. Unstable angina or myocardial infarction. 
b. Transient ischemic attack (TIA)/Cerebrovascular accident (CVA). 
c. Congestive heart failure (CHF) (any New York Heart Association [NYHA] Class). 
d. Uncontrolled clinically significant arrhythmias. 
8. 
Patients with a history of autoimmune disease. 
9. 
History of pulmonary embolism (PE), deep vein thrombosis (DVT), or prior clinically 
significant venous or non-CVA/TIA arterial thromboembolic event. 
10. Patients with central nervous system disease or evidence of central nervous system 
dysfunction. 
11. Patients with any history of pulmonary disease, including cystic fibrosis. 
12. Patients with a history of sickle cell disease. 
13. Patients with a history of type 2 diabetes mellitus. 
14. Patients with organ allografts. 
15. Requirement for > 2 anti-hypertensive medications for management of hypertension 
(including diuretics). Patients with hypertension must be on a stable anti-hypertensive 
regimen for the 14 days prior to enrollment. 
Note: An antihypertensive medication that contains 2 drugs under one formulation is 
counted as 2 antihypertensive medications (eg, angiotensin-converting-enzyme [ACE] 
inhibitor plus diuretic, calcium channel blocker plus ACE inhibitor). 
16. Use of an investigational agent or an investigational device within 28 days of enrollment 
and throughout the course study, except if the patient’s condition has worsened to 
moderate, severe, or critical per the Investigator. 
17. Female patients who are pregnant or lactating, who plan to get pregnant, or who have a 
positive serum or urine pregnancy test. 


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18. History of allergy to bempegaldesleukin or its components, sodium citrate and trehalose 
dihydrate. 
19. Patients on chronic immune-suppressive agents (use of 10 mg/day or less of prednisone or 
equivalent is allowed). 
20. Has known hepatitis B virus (HBV) infection (eg, hepatitis B surface antigen [HbsAg] 
reactive) or hepatitis C virus (HCV) infection (eg, HCV ribonucleic acid [RNA] qualitative 
is detected). 
21. Has known immunodeficiency or active human immunodeficiency virus (HIV-1 and HIV-2 
antibodies). 
22. Prolonged Fridericia’s corrected QT interval (QTcF) > 500ms. 
23. Unwilling to refrain from alcohol consumption from Day 1 of admission to the in-patient 
facility until discharge from the facility. 
24. Patients with adrenal insufficiency. 
25. Anticipated transfer to another hospital which is not a study site within the study duration. 
26. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of 
the Investigator, would preclude the patient 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). 


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5.0 
INVESTIGATIONAL PLAN 
5.1 
Study Design 
This study is a multicenter, Phase 1b, randomized, double-blind, placebo-controlled trial to 
assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
bempegaldesleukin/SOC in adults with mild COVID-19, as well as to determine the RP2D of 
bempegaldesleukin. 
5.2 
Screening Period 
Patients will provide written informed consent to participate in the study before completing any 
protocol-specified procedures or evaluations not considered to be part of the patient’s standard 
care. After signing the ICF, patients will be evaluated for entry criteria during the up to 7-day 
Screening period based on assessments outlined in Section 1.2. Rescreening after screen failure 
may be allowed after discussion with the Medical Monitor. 
5.2.1 
Screening Failure 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements, as applicable, and to respond to queries from 
regulatory authorities. 
Patient re-screening: this study permits the re-screening of a patient who has discontinued the 
study as a pre-treatment screen failure (ie, patient has not been enrolled). If re-screened, the 
patient must be re-consented. 
Retesting of laboratory parameters and/or other assessments included in the Schedule of Events 
(Section 1.2) within any single Screening period will be permitted if the Investigator deems the 
assessment does not accurately represent the patient’s clinical status. 
If laboratory parameters or other assessments were tested more than once, only the most current 
results obtained prior to enrollment will be used for assessment of eligibility. Results from earlier 
laboratory testing may not be substituted if repeat laboratory testing yields an exclusionary value. 
5.3 
Dose Finding 
Dose finding is described in Table 8 and will follow the rules described in Section 5.3.1. 
The first bempegaldesleukin dose to be studied (0.00075 mg/kg) was determined in 
consideration of a monotherapy trial with bempegaldesleukin in the oncology setting 
(ie, 0.003 mg/kg q3w; see Section 2.2.4.1) as well as non-clinical toxicology data (see 
Section 2.2.4.2) and clinical pharmacology and pharmacodynamic data (see Section 2.2.4.3, 
respectively). The starting dose is 12 times lower than the MTD for bempegaldesleukin 


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monotherapy established in patients with late-stage cancer. This dose has the potential to be 
pharmacologically active with a low risk of inducing hyperinflammation or toxicity in patients 
enrolled in Study 20-214-34 (Section 2.2.4). 
Table 8: 
Dose Finding Scheme 
Cohort 
Bempegaldesleukin 
Dose 
Schedule 
-1a 
0.000375 mg/kg 
single dose on Day 1 
1 
0.00075 mg/kg 
single dose on Day 1 
2a 
0.0015 mg/kg 
single dose on Day 1 
3a 
0.003 mg/kg 
single dose on Day 1 
a. 
Doses which may be chosen based on patient response to initial 0.00075 mg/kg dose. 
In each dose cohort, the first two patients randomized and treated (1 with 
bempegaldesleukin/SOC and 1 with placebo/SOC) will serve as sentinel patients. Enrollment in 
each cohort will be staggered as presented in Figure 2 and Table 9. The Cohort Review 
Committee (CRC; see Section 7.16) will monitor blinded safety and tolerability data for the first 
72 hours after study drug administration from the 2 sentinel patients before additional patients in 
that cohort are treated. If the CRC determines additional patients may be randomized, 2 patients 
will be randomized (1 with bempegaldesleukin/SOC and 1 with placebo/SOC), treated with 
study drug, and observed for 72 hours. For every 2 patients, the Medical Monitor will review the 
blinded safety and tolerability data from the first 72 hours after study drug administration to 
determine if the next 2 patients may be randomized (see Section 5.15). If it is not possible to 
assess the protocol-defined DLT criteria (see Section 5.3.2.1.1), the Medical Monitor will 
request a review of the safety data by the CRC. After 10 patients have completed a 7-day 
observation period for DLT (see Section 5.3.2.1 for additional details), the CRC will determine 
whether dose escalation or de-escalation from the tested bempegaldesleukin dose level can 
proceed. The CRC will document this decision that will be based on blinded data using pre-
defined criteria, including the proportion of patients who experience a DLT (see Section 5.3.2). 
Patients who drop out of the study for reasons other than a DLT, before the DLT evaluation 
period (Days 1 to 7) has elapsed, may be replaced. 


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Table 9: 
Staggered Dosing Procedures for Each Dose Cohort 
Patient 
Procedure 
Patients 1 and 2 
Randomize Patients 1 and 2. 
 
CRC reviews blinded safety and tolerability data for the first 72 hours after study drug 
administration to determine if Patients 3 and 4 can be randomized. 
Patients 3 and 4 
Randomize Patients 3 and 4 if CRC approves.  
 
Medical Monitor reviews blinded safety and tolerability data for the first 72 hours after 
study drug administration to determine if Patients 5 and 6 can be randomized.a 
Patients 5 and 6 
Randomize Patients 5 and 6 if Medical Monitor approves. 
 
Medical Monitor reviews blinded safety and tolerability data for the first 72 hours after 
study drug administration to determine if Patients 7 and 8 can be randomized.a 
Patients 7 and 8 
Randomize Patients 7 and 8 if Medical Monitor approves. 
 
Medical Monitor reviews blinded safety and tolerability data for the first 72 hours after 
study drug administration to determine if Patients 9 and 10 can be randomized.a 
Patients 9 and 10 
Randomize Patients 9 and 10 if Medical Monitor approves. 
 
After 10 patients receive study drug and a 7-day observation period has elapsed, CRC 
review to determine if dose escalation or de-escalation from the tested bempegaldesleukin 
dose level can proceed. 
a. 
If it is not possible to assess the protocol-defined DLT criteria (see Section 5.3.2.1.1), the Medical Monitor will 
request a review of the safety data by the CRC. 
The CRC will decide the following: 
• Continued dosing of additional patients after the first 2 sentinel patients in a new cohort are 
treated and a 72-hour safety review period has elapsed. If it is not possible to assess the 
protocol-defined DLT criteria (see Section 5.3.2.1.1), the CRC may review unblinded data in 
accordance with Nektar Therapeutics internal procedures for unblinding. 
• If reports of Grade 3 dose-limiting toxicities meet the protocol-defined criteria for a DLT and 
demonstrate evidence indicating at least a possible relationship to study drug in patients 
confirmed to have received bempegaldesleukin. If it is not possible to assess the 
protocol-defined DLT criteria (see Section 5.3.2.1.1), the CRC may review unblinded data in 
accordance with Nektar Therapeutics internal procedures for unblinding. 
• Whether dose escalation or de-escalation from the tested bempegaldesleukin dose level can 
proceed after 10 patients are treated in a dose cohort and a 7-day observation period has 
elapsed. The CRC decision will be based on the accumulated, blinded safety and tolerability 
data, as well as any available pharmacokinetic, pharmacodynamic, and disease measurement 
data. If it is not possible to assess the protocol-defined DLT criteria (see Section 5.3.2.1.1) 
for the entire cohort to determine dose escalation, the CRC may review unblinded data in 
accordance with Nektar Therapeutics internal procedures for unblinding. 


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• The RP2D of bempegaldesleukin based on the totality of the blinded, safety, tolerability, 
pharmacokinetic, pharmacodynamic, and disease measurement data. The RP2D may be 
determined based on the MTD dose or a dose lower than MTD. The RP2D may also be 
determined based on the immunologic effects of the study drugs, which could include effects 
on lymphocyte counts, cytokines, natural killer cells, T-cells, and other serum proteins and 
immune modulators. If it is not possible to assess the protocol-defined DLT criteria (see 
Section 5.3.2.1.1) for the entire cohort to determine dose escalation, the CRC may review 
unblinded data in accordance with Nektar Therapeutics internal procedures for unblinding. 
• Whether dose levels other than those shown in Table 8 should be evaluated in consideration 
of the severity, duration, frequency of toxicities, pharmacokinetics, and/or 
pharmacodynamics observed at any dose. 
5.3.1 
Rules for Dose Finding 
The DLT evaluation period will be a minimum of 1 week (7 days) (see Section 5.3.2.1). 
Patients will be randomized (1:1 ratio) in groups of at least 10 patients 
(5 bempegaldesleukin/SOC and 5 placebo/SOC) in each dose cohort unless unacceptable toxicity 
is observed. 
Unblinding patient treatment assignment, if required, for the purpose of dose-limiting toxicity 
(DLT) adjudication will be performed in accordance with Nektar Therapeutics internal 
procedures for unblinding and associated documentation. 
The definition of a DLT is provided in Section 5.3.2.1. If no DLTs occur in a cohort of at least 
5 patients who received bempegaldesleukin, a new cohort of 10 patients may be randomized and 
treated at the next higher dose level (Table 8). If only 1 of the 5 patients who received 
bempegaldesleukin in a dose cohort experiences a CRC-confirmed DLT, then the next cohort of 
10 patients may be treated at the next higher dose level. If 2 or more patients who received 
bempegaldesleukin within a cohort experience CRC-confirmed DLTs, then that dose level will 
be above the MTD (the highest dose tested where no more than 1 of 5 patients who received 
bempegaldesleukin has experienced a CRC-confirmed DLT). If 10 patients have already been 
enrolled into a cohort and additional patients have signed the ICF and are undergoing the 
screening process, they may be enrolled to the cohort with Sponsor approval; however, these 
patients are not required to be included in the dose escalation or de-escalation decision for that 
cohort.  
Approximately 30 patients will be enrolled. 


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5.3.2 
Dose-Limiting Toxicities (DLTs) 
5.3.2.1 
Determination of Dose-Limiting Toxicities (DLTs) 
The DLT evaluation period will be a minimum of 1 week (7 days) because possible drug-related 
AEs are most likely to occur 1 to 5 days following bempegaldesleukin treatment based on the 
following: 
• Previous experience with bempegaldesleukin in cancer patients including clinical safety data 
from 605 patients treated primarily with bempegaldesleukin at higher, oncology dose levels 
(most often, bempegaldesleukin 0.006 mg/kg) than will be used in this trial (see 
Section 2.2.4.1). 
• The clinical half-life of bempegaldesleukin, which is approximately 20 hours (see 
Section 2.1.3.1). 
• The rate of active species formation from the inactive bempegaldesleukin pro-drug (see 
Section 2.1.3). 
• The chronic nonclinical toxicology studies (see Section 2.2.4.2). 
DLTs will be assessed by the CRC during the DLT evaluation period. If DLTs are not observed, 
dose escalation will be permitted and enrollment of the next dosing cohort may begin. If DLTs 
are not observed, patients will continue to enroll until no more than 30 patients have been 
evaluable for safety. Grading of AEs is described in Section 7.3. Patients who drop out of the 
study for reasons other than a DLT, before the DLT evaluation period has elapsed, may be 
replaced. 
5.3.2.1.1 
DLTs Related to Study Drug 
AEs related to study drug(s) that will be defined as a DLT include the following: 
• Any Grade ≥ 3 drug-related AE.  
• Any Grade ≥ 3 drug-related laboratory abnormality that is clinically significant per the 
Investigator. 
• Respiratory compromise or other virus-related AE attributed to worsening COVID-19, such 
as severe hypoxia, cyanosis, or chest pain/pressure. 
All AEs that meet DLT criteria must be recorded in the electronic data capture system within 
approximately 24 hours of awareness. 
Each AE reported as related to study drug that meet any of the above definitions will be 
adjudicated by the CRC. If the event is confirmed to be at least possibly related to study drug, 
meets any of the above definitions, and is confirmed to have occurred in a patient treated with 
bempegaldesleukin, the event will be considered to be a DLT. 


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5.4 
Study Stopping Criteria 
The study will be promptly paused if any of the following are met: 
• Death in any patient in which the cause of death is judged to be related to the study drug by 
the treating Investigator. 
• The occurrence in any patient of a life-threatening SAE whose causal relationship to study 
drug is judged to be related by the treating Investigator. 
• If at any dose tested, there are 2 occurrences of treatment-related dose-limiting toxicities 
defined in Section 5.3.2.1.1 observed in the first 5 or fewer patients dosed with 
bempegaldesleukin that are adjudicated by the CRC as meeting the criteria of 
Section 5.3.2.1.1 and are confirmed as related to study drug in patients actually treated with 
bempegaldesleukin. 
If any of the above listed event(s) occur, patient accrual will be suspended pending further 
review by the CRC and prompt consultation with the US FDA and Institutional Review Boards 
(IRBs)/ Independent Ethics Committees (IECs). 
5.5 
Treatment Period 
Patients who are not hospitalized on Day 1 will be admitted to an in-patient facility for 
monitoring. 
Patients will receive a maximum of 1 dose of study drug (bempegaldesleukin or placebo) and 
will remain in the hospital or in-patient facility for monitoring until at least Day 8. 
Study assessments for all patients will be performed as specified in Section 1.2. The following 
assessments should be collected for patients who are discharged prematurely from the in-patient 
facility: 
• For patients who are discharged prior to Day 6:  collect a sample between Days 6 to 10, 
inclusive, for the following: 
o Hematology and chemistry 
o Pregnancy test 
o PK assessments 
o Immunogenicity assessments 
o Respiratory specimens for detection of SARS-CoV-2 nucleic acid 
o SARS-CoV-2 serology 
o DNA/RNA sequencing 
o Immune cell profiling 


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o Cytokine assessments 
If the patient is unable to return to the clinic, the samples may be collected by research staff 
or designee at an alternate location. 
• For patients who are prematurely discharged:  site personnel should contact the patient by 
telephone each day until Day 8 for collection of AEs and concomitant medications. 
If the timing of a protocol-mandated study procedure is skipped due to the patient’s medical 
condition that precludes capturing the data or laboratory sample, the procedure or data should be 
captured on the nearest following feasible date. 
5.5.1 
Administration of Study Drug 
Table 10 provides the timing of study drug administration. 
Table 10: 
Selection and Timing of Dose 
Study Treatment 
Dose 
Frequency of Administration 
Route of Administration 
Bempegaldesleukin 
(NKTR-214) 
Starting dose: 
0.00075 mg/kga 
Single dose on Day 1 
IV over 15 (± 5) minutes 
Placebo 
Not applicable 
Single dose on Day 1 
IV over 15 (± 5) minutes 
Standard of care 
Determined by the Investigator and/or institutional guidelines. 
a. 
Other doses may be explored as described in Table 8. 
 
5.5.2 
Study Drug Dosing 
Each patient’s dose of study drug will be determined by the patient’s dose cohort and weight in 
kilograms, which will be determined on the day of study drug dosing. 
Patients should receive study drug at the starting dose determined by the patient’s dose cohort on 
Day 1. Study agent(s) should be administered in an area with access to resuscitation equipment. 
Study drug will be administered IV over 15 (± 5) minutes. The duration of infusion of study drug 
may be increased if necessary (eg, patient history of infusion reaction) (see Pharmacy Manual for 
details). The study drug infusion must be promptly followed by a flush with diluent to clear the 
IV line to ensure the full dose is administered. The total volume of study drug infusion should 
include the flush of diluent.  
Patients should be carefully monitored for infusion reactions during study drug administration. If 
an acute infusion reaction is noted, patients should be managed according to the guidelines in 
Section 5.6.2. 


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Please refer to the Pharmacy Manual/current Investigator’s Brochure for details regarding study 
drug reconstitution, preparation, storage, and administration. 
5.5.3 
Standard of Care Treatment Dosing 
Patients will receive standard of care treatment determined by the Investigator or institution, 
which should follow the approved prescribing guidelines in the country. Study patients will not 
be permitted to receive other investigational treatments during the study period except if their 
condition has worsened to be considered “severe” or “critical” by the Investigator. 
5.5.4 
Monitoring, Vital Signs, and Hydration Guidelines 
The study site must be equipped to monitor vital signs, respiratory status, cardiovascular status, 
among others, as well as being equipped to manage medical emergencies. 
5.5.4.1 
Vital Signs 
Refer to Section 7.14 for vital sign measurements, which are to be monitored according to the 
Schedule of Events (Section 1.2). 
5.5.4.2 
Hydration Guidelines  
Important safety information and hydration instructions are to be provided to patients. Details 
regarding IV hydration will be captured in the electronic data capture (EDC). 
Adequate hydration mitigates the development of hypotension associated with 
bempegaldesleukin administration. Underlying reasons for decreased oral intake (eg, nausea) 
should be addressed and alternate hydration (eg, IV hydration) should be provided. The 
Investigator may modify these recommendations based on the needs of the individual patient. 
Patients should receive IV fluid as tolerated on the day of study drug dosing and continue with 
oral hydration as tolerated for the subsequent 3 days. In the event patients cannot adhere to the 
oral hydration guidelines, IV hydration should be administered as clinically indicated. Patients 
should avoid activity that may contribute to dehydration. 
As patients will be treated in an in-patient facility or a hospital, the aforementioned hydration 
guidelines may require adjustment. Therefore, IV hydration may be utilized for repletion of 
fluids on Days 2 to 4 post-dosing, rather than oral hydration. Hydration, whether IV or oral, 
should be titrated to the patient’s degree of hypotension and should take into consideration the 
Investigator’s assessment of the patient’s clinical status. Per clinical judgment, IV fluids may be 
administered at any time during the study. The Investigator may decide to forego administering 
IV fluids to a patient or adjust the recommendation for self-oral hydration to a particular patient 
if this is deemed in the best interest of the patient (eg, evidence of fluid overload). Should fluid 
administration, whether oral or IV, be contraindicated, Investigators may utilize other methods of 
blood pressor support (eg, pressors) at their discretion. 


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If a patient is prematurely discharged from the in-patient facility before Day 4, site personnel 
must contact the patient (by telephone or clinic visit) once between Days 2 to 4, inclusive, to 
remind the patient of the oral hydration guidelines and to assess for any symptomatology and 
compliance with the hydration guidelines. Site personnel must document the hydration and the 
results of the discussion. Additionally, advise patients who are discharged from the in-patient 
facility before Day 8: 
• To restrain from activities that may contribute to dehydration (including, but not limited to, 
strenuous activity, long hot showers, and saunas) from Days 1 to 8. 
• If experiencing orthostatic symptoms, the patient should contact site personnel and consider 
increasing oral hydration. 
5.6 
Monitoring and Management Algorithms 
5.6.1 
Monitoring and Management of Elevated Hepatic Transaminases 
Elevated hepatic transaminases can occur with bempegaldesleukin. The elevations in hepatic 
transaminases associated with bempegaldesleukin typically occur at the time of peak active 
cytokine concentration in the blood (Days 2-4), and are often accompanied by other AEs such as 
flu-like symptoms, rash, or pruritus. The transient elevations in hepatic transaminases are usually 
mild or moderate in severity, are not associated with increased total bilirubin, and resolve 
spontaneously without treatment. 
5.6.2 
Treatment of Study Drug-Related Infusion Reactions 
Infusion reactions have been reported during infusions with bempegaldesleukin. If such a 
reaction were to occur with the study drug infusion, it might manifest with fever, chills, rigors, 
headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other 
allergic-like reactions. Infusion reactions should be graded as outlined below (consistent with 
CTCAE version 5.0 grading of infusion-related reaction); please also refer to Section 7.3. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
• For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):  Remain at the bedside and monitor the patient until recovery from symptoms. 
• For Grade ≥ 2 symptoms: Immediately discontinue study drug infusion and begin an 
IV infusion of normal saline, and treat the patient with diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg; remain at the bedside and 
monitor the patient until resolution of symptoms. Corticosteroid and/or bronchodilator 
therapy may also be administered as appropriate. Corticosteroid doses should be minimized 
(eg, ≤ 80 mg/day methylprednisolone) to avoid exacerbating impairment of immune 
function. Salbutamol may be given as 4 puffs (400 mcg) as the initial dose and increase by 
2 puffs every 2 min up to 10 puffs if needed. 


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• For Grade 3 or Grade 4 symptoms: immediately discontinue study drug infusion. Begin an 
IV infusion of normal saline and treat the patient as follows: recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 
0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. 
Study drug will be permanently discontinued. The patient 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 patient 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). 
5.6.3 
Management of Potential Cytokine Release Syndrome  
Cytokine release syndrome (CRS) comprises a set of clinical sequelae arising from increased 
levels of circulating cytokines, including IL-6 and TNF-α. Potential clinical signs and symptoms 
include high fever, fatigue, nausea, headache, dyspnea, tachycardia, rigors, hypotension, 
hypoxia, myalgia/arthralgia, anorexia, and neurologic abnormalities (eg, altered mental status, 
myoclonus, and seizures or seizure-like activity). 
Cytokine release syndrome has been reported in 5 of 605 (0.8%) cancer patients who received 
bempegaldesleukin as either monotherapy or in combination with other therapeutics. There have 
been no CRS-related fatalities for any patient treated with bempegaldesleukin. Following the 
release of Edition 8.0 of the bempegaldesleukin Investigator’s Brochure, a Grade 4 cytokine 
release syndrome event was reported in a patient from Study 17-262-01 after 1 cycle of treatment 
with 0.006 mg/kg bempegaldesleukin followed by 4 cycles of treatment with 0.003 mg/kg 
bempegaldesleukin, each combined with 1.92 mg of NKTR-262, an intratumorally administered 
toll-like receptor agonist (see Sections 2.1.4.2.7 and 2.2.4.3 for additional information). 
In all cases of suspected CRS, contact the Medical Monitor as soon as feasible. Administration 
of low-dose corticosteroids (eg, 10 mg dexamethasone IV) and/or tocilizumab has demonstrated 
resolution of CRS symptoms and should be considered for first-line management of CRS in 
patients who are not at risk for life-threatening complications (Davila 2014). 
5.7 
Safety Follow-up 
The Safety Follow-Up telephone call should occur 30 days (± 7 days) after discharge from the 
hospital or in-patient facility as described in Section 1.2. If a patient remains at the inpatient 
facility after Day 8, the Safety Follow-Up call should occur no later than 38 days (± 7 days) after 
Day 1, the day of study drug administration. 
Collection of samples for immunogenicity, DNA/RNA sequencing, SARS-CoV-2 serology, 
immune cell profiling, and detection of SARS-CoV-2 nucleic acid should occur 30 days 


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(± 7 days) after discharge from the hospital or in-patient facility as described in Section 1.2. If a 
patient remains at the in-patient facility after Day 8, samples should be collected no later than 
38 days (± 7 days) after Day 1, the day of study drug administration. If the patient is unable to 
return to the clinic, samples may be collected by research staff or designee at an alternate 
location. 
The patient will be followed for safety until resolution or permanent sequelae of all toxicities 
attributable to study drug as outlined in Sections 7.5 and 7.8. If the patient discontinues study 
drug for a clinically significant AE, the patient will be followed until resolution of the AE or the 
event is considered to be stable and/or chronic. 
For AE and SAE reporting periods, please refer to Sections 7.5 and 7.7. 
5.8 
Patient Discontinuation from Study  
Reasons for patient discontinuation from the study include: 
• Between Screening and Day 1, the patient’s COVID-19 disease severity worsens to 
moderate, severe, or critical per the Investigator. 
• Patient completes the study as follows: 
o Patient remains in the in-patient facility until Day 8 and completes the Safety Follow-Up 
30 days after discharge from the in-patient facility. 
o Patient does not remain in the in-patient facility until Day 8, but completes the Safety 
Follow-Up 30 days after discharge from the in-patient facility. 
• Patient decision to discontinue the study (follow-up data collection is allowed). 
• Patient voluntarily withdraws consent from the study and all additional data collection. 
• Death. 
• Patient is lost to follow-up. 
• Investigator’s decision. 
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or IRBs/ IECs. 
Patients who have received study drug but discontinued early will be followed for safety when 
possible. Patients who receive study drug and are discharged from the hospital or in-patient 
facility will be monitored closely as outlined in Section 1.2. 


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5.8.1 
Standard of Care Discontinuation Criteria  
Investigators should follow the approved prescribing guidelines in the country, or institutional 
standard of care regarding dose discontinuation, dose modifications, and AE management for 
standard of care treatment. 
5.9 
End of Study 
End of study is defined as no more than 6 months from enrollment of the last patient, or Sponsor 
decision. 
5.10 
Pharmacokinetic and Immunogenicity Measurements 
Pharmacokinetic (PK) and immunogenicity (anti-drug antibodies [ADA]) assessment data will 
be collected from study patients at the sampling times indicated in Section 1.2. 
All sampling times are relative to the start of the study drug administration. 
Further details of sample collection, processing, and shipment will be provided in the Laboratory 
Manual. 
Plasma PK samples will be analyzed for NKTR-214-RC (related cytokines; mixture of 
compounds containing IL-2 independent of PEG conjugation status) using a validated ligand 
binding assay. 
Serum samples will be analyzed by multi-tiered ADA testing as per the 2019 FDA guidance 
(FDA 2019) to determine whether they contain ADAs that can bind to and neutralize 
bempegaldesleukin in the presence of the expected serum concentration of bempegaldesleukin. 
Validated methods to detect anti-bempegaldesleukin and anti-IL-2 ADA will be used to analyze 
immunogenicity samples. These assays are highly sensitive, demonstrate good drug tolerance, 
and were validated as per the 2019 FDA guidance (FDA 2019). Samples will be first tested with 
screening electrochemiluminescence assays (ECLA). Putative positive samples for 
anti-bempegaldesleukin or anti-IL-2 ADA will then be analyzed in a competition ECLA to 
confirm positivity. Confirmed anti-bempegaldesleukin 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 bempegaldesleukin. Confirmed 
positive samples from anti-bempegaldesleukin and anti-IL-2 ADA assays will then be tested to 
obtain a titer. Samples confirmed to be positive for anti-bempegaldesleukin and anti-IL-2 ADA 
will also be tested for neutralizing activity for IL-2 using a validated cell-based assay. A 
risk-based approach to evaluate and mitigate immune responses to or adverse immunologically 
related responses associated with bempegaldesleukin that affect its safety and efficacy would be 
adopted as per the 2014 FDA guidance (FDA 2014). 


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Blood samples designated for assessments (eg, PK, immunogenicity, serology, immune 
profiling) from the same collection time point may be used interchangeably for analyses, if 
required (eg, insufficient volume for complete assessment). 
For all PK and ADA blood samples, the date and actual time collected must be recorded. For 
patients 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. 
5.11 
Biomarkers 
Section 1.2 provides the biomarker sampling schedule, which includes samples for assessment of 
absolute lymphocyte counts, immune cell profiling, including profiling of SARS-CoV-2 specific 
T cells, assessment of cytokines, SARS-CoV-2 serology, sequencing of RNA/DNA (including 
whole genome sequencing of germline DNA, T and B cell receptor sequencing, and HLA 
haplotyping), and detection of SARS-CoV-2 nucleic acid in upper respiratory specimens. Further 
details of sample collection, processing, and shipment will be provided in the Laboratory 
Manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.12 
Prior and Concomitant Medications 
All medications (prescription and over the counter [OTC]), vitamin and mineral supplements, 
and/or herbs taken by the patient from Screening through the Safety Follow-Up call will be 
documented and recorded, including start and stop date, dose and route of administration, 
frequency, and indication. Medications taken for a procedure (eg, venipuncture) or prophylaxis 
of an infusion-related reaction should also be included. 
Details regarding IV hydration will be recorded in the EDC. 


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5.12.1 
Prophylaxis and Management of Symptoms Related to Immediate 
Infusion-Related Reactions (including Flu-Like Symptoms and Hypersensitivity 
Events) 
Prophylactic treatment with a nonsteroidal anti-inflammatory, antipyretic, and antihistamine 
medications for flu-like symptoms and hypersensitivity events (eg, rash and/or pruritis), 
respectively, is recommended prior to bempegaldesleukin infusion at the discretion of the 
Investigator. 
For post-infusion, flu-like symptoms and hypersensitivity events, treatment with nonsteroidal 
anti-inflammatory, antipyretic, and antihistamine medications may continue at the Investigator’s 
discretion to manage the patient’s symptoms. Additional treatment measures may be 
administered based on local treatment standards and guidelines, see Section 5.6.2. 
5.12.2 
Permitted Concomitant Medications 
5.12.2.1 
COVID-19 Treatment 
Patients are permitted to receive any agent to treat COVID-19 (eg, antivirals) except for 
investigational agents or investigational devices within 28 days of enrollment and throughout the 
course of the study, except if the patient’s condition has worsened to moderate, severe, or critical 
per the Investigator (see Section 4.2). 
5.12.2.2 
Antihypertensive Medications 
Consideration should be given to temporarily withholding antihypertensive medications 
including diuretics, as well as other drugs with hypotensive properties (eg, alpha blockers for 
benign prostatic hypertrophy), to minimize the risk of hypotensive events following 
administration of bempegaldesleukin. However, the discovery that COVID-19 binds to the 
ACE-2 receptor to gain entrance into cells highlights the potential role of the renin-angiotensin 
system (RAS) in the infectious process. Abrupt withdrawal of RAS inhibitors in high-risk 
patients, including those who have heart failure or have had myocardial infarction, may result in 
clinical instability. While other antihypertensive therapy may be temporarily suspended for 
bempegaldesleukin administration, until further data are available it may be in the best interest of 
the patient to continue ACE inhibitors and angiotensin II receptor blockers (ARB). Study 
patients who are on medications such as beta-blockers, alpha blockers, calcium channel blockers, 
and nitrates should be able to temporarily discontinue these drugs. If withholding 
antihypertensive medications, withhold no less than 12 hours and no more than 48 hours prior to 
study drug administration. Antihypertensive medications may be reinstituted at any time as 
clinically indicated (eg, based on blood pressure monitoring result) (refer to Section 5.5.4.2). 
5.12.2.3 
Other Supportive and Palliative Care 
Supportive and palliative medications used to treat symptoms of COVID-19 are allowed per 
institutional guidelines. Vaccination with inactivated viruses is permitted consistent with the 
institutional guidelines. Allow appropriate time interval between the most recent study treatment 


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administration and the next date of study treatment. If the patient experiences side effects after 
the flu vaccine or another inactivated vaccine, please manage study treatment administration per 
protocol guideline. 
5.12.3 
Effect of Bempegaldesleukin on the PK of Concomitant Medications 
At the dose levels proposed for patients with COVID-19, bempegaldesleukin is expected to 
cause mild increases in circulating cytokines, some of which are known to have the potential to 
decrease the activity of multiple enzymes (CYP enzymes, hepatic flavin monooxygenases, 
UDP-glucuronosyltransferases, sulfotransferases, and glutathione S-transferases) and drug 
transporters, and the suppressive effects can be additive (Haas 2005; Zidek 2009). The increases 
in circulating cytokines generally occur from day 3 to day 7 postdose, coinciding with the 
pharmacokinetic time course of bempegaldesleukin-related active cytokines (NKTR-214-AC). 
Consequently, treatment with bempegaldesleukin may lead to decrease in clearance of drugs that 
are substrates of these Phase I and Phase II drug metabolizing enzymes, or drug transporters 
from days 3 to 7 postdose. Several of the symptomatic or off-label treatments for COVID-19 
have the potential to be subject to drug interactions. The magnitude of potential drug-interactions 
with bempegaldesleukin is unknown. Doses of drugs with narrow therapeutic index, including 
but not limited to chloroquine, and hydroxychloroquine, should be withheld from days 3 to 7 
after administration of bempegaldesleukin. No pharmacokinetic drug interactions are expected 
with immunomodulatory treatments, including tocilizumab, sarilumab, and anakinra. 
Tocilizumab has been co-administered with bempegaldesleukin in studies 15-214-01 (2/28 [7%]) 
and 16-214-02 (3/541 [0.55%] patients), and corticosteroids have been co-administered with 
bempegaldesleukin in studies 15 214-01 (13/28 [36%] patients) and 16-214-02 (233/541 [43%] 
patients without definitive evidence of drug interactions. Consistent with guidance for 
remdesivir, hepatic laboratory testing should be performed prior to starting remdesivir and daily 
while receiving remdesivir. Close monitoring for known adverse reactions of azithromycin, such 
as liver enzyme abnormalities and hearing impairment, is warranted between Days 3 and Days 7 
after bempegaldesleukin. Dose, timing, and duration of treatment for co-administered drugs for 
symptomatic or off-label treatment of COVID-19 must be recorded. 
5.13 
Adverse Events 
All AEs, either reported by the patient or observed by study staff, will be reported from the time 
of first study drug(s) administration until 30 days after the last dose of study drug as described in 
Section 7.2. 
5.14 
Blinding 
The Investigator, the patients, and all study site and Nektar personnel involved in study activities 
other than those involved in dispensing the study drugs must remain blinded to each patient’s 
treatment assignment.  
In circumstances when knowledge about the study drug received is required to adequately 
manage serious side effects or AEs experienced by the patient, for expedited reporting of SAEs 


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to the regulatory authorities or evaluation of severe AEs per the stopping rules described in 
Section 5.6.2 it may be necessary to unblind a patient’s treatment regimen before all outcome 
assessments have been performed. If the Investigator believes that the study blind needs to be 
broken for a patient, the Investigator must contact the Nektar Medical Monitor. Unblinding will 
follow Nektar Therapeutics’ internal procedures for unblinding and associated documentation. If 
the blind is broken, details surrounding the breaking of the blind (eg, date, time, and reason) are 
to be recorded in the patient’s study file.  
Bempegaldesleukin will be supplied open label to the clinical site. 
An unblinded pharmacist not involved in any other aspect of the study conduct will be 
designated to manage and account for bempegaldesleukin, and to prepare the bempegaldesleukin 
or placebo dosing solution for blinded administration to each patient. The pharmacist will ensure 
that all other study personnel and patients remain blinded to treatment assignment. Study drug 
accountability for each dose cohort will also be performed by an unblinded monitor not 
otherwise associated with the day to day operational conduct of the study. 
In the course of DLT adjudication, if it is not possible to assess the protocol-defined DLT criteria 
(see Section 5.3.2.1.1), the CRC may review unblinded data in accordance with Nektar 
Therapeutics internal procedures for unblinding. Additionally, after 10 patients in a dose cohort 
have completed a 7-day observation period, if it is not possible to assess the protocol-defined 
DLT criteria for the entire cohort (see Section 5.3.2.1.1), the CRC may review unblinded data in 
accordance with Nektar Therapeutics internal procedures for unblinding to characterize the 
safety profile of bempegaldesleukin relative to placebo treatment to determine if dose escalation 
or de-escalation is warranted. 
Unblinding of patient treatment assignment will follow Nektar Therapeutics’ internal procedures 
for unblinding and associated documentation. 
5.15 
Method of Assigning Patients to Treatment Groups 
For each dose cohort, two sentinel patients who meet all screening and eligibility criteria will be 
assigned randomly in a 1:1 ratio on Day 1 to receive either bempegaldesleukin/SOC or 
placebo/SOC. Following CRC review of the blinded safety and tolerability data from the first 
72 hours after study drug administration for the 2 sentinel patients, the CRC will determine 
whether additional patients who meet all screening and eligibility criteria will be randomized in a 
1:1 ratio within the dose group. Study drug administration will be staggered by 72 hours for 
every 2 patients (1 bempegaldesleukin/SOC and 1 placebo/SOC) to allow for Medical Monitor 
review of the blinded safety and tolerability data before the next 2 patients are randomized. As 
stated in Section 5.3.1, patients who drop out of the study for reasons other than a DLT, before 
the DLT evaluation period (Days 1 to 7) has elapsed, may be replaced. Therefore, in each dose 
cohort, a maximum of 10 patients will complete the 7-day DLT evaluation period (ie, a total of 
5 patients who receive bempegaldesleukin/SOC and 5 patients who receive placebo/SOC). Study 


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drug assignment will occur in a blinded fashion in accordance with a computer-generated 
randomization scheme prepared by Nektar or its designee. 
Each patient will be assigned a unique patient number after signing the ICF. Patient numbers will 
be used on all patients’ study information. Patient numbers will not be reassigned. 
An Interactive Response Technology (IRT) will be employed to manage patient randomization. 
Nektar will supply bempegaldesleukin from a central source. Choice of standard of care for an 
individual patient will depend on what drug products are available at each medical center and the 
Investigator's choice. 


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6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS 
Table 12 provides the study treatments that will be administered in this study. 
Table 12: 
Study Treatments Administered  
Product Description 
Content 
Packaging / 
Appearance 
Storage Conditions 
(per label) 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1 
Bempegaldesleukin (NKTR-214)  
Bempegaldesleukin is the International Nonproprietary Name (INN) for NKTR-214. 
6.1.1 
Drug Description and Formulation 
 
 
 
 
 
 
 
 
6.1.2 
Drug Packaging and Labeling 
 
 
 


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Each vial will be labeled with the study drug number/name, strength, name of the Sponsor, 
storage condition, lot number, and the required cautionary statement. 
6.1.3 
Drug Reconstitution and Handling 
 
 
 
 
 
 
Refer to the Pharmacy Manual for detailed drug handling and administration information. 
6.1.4 
Drug Storage 
 
 
6.1.5 
Drug Shipment 
 
 Refer to the Pharmacy Manual for 
additional details for ordering drug supply. 
6.2 
Placebo: Preparation, Storage, and Packaging 
An unblinded pharmacist will prepare the placebo for infusion according to the instructions in 
the Pharmacy Manual. 
The placebo dosing solution will be obtained as commercially available 0.9% Sodium Chloride 
Solution for Injection (USP). 
6.3 
Standard of Care: Preparation, Storage, and Packaging 
Refer to the appropriate labeling requirements for details. 
6.4 
Study Drug Accountability and Reconciliation 
Bempegaldesleukin will be supplied to the Investigator by Nektar Therapeutics or its designee. 
Depending on local health authority guidelines and drug availability, the standard of care may be 
obtained through commercial supply, the site pharmacy, or through a central depository. 
Depending on source of supply per specific country requirements, the packaging and labeling 
may vary. Products will be labeled to meet local country requirements. Please refer to the 
Pharmacy Manual for detailed information. 


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Study drug supplies must be kept in an appropriate, secure, locked area and stored in accordance 
with the conditions specified on the labels. Depending on local health authority guidelines, IV 
fluids and associated supplies (IV administration sets, calibrated pumps) may be obtained 
through commercial supply, the site pharmacy, or through a central depository. 
The Investigator, pharmacist, or designee must maintain an accurate record of dispensing the 
study drug in a Drug Accountability Log, a copy of which must be given to Nektar Therapeutics. 
The Drug Accountability Log may record specifics to study drug dispensation such as: 
• Records of product delivery, inventory, temperature monitoring, destruction, and return as 
per Sponsor’s instructions. 
• Doses prepared, time prepared, doses dispensed. 
• Doses and/or vials destroyed. 
The Drug Accountability Log will be reviewed by the monitor during site visits and at the 
completion of the study. 


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7.0 
ASSESSMENT OF SAFETY 
7.1 
AE Definition and Assessment 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, at any dose, not necessarily related to the treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can also arise from any use of the drug and from any route of 
administration, formulation, dose, or overdose. This definition includes intercurrent illnesses or 
injuries, and exacerbation of preexisting conditions. Clinical laboratory, vital sign, or physical 
examination abnormalities will only be reported as AEs if they are deemed clinically significant 
by the Investigator (eg, associated with signs and symptoms, require treatment, or require follow-
up). 
An AE does not include: 
• Pre-existing diseases or conditions present or detected before start of study drug(s) 
administration that do not worsen or increase in severity or frequency after the administration 
of study drug(s). 
• Overdose of either study drug(s) or concomitant medication without any signs or symptoms. 
7.2 
Monitoring AEs 
All AEs will be assessed by the Investigator and recorded, including but not limited to, the 
following: the event term, the date of onset and resolution, seriousness, severity, relationship to 
study drug(s), outcome, treatment of the event, and action taken with the study drug(s). AEs will 
be reported starting immediately after the patient has been administered the first dose of study 
drug(s) until 30 days following the last dose of study drug(s). 
An event occurring after the patient has provided informed consent, but before the first dose of 
study treatment, will be collected as medical history unless the event is either new and attributed 
to protocol-mandated procedures by the Investigator or there is a significant change in the rate of 
occurrence or an increase in the severity of the pre-existing condition which is judged to be 
clinically important and attributed to the protocol-mandated procedures by the Investigator. 
Under the latter 2 circumstances, the event will be considered an AE and will be captured as 
such. 
• Example 1: Thrombophlebitis associated with a blood draw for assessments required prior to 
dosing per protocol is an event that is related to protocol-mandated procedures. In this 
scenario, the event of “thrombophlebitis” will be captured as an AE, and it will be 
documented as being “unrelated” to study drug(s), as applicable. 


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• Example 2: An ankle sprain following an unexpected fall from a flight of stairs while at 
home, after the patient has provided informed consent, but before the first dose of study 
drug(s), is clearly unrelated to any protocol-mandated procedures and would therefore be 
captured as medical history. 
7.3 
Grading of AEs 
The severity of an event and the seriousness are not to be considered synonymous. The severity 
is grading the intensity of an event. The seriousness of event is based on the patient/event 
outcome or action criteria. All AEs, except for cytokine release syndrome, will be assessed for 
severity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 guidelines. For cytokine release syndrome, the modified CTCAE 
CRS grading scale should be used to assess severity (see Appendix 3). If a particular AE is not 
listed in the NCI CTCAE, the following criteria will be used: 
• Grade 1 = Mild (event results in mild or transient discomfort, not requiring or needing only 
minimal intervention or treatment; does not limit or interfere with daily activities [eg, 
insomnia, mild headache]). 
• Grade 2 = Moderate (event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment [eg, fever requiring antipyretic medication]). 
• Grade 3 = Severe (event results in significant symptoms that prevent normal daily activities; 
may require hospitalization or invasive intervention). 
• Grade 4 = Life threatening or disabling. 
• Grade 5 = Death. 
AEs will be reported with an individual start and stop date for each level of severity. 
7.4 
Causality Relationship of AEs 
The relationship of each AE to each study drug (bempegaldesleukin or placebo) as applicable 
will be evaluated by the Investigator using the following definitions: 
• Not related: An AE that does not follow a reasonable temporal sequence from administration 
of study drug(s), and/or that can be reasonably explained by other factors such as the 
patient’s medical history, preexisting medical condition, underlying disease, concurrent 
illness, or concomitant medications/therapies. 
• Related: There is a reasonable possibility that the AE is caused by the study drug(s). A 
plausible temporal sequence exists between the time of administration of the study drug(s) 
and the development of the AE, or follows a known pattern to the study drug(s). The AE 
cannot be reasonably explained by the known characteristics of the patient’s clinical state or 
other concomitant therapies or interventions administered to the patient. 


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7.5 
AE Reporting and Follow-up 
After initiation of study drug treatment, all AEs will be reported from the time of first study 
drug(s) administration until 30 days of last dose of study drug(s). For SAEs, additional reporting 
requirements also apply (see Section 7.7). 
All ongoing AEs will be followed until resolution, the patient is lost to follow-up, patient death, 
or until the Safety Follow-Up call, whichever is earlier. In case the AE has not completely 
resolved by the Safety Follow-Up call, the final outcome of these ongoing AEs that are not 
related to study drug will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable. Any ongoing AEs at the Safety Follow-up call 
that are considered related to study drug will be followed until the event is resolved (with or 
without sequelae) or deemed stable. Any new AEs occurring after the Safety Follow-Up call will 
not be captured unless related to a study drug. 
For specific instructions on identifying and reporting SAEs, see Sections 7.6 and 7.7. 
7.6 
Serious AE Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life threatening, ie, in the opinion of the Investigator, the AE places the patient at 
immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a patient’s participation in a clinical study. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed above. 
Death is an outcome of an AE and not an AE in itself. All events leading to death, regardless of 
causality, must be reported. An efficacy failure is not considered an SAE. “Life-threatening” 
means that the patient was at immediate risk of death from the event as it occurred. This does not 
include an event that might have led to death if it had occurred with greater severity. “Inpatient 
hospitalization” means the patient has been admitted to a hospital for medical reasons for any 
length of time. The Investigator should attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms. 


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7.7 
Serious AE Reporting 
Serious AEs occurring after the patient has provided informed consent, but before the first dose 
of study treatment, will be collected as medical history unless the event is either new and 
attributed to protocol-mandated procedures by the Investigator or there is a significant change in 
the rate of occurrence or an increase in the severity of the pre-existing condition which is judged 
to be clinically important and attributed to the protocol-mandated procedures by the Investigator. 
Any new or clinically significant changes in the patient’s medical that occur after the first dose 
of drug and meet the SAE criteria will be recorded as SAEs. 
All SAEs, regardless of causality, with an onset within 30 days after the last dose of study 
drug(s) will be reported to Nektar Therapeutics Drug Safety immediately without undue delay, 
under no circumstances later than 24 hours following knowledge of the event. 
In addition, SAEs that are assessed by the Investigator as related to study drug(s) and occurring 
after the SAE reporting period will also be reported to Nektar Therapeutics Drug Safety 
immediately without undue delay, under no circumstances later than 24 hours following 
knowledge of the event. 
SAEs must be reported to Nektar Therapeutics Drug Safety via email or Fax as listed at the 
beginning of this protocol. Nektar Therapeutics may transition to reporting of SAEs via EDC 
while the study is ongoing. If this occurs, all sites will receive documented instructions regarding 
how to enter SAEs into EDC. If the study were to transition to reporting of SAEs in EDC, sites 
would continue to submit SAEs via email or Safety Fax as a backup system should there be EDC 
system access issues. 
The Investigator must complete the SAE Report Form, assess the causality relationship to the 
study treatment as applicable, and send the completed SAE form via email or fax to Nektar 
Therapeutics Drug Safety. A follow-up report and any additional records (such as hospital 
records, consultant reports, and autopsy findings) will be emailed or faxed to Nektar 
Therapeutics Drug Safety immediately without undue delay, under no circumstances later than 
24 hours following knowledge of the follow-up information. Any medication or other therapeutic 
measures used to treat the event will be recorded. 
All SAEs will be followed as described in Section 7.8. 
Reporting of SAEs to the IRB/IEC will be done in accordance with the standard operating 
procedures (SOPs) and policies of the IRB/IEC. Adequate documentation must be provided to 
Nektar Therapeutics showing that the IRB/IEC was properly notified. Serious AEs will be 
reported by Nektar Therapeutics or designee to the Regulatory Authorities per local regulations. 


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7.8 
Serious AE Follow-up 
All study treatment-related SAEs that have not resolved by the Safety Follow-Up call will be 
followed until any of the following occur (whichever comes first): 
• The event resolves. 
• The event has stabilized. 
• The event returns to baseline, if a baseline value is available. 
• It is unlikely that any additional information can be obtained (eg, patient or health care 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
• The patient dies or is lost to follow-up. 
All ongoing SAEs will be followed until resolution or until the Safety Follow-Up call, whichever 
is earlier. In the case where an SAE has not completely resolved by the Safety Follow-Up call, 
the final outcome of these ongoing SAEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable. 
7.9 
Adverse Events of Special Interest 
Cytokine release syndrome (CRS) is considered an “adverse event of special interest” (AESI) 
and should be assessed for seriousness using the standard seriousness definition. However, all 
CRS events are required to follow the process and timeline for SAE reporting (within 24 hours as 
described in Section 7.7) from the sites to Nektar Drug Safety: pharmacovigilance@nektar.com. 
Grading criteria for CRS are provided in Appendix 3. 
7.10 
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 (DILI) event. All occurrences 
of potential DILIs, meeting the defined criteria, must be reported as SAEs (see Section 7.7 for 
reporting details). A potential DILI is defined as: 
• Treatment-emergent ALT or AST > 3 times ULN. 
AND 
• Total bilirubin > 2 times ULN or clinical jaundice, without initial findings of cholestasis (eg, 
elevated serum alkaline phosphatase > 2 times ULN). 
AND 
• No other immediately apparent possible causes of elevated liver enzymes and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 


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7.11 
Pregnancy Tests/Pregnancy 
7.11.1 
Pregnancy Tests 
Serum or urine pregnancy tests will be performed on WOCBP according to the Schedule of 
Events (Section 1.2). Urine pregnancy tests should have a minimum sensitivity of 25 IU/L or 
equivalent units of HCG. A negative pregnancy test result must be obtained before the 
administration of the study drug(s) and on the day of hospital discharge. 
A pregnancy test does not need to be performed on women who are postmenopausal (see 
Appendix 2) for at least 1 year or surgically sterile for at least 3 months before signing the ICF. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. Requirements for reporting a pregnancy are provided in Section 7.11.2. 
If, for whatever reason, the pregnancy has ended, confirmed by a negative serum pregnancy test, 
treatment may be resumed at the discretion of the Investigator (at least 3 weeks and not greater 
than 6 weeks after the pregnancy has ended) following approvals of the patient/IRB/EC, as 
applicable. 
7.11.2 
Pregnancy 
7.11.2.1 
Pregnancies in Female Patients 
The Sponsor must be notified immediately without undue delay, under no circumstances later 
than 24 hours following knowledge of the initial report and any follow-up reports of a female 
patient becoming pregnant during the course of the study. All reports should be submitted via the 
Pregnancy Notification Form. Pregnancy, although reportable, is not considered an AE/SAE 
unless a female patient experiences signs or symptoms of pregnancy complications; however, the 
contact information for pregnancy reporting is the same as for SAE reporting and listed in 
Section 7.7. Female patient(s) who become pregnant will be followed until the outcome of the 
pregnancy is known. Pregnancy follow-up should describe the outcome of the pregnancy, 
including any voluntary or spontaneous termination, details of the birth, and the presence or 
absence of any congenital abnormalities or birth defects in the offspring. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. 
7.12 
Clinical Laboratory Tests 
Clinical laboratory tests will be conducted at both a local laboratory and central laboratory 
according to the Schedule of Events (Section 1.2). A list of the clinical laboratory analytes to be 
tested is provided in Appendix 1. Local lab samples should be collected according to the 
Schedule of Events and the local lab will perform the tests listed in Appendix 1A. Central lab 
samples should be collected according to the Schedule of Events and the central lab will perform 


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the tests listed in Appendix 1B. All blood samples collected for central lab processing will be 
collected and sent to the central laboratory on the day of collection unless otherwise instructed. 
For enrollment, if the central laboratory tests are cancelled, lost, unavailable, or considered 
inadequate for analysis, the site may forward an identical set of local laboratory results for 
eligibility review (with central laboratory testing repeated prior to the first dose of study drug). If 
local laboratory results are determined to be acceptable during eligibility review, enrollment may 
proceed. 
Clinical laboratory test data will be reviewed by the Investigator or Sub-Investigator. Additional 
clinical laboratory tests may be ordered at the Investigator’s or Sub-Investigator’s discretion. 
The Investigator or Sub-Investigator will review all laboratory results for clinical significance. 
Any laboratory result deemed clinically significant (ie, is associated with signs and symptoms, 
requires treatment, or requires follow up) will be recorded as an AE as described in Section 7.1. 
7.13 
Physical Examinations 
Physical examinations should be conducted according to the Schedule of Events (Section 1.2). 
Full physical examinations should be conducted at screening, and prior to dosing (evaluate all 
major organ systems, including the following categories: general, head, eyes, ears, mouth/throat, 
neck, heart, lungs, abdomen, lymph nodes, joints, extremities, integumentary, neurologic, and 
psychiatric). Other examinations may be targeted, at the discretion of the Investigator, to identify 
changes from baseline or evaluate changes based on the patient’s clinical symptoms. 
7.14 
Vital Signs 
Vital sign measurements will be recorded according to the Schedule of Events (Section 1.2). 
Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, oxygen 
saturation, and temperature. It is preferred that the same arm be used for all blood pressure 
readings, if possible. Weight is to be reported at screening and on the day of dosing, height at 
screening visit only. 
7.15 
Electrocardiograms 
All patients will have 12-lead electrocardiogram (ECG) done during Screening as specified in 
the Schedule of Events (Section 1.2). ECG data will be locally assessed. After enrollment, the 
frequency of ECGs may be increased if clinically indicated. 
7.16 
Cohort Review Committee 
A Cohort Review Committee (CRC) consisting of representatives from the Sponsor’s Clinical 
Development, Drug Safety, Biostatistics, and other functional representatives as needed, and at 
least one Principal Investigator will meet to review safety and tolerability data, review the safety 
profile in the first 72 hours after study drug administration in the sentinel patients at the 


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beginning of each cohort, adjudicate AEs reported as DLTs, make decisions about escalating or 
de-escalating the dose of bempegaldesleukin, and identify the RP2D. 


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8.0 
ASSESSMENT OF DISEASE MEASUREMENT 
8.1 
Disease Measurement Assessments 
Screening and follow-up assessments should be acquired as outlined in Section 1.2. 
8.1.1 
Measures of Clinical Support and Limitations 
The following measures of clinical support will be assessed at the first assessment of a given 
study day as outlined in Section 1.2: 
• Limitations of physical activity. 
• Hospitalization status (yes versus no). 
• Oxygen requirement by mask or nasal prongs. 
• Oxygen by non-invasive ventilation or high-flow. 
• Intubation and mechanical ventilation requirement. 
• ECMO requirement. 
 
8.1.2 
WHO Clinical Progression Scale 
Table 13 provides the WHO Clinical Progression Scale, an 11-point clinical status ordinal scale, 
which will be used to measure COVID-19 clinical status and resource use over the course of the 
study (WHO 2020). The scale is an assessment of the clinical status at the first assessment of a 
given study day. 
Table 13: 
WHO Clinical Progression Scale 
 
Patient state 
Descriptor 
Score 
Uninfected 
Uninfected; no viral RNA detected 
0 
Ambulatory mild 
disease 
Asymptomatic; viral RNA detected 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Hospitalized:  
Moderate disease 
Hospitalized, no oxygen therapya 
4 
Hospitalized; oxygen by mask or nasal prongs 
5 
Hospitalized:  
Severe disease 
Hospitalized; oxygen by non-invasive ventilation or high-flow 
6 
Intubation and mechanical ventilation, PaO2/FiO2 ≥ 150 or SpO2/FiO2 ≥ 200 
7 
Mechanical ventilation, PaO2/FiO2 < 150 (SpO2/FiO2 < 200) or vasopressors 
8 
 
Mechanical ventilation, PaO2/FiO2 < 150 and vasopressors, dialysis, or ECMO 
9 
Dead 
Death 
10 
Abbreviations: ECMO = extracorporeal membrane oxygenation; FiO2  = fraction of inspired oxygen; PaO2 = partial pressure 
of arterial oxygen; SpO2 = oxygen saturation 
a. 
If hospitalized for isolation only, record status as for ambulatory patient. 
Source:  WHO 2020 


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8.2 
Other Assessment: Pharmacodynamic Measurement 
A complete blood count with differential will be obtained to measure absolute lymphocyte 
counts as outlined in Section 1.2. 


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9.0 
STATISTICAL PLAN 
9.1 
General Considerations 
In general, continuous data will be summarized by descriptive statistics, including number of 
patients, mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized by the number and percentage of patients. Unless otherwise specified, data will be 
summarized by treatment arm. 
All disease measurement endpoints will be analyzed using all the patients who are enrolled. All 
safety endpoints will be summarized using the Safety population. 
A detailed description of analysis methods will be provided in the statistical analysis plan (SAP). 
9.2 
Determination of Sample Size 
This Phase 1b study will assess the safety and tolerability of different doses of 
bempegaldesleukin. No formal sample size calculation is done. Around 10 patients per dose 
cohort with a 1:1 randomization ratio (5 bempegaldesleukin/SOC and 5 placebo/SOC) to 
bempegaldesleukin/SOC or placebo/SOC will be enrolled. 
9.3 
Analysis Sets 
For the purpose of analysis, the following populations are defined: 
Population 
Description 
Safety Population  
All patients who receive at least 1 dose (or partial dose) of study drug. 
Pharmacokinetic Population  
All patients in the Safety Population who have evaluable 
concentration-time profiles that allow for computation of meaningful PK 
parameter values. 
 
9.4 
Demographics and Baseline Characteristics 
A descriptive summary of demographics and key baseline characteristics will be provided. 
Details will be included in the SAP. 
9.5 
Safety Analyses 
The safety analyses will be based on the Safety population. For patients who receive placebo, the 
safety data will be pooled. Treatment-emergent AEs (TEAEs) will be defined as AEs that occur 
on or after receiving the first dose of study drug. The frequency of TEAEs will be tabulated 
using the Medical Dictionary for Regulatory Activities (MedDRA) by system organ class and 
preferred terms and treatment. In addition, by patient listings will be provided for TEAEs and 
SAEs. 


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9.6 
Disease Measurement Analyses 
Disease measurement analyses will be based on the Safety population.  
The percentage of patients who require supplemental oxygen will be summarized by treatment 
group. The mean change from baseline in the WHO Clinical Progression Scale will be 
summarized by treatment group; changes to the analysis of this endpoint may be made in the 
SAP prior to database lock and unblinding of patient treatment assignment once more 
information is obtained about the clinical meaning and interpretation of the WHO Clinical 
Progression Scale (see Table 13). 
9.7.1 
Pharmacodynamics 
The fold change from baseline at each evaluation time and the maximum fold change of absolute 
lymphocyte counts will be summarized descriptively by treatment group and a data listing will 
be provided. Changes to these pharmacodynamic endpoints may be made in the SAP prior to 
database lock and unblinding of patient treatment assignment. 
9.7.2 
Pharmacokinetics 
Pharmacokinetic parameters such as Cmax, time to Cmax (Tmax), and AUC will be estimated from 
plasma concentration-time data where possible. Pharmacokinetic parameters will be tabulated 
and summarized with descriptive statistics. Pharmacokinetic data obtained in this study may also 
be combined with data from other studies in the clinical development for the purpose of 
population PK modeling. These models may be used to evaluate the effects of intrinsic and 
extrinsic covariates on the PK of bempegaldesleukin. 


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10.0 
STUDY OR STUDY SITE TERMINATION 
The Sponsor has the right to suspend or terminate the study or part of the study at any time for 
any reason. 
If an Investigator suspends or terminates their study site, the Investigator will promptly inform 
the Sponsor and the IRB/IEC and provide them with a detailed written explanation. Upon study 
completion, the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency with final 
reports and summaries as required by regulations. 


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11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Subject to Institutional or other restrictions imposed as a consequence of the COVID-19 
pandemic, the Sponsor will implement and maintain quality control and quality assurance 
procedures with written SOPs to ensure that the study is conducted and data are generated, 
documented, and reported in compliance with the protocol, Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
11.1 
Changes to the Protocol 
The Investigator may not deviate from the protocol without express permission from the Medical 
Monitor or a formal protocol amendment having been established and approved by an 
appropriate IRB/IEC, except when necessary to eliminate immediate hazards to the patient or 
when the change(s) involve only logistical or administrative aspects of the study. Any deviation 
may result in the patient having to be withdrawn from the study and rendering that patient 
nonevaluable. All protocol deviations and the reasons for such deviations are to be documented 
in the source documents and reported to the Sponsor. 
11.2 
Monitoring 
In accordance with Code of Federal Regulations 21 CFR 312.56, International Council on 
Harmonisation (ICH) GCP, and local regulations, the clinical monitor will periodically inspect 
all electronic case report forms (eCRFs), study documents, research facilities, and clinical 
laboratory facilities associated with this study at mutually convenient times during and after 
completion of the study. As required by 21 CFR 312 Subpart D (Responsibilities of Sponsors 
and Investigators), ICH GCP, and local regulations, the monitoring visits provide the Sponsor 
with the opportunity to evaluate the progress of the study; verify the accuracy and completeness 
of eCRFs; ensure that all protocol requirements, applicable FDA, ICH GCP, and local 
regulations, and Investigator’s obligations are being fulfilled; and resolve any inconsistencies in 
the study records. This includes inspection of all documents and records that are required to be 
maintained by the Investigator, including but not limited to medical records (office, clinic, or 
hospital) for the patients in this study. The names and identities of all research patients will be 
kept in strict confidence and will not appear on eCRFs or other records provided to or retained 
by the Sponsor. The Investigational New Drug Application (IND) regulations and ICH E6 
guidelines also require the Investigator to allow authorized representatives of the Sponsor, 
IRB/IEC, FDA, and other relevant regulatory authorities direct access to study source records, 
and to inspect and make copies of the same records. The names and identities of the patients 
need not be divulged to the Sponsor; however, the records must nevertheless be available to be 
inspected for review. This can be accomplished by blacking out the patient’s name and replacing 
the name with the patient’s study identification number. If these requirements are in conflict with 
local regulatory restrictions or institutional requirements, the Investigator must inform the 
Sponsor of these restrictions before initiation of the study. 


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11.3 
Direct Access to Source Data/Documents for Audits and Inspections 
Members of the Sponsor or designees may conduct monitoring and auditing activities of a 
clinical site at any time during or after completion of the study. The Investigator will be 
informed of such activities. 
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives, 
may also conduct an inspection or perform an audit of the study. The 
Investigator(s)/institution(s) will permit trial-related audits, IRB/IEC review, and regulatory 
inspection(s) by providing direct access to source data/documents and study records. If informed 
of such an inspection, the Investigator should notify the Sponsor immediately. The Investigator 
will ensure that the inspectors and auditors have access to the clinical supplies, study site 
facilities, and laboratory, and that all data (including original source documentation) and all 
study files are available, if requested. 


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12.0 
ETHICAL CONSIDERATIONS 
This study will be conducted to be consistent with the principles that have their origin in 
Declaration of Helsinki and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, and 
312), with the current ICH GCP guidelines (ICH E6), as well as with any applicable regulatory 
authority, federal, state, and/or local laws and regulations. 
12.1 
IRB/IEC Approval 
Before enrollment of patients into the study, as required by FDA regulations (21 CFR § 56), ICH 
GCP, applicable regulatory authority requirements, and local regulations, the current protocol 
and ICF will be reviewed and approved by an appropriate IRB or IEC. A letter documenting the 
IRB or IEC approval must be received by the Sponsor before the initiation of the study at a 
clinical site. Amendments to the protocol will be subject to the same requirements as the original 
protocol. 
The Investigator, Sponsor, or designee will submit a progress report at least once yearly to the 
IRB or IEC. However, the frequency of these reports will depend on IRB or IEC requirements. 
As soon as possible after completion or termination of the study, the Investigator will submit a 
final report to the IRB or IEC per the IRB or IEC requirements, and in compliance with FDA 
regulations, applicable regulatory authority requirements, and ICH GCPs. 
The Investigator, the Sponsor, or designee shall notify the IRB or IEC of any SAEs, suspected 
unexpected serious adverse reactions (SUSARs), or any other information that may affect the 
safe use of the study drug(s) during the study, per the IRB or IEC local requirements, and in 
compliance with FDA regulations, country and local regulatory authority regulations, and ICH 
GCPs. 
12.2 
Written Informed Consent 
Written documentation of informed consent must be obtained from each patient or (if permitted 
by the local health authority) a patient’s legal representative before entering the study. Patients 
will be informed of the nature of the study, and the ICF must be presented to each patient in the 
language in which the patient is fluent. 
Informed consent will be obtained from and documented for each patient prior to the conduct of 
any protocol-specific procedures. Signed and dated ICFs will be retained by the Investigator with 
the study records. Each patient will be given a copy of the signed and dated ICF. 
Any pregnancy that occurs in a study patient should be reported to the Sponsor or designee. For 
the Sponsor or designee to collect any pregnancy surveillance information, the pregnant patient 
must sign an informed consent form for disclosure information. Information on this pregnancy 
will be collected on the Pregnancy Surveillance Form. 


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Some health agencies have permitted alternate methods of obtaining informed consent from 
COVID-19 patients. These methods are acceptable per this protocol if the method of obtaining 
and documented informed consent is written in advance by the site and agreed to by the 
IRB/IEC. 


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13.0 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Collection Instruments and Source Documents 
13.1.1 
Study Records 
During the study, the Investigator/institution should maintain adequate and accurate source 
documents and trial records that include all pertinent observations on each of the site’s trial 
patients. Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, and 
should be explained if necessary (eg, via an audit trail). The Investigator should ensure the 
accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs 
and in all required reports. The Investigator/institution should, at a minimum, maintain the trial 
documents as specified in Essential Documents for the Conduct of a Clinical Trial (ICH E6 
Section 8) and as required by the applicable regulatory requirement(s). The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
13.1.2 
Data Collection Instruments 
Data collection instruments (DCIs) (eg, eCRFs, electronic clinical outcomes assessments 
[eCOA], and/or paper forms) will be used in this study. These instruments are used to transmit 
the information collected during the performance of this study to the Sponsor or Sponsor’s 
designee and regulatory authorities. 
The Investigator must review the DCIs for completeness and accuracy and must approve all data, 
including any changes made. Furthermore, the Investigator retains full responsibility for the 
appropriateness and accuracy of all data collected in the DCIs. 
13.2 
Retention of Essential Documents 
For sites in the US: All records and documents pertaining to the study including, but not limited 
to, those outlined above will be maintained by the Investigator for a period of at least 2 years 
after FDA approval of the drug or at least 2 years after withdrawal of the IND under which this 
study was conducted, whichever is longer.  
For sites outside the US:  Essential documents should be retained until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the Investigator/institution when these documents no longer need to be retained. 


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To avoid any possible errors, the Investigator will contact the Sponsor before transferring or 
destroying any study records. The Investigator will also promptly notify the Sponsor in the event 
of accidental loss or destruction of any study records. 
13.3 
Confidentiality 
Patient confidentiality will be maintained per local legal and regulatory requirements and 
applicable US federal regulations and ICH GCP guidelines. To comply with GCP guidelines and 
requirements, patient records will be reviewed during monitoring visits and audits conducted by 
the Sponsor, Sponsor's representatives, or health authorities. During these activities, every 
reasonable effort will be made to keep medical information, including patient identifying 
information, as confidential as possible as required by law. 
Study data given to, and used by, Nektar are protected by the use of a patient identification 
number. The assignment of unique patient identification number to each patient by Interactive 
Response Technology (IRT) system enables de-identification. 
Demographic identifiers that will be collected as part of Study Data include year of birth, age, 
gender, race, and ethnicity. Exact date of birth and patient name/initials are not collected. 
The study site is not to provide any personal data relating to the patient from Study Data that will 
be transferred to Nektar. Only the study site will be able to connect the patient identification 
number a patient’s personal data. 
13.4 
Security Measures 
Sites will employ both technical and organizational measures (such as, but not limited to, 
controlling access to personal patient data to only those with a need to know such data, data 
encryption, data anonymization and pseudonymization, and so forth) to ensure patient and 
patient data privacy. Sites will adhere to a “privacy by design” and “privacy by default” 
approach in collecting, storing, and processing personal patient data. 
In the event of a breach of the security measures used by the Site to ensure patient and patient 
data privacy, the Site will immediately notify the Sponsor. 


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14.0 
PUBLICATION PLAN 
All data are the property of the Sponsor. Any formal presentation or publication of data from this 
study will be considered for joint publication by the Sponsor personnel and Investigator(s). 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the clinical trial agreement governing participation in the study. Study data shared by 
Nektar will not contain patient identifiable information. 
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries. 


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15.0 
REFERENCES 
1. Bentebibel S-E, Hurwitz ME, Bernatchez C, et al. A first-in-human study and biomarker 
analysis of NKTR-214, a novel IL2Rαβ-biased cytokine, in patients with advanced or 
metastatic solid tumors. Cancer Discov. 2019;9:711-21. 
2. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): People 
who are at increased risk for severe illness. [Internet] US Department of Health and Human 
Services; [updated 11Sep2020a; cited 21Sep2020]. Available from: 
https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-
conditions.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F20
19-ncov%2Fneed-extra-precautions%2Fgroups-at-higher-risk.html. 
3. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): Interim 
Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19. 
[Internet] US Department of Health and Human Services; [updated 8Jul2020b; cited 
08Sep2020]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/lab/guidelines-
clinical-specimens.html. 
4. Charych DH, Rubas W, Dixit V, et al. Immune memory in nonclinical models after treatment 
with NKTR-214, an engineered cytokine biased towards expansion of CD8+ T cells in 
tumor. Poster presented at the Annual Meeting of the American Society of Clinical Oncology 
(ASCO); 3-7 Jun 2016; Chicago, IL. 
5. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with 
coronavirus disease 2019: retrospective study. BMJ 2020c;368:m1091. 
http://dx.doi.org/10.1136/bmj.m1091. 
6. Coomes EA and Haghbayan H. Interleukin-6 in COVID-19: A systematic review and meta-
analysis. 2020. medRxiv preprint doi: https://doi.org/10.1101/2020.03.30.20048058. 
7. Davila ML, Riviere I, Wang X, et al.  Efficacy and toxicity management of 19-28z CAR T 
cell therapy in B cell acute lymphoblastic leukemia.  Sci Transl Med. 2014 Feb 
19;6(224):224ra25. 
8. Diao B, Wang C, Tan Y, et al. Reduction and functional exhaustion of T cells in patients 
with coronavirus disease 2019 (COVID-19). Front Immunol. 2020;11: 827. doi: 
https://doi.org/10.3389/fimmu.2020.00827. 
9. Gralinski LE, Menachery VD. Return of the Coronavirus: 2019-nCoV. Viruses 
2020;12(2):135; https://doi.org/10.3390/v12020135. 
10. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. 
N Engl J Med. 2020;382:1708-20.  https://doi.org/10.1056/NEJMoa2002032. 
11. Haas CE, Nelsen JL. Drug-cytokine interactions. In Piscitelli SC, Rodvold KA, eds. Drug 
Interactions in Infectious Diseases. Human Press Inc, Totowa NJ, USA. 2005 pp 431-61. 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
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21 Sep 2020 
12. Han H, Ma Q, Li C, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and 
IL-10 are disease severity predictors. Emerging Microbe Infecti. 2020;9:1123-1130. 
DOI:10.1080/22221751.2020.1770129. 
13. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet. 2020;395:497-506. 
14. Kim ES, Chin BS, Kang CK, et al. Clinical Course and Outcomes of Patients with Severe 
Acute Respiratory Syndrome Coronavirus 2 Infection: a Preliminary Report of the First 28 
Patients from the Korean Cohort Study on COVID-19. J Korean Med Sci. 2020;35(13):e142. 
Published 2020 Apr 6. doi:10.3346/jkms.2020.35.e142 
15. Kujawski, S.A., Wong, K.K., Collins, J.P. et al. Clinical and virologic characteristics of the 
first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat 
Med 26, 861–868 (2020). https://doi.org/10.1038/s41591-020-0877-5. 
16. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of 
cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-95. 
17. Liu J, Lia S, Liu J. Longitudinal characteristics of lymphocyte responses and cytokine 
profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine. 
2020:55;102763. https://doi.org/10.1016/j.ebiom.2020.102763. 
18. Long Q-X, Tang X-J, Shi Q-L, et al. Clinical and immunological assessment of 
asymptomatic SARS-CoV-2 infections. Nature Med. 2020 Apr 29. 
https://doi.org/10.1038/s41591-020-0965-6. 
19. Ma C, Gu J, Hou P, et al.  Incidence, clinical characteristics and prognostic factor of patients 
with COVID-19: a systematic review and meta-analysis. 2020. medRxiv preprint doi: 
https://doi.org/10.1101/2020.03.17.20037572. 
20. Proleukin (aldesleukin) [package insert]. Germany: Boehringer Ingelheim Pharma; 2018. 
21. Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in 
Wuhan, China.  Clin Infect Diseases. 2020;ciaa248, https://doi.org/10.1093/cid/ciaa248. 
22. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. 
JAMA. 2020. doi:10.1001/jama.2020.6775. 
23. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without 
BRAF mutation. N Engl J Med.  2015;372:320-30. 
24. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID‑19 based on 
an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020. 
https://doi.org/10.1007/s00134-020-05991-x. 
25. Shi H, Wang W, Yin J, et al. The inhibition of IL-2/IL-2R gives rise to CD8+ T cell and 
lymphocyte decrease through JAK1-STAT5 in critical patients with COVID-19 pneumonia. 
Cell Death Dis. 2020;11:429. https://doi.org/10.1038/s41419-020-2636-4. 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
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26. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus Disease 2019 Case Surveillance 
- United States, January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep 2020;69:759–
65. DOI: http://dx.doi.org/10.15585/mmwr.mm6924e2 
27. Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a 
descriptive and predictive study. Sig Transduct Target Ther. 2020a;5(1):33. 
https://doi:10.1038/s41392-020-0148-4. 
28. Tan M, Liu Y, Zhou R, et al. Immunopathological characteristics of coronavirus disease 
2019 cases in Guangzhou, China. Immunology. 2020b; 160:261–68. 
29. Thevarajan I, Nguyen THO, Koutsakos M, et al. Breadth of concomitant immune responses 
prior to patient recovery: a case report of non-severe COVID-19. Nat Med. 2020: 
https://doi.org/10.1038/s41591-020-0819-2. 
30. Tian S, Chang Z, Wang Y, et al.  Clinical characteristics and reasons of different duration 
from onset to release from quarantine for patients with COVID-19 Outside Hubei province, 
China. 2020. medRxiv preprint doi: https://doi.org/10.1101/2020.03.21.20038778. 
31. US Food and Drug Administration. Immunogenicity Assessment for Therapeutic Protein 
Products Guidance for Industry FDA-2013-D-0092. [Internet]. Rockville, MD: US 
Department of Health and Human Services; August 2014 [cited 9 Sep 2020]. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/immunogenicity-assessment-therapeutic-protein-products. 
32. 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. [Internet]. Rockville, MD: US Department of Health and 
Human Services; January 2019 [cited 9 Sep 2020]. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/immunogenicity-testing-therapeutic-protein-products-developing-and-validating-
assays-anti-drug. 
33. US Food and Drug Administration. COVID-19: Developing Drugs and Biological Products 
for Treatment or Prevention Guidance for Industry. FDA-2020-D-1370. [Internet]. Rockville, 
MD: US Department of Health and Human Services; May 2020 [cited 7 Jul 2020]. Available 
from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-
developing-drugs-and-biological-products-treatment-or-prevention. 
34. Wang D, Hu B, Hu C, et al.  Clinical characteristics of 138 hospitalized patients with 2019 
novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020a;323(11):1061-69. 
doi:10.1001/jama.2020.1585. 
35. WHO Working Group on the Clinical Characterisation and Management of COVID-19 
infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet 
Infect Dis. 2020; https://doi.org/10.1016/S1473-3099(20)30483-7. 


Protocol No. 20-214-34 
 
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36. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From 
the Chinese Center for Disease Control and Prevention. JAMA 2020;323(13): 1239-42. 
37. Xu J, Zhao S, Teng T. Systematic comparison of two animal-to-human transmitted human 
coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses. 2020;12:244. 
doi:10.3390/v12020244. 
38. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-
CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. 
Lancet Resp Med. 2020a. Accessed at 
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30079-
5/fulltext#articleInformation, 23 April 2020. 
39. Yang Y, Shen C, Li J, et al. Plasma IP-10 and MCP-3 levels are highly associated with 
disease severity and predict the progression of COVID-19. J Allergy Clin Immunol 
2020b;146:119-27. 
40. Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-
19 patients.  Cell Mol Immunol. 2020;17:533-5. https://doi.org/10.1038/s41423-020-0402-2. 
41. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients 
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020. 
https://doi.org/10.1016/S0140-6736(20)30566-3. 
42. Zidek Z, Anzenbacher P, Kmoníčková E. Current status and challenges of cytokine 
pharmacology. Br J Pharmacol. 2009;157:342–36. 


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APPENDIX 1: 
CLINICAL LABORATORY TESTS 
Descriptions of the laboratory tests performed in this study and study drug dosing criteria are 
provided in the following appendices: 
• Appendix 1A: 
Local Laboratory Tests Performed in this Study 
• Appendix 1B: 
Central Laboratory Tests Performed in this Study 
 
 






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APPENDIX 2: 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTON 
DEFINITIONS 
Women 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: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, 
females under the age of 55 years must have a serum follicle-stimulating hormone, 
(FSH) level > 40 mIU/mL to confirm menopause. 
CONTRACEPTION GUIDANCE FOR FEMALE PATIENTS OF CHILDBEARING 
POTENTIAL 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as during study participation or 
2 weeks after the last dose of study drug, whichever is longer (Note:  local laws and regulations 
may require use of alternative and/or additional contraception methods). 


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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 
ovulationb  
• 
oral  
• 
intravaginal  
• 
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
oral  
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Hormonal methods of contraception including oral contraceptive pills containing a combination of estrogen 
and progesterone, vaginal ring, injectables, implants and intrauterine hormone-releasing system (IUS)c 
• 
Intrauterine device (IUD)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.  
• 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the patient. 
• 
It is not necessary to use any other method of contraception when complete abstinence is elected.  
• 
WOCBP patients who choose complete abstinence must continue to have pregnancy tests, as specified in 
Section 1.2.  
• 
Acceptable alternate methods of highly effective contraception must be discussed in the event that the 
WOCBP patients chooses to forego complete abstinence  
NOTES:  
a. Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients participating in 
clinical studies.  
b. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence 
that the investigational medical products 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 devices and intrauterine hormone releasing systems are acceptable methods of contraception in 
the absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not 
alter contraception effectiveness 
 


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Unacceptable Methods of Contraceptiona 
• 
Male or female condom with or without spermicide. Male and female condoms cannot be used 
simultaneously 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal Sponge with spermicide 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mechanism 
of action 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus). 
• 
Spermicide only 
• 
Lactation amenorrhea method (LAM) 
a. 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
CONTRACEPTION GUIDANCE FOR MALE PATIENTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the Investigator. 
• Male patients are required to use a condom for study duration and until end of relevant 
systemic exposure defined as during study participation or 2 weeks after the last dose of 
study drug, whichever is longer. 
• Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined during study participation 
or 2 weeks after the last dose of study drug, whichever is longer in the male patient. 
• Male patients with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during study participation or 2 weeks after the last dose of study drug, whichever is longer.  
• Refrain from donating sperm for the duration of study participation or 2 weeks after the last 
dose of study drug, whichever is longer. 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information is provided in Section 7.11.2. 


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APPENDIX 3: 
GRADING CRITERIA FOR CYTOKINE RELEASE SYNDROME 
Grade 
Description of Symptoms 
1 
Mild 
Not life-threatening, require only symptomatic treatment such as antipyretics and anti-emetics 
(eg, fever, nausea, fatigue, headache, myalgias, malaise) 
2 
Moderate 
Require and respond to moderate intervention: 
• 
Oxygen requirement < 40%, OR 
• 
Hypotension responsive to fluids, OR 
• 
Grade 2 organ toxicity (by CTCAE version 5) 
3 
Severe 
Require and respond to aggressive intervention: 
• 
Oxygen requirement ≥ 40%, OR 
• 
Hypotension requiring vasopressor support, OR 
• 
Grade 3 organ toxicity (by CTCAE version 5) 
4 
Life-threatening 
Life-threatening 
• 
Requirement for ventilator support OR 
• 
Grade 4 organ toxicity (by CTCAE version 5) 
5 
Fatal 
Death 
Source: Grading criteria modified from Lee 2014. 
 


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APPENDIX 4: 
BREAKTHROUGH DESIGNATION STATUS: MELANOMA 
Breakthrough therapy designation was granted on 29 July 2019 for bempegaldesleukin in 
combination with nivolumab for the treatment of patients with untreated unresectable or 
metastatic melanoma based on data from the melanoma cohort in Study 16-214-02 (PIVOT-02). 
More recent study results for the melanoma cohort with the data cut of 25 September 2019 
(18.6 months median follow-up) are consistent regarding the benefit/risk previously reported for 
this cohort in the breakthrough therapy designation application (12.7 months median follow-up). 
A continued deepening of the response to treatment with bempegaldesleukin plus nivolumab has 
been observed in this cohort as the median duration of follow-up has increased. 
The complete response rate of 34.2% (13/38) (95% CI 19.6%, 51.4%) based on the response 
evaluable population, or 31.7% (13/41) based on the intent-to-treat (ITT) population, at both 
12.7 months and 18.6 months of median follow-up, suggested a synergistic effect when these 
two agents are combined. In particular, of the patients showing responses (n=20), 65% (13/20) 
achieved a complete response. Median duration of response to bempegaldesleukin plus 
nivolumab at 18.6 months of follow-up has not been reached, consistent with prior trials that 
show responses to immunotherapy are durable. In addition, the median progression-free survival 
has not been reached. As a comparison, with a median follow-up of approximately 1 year, the 
complete response rate for nivolumab was 8.9% and the median progression-free survival was 
6.9 months (Robert 2015). It is noteworthy that median time to complete response for treatment 
with bempegaldesleukin plus nivolumab was only 7.9 months. The early achievement of the 
complete response rate of 34.2% and apparent durability with bempegaldesleukin plus 
nivolumab as first-line therapy in patients with locally advanced and metastatic melanoma 
appears to offer a substantial improvement over available therapies. These results stress the 
importance of the activation of the IL-2 receptor pathway as a fundamental component of human 
immunity and a continued role for IL-2 in cancer immunotherapy, and underscore the relevance 
of bempegaldesleukin in combination with checkpoint inhibitors. 
 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 105 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
APPENDIX 5: 
CLINICAL STUDIES OF BEMPEGALDESLEUKIN (NKTR-214) 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
Phase 1 Study 
CA045-010/ 
18-214-14 
1 site in Japan 
A Phase 1 Study to Evaluate 
Safety and Tolerability of 
NKTR-214 (BMS-986321) 
Administered in Combination 
with Nivolumab (BMS-
936558) in Advanced 
Malignant Tumors 
(Bristol Myers Squibb) 
To assess the safety and 
tolerability of 
bempegaldesleukin in 
combination with nivolumab 
in participants with advanced 
malignant tumors 
Patients aged 
≥ 20 years 
with 
advanced 
(metastatic 
and/or 
unresectable) 
malignant 
solid tumor 
Bempegaldesleukin 0.006 mg/kg q3w 
+ nivolumab 360 mg q3w 
6/3  
Completed 
Phase 1/2 Studies 
15-214-01 
(EXCEL)a 
(Part 1) 
1 site in US 
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 
(Nektar Therapeutics) 
To evaluate: 
• 
safety and tolerability, 
and define the MTD, of 
bempegaldesleukin 
• 
efficacy of 
bempegaldesleukin by 
assessing the ORR at the 
MTD or the dose below 
the MTD 
Patients with 
locally 
advanced or 
metastatic 
solid tumors 
Part 1 (dose escalation): 
Bempegaldesleukin Dose (mg/kg)
 
Schedule 
 
0.003  
q3w  
(n = 4) 
 
0.006  
q3w  
(n = 11) 
 
0.006  
q2w  
(n = 6) 
 
0.009 
q3w  
(n = 6) 
 
0.012  
q3w 
(n = 1) 
50/28 
Completeda 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 106 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
VB N-01 
Open Labelled First Human 
Dose Phase 1/2a Study to 
Evaluate Safety, Feasibility, 
Efficacy of Multiple Dosing 
With Individualised 
VB10.NEO and 
Bempegaldesleukin (NKTR-
214) Immunotherapy in 
Patients With Locally 
Advanced or Metastatic 
Melanoma, Non-small Cell 
Lung Cancer (NSCLC), Clear 
Renal Cell Carcinoma, 
Urothelial Cancer or 
Squamous Cell Carcinoma of 
Head and Neck, Who Did Not 
Reach Complete Responses 
With Current Standard of 
Care Immune Checkpoint 
Blockade. 
(Vaccibody) 
• 
To assess the 
safety/tolerability of 
multiple doses of 3 mg 
VB10.NEO 
immunotherapy and of 
multiple doses of 3 mg 
VB10.NEO 
immunotherapy in 
combination with 0.006 
mg/kg 
bempegaldesleukin 
(NKTR-214) 
• 
To determine the 
feasibility of VB10.NEO 
(overall process 
feasibility from biopsy, 
sequencing, neoepitope 
selection and vaccine 
manufacturing) 
Patients with 
locally 
advanced or 
metastatic 
solid tumors 
VB10.NEO, 3 mg VB10.NEO (DNA 
plasmid pUMVC4a -VB10.NEO; 
individualised VB10.NEO 
immunotherapy) with 3 vaccinations 
q3w during induction period, followed 
by maintenance period with 
vaccinations q4w for up to 1 year from 
first immunization (total of 14 
vaccinations). Intramuscular 
administration 
Bempegaldesleukin 0.006 mg/kg 
administered intravenously starting 
from Week 11 (Visit 8A or at any 
dosing visit up to week 34 [visit 14]) 
and for up to week 50 (up to 11 doses). 
The first 2 doses will be q3w interval 
and following doses q4w. 
50/4 
Ongoing 
(As of 27 March 2020 no 
patients have received 
bempegaldesleukin) 
B9991040 
A Phase1b/2 Study to 
Evaluate Safety and Clinical 
Activity of Avelumab in 
Combination with 
Bempegaldesleukin 
(NKTR-214) with or without 
Talazoparib or Enzalutamide 
in Participants with Locally 
Advanced or Metastatic Solid 
Tumors  
(Pfizer) 
• 
Phase 1b: 
• 
To assess the dose-
limiting toxicity (DLT) 
rate of avelumab in 
combination with 
bempegaldesleukin 
(NKTR-214) 
(Combination A) and 
talazoparib (Combination 
B) or enzalutamide 
(Combination C) in order 
to determine the 
recommended Phase 2 
Patients with 
locally 
advanced or 
metastatic 
squamous 
cell 
carcinoma of 
the head and 
neck  
Patients with 
metastatic 
castration-
resistant 
Combination A starting dose: 
800 mg avelumab IV q2w + 0.006 
mg/kg bempegaldesleukin IV q2w 
Combination B starting dose: 
800 mg avelumab IV q2w +  
0.003 or 0.006 mg/kg 
bempegaldesleukin IV q2w (depending 
on dose established in combination A) 
+ talazoparib PO 1 mg once daily 
Combination C starting dose: 
800 mg avelumab IV q2w +  
0.003 or 0.006 mg/kg 
160/2 (as of 27 March 
2020) 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 107 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
dose (RP2D) for the 
combinations. 
Phase 2: 
• 
Combination A: To 
assess ORR of avelumab 
in combination with 
bempegaldesleukin 
(NKTR-214) in 
participants with locally 
recurrent or metastatic 
SCCHN.  
• 
Combination B: To 
assess soft tissue ORR of 
avelumab in combination 
with bempegaldesleukin 
(NKTR-214) and 
talazoparib in participants 
with DDR defect positive 
mCRPC 
• 
Combination C: To 
assess the PSA response 
rate of avelumab in 
combination with 
bempegaldesleukin 
(NKTR-214) and 
enzalutamide in 
participants with mCRPC 
after progression on 
abiraterone 
prostate 
cancer 
bempegaldesleukin IV q2w (depending 
on dose established in combination A) 
+ enzalutamide PO 160 mg once daily 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 108 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
16-214-02 
(PIVOT-02)b 
~75 sites: 
Part 1: US 
Part 2: US, 
Canada, UK, 
France, Spain, 
Australia, and 
Hong Kong 
Part 3: US 
Part 4: US 
A Phase 1/2, Open-label, 
Multicenter Study of the 
Combination of NKTR-214 
and Nivolumab or the 
Combination of NKTR-214, 
Nivolumab, and Other Anti-
Cancer Therapies in Patients 
with Select Locally Advanced 
or Metastatic Solid Tumor 
Malignanciesb 
(Nektar Therapeutics) 
• 
To evaluate the safety 
and tolerability, and 
define the MTD and/or 
RP2D of 
bempegaldesleukin in 
combination with 
nivolumab or in 
combination with 
nivolumab and other 
anti-cancer therapies 
• 
To evaluate the efficacy 
of bempegaldesleukin in 
combination with 
nivolumab or in 
combination with 
nivolumab and other anti-
cancer therapies by 
assessing the ORR by 
RECIST v1.1 at the 
RP2D 
Adults aged 
18 years and 
older with 
select locally 
advanced or 
metastatic 
solid tumor 
malignancies 
who have 
measurable 
disease. 
Melanoma, 
RCC, 
NSCLC, 
urothelial 
carcinoma, 
TNBC, 
hormone- 
receptor- 
positive 
breast cancer, 
gastric 
cancer, CRC, 
or SCLC. 
Part 1 (dose escalation) 
Bempegaldesleukin (mg/kg) + 
Nivolumab (mg) 
0.006 q3w + 240 q2w (n = 4) 
0.006 q2w + 240 q2w (n = 3) 
0.003 q2w + 240 q2w (n = 3) 
0.006 q3w + 360 q3w (n = 25) 
0.009 q3w + 360 q3w (n = 3) 
Part 1:  
50/38 Completedc 
Part 2 (RP2D):   
Bempegaldesleukin 0.006 mg/kg q3w 
+ nivolumab 360 mg q3w  
Part 2:  
936/476 
Ongoingc 
Part 3 (Schedule finding for triplet 
combination) 
Bempegaldesleukin (mg/kg) + 
nivolumab (mg or mg/kg), + 
ipilimumab (mg/kg) 
0.006 q3w + 360 mg q3w + 1 q6w 
(n=10) 
0.006 q3w + 1 mg/kg × 4 doses q3w + 
3 q3w × 4 doses + maintenance 
0.006 q3w + 3 mg/kg × 4 doses q3w + 
ipilimumab 1 q3w × 4 doses + 
maintenance 
Maintenance dose: bempegaldesleukin 
0.006 mg/kg + nivolumab 360 mg q3w. 
Part 3: 
36/24  
Ongoingc 
Part 4 (RP2D dose expansion for 
triplet combination):  
bempegaldesleukin 0.006 mg/kg q3w + 
nivolumab 360 mg + ipilimumab) 
Part 4:  
106/19  
Ongoingc 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 109 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
16-214-05 
(PROPEL)f 
~60 sites 
Dose 
Optimization: 
US 
Dose 
Expansion:  
US, Australia, 
France, 
Germany, 
Italy, Spain  
A Phase 1/2, Open-label, 
Multicenter Study to 
Investigate the Safety and 
Preliminary Efficacy of 
NKTR-214 in Combination 
with Pembrolizumab in 
Patients with Locally 
Advanced or Metastatic Solid 
Tumors 
(Nektar Therapeutics) 
Dose optimization cohorts:  
• To evaluate the safety and 
tolerability of 
bempegaldesleukin in 
combination with 
pembrolizumab  
• To define the MTD/RP2D 
and optimal dosing schedule 
of bempegaldesleukin in 
combination with 
pembrolizumab  
Dose expansion cohort:  
• To determine the ORR by 
RECIST 1.1 of 
bempegaldesleukin plus 
pembrolizumab in patients 
with untreated metastatic 
NSCLC 
Adults aged 
18 years and 
older with 
locally 
advanced or 
metastatic 
solid tumors  
Dose Optimization: 
Cohort 1a: 
Bempegaldesleukin 0.008 mg/kg 
(starting dose) + pembrolizumab per PI 
Cohort 1b: 
Bempegaldesleukin at previously 
tolerated dose + pembrolizumab per PI 
(determined by the SRC for step-up 
dosing schema); dose may increase at 
each cycle for individual patients 
(increments of 0.002 mg/kg) per dose 
optimization schema  
Dose Expansion: 
Bempegaldesleukin 0.006 mg/kg q3w 
(starting dose) + pembrolizumab per 
PI; additional patients may receive 
dose established by dose optimization 
cohorts. 
Dose Optimization: 
up to ~40/3 
 
Dose Expansion:  
~58/7g 
Ongoing 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 110 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
17-262-01 
(REVEAL) 
A Phase 1/2, open-label, 
multicenter, dose escalation 
and dose expansion study of 
NKTR-262 in combination 
with NKTR-214 and in 
combination with NKTR-214 
plus nivolumab in patients 
with locally advanced or 
metastatic solid tumor 
malignancies. 
(Nektar Therapeutics) 
• 
To evaluate the safety 
and tolerability, and 
define the maximum 
tolerated dose (MTD) or 
RP2D of NKTR-262 in 
combination with 
bempegaldesleukin 
(doublet) and the safety 
and tolerability of 
NKTR-262 and 
bempegaldesleukin plus 
nivolumab (triplet). 
• 
To evaluate the anti-
tumor activity of the 
combination of 
NKTR-262 plus 
bempegaldesleukin 
(doublet) and the 
combination of 
NKTR-262 and 
bempegaldesleukin plus 
nivolumab (triplet) by 
assessing the objective 
response rate (ORR) by 
RECIST 1.1.  
Patients with 
selected 
tumor types 
Phase 1: 
Part 1 (dose escalation, ongoing) 
Planned: NKTR-262 0.03 mg to1.92 
mg + bempegaldesleukin 0.006 mg/kg 
q3w (NKTR-262: 0.03 mg: n=3; 0.06 
mg: n=7; 0.12 mg: n=3; 0.24 mg: n=4; 
0.48 mg: n=4; 0.96 mg: n=4; 1.92 mg: 
n=3) 
 
NKTR-262 (escalating doses) + 
bempegaldesleukin 0.006 mg/kg q3w + 
nivolumab 360 mg q3w.  
 
Part 2 (RP2D, dose expansion): 
Cohorts A and B 
NKTR-262 RP2D + 
bempegaldesleukin 0.006 mg/kg q3w.  
NKTR-262 RP2D + 
bempegaldesleukin 0.006 mg/kg q3w + 
nivolumab 
 
Phase 2 
Doublet regimen: NKTR-262 RP2D + 
bempegaldesleukin 0.006 mg/kg q3w.  
Triplet regimen: NKTR-262 RP2D + 
NKTR‑214 0.006 mg/kg q3w + 
nivolumab 360 mg q3w. 
Phase 1: 48 
Phase 2: ~400 
36 enrolled as of 27 Mar 
2020 
Ongoing 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 111 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
Phase 2 Studies 
18-214-10/ 
CA045-012 
(PIVOT-10)h 
~100 
Global 
A Phase 2, single-arm study 
of bempegaldesleukin 
(NKTR-214) in combination 
with nivolumab in cisplatin 
ineligible, locally advanced or 
metastatic urothelial cancer 
patients 
(Nektar Therapeutics) 
To evaluate the anti-tumor 
activity of bempegaldesleukin 
(NKTR-214) in combination 
with nivolumab by assessing 
the ORR by RECIST v1.1 per 
BICR in patients whose 
tumors have low PD-L1 
expression 
Patients with 
locally 
advanced or 
metastatic 
urothelial 
cancer that 
are cisplatin 
ineligible and 
previously 
untreated 
Bempegaldesleukin 0.006 mg/kg and 
nivolumab 360 mg q3w  
190/129i 
Phase 3 Studies 
CA045-001/ 
17-214-08 
(PIVOT-IO-
001) 
130 sites 
US, Australia, 
New Zealand, 
Canada, 
France,  Italy  
A Phase 3, Randomized, 
Open-label Study of 
NKTR-214 Combined with 
Nivolumab Versus 
Nivolumab in Participants 
with Previously Untreated 
Unresectable or Metastatic 
Melanoma 
(Bristol Myers Squibb) 
• 
To compare the ORR 
using RECIST v1.1 of 
bempegaldesleukin 
combined with 
nivolumab and that of 
nivolumab monotherapy 
in participants with 
previously untreated 
unresectable or metastatic 
melanoma 
• 
To compare PFS using 
RECIST v1.1 of 
bempegaldesleukin 
combined with 
nivolumab and that of 
nivolumab monotherapy 
in participants with 
previously untreated 
unresectable or metastatic 
melanoma  
Adult and 
adolescent 
(≥12 years of 
age) 
participants 
with 
previously 
untreated 
unresectable 
or metastatic 
melanoma 
(AJCC stage 
III or stage 
IV). 
Arm A:  
Bempegaldesleukin 0.006 mg/kg 
q3w+nivolumab 360mg 
q3w(sequential) 
Arm B:  
Nivolumab 360 mg q3w 
764/258j 
Ongoing 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 112 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
• 
To compare OS of 
bempegaldesleukin 
combined with 
nivolumab and that of 
nivolumab monotherapy 
in participants with 
previously untreated 
unresectable or metastatic 
melanoma 
17-214-09/ 
CA045002 
(PIVOT-09)k 
~150 sites 
Global 
A Phase 3 Randomized Open 
Label Study to Compare 
NKTR-214 Combined with 
Nivolumab to the 
Investigator’s Choice of 
Sunitinib or Cabozantinib in 
Patients with Previously 
Untreated Advanced Renal 
Cell Carcinoma 
(Nektar Therapeutics) 
• 
To compare the ORR by 
BICR assessment using 
modified RECIST v1.1 of 
bempegaldesleukin 
(NKTR-214) combined 
with nivolumab to that of 
TKI monotherapy 
(sunitinib or 
cabozantinib) in IMDC 
intermediate- or poor-risk 
patients with previously 
untreated advanced RCC  
• 
To compare the ORR by 
BICR using mRECIST 
v1.1 of NKTR-214 
combined with 
nivolumab to that of TKI 
monotherapy (sunitinib or 
cabozantinib) in IMDC 
all-risk patients with 
previously untreated 
advanced RCC  
• 
To compare the OS of 
bempegaldesleukin 
combined with 
Patients aged 
18 years and 
older with 
advanced or 
metastatic, 
histologically 
confirmed 
RCC 
(advanced 
RCC) with a 
clear-cell 
component, 
who have not 
received 
prior therapy 
for the 
treatment of 
RCC. 
Arm A:  
Bempegaldesleukin 0.006 mg/kg q3w 
+ nivolumab 360 mg q3w  
Arm B:  
Investigator’s choice of either one of 
the following treatments:    
Sunitinib 50 mg orally (po) once daily 
for 4 weeks followed by 2 weeks off   
OR  
Cabozantinib 60 mg po once daily   
600/277l 
Ongoing 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 113 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Protocol ID 
Number of 
Study Sites 
and Location 
Protocol Title and Design 
(Sponsor) 
Primary Objective(s) 
Study 
Population 
Dosing Regimen 
Number of Patients 
Planned/Enrolled 
Status 
nivolumab to that of TKI 
monotherapy (sunitinib or 
cabozantinib) in IMDC 
intermediate- or poor-risk 
patients with previously 
untreated advanced RCC  
• 
To compare the OS of 
bempegaldesleukin 
combined with 
nivolumab to that of TKI 
monotherapy (sunitinib or 
cabozantinib) in IMDC 
all-risk patients with 
previously untreated 
advanced RCC 
CA045-009/ 
18-214-13 
(PIVOT-IO-
009) 
~ 120 sites 
 
A Phase 3, Randomized, 
Study of Neoadjuvant and 
Adjuvant Nivolumab Plus 
NKTR-214, Versus 
Nivolumab Alone Versus 
Standard of Care in 
Participants with Muscle-
Invasive Bladder Cancer 
(MIBC) Who Are Cisplatin 
Ineligible 
(Bristol Myers Squibb) 
• 
To compare the pCR rate 
of neoadjuvant 
nivolumab + NKTR-214 
to Standard of Care 
(SOC, no neoadjuvant 
therapy) in all 
randomized participants  
• 
To compare the EFS of 
neoadjuvant nivolumab + 
bempegaldesleukin 
followed by adjuvant 
nivolumab + 
bempegaldesleukin after 
radical cystectomy (RC) 
versus SOC (no 
neoadjuvant or adjuvant 
therapy) 
Patients, aged 
18 years or 
older with 
previously 
untreated 
MIBC who 
are cisplatin 
ineligible. 
Arm A:  
Bempegaldesleukin 0.006mg/kg q3w + 
nivolumab 360 mg q3w x 3 cycles as 
neoadjuvant therapy, followed by 
radical cystectomy, followed by 
bempegaldesleukin 0.006mg/kg q3w + 
nivolumab 360 mg q3w up to an 
additional 12 cycles (approximately 9 
months of adjuvant therapy). 
Arm B:  
Nivolumab 360 mg q3w x 3 cycles as 
neoadjuvant therapy, followed by 
radical cystectomy, followed by 
nivolumab 360 mg q3w up to an 
additional 12 cycles (approximately 9 
months of adjuvant therapy). 
Arm C: Standard of care (cystectomy 
alone, without neoadjuvant or adjuvant 
therapy) 
Approximately 720 
participants will be 
screened for 
approximately 540 
participants to be 
randomized /2m 
Ongoing 


Protocol No. 20-214-34 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 114 of 114 
Confidential and Proprietary 
 
21 Sep 2020 
Abbreviations: ~=approximately; AST= aspartate aminotransferase; BICR=blinded independent central review; CRC= colorectal cancer; 
ECG=electrocardiogram; EoA= end of administration; FDBK=FujiFilm UK; IMDC=International Metastatic Renal Cell Carcinoma Database Consortium; 
MIBC= muscle-invasive bladder cancer; MTD= maximum tolerated dose; NSCLC=non-small cell lung cancer; ORR= objective response rate; OS=overall 
survival; PD-L1=programmed cell death ligand 1; PFS=progression-free survival; PK=pharmacokinetic; q3w=every 3 weeks; RCC=renal cell carcinoma; 
RECIST= Response Evaluation Criteria in Solid Tumors; RP2D=recommended Phase 2 dose; SCLC= small cell lung cancer; SRC=Safety Review Committee; 
TKI=tyrosine kinase inhibitor; TNBC=triple-negative breast cancer; v1.1=version 1.1 
a. 
The planned Phase 2 dose expansion part of the study was not conducted, per Sponsor decision. Enrollment was discontinued after 28 patients were enrolled 
in the dose-escalation part of the study and the MTD determined to allow the clinical development program for bempegaldesleukin to continue with other 
studies in which NKTR-214 is administered in combination with checkpoint inhibitors. 
b. Based on Amendment 7.0. 
c. 
Study 15-214-02 (PIVOT-02) was closed to enrollment and screening on 22 January 2010; last patient enrolled on 29 January 2020.  
d. Based on mono-SPC level in Drug Substance Lot 1-PRO-0526 (46%), which constitutes 73% of Drug Product Lot 1-FIN-2590. 
e. 
Based on mono-SPC level in Drug Substance Lot 1-PRO-0783 (32%), which constitutes 72% of Drug Product Lot 1-FIN-2881. 
f. 
Based on Amendment 5.0, dated 20 August 2019. 
g. Enrollment as of 25 March 2020 
h. Based on Amendment 4.0, dated 06 February 2020. 
i. 
Enrollment as of 26 March 2020 
j. 
Enrollment as of 26 March 2020. 
k. Based on Amendment 2.0, dated 03 February 2020. 
l. 
Enrollment as of 26 March 2020 
m. Enrollment as of 26 March 2020 
 

SAP_001.pdf: 
Study No. 20-214-34 Statistical Analysis Plan 
 
bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 1 of 24 
Confidential and Proprietary 
 
09 Sep 2021 
 
 
Nektar Therapeutics 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Multicenter, Phase 1b, Randomized, Double-Blind, Placebo-Controlled Trial of the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Dose of Bempegaldesleukin 
(NKTR-214) Plus Standard of Care versus Placebo Plus Standard of Care in Adults with Mild 
COVID-19 
 
 
 
Protocol Number:  
20-214-34 
Protocol Version:  
Original 
Statistical Analysis Plan Version: 1.0 
Date: 9 September 2021 
 
 


Study No. 20-214-34 Statistical Analysis Plan
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Approved by:
Approved by:
Approved by:


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TABLE OF CONTENTS 
1.0 
INTRODUCTION..............................................................................................................9 
2.0 
STUDY OBJECTIVES ......................................................................................................9 
2.1 
Primary Objectives ...................................................................................................9 
2.2 
Secondary Objectives ...............................................................................................9 
3.0 
STUDY DESIGN AND PLAN ..........................................................................................9 
4.0 
DETERMINATION OF SAMPLE SIZE ......................................................................10 
5.0 
GENERAL ANALYSIS CONSIDERATIONS .............................................................10 
5.1 
Definition of Common Variables ...........................................................................11 
5.2 
Handling Missing Data ..........................................................................................12 
6.0 
ANALYSIS POPULATIONS .........................................................................................13 
7.0 
STATISTICAL ANALYSIS ...........................................................................................13 
7.1 
Subject Disposition ................................................................................................13 
7.2 
Important Protocol Deviations ...............................................................................13 
7.3 
Demographic and Baseline Characteristics ...........................................................13 
7.4 
Prior and Concomitant Medications and Procedures .............................................14 
7.5 
Study Treatment Exposure .....................................................................................14 
7.6 
Efficacy Analyses ..................................................................................................14 
7.6.1 
Analysis of Percentage of Patients Who Require Supplemental 
Oxygen ..................................................................................................14 
7.6.2 
Analysis of Shift from Baseline to Post-Baseline in Clinical Status ....15 
7.6.3 
Analysis of Clinical Status Based on the WHO Clinical Progression 
Scale on Days 3, 5, 8 .............................................................................15 
7.6.4 
Analysis of Number of Days Receiving Supplemental O2, Non-
Invasive, High-Flow, Mechanical Ventilation, ECMO ........................15 
 
 
 
 
 
 
 
 
9.0 
PHARMACOKINETIC ANALYSES ............................................................................18 
10.0 
IMMUNOGENICITY ANALYSES ...............................................................................20 
10.1 
Immunogenicity .....................................................................................................20 
10.2 
Safety Evaluation of ADA .....................................................................................20 
10.3 
Definitions..............................................................................................................21 
11.0 
SAFETY ANALYSES .....................................................................................................22 
11.1 
Analysis of Dose-Limiting Toxicity ......................................................................22 
11.2 
Adverse Events ......................................................................................................22 


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11.3 
Medical History .....................................................................................................23 
11.4 
Visit Window for Safety Endpoints: ......................................................................23 
11.5 
Clinical Laboratory Evaluation ..............................................................................23 
11.6 
Vital Signs ..............................................................................................................23 
11.7 
Electrocardiogram ..................................................................................................24 
12.0 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ............................................24 
13.0 
REFERENCES .................................................................................................................24 
 
LIST OF TABLES 
Table 1: 
Pharmacokinetic Parameter Definitions ....................................................19 
Table 2: 
Noncompartmental Analysis Requirements ..............................................19 
Table 3: 
ADA Status: Individual Samples ...............................................................21 
Table 4: 
ADA Response Categories:  Patient Level ................................................21 
 


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ABBREVIATIONS 
Abbreviation  
Term Definition 
ACE  
angiotensin converting enzyme 
ADA  
anti-drug-antibodies 
AE  
adverse event 
AESI  
adverse event of special interest 
ALC  
absolute lymphocyte count 
ALT (SGPT)  
alanine transaminase (serum glutamic pyruvic transaminase) 
ANC  
absolute neutrophil count 
ARDS  
acute respiratory distress syndrome 
AST (SGOT)  
aspartate transaminase (serum glutamic oxaloacetic transaminase) 
ATC 
Anatomical Therapeutic Chemical  
AUC  
area under the concentration-time curve 
Bempeg, BEMPEG 
abbreviation for bempegaldesleukin, the International Nonproprietary Name (INN) 
for NKTR-214 
Bempegaldesleukin  
International Nonproprietary Name (INN) for NKTR-214 
BLQ 
below the limit of quantification 
bpm  
beats per minute 
CDC  
Centers for Disease Control and Prevention 
CFR  
Code of Federal Regulations 
CI  
confidence interval 
Cmax  
maximum concentration 
COVID-19 
coronavirus disease 2019, caused by the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) 
CRC  
Cohort Review Committee 
CRF  
case report form 
CRS  
cytokine release syndrome 
CTCAE  
Common Terminology Criteria for Adverse Events 
CVA  
cerebrovascular accident 
CV% 
coefficient of variation(%) 
DCI  
data collection instrument 
DILI  
drug-induced liver injury 
DLT  
dose-limiting toxicity 
ECG 
electrocardiogram 


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Abbreviation  
Term Definition 
ECLA  
electrochemiluminescence assay 
eCOA  
electronic clinical outcomes assessments 
ECMO  
extracorporeal membrane oxygenation 
eCRF  
electronic case report form 
EDC  
electronic data capture 
eGFR  
estimated glomerular filtration rate 
EOI  
end of infusion 
FDA  
Food and Drug Administration 
FiO2  
fraction of inspired oxygen 
FSH  
follicle-stimulating hormone 
GCP  
Good Clinical Practice 
HBsAg  
hepatitis B surface antigen 
HBV  
hepatitis B virus 
HCG  
human chorionic gonadotropin 
HCV  
hepatitis C virus 
HIV  
human immunodeficiency virus 
HLA  
human leukocyte antigen 
ICF  
informed consent form 
ICH  
International Council for Harmonization 
IEC  
independent ethics committee 
IFN  
interferon 
IL-2, IL-3, IL-4, IL-5, IL-6, 
IL-7, IL-8, IL-10, IL-18 
interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, 
interleukin-8, interleukin-10, interleukin-18 
IND  
Investigational New Drug application 
IRB  
institutional review board 
IRT  
Interactive Response Technology 
IV  
intravenous 
kg  
kilogram 
LDH  
lactate dehydrogenase 
LLOQ  
lower limit of quantitation 
MCP  
monocyte chemotactic protein 
MDRD  
Modification of Diet Renal Disease 


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Abbreviation  
Term Definition 
MedDRA  
Medical Dictionary for Regulatory Activities 
MERS-CoV  
Middle East respiratory syndrome coronavirus 
mg  
milligram 
min  
minute(s) 
mL  
milliliter 
mm Hg  
millimeters of mercury 
msec  
millisecond 
MTD  
maximum tolerated dose 
NaCl  
sodium chloride 
NCA 
noncompartmental analysis 
NCI  
National Cancer Institute 
NK  
natural killer 
NKTR-214  
bempegaldesleukin (International Nonproprietary Name) 
NOAEL  
no observed adverse effect level 
NSAIDs  
nonsteroidal anti-inflammatory drugs 
NSCLC  
non-small cell lung cancer 
NYHA  
New York Heart Association 
OTC  
over-the-counter 
PaO2  
partial pressure of arterial oxygen 
PaO2/FiO2  
ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen 
PD-L1  
programmed cell death ligand 1 
PE  
pulmonary embolism 
PEG  
polyethylene glycol 
PK  
pharmacokinetic 
Q1 
first quartile 
Q3 
third quartile 
q3w  
every 3 weeks 
QTc  
corrected QT interval 
QTcF  
QT interval corrected using Fridericia’s formula 
RECIST  
Response Evaluation Criteria in Solid Tumors 
rhIL-2  
recombinant human interleukin-2 
RT-PCR  
reverse transcription polymerase chain reaction 


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Abbreviation  
Term Definition 
RP2D  
recommended Phase 2 dose 
SAE  
serious adverse event 
SAP  
statistical analysis plan 
SARS  
severe acute respiratory syndrome 
SARS-CoV-2  
severe acute respiratory syndrome coronavirus 2, the virus causing COVID-19 
SD 
Standard deviation 
SEM 
standard error of mean 
SIRS  
systemic inflammatory response syndrome 
SOC  
standard of care 
SOP  
standard operating procedure 
SpO2  
oxygen saturation 
SUSAR  
suspected unexpected serious adverse reaction 
TEAE  
treatment-emergent adverse event 
TIA  
transient ischemic attack 
Tmax  
time to maximum concentration 
TNF  
tumor necrosis factor 
Treg  
regulatory T cell 
ULN  
upper limit of normal 
US, USA  
United States of America 
WFI  
Water for Injection 
WHO  
World Health Organization 
WHO-DDE 
WHO Drug Dictionary Enhanced  
WOCBP  
Women of childbearing potential 
 


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1.0 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Nektar Therapeutics Protocol 20-214-34 “A Multicenter, Phase 1b, 
Randomized, Double-Blind, Placebo-Controlled Trial of the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of a Single Dose of Bempegaldesleukin (NKTR-214) 
Plus Standard of Care versus Placebo Plus Standard of Care in Adults with Mild COVID-19”. 
The purpose of this plan is to provide specific guidelines from which the analysis will proceed. 
Any deviations from these guidelines will be documented in the clinical study report (CSR). 
2.0 
STUDY OBJECTIVES  
2.1 
Primary Objectives 
x To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 
bempegaldesleukin plus standard of care (referred to in this document as 
bempegaldesleukin/SOC) compared with placebo plus standard of care (referred to in this 
document as placebo/SOC) in patients with mild COVID-19 (coronavirus disease 2019; 
SARS-CoV-2). 
x To evaluate the safety and tolerability of bempegaldesleukin administered as a single 
intravenous (IV) dose and to define the recommended Phase 2 dose (RP2D) of 
bempegaldesleukin in patients with mild COVID-19. 
x To assess the effect of bempegaldesleukin on the time course and extent of changes in 
absolute lymphocyte counts. 
2.2 
Secondary Objectives 
The secondary objectives listed below involve comparison of bempegaldesleukin/SOC versus 
placebo/SOC in patients with mild COVID-19: 
x To estimate the incidence of adverse events (AEs). 
x To evaluate the frequency of serious AEs (SAEs). 
x To determine the percentage of patients who require supplemental oxygen. 
x To evaluate clinical status based on the World Health Organization (WHO) Clinical 
Progression Scale.  
x To assess the immunologic effects in blood before and after study drug administration, 
including effects on cytokines, natural killer cells, T-cells, and other serum proteins and 
immune modulators. 
3.0 
STUDY DESIGN AND PLAN 
This is a multicenter, Phase 1b, randomized double-blind, placebo-controlled trial to assess the 
safety, tolerability, pharmacokinetics, and pharmacodynamics of bempegaldesleukin/SOC in 
adults with mild COVID-19, as well as to determine the RP2D of bempegaldesleukin. During the 


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study, patients will receive 1 dose of bempegaldesleukin or placebo and must remain in the 
hospital or be admitted to an in-patient facility for monitoring until at least Day 8. 
Patients will be randomized (1:1 ratio) in groups of 10 patients (5 bempegaldesleukin/SOC and 5 
placebo/SOC) in each cohort to receive one IV infusion of bempegaldesleukin in combination 
with standard of care or one IV infusion of placebo in combination with standard of care. 
Eligible patients will be enrolled into 1 of 3 dose cohorts with doses ranging from 0.00075 
mg/kg to 0.003 mg/kg. The first two patients randomized and treated in each dose cohort (1 with 
bempegaldesleukin/SOC and 1 with placebo/SOC) will serve as sentinel patients. Enrollment in 
each cohort will be staggered as follows. A Cohort Review Committee (CRC) will monitor 
blinded safety and tolerability data for the first 72 hours after study drug administration from the 
2 sentinel patients before additional patients in that cohort are treated. If the CRC determines 
additional patients may be randomized, 2 patients will be randomized (1 with 
bempegaldesleukin/SOC and 1 with placebo/SOC), treated with study drug, and observed for 72 
hours. For every 2 patients, the Medical Monitor will review the blinded safety and tolerability 
data for the first 72 hours after study drug administration to determine if the next 2 patients may 
be randomized. If it is not possible to assess the protocol defined DLT criteria (see Protocol 
Section 5.3.2.1.1), the Medical Monitor will request a review of the safety data by the CRC. 
After 10 patients have completed a 7-day observation period for dose-limiting toxicity (DLT; see 
Protocol Section 5.3.2.1 for additional details), the CRC will assess the accumulated, blinded 
safety and tolerability data, as well as any available pharmacokinetic, pharmacodynamic, and 
disease measurement data, to determine whether dose escalation or de-escalation from the tested 
bempegaldesleukin dose level is warranted. This decision will be based on blinded data using 
pre-defined criteria, including the proportion of patients who experience a DLT (see Protocol 
Section 5.3.1). Patients who drop out of the study for reasons other than a DLT, before the DLT 
evaluation period (Days 1 to 7) has elapsed, may be replaced. 
The RP2D of bempegaldesleukin in patients with mild COVID-19 will be based on the totality of 
safety, tolerability, pharmacokinetic, pharmacodynamic, and disease measurement data. 
4.0 
DETERMINATION OF SAMPLE SIZE 
This Phase 1b study will assess the safety and tolerability of different doses of 
bempegaldesleukin. No formal sample size calculation is done. Around 10 patients per dose 
cohort with a 1:1 randomization ratio (5 bempegaldesleukin/SOC and 5 placebo/SOC) to 
bempegaldesleukin/SOC or placebo/SOC will be enrolled. It is expected that a total of 
approximately 30 patients will be enrolled into the study.  
5.0 
GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables and data listings. Continuous 
variables will be summarized with means, standard deviations, medians, minimums, and 
maximums. Categorical variables will be summarized by counts and by percentage of patients in 


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corresponding categories. All summary tables will be presented by treatment. For patients who 
receive placebo, the data will be pooled as one placebo group. 
Individual subject data obtained from the case report forms (CRFs) and any derived data will be 
presented by subject in data listings. Data listings will be sorted by the treatment group, subject, 
visit date, and time, if applicable. 
All analyses and tabulations will be performed using SAS Version 9.4 or higher. All outputs will 
be presented in rich text format (RTF). 
5.1 
Definition of Common Variables 
x Reference date (Day 1) = first dose date of study medication. If a patient has not been treated, 
the reference day will be set as missing.   
x Study Day = assessment date – reference date + 1 for assessments performed on or after the 
reference date or assessment date – reference date for assessments performed before the 
reference date.  
x Baseline: Baseline will be defined as the last non-missing value on or before the date of 
administration of the first dose of study medication (and time if available) unless it is 
identifiable by time that the value is after the first dose.  For patients who have been not 
treated with any dose, then the baseline is defined as the screening value.  
Time on study will be calculated as follows: 
For visits/assessments/medications/therapies on or post study drug: 
x Study hour will be calculated as follows: 
x Study Hour = (assessment date time – date time of the start of the first study dose)/60 
x Study Day = (assessment date – date of the first study dose) + 1, if assessment date is on or 
after the study dose date in that cohort 
x Study Day = (assessment date – date of the first study dose), if assessment date is prior to the 
study dose date in that cohort 
For visit window derivation purpose, Study Day will be derived as ceiling of (Study Hour)/24. 
For purposes of analysis and data display (i.e., means over time), actual visit hours/days are 
mapped to the planned study visit (i.e., nominal visits such as Hour 1, 2, Day 2, etc.) using visit 
windows. Acceptable visit windows around each scheduled procedure visit will be given for each 
measurement in the forthcoming sections. Due to the different data collection schedules for the 
various measurements, however, visit windows for different parameters might not be identical. 
Unless otherwise specified, in mean and mean change from baseline/pre-dose summaries or 
analyses, if more than one value is obtained for the same measure within a given visit window, 


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the value closest to the planned study visit day and/or time will be used for reporting and 
analysis. If multiple values are equally away from the nominal visit day and/or time, the latter 
one will be used. However, for shift tables, the worst value mapped to that visit window will be 
used for summary purposes. 
5.2 
Handling Missing Data 
Missing data will be handled as follows: 
x For prior systemic cancer therapies and medical history of cancer, the study day 
corresponding to the start and stop date of the regimen will be calculated when calculating 
duration of the therapy/history and relevant time to the first study dose, etc.  For partially 
missing start dates, missing day of the month will be imputed as the first of the month and 
missing month will be imputed as January.  For partially missing stop dates, missing day of 
the month will be imputed as the last day of the month and missing month will be imputed as 
December and at least 1 day after the start date.  No imputation will be done if the year is 
missing. 
For the duration of AEs, AE start date with missing month and year and AE stop date with 
missing year will not be imputed. 
In general, no imputation will be considered for missing date or partial dates with the following 
exceptions: 
x For duration of AEs, partially missing dates for start of AE, will be imputed as follows: 
 
o Start day of AE is missing 
- If the reported month of occurrence of the AE is after the study dose, then day 
will be imputed as the first day of the month of occurrence of AE. 
- If the reported month of occurrence of the AE is the current month as the dose, 
then the missing day will be imputed as the same day as study dose date. 
 
x For duration of AEs, a partially missing stop date of the AE will be imputed as follows: 
o If the month is missing, but year is present, either 31st December, the date of 
discontinuation from the study, or the date of death, whichever is earlier, will be used 
as the stop date. 
o If the day is missing, but year and month are present, either the last day of that month, 
the date of discontinuation from the study, or the date of death, whichever is earlier, 
will be used as the stop date. 
 
Some laboratory analytes may be reported by range (e.g., gamma-glutamyl transferase [GGT] < 
17 U/L) and will be imputed by the corresponding boundary (e.g., 17 U/L). 


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6.0 
ANALYSIS POPULATIONS 
Screened patients: All patients who signed study participation informed consent.  
Enrolled patients: All patients who are assigned/randomized to either the 
bempegaldesleukin/SOC or placebo/SOC treatment groups.  
Safety/Treated Population: All patients who receive at least 1 dose (full or partial dose) of 
study drug. 
Pharmacokinetic Population: All patients in the Safety Population with at least one measurable 
concentration. 
Immunogenicity Population: All patients in the Treated Population with at least baseline and 
one post-baseline ADA assessment. 
 
 
7.0 
STATISTICAL ANALYSIS 
7.1 
Subject Disposition 
Subject disposition information will be summarized for all patients. Summaries will include: the 
number and percentage of patients in each analysis population, the number and percentage of 
patients who completed the study, and the number and percentage of patients who discontinued 
the study and the reason for discontinuation. All patients randomized/enrolled in the study will 
be included in the summary table. 
7.2 
Important Protocol Deviations 
Important protocol deviations are a subset of the protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of the study data or that may significantly 
affect a patient’s rights, safety, or well-being.   
Final list of the important protocol deviations and the associated categories will be determined by 
the study team before the database lock. 
The number and percentage of patients in each important protocol deviations category and sub-
category will be summarized by treatment group and total. All protocol deviations will be listed. 
7.3 
Demographic and Baseline Characteristics 
Demographic variables include age, sex, ethnicity, and race. Other baseline characteristics 
include height, weight, calculated body mass index (BMI), and vital signs. Demographic and 
baseline characteristics will be summarized for the Treated Population. 


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Age will be calculated as: 
 
Integer [(Date informed consent signed – Date of birth) / 365.25]. 
 
BMI will be calculated as: 
 
Weight (kg) / Height (m2). 
 
7.4 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications will be coded to ATC level and preferred drug name using 
WHO-DDE.   
Prior medications are defined as medications taken starting prior to the first dose.  Prior 
medications will be summarized for the Treated Population using the same analytical procedures 
as concomitant medications.  Concomitant medications are defined as medications taken on or 
after the date of first study dose, including medications initiated prior to the date of first dose and 
continued during treatment, and medications initiated on or after the date of first dose, but before 
the last study dose + 30 days or start of subsequent anticancer therapy, whichever is earlier.  
Concomitant medications will be tabulated for the Treated Population by WHO-DDE ATCL-2 
classifications and preferred term.  If the ATCL-2 classifications is missing, the next 
non-missing higher level of classification will be used (Level 1).  If a patient reports the same 
medication multiple times, then the frequency reported for that medication will be incremented 
by only one.  As with the medication, if a patient reports multiple medications within the same 
ATCL-2 classification then the frequency for that ATCL-2 classification will be incremented by 
only one.  Percentages will be calculated using the total number of patients in the Treated 
Population.   
Prior and concomitant medications will also be presented in a data listing.   
7.5 
Study Treatment Exposure 
Total dose administered (mg, mg/kg) will be summarized by N (observed), mean, SD, median, 
Q1, Q3, min, and max for each bempegaldesleukin dose level in Treated Population. Number 
and percentage of patients with full dose will be provided for each bempegaldesleukin dose level 
and total in the Treated Population. 
7.6 
Efficacy Analyses 
7.6.1 
Analysis of Percentage of Patients Who Require Supplemental Oxygen 
Number and percentage of patients who require supplemental oxygen will be provided by 
treatment group and total for Treated Population. 


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7.6.2 
Analysis of Shift from Baseline to Post-Baseline in Clinical Status  
Shift from baseline to post-baseline clinical status based on the World Health Organization 
(WHO) Clinical Progression Scale will be provided for patients with no change, with 1, 2, and 
≥3 points of improvement or worsening in the Treated Population. The 10-point WHO Clinical 
Progression Scale is as follows: 
Patient state  
Descriptor 
Score 
Uninfected  
Uninfected; no viral RNA detected 
0 
Ambulatory mild 
disease 
Asymptomatic; viral RNA detected  
1 
Symptomatic; independent  
2 
Symptomatic; assistance needed  
3 
Hospitalized: Moderate 
disease 
Hospitalized, no oxygen therapya  
4 
Hospitalized; oxygen by mask or nasal prongs  
5 
Hospitalized: Severe 
disease 
Hospitalized; oxygen by non-invasive ventilation or high-flow 
6 
Intubation and mechanical ventilation, PaO2/FiO2 ≥ 150 or SpO2/FiO2 ≥ 
200 
7 
Mechanical ventilation, PaO2/FiO2 < 150 (SpO2/FiO2 < 200) or 
vasopressors 
8 
Mechanical ventilation, PaO2/FiO2 < 150 and vasopressors, dialysis, or 
ECMO 
9 
Dead  
Death 
10 
Abbreviations: ECMO = extracorporeal membrane oxygenation; FiO2 = fraction of inspired oxygen; PaO2 = partial 
pressure of arterial oxygen; SpO2 = oxygen saturation 
a. 
If hospitalized for isolation only, record status as for ambulatory patient. 
Source: WHO 2020 
 
7.6.3 
Analysis of Clinical Status Based on the WHO Clinical Progression Scale 
on Days 3, 5, 8 
Number and percentage of patients will be provided for each clinical status (i.e. WHO 
progression scale point) on Days 3, 5, and 8 by treatment group and total.  
7.6.4 
Analysis of Number of Days Receiving Supplemental O2, Non-Invasive, High-
Flow, Mechanical Ventilation, ECMO  
Oxygen days are defined as days where the clinical status score is equal to 5, 6, 7, 8, or 9. The 
total number of oxygen days is the sum of all reported oxygen days. 
Number of oxygen days will be summarized by N (observed), mean, SD, median, Q1, Q3, min, 
and max for each treatment group and total in Treated Population. Number and percentage of 


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patients will be provided for number of oxygen days by treatment group and total in Treated 
Population, if deemed necessary. 


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9.0 
PHARMACOKINETIC ANALYSES 
Listings for blood collection dates, times and concentrations will be generated by patient for each 
analyte. Sampling time deviations will be computed as differences between scheduled (nominal) 
and actual sampling times and expressed in hours and as a percentage of the nominal time. 
Observed plasma NKTR-214-RC (bempegaldesleukin-related molecules; mixture of compounds 
containing IL-2 independent of PEG conjugation status) at each nominal PK sampling time will 
be tabulated using descriptive statistics, including but not limited to N (number of non-missing 
data), N (missing), arithmetic mean, standard deviation (SD), standard error of the mean (SEM), 
arithmetic coefficient of variation (CV%), geometric mean, geometric CV%, median, minimum, 
and maximum.   
Individual and overlay plots of observed plasma NKTR-214-RC concentration-time profiles will 
be generated on linear and semi-logarithmic scales using actual times.   
Plots of mean (+ standard deviation) observed plasma NKTR-214-RC concentrations versus 
nominal time will be generated on linear and semi-logarithmic scales based on nominal sampling 
times.   
PK samples that were collected outside the protocol accepted time windows will be excluded 
from summary tables and summary figures. 
The PK analyses will use Quality Assured (QA) final bioanalytical data.  Missing concentration 
values will not be imputed.  When summarizing concentrations, zero values will be excluded 
from the calculation of geometric means and CV% geometric mean, however, they will be 
included for all other summary statistics and the number of non-zero concentrations will be 
reported. Missing values for any PK parameters will not be imputed and will be handled as 
missing.  
When calculating PK parameters, all Cycle 1 pre-dose concentrations that are below the limit of 
quantification (BLQ) will be set to 0; all other concentrations that are BLQ will be set to missing 
for calculation of PK parameters and will be set to 0 for summary statistics. 
PK parameters will be derived by Phoenix WinNonlin (version 8.3 or higher) based on 
noncompartmental (NCA) methods. PK parameters (Error! Reference source not found.) will 
include Cmax, Tmax, AUClast, AUCinf, Vz, CL, and t1/2 for NKTR-214-RC. Time zero will be 


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defined as the start time of the infusion. Linear-up/log-down NCA methods will be used to 
estimate AUC. 
NCA PK parameters listed in  
Table 2: 
 will only be derived when all specified requirements are met. Where 
requirements are not met, PK parameter values will be reported as “not determinable”. 
Table 1: 
Pharmacokinetic Parameter Definitions 
PK Parameter 
Description 
AUCinf 
Area under the concentration-time curve calculated from time 0 to infinity 
AUClast 
Area under the concentration-time curve calculated from time 0 to the last measurable 
concentration 
AUC0-96h 
Area under the concentration-time curve calculated from time 0 to 96 hours after dosing 
AUC0-168h 
Area under the concentration-time curve calculated from time 0 to 168 hours after dosing 
CL 
Systemic clearance  
Cmax 
Maximum observed concentration following study drug administration 
t1/2 
Half-life: the time required for the concentration to reach half of its original value 
Tmax 
Time to reach maximum concentration 
Vz 
Volume of distribution during the terminal elimination phase following intravenous 
administration 
 
Table 2: 
Noncompartmental Analysis Requirements 
PK Parameter 
Requirement 
t1/2, AUCinf, CL, 
Vz 
A minimum of 3 time points should be used for determining lambda_z, not including the Cmax 
time point. 
The span of the terminal phase must be at least 2 times the half-life for lambda_z to be 
determined. 
Where Rsq_adj < 0.75, lambda_z will not be determined 
If lambda_z is not determined then t1/2, AUCinf, CL, or Vz will not be reported. 
AUCinf 
The extrapolated area should not contribute more than 20% to the total AUCinf for the 
estimation of AUCinf  
 
PK parameters will be listed by patient and summarized using descriptive statistics, including but 
not limited to N (observed), geometric mean, mean, SEM, SD, CV%, geometric CV%, median, 
minimum and maximum.  PK parameters will be summarized for each treatment group.  Tmax, 
CL, t1/2, and Vz will also be summarized in total Treated Population. 


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Rounding for the reporting of PK parameters will be to three significant digits. Percentages such 
as CV% presented in tables will be rounded to one decimal place.  The same convention will be 
followed for descriptive statistics, except for n, which will be rounded to the whole value.  
10.0 
IMMUNOGENICITY ANALYSES 
10.1 
Immunogenicity 
Validated methods to detect anti-bempegaldesleukin, anti-PEG and anti-IL-2 anti-drug 
antibodies (ADA) will be used to analyze immunogenicity samples. Serum samples will be 
analyzed by multi-tiered ADA testing as per the 2019 FDA guidance (FDA 2019). 
Immunogenicity sample testing will be done in tiers.  Samples will be first tested with screening 
electrochemiluminescence assays (ECLA).  Putative positive samples for anti-
bempegaldesleukin or anti-IL-2 antibodies will then be analyzed in competition ECLA to 
confirm positivity. Confirmed anti-bempegaldesleukin antibodies-positive samples will be tested 
further in a polyethylene glycol (PEG) immuno-competition assay to determine the antibody 
specificity of the reactivity to the PEG or non-PEG (IL-2, linker) moiety of bempegaldesleukin.  
Confirmed positive samples from each assay (anti-bempegaldesleukin and anti-IL-2) will then be 
tested to obtain a titer. Samples confirmed to be positive for anti-bempegaldesleukin and anti-
IL-2 antibodies will also be tested for neutralizing activity for IL-2 using a validated cell-based 
assay. The data will be summarized for anti-bempegaldesleukin, anti-PEG, anti-IL-2 antibodies 
and will be reported by sample and patient status.  
For sample status, immunogenicity data will be summarized by the number and percentage of 
confirmed anti-drug antibodies (ADA) to bempegaldesleukin, PEG, IL-2 by analyte and visit. 
The samples will be classified as baseline ADA-positive, if ADA is detected in the 
immunogenicity sample collected before initiation of the treatment and baseline ADA-negative, 
if ADA is not detected in the immunogenicity sample collected before initiation of the treatment. 
ADA samples will be classified as positive if after initiation of the treatment, the ADA is 
detected in a sample from a subject who was baseline negative, or if there is at least 4-fold or 
greater (≥) increase in ADA titer in comparison to the baseline positive titer. 
For patient status, immunogenicity will be reported by summarizing the number and percentage 
of ADA-positive patients and ADA-negative patients at baseline and after drug administration 
with positive status of anti-bempegaldesleukin, anti-PEG, anti-IL-2 ADA.  In the 
immunogenicity evaluable population, the patients will be classified as treatment-induced 
ADA-positive if they were ADA-negative at baseline and became ADA-positive at any time 
after starting the treatment, or if they were ADA-positive at baseline and had a post-baseline 
ADA-positive titer that was at least 4-fold or greater (≥) than baseline positive titer 
(Treatment-boosted). Treatment-emergent ADA-positive patients will be the sum of treatment-
induced and treatment-boosted ADA-positive patients. Patients with at least one ADA-positive 
sample with neutralizing activity will be classified as neutralizing positive.  All other 
ADA-evaluable patients are considered as treatment-emergent ADA negative. 


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10.2 
Safety Evaluation of ADA 
All patients with ADA as mentioned above will be assessed for infusion related reactions 
(including hypersensitivity/angioedema/anaphylaxis) and will be compared against ADA 
negative patients. 
10.3 
Definitions 
There are two sets of definitions: one for categorizing individual samples in Table 3 and another 
for categorizing patient responses in Table 4. 
Table 3: 
ADA Status: Individual Samples 
ADA Status 
Definition 
Baseline Negative 
ADA is not detected in the last sample before initiation of treatment 
Baseline positive 
ADA is detected in the last sample before initiation of treatment 
Anti-bempegaldesleukin 
ADA-positive sample 
After initiation of treatment,  
(1) an ADA detected (positive seroconversion) sample in a patient for whom anti-
bempegaldesleukin ADA is not detected at baseline, or  
(2) an ADA detected sample with anti-bempegaldesleukin titer to be at least 4-fold or 
greater (≥) than baseline positive titer 
Anti-PEG ADA-positive 
sample 
 Sample with a positive result in PEG -specificity assay.  
Anti-IL-2 ADA-positive 
sample 
After initiation of treatment,  
(1) an ADA detected (positive seroconversion) sample in a patient for whom anti-IL-2 
ADA is not detected at baseline, or  
(2) an ADA detected sample with anti-IL-2 titer to be at least 4-fold or greater (≥) 
than baseline positive titer 
 
Table 4: 
ADA Response Categories:  Patient Level 
ADA status 
Description 
Baseline ADA-positive A patient with baseline ADA-positive sample 
ADA-Negative Patient 
Patient with no ADA-positive sample after the initiation of treatment. 
Note: due to the definition of an ADA positive sample for a patient testing positive at 
baseline (see sample status table, above), it is possible (but highly unlikely) for a patient 
with a stable anti-drug titer throughout the study to be classified as ‘ADA-negative’ 
ADA-Positive Patient  
(Treatment-Emergent 
positive) 
Patient with at least 1 ADA positive-sample (relative to baseline) at any time after 
initiation of treatment 
Neutralizing positive 
At least 1 ADA-positive sample with neutralizing antibodies detected 
 


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11.0 
SAFETY ANALYSES 
All safety analyses will be based on the Safety Population. 
11.1 
Analysis of Dose-Limiting Toxicity  
Dose finding for this study is based on the assessment of dose-limiting toxicity (DLT) of 
bempegaldesleukin dose levels. Number and percentage of patients with any DLT will be 
summarized by bempegaldesleukin dose level in bempegaldesleukin/SOC treatment groups and 
placebo for the Safety Population. 
11.2 
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject who is administered a 
medicinal product and that does not necessarily have a causal relationship to the treatment. All 
AEs will be included in the data listings. Verbatim terms on case report forms will be mapped to 
preferred terms and system organ classes (SOC) using the Medical Dictionary for Regulatory 
Activities (MedDRA) (version 20.0). 
A Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event that occurs on or 
after the treatment dose, and treatment-emergent period is from the study dose date to 30 days 
after the study dose. The TEAE summary will be displayed by treatment using treatment-
emergent period. Unless otherwise specified, summaries that are displayed by SOC and preferred 
terms will be ordered alphabetically by SOC, and within each SOC, preferred terms will also be 
ordered alphabetically. Summaries of the following types will be presented: 
x TEAEs by MedDRA SOC and preferred term. 
x TEAEs by MedDRA SOC, preferred term, and worst CTCAE grade (version 5.0). At each 
level of subject summarization, a subject is classified according to the worst CTCAE grade if 
the subject reported one or more CTCAE grade. 
x TEAEs related to study drug by MedDRA SOC, preferred term, and worst CTCAE grade. 
x TEAEs by descending incidence of preferred terms. 
x Serious TEAEs by MedDRA SOC, preferred term and worst CTCAE grade. 
x Serious TEAEs related to study drug by MedDRA SOC, preferred term, and worst CTCAE 
grade. 
x TEAEs leading to early termination by MedDRA SOC, preferred term, and worst CTCAE 
grade. 
x Any Grade ≥ 3 drug-related AE.  
x Respiratory compromise or other virus-related AE attributed to worsening COVID-19, such 
as severe hypoxia, cyanosis, or chest pain/pressure. 
x TEAEs leading to deaths. 


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For each subject and for each adverse event, the duration of the event (days) will be calculated 
as:  
Duration of AE (Days) = AE stop date – AE start date +1.  
The duration of AEs will be displayed in the data listing. 
11.3 
Medical History  
An event occurring after the patient has provided informed consent, but before the first dose of 
study treatment, will be collected as medical history unless the event is either new and attributed 
to protocol-mandated procedures by the Investigator or there is a significant change in the rate of 
occurrence or an increase in the severity of the pre-existing condition which is judged to be 
clinically important and attributed to the protocol-mandated procedures by the Investigator. 
Under the latter 2 circumstances, the event will be considered an AE and will be captured as 
such. 
Medical history will be listed and summarized by System Organ Class and Preferred Term. 
11.4 
Visit Window for Safety Endpoints: 
If more than one value is obtained for the same measure within a given visit window, the value 
closest to the planned study visit day/time will be used for reporting and analysis. If multiple 
values are the same number of days/times away from the nominal visit day/time, the latter one 
will be used. 
11.5 
Clinical Laboratory Evaluation 
Hematology and chemistry parameters will be summarized using descriptive statistics at baseline 
and post-dose. Changes from baseline will also be summarized. 
Shift tables will be provided to assess changes in laboratory values from baseline to worst 
post-dose CTCAE grade. Only non-missing assessments at baseline and post-dose will be 
analyzed. 
Any clinically significant lab abnormalities will be determined by the Principal Investigator and 
will be reported in the AE table summaries. 
11.6 
Vital Signs 
Vital signs, including oxygen saturation (SpO2), will be summarized using descriptive statistics 
at baseline and at each post-dose time point. Changes from baseline will also be summarized 
using descriptive statistics. 


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11.7 
Electrocardiogram 
ECG parameters (numeric) at baseline will be summarized using descriptive statistics. 
The number and percentage of patients with abnormal (not clinically significant or clinically 
significant) and number and percentage of patients in each of the following categories based on 
QTcF at baseline will be provided in the safety Population: 
 QTc interval ≤ 450 ms,  
 QTc interval > 480 ms, 
 QTc interval > 500 ms. 
 
12.0 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
No changes from the protocol-specified analyses are planned. 
13.0 
REFERENCES 
1. 
WHO Working Group on the Clinical Characterisation and Management of COVID-19 
infection. A minimal common outcome measure set for COVID-19 clinical research. 
Lancet Infect Dis. 2020; https://doi.org/10.1016/S1473-3099(20)30483-7.