Clinical trial NCT03138889
Conditions: Non-Small Cell Lung Cancer
Keywords: NKTR-214 Metastatic Non-Small Cell Lung Cancer Pembrolizumab Keytruda® NSCLC Bempegaldesleukin
Sponsor: Nektar Therapeutics
Start date: 2017-06-09; Completion date: 2022-08-24
Enrollment: 162 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is to assess the safety and tolerability, and to assess the preliminary clinical benefit of NKTR-214 when combined with pembrolizumab (KEYTRUDA®) with or without chemotherapy.

The study is comprised of two groups; dose optimization and dose expansion cohorts.

Dose Optimization included first-line and second-line advanced or metastatic solid tumors including non-small cell lung cancer (NSCLC)

The dose expansion cohort will include first-line NSCLC patients.

Detailed description:
NKTR-214 is a cytokine (investigational agent) that is designed to target CD122, a protein which is found on certain immune cells (known as CD8+ T Cells and Natural Killer Cells) to expand these cells to promote their anti-tumor effects. Pembrolizumab is a programmed death receptor -1 (PD-1) blocking, fully humanized, engineered monoclonal antibody of IgG1 isotype that promotes anti-tumor effects.

The study will evaluate the clinical benefit, safety and tolerability of combining NKTR-214 with pembrolizumab with or without chemotherapy. Each dose expansion cohort will enroll approximately 100 new patients.

Dose Optimization evaluated an every three-week dose regimen (q3w) of NKTR-214 in combination with pembrolizumab given that the optimal dose and dosing schedule of NKTR-214 in combination with pembrolizumab remains unknown. The previously established recommended Phase 2 dose (0.006 mg/kg) of NKTR-214 was studied in combination with nivolumab.

Dose Expansion: NKTR-214 in combination with pembrolizumab will be evaluated in first-line non-small cell lung cancer (NSCLC). The NKTR-214 dose to be studied is 0.006 mg/kg q3w. This dose is based on the recommended phase 2 dose noted in the monotherapy trial with NKTR-214 (Study 15-214-01, NCT02869295) and an ongoing combination trial (16-214-02, NCT02983045). Pembrolizumab will be administered at a dose of 200mg q3w. Following data review for safety and efficacy, additional patients may be dosed using the findings from the dose optimization cohorts.

Arms: arm 1: Cohort 1: NKTR-214 will be combined with pembrolizumab arm 2: Cohort 2: NKTR-214 will be combined with pembrolizumab arm 3: Cohort 3: NKTR-214 will be combined with pembrolizumab arm 4: Cohort 4: NKTR-214 will be dosed in combination with pembrolizumab and either cisplatin, or carboplatin and pemetrexed, per investigator discretion arm 5: Cohort 5: NKTR-214 will be dosed in combination with pembrolizumab and carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion arm 6: Cohort 0 (Before Protocol Amendment 5.0): NKTR-214 will be combined with pembrolizumab or atezolizumab
Interventions: intervention 1: NKTR-214 intervention 2: Pembrolizumab intervention 3: NKTR-214 intervention 4: NKTR-214 intervention 5: Cisplatin intervention 6: Carboplatin intervention 7: Nab paclitaxel intervention 8: Paclitaxel intervention 9: Pemetrexed intervention 10: Atezolizumab
Intervention descriptions: intervention 1: NKTR-214: The dose will be 0.008 mg/kg intravenous (IV) infusion administered over 30 (± 5) minutes q3w. The maximum dose of NKTR-214 will be 0.012 mg/kg. This will include a fixed 3+3 dose escalation followed by intra-patient step-up dose escalation based on tolerability. intervention 2: Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual. intervention 3: NKTR-214: The dose will be 0.006 mg/kg intravenous (IV) infusion. intervention 4: NKTR-214: The dose will be 0.010 mg/kg intravenous (IV) infusion. intervention 5: Cisplatin will be dosed per the pharmacy manual intervention 6: Carboplatin will be dosed per the pharmacy manual intervention 7: Nab-paclitaxel will be dosed per local practice and label intervention 8: Paclitaxel will be dosed per local practice and label intervention 9: Pemetrexed will be dosed per the pharmacy manual intervention 10: Atezolizumab will be dosed per current label indication

Protocol documents:
Prot_000.pdf: 


Protocol No. 16-214-05 Amendment 7.0 
 
bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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INVESTIGATOR SIGNATURE PAGE 
Nektar Therapeutics 
TITLE: 
A Phase 1/2, Open-label, Multicenter Study to Investigate the 
Safety and Preliminary Efficacy of Combined Bempegaldesleukin 
(NKTR-214) and Pembrolizumab with or without Chemotherapy 
in Patients with Locally Advanced or Metastatic Solid Tumors 
PROTOCOL NUMBER: 
16-214-05 
PHASE OF STUDY: 
Phase 1/2 
PROTOCOL DATE: 
23 December 2020 
STUDY SPONSOR: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
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 Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 






Protocol No. 16-214-05 Amendment 7.0 
 
bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .......................................................................................................................10 
LIST OF FIGURES .....................................................................................................................11 
LIST OF APPENDICES .............................................................................................................11 
ABBREVIATIONS ......................................................................................................................12 
1.0 
STUDY SYNOPSIS .........................................................................................................17 
1.1 
Schedule of Events .................................................................................................26 
2.0 
INTRODUCTION............................................................................................................46 
2.1 
Background ............................................................................................................46 
2.1.1 
NKTR-214 Mechanism of Action .........................................................46 
2.1.2 
Rationale for the Combination of NKTR-214 and Immune 
Checkpoint Inhibitors ............................................................................46 
2.1.3 
Clinical Experience with IL-2 and Checkpoint Inhibitors ....................47 
2.1.4 
Clinical Experience with NKTR-214 ....................................................48 
2.1.4.1 
Study 15-214-01 (EXCEL) ............................................................48 
2.1.4.2 
Study 16-214-02 (PIVOT-02) ........................................................50 
2.1.4.3 
Observed Events of Cerebrovascular Accident in Study 16-
214-02 ............................................................................................52 
2.1.5 
Pembrolizumab Safety Summary ..........................................................53 
2.1.6 
Rationale for Dose Optimization Cohorts .............................................53 
2.1.7 
Rationale for Dose Expansion Cohorts 2, 3, 4, and 5 ...........................53 
2.2 
Overall Benefit/Risk ..............................................................................................54 
2.3 
Data Monitoring Committee ..................................................................................54 
3.0 
STUDY OBJECTIVES ....................................................................................................55 
3.1 
Primary Objectives: Dose Optimization or Dose Expansion Cohorts ...................55 
3.2 
Secondary Objectives: Dose Optimization and/or Dose Expansion Cohorts ........55 
 
 
4.0 
SELECTION OF STUDY POPULATION ...................................................................57 
4.1 
Inclusion Criteria ...................................................................................................57 
4.1.1 
Dose Optimization Cohorts (Cohorts 1a and 1b) ..................................60 
4.1.2 
Dose Expansion Cohorts (Cohorts 2, 3, 4, and 5) .................................60 
4.2 
Exclusion Criteria ..................................................................................................61 
5.0 
TREATMENT PLAN ......................................................................................................64 
5.1 
Overview ................................................................................................................64 




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5.13 
Dose Delay and Reduction Criteria .......................................................................87 
5.13.1 
Pembrolizumab and Chemotherapy Dose Delay and Reduction 
Criteria ..................................................................................................87 
5.13.1.1 
Pembrolizumab (All Cohorts) ........................................................87 
5.13.1.2 
Chemotherapy (Cohorts 4 and 5 Only) ..........................................87 
5.13.2 
NKTR-214 Dose Delay and Reduction Criteria ...................................88 
5.13.3 
Dose-Modification Criteria for NKTR-214 for Cycle 1 ALT/AST 
Elevations ..............................................................................................89 
5.13.4 
Monitoring and Management of Elevated Hepatic Transaminases ......90 
5.13.5 
Monitoring and Management of NKTR-214-Induced Eosinophilia .....91 
5.13.6 
Criteria to Resume NKTR-214 .............................................................91 
5.14 
Management Algorithms for Immune-Mediated AEs and Cytokine Release 
Syndrome ...............................................................................................................92 
5.14.1 
Management Algorithms for Immune-Mediated AEs Associated 
with Immuno-Oncology Agents ............................................................92 
5.14.2 
Management Algorithm for Cytokine Release Syndrome ....................92 
5.15 
Discontinuation from Study Treatment .................................................................93 
5.16 
Treatment of NKTR-214 and Pembrolizumab, Related Infusion Reactions .........95 
5.17 
Prior and Concomitant Medications ......................................................................97 
5.18 
Permitted Concomitant Medications/Treatment ....................................................97 
5.18.1 
Thromboembolism Prophylaxis and Treatment ....................................98 
5.19 
Prohibited Concomitant Medications ....................................................................98 
5.20 
Effect of NKTR-214 on Concomitant Medication Metabolism ............................99 
5.20.1 
Interaction of NKTR-214 and Warfarin ................................................99 
5.21 
Adverse Events ......................................................................................................99 
5.22 
Treatment Assignment and Patient Number Assignment ....................................100 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ............................................100 
6.1 
Pembrolizumab ....................................................................................................101 
6.2 
NKTR-214 Drug Description and Formulation ...................................................101 
6.3 
NKTR-214 Drug Packaging and Labeling ..........................................................101 
6.4 
NKTR-214 Drug Reconstitution and Handling ...................................................102 
6.5 
NKTR-214 Drug Storage .....................................................................................102 
6.6 
NKTR-214 Drug Shipment ..................................................................................102 
6.7 
Pembrolizumab, Pemetrexed, Cisplatin, Paclitaxel, Nab-paclitaxel, and 
Carboplatin Formulation, Reconstitution, Storage and Packaging ......................102 
6.8 
NKTR-214 Pembrolizumab, Pemetrexed, Cisplatin, Paclitaxel, Nab-
paclitaxel, and Carboplatin Drug Accountability and Reconciliation .................102 


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7.0 
ASSESSMENT OF SAFETY ........................................................................................103 
7.1 
AE Definition and Assessment ............................................................................103 
7.2 
Monitoring AEs ...................................................................................................103 
7.3 
Grading of AEs ....................................................................................................104 
7.4 
Causality Relationship of AEs .............................................................................105 
7.5 
AE Reporting and Follow-up ...............................................................................105 
7.6 
Serious AE Definition ..........................................................................................105 
7.7 
Serious AE Reporting ..........................................................................................106 
7.8 
Serious AE Follow-up..........................................................................................107 
7.9 
Disease Progression and Death Due to Disease Progression – Not Reportable 
as an AE/SAE ......................................................................................................107 
7.10 
Immune-mediated AEs (IMAEs) and Other Monitored Events ..........................108 
7.11 
Adverse Events of Special Interest ......................................................................108 
7.12 
Pregnancy .............................................................................................................109 
7.13 
Potential Drug Induced Liver Injury ....................................................................109 
7.14 
Clinical Laboratory Tests .....................................................................................109 
7.15 
Physical Examinations .........................................................................................110 
7.16 
Vital Signs ............................................................................................................110 
7.17 
Electrocardiograms ..............................................................................................110 
7.18 
Echocardiograms..................................................................................................110 
7.19 
Pregnancy Tests ...................................................................................................111 
8.0 
ASSESSMENT OF EFFICACY EVALUATIONS.....................................................112 
8.1 
Definitions............................................................................................................112 
8.1.1 
Measurable Disease .............................................................................112 
8.1.2 
Non-measurable Disease .....................................................................112 
8.2 
Specifications by Methods of Measurements ......................................................112 
8.2.1 
Tumor Response Evaluation ...............................................................113 
8.2.1.1 
Assessment of Overall Tumor Burden at Baseline and 
Measurable Disease .....................................................................113 
8.2.1.2 
Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions ..113 
8.2.1.3 
Special Notes on the Assessment of Target Lesions ...................114 
8.2.2 
Response Criteria using RECIST 1.1 ..................................................114 
8.2.2.1 
Evaluation of Target Lesions .......................................................114 
8.2.2.2 
Evaluation of Non-target Lesions ................................................114 
8.2.2.3 
Confirmatory Measurement/Duration of Response .....................115 
8.2.2.3.1 
Confirmation ................................................................................115 
8.2.2.4 
Evaluation of Overall Response Using RECIST 1.1 ...................115 


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9.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE ....................................................................117 
9.1 
General Considerations ........................................................................................117 
9.2 
Determination of Sample Size .............................................................................117 
9.3 
Safety Monitoring ................................................................................................119 
9.4 
Replacement of Patients .......................................................................................119 
9.5 
Analysis Sets ........................................................................................................119 
9.6 
Planned Analyses .................................................................................................119 
9.6.1 
Demographics and Baseline Characteristics .......................................119 
9.6.2 
Safety ..................................................................................................120 
9.6.3 
Efficacy ...............................................................................................120 
9.6.4 
Immunogenicity ..................................................................................122 
 
 
9.6.6 
Pharmacokinetics ................................................................................122 
9.7 
Concomitant Medications ....................................................................................123 
9.8 
Missing Data ........................................................................................................123 
10.0 
STUDY OR STUDY SITE TERMINATION ..............................................................124 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...........................................125 
11.1 
Changes to the Protocol .......................................................................................125 
11.2 
Monitoring ...........................................................................................................125 
11.3 
Direct Access to Source Data/Documents for Audits and Inspections ................126 
12.0 
ETHICS ..........................................................................................................................127 
12.1 
IRB/IEC Approval ...............................................................................................127 
12.2 
Written Informed Consent ...................................................................................127 
13.0 
DATA HANDLING AND RECORD KEEPING ........................................................128 
13.1 
Data Collection Instruments and Source Documents ..........................................128 
13.1.1 
Study Records .....................................................................................128 
13.1.2 
Data Collection Instruments ................................................................128 
13.2 
Retention of Essential Documents .......................................................................128 
13.3 
Confidentiality .....................................................................................................129 
14.0 
PUBLICATION POLICY .............................................................................................130 
15.0 
REFERENCES ...............................................................................................................131 
 


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Nektar Therapeutics 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events for Dose Optimization Cohorts ..................................26 
Table 2: 
Schedule of Events for Dose Expansion Cohorts 2 and 3 .........................31 
Table 3: 
Schedule of Events for Dose Expansion Cohort 4 .....................................36 
Table 4: 
Schedule of Events for Dose Expansion Cohort 5 .....................................41 
Table 5: 
Definitions of Adequate Organ Function (Inclusion Criteria) ...................57 
Table 6: 
Tumor Types to be Included in Dose Optimization Cohorts 
(NKTR-214 and Pembrolizumab)..............................................................60 
Table 7: 
Dose Optimization Cohort Decision Guide for the 3 + 3 Dose Design .....69 
Table 8: 
Dose Optimization Cohort Decision Guide for the Step-up Dose 
Design ........................................................................................................69 
Table 9: 
Treatment Cycle Duration and DLT Window (3 + 3 and Step-up 
Cohorts)......................................................................................................70 
Table 10: 
Patient Exposure Supporting the RP2D of NKTR-214 0.006 mg/kg in 
Combination with Nivolumab 360 mg q3w ...............................................72 
Table 11: 
Overall Tumor Response by Cancer Type: PIVOT-02 Combination 
Therapy Study 16-214-02 (Dose Escalation Phase) ..................................74 
Table 12: 
Overall Tumor Response by Cancer Type: PIVOT-02 Combination 
Therapy Study 16-214-02 - Patients who met Pre-specified Efficacy 
Parameters ..................................................................................................76 
Table 13: 
Tumor Biopsy Requirements (Dose Optimization and Dose 
Expansion) .................................................................................................85 
Table 14: 
Pemetrexed, Carboplatin, and Cisplatin Dose Delay, Reduction, and 
Discontinuation Criteria .............................................................................88 
Table 15: 
Investigational Products ...........................................................................100 
Table 16: 
Criteria to Determine Objective Tumor Response for Target Lesions 
per RECIST 1.1 ........................................................................................114 
Table 17: 
Criteria to Determine Tumor Response for Non-Target Lesions per 
RECIST 1.1 ..............................................................................................115 
Table 18: 
Best Overall Response When Confirmation of CR and PR Required .....116 
Table 19: 
True (Target) and Historic Objective Response Rate for First-line 
NSCLC by PD-L1 Categorization (Cohorts 2 and 3) ..............................118 
Table 20: 
Cerebrovascular Accident Adverse Event Management Algorithm ........134 
 


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Nektar Therapeutics 
 
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LIST OF FIGURES 
Figure 1: 
Study Schematic.........................................................................................25 
Figure 2: 
Dose Optimization Cohorts Schema: 3 + 3 and Step-up Dosing ...............68 
 
LIST OF APPENDICES 
Appendix 1: 
Clinical Laboratory Tests .........................................................................133 
Appendix 2: 
Cerebrovascular Accident Adverse Event Management Algorithm ........134 
Appendix 3: 
Women of Childbearing Potential Definitions and Methods of 
Contraception ...........................................................................................135 
Appendix 4: 
Cytokine Release Syndrome (CRS) Management Algorithm .................138 


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Nektar Therapeutics 
 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
1L 
first line 
2L 
second line 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
area under the curve 
BICR 
blinded independent central review 
BMI 
body mass index 
BOR 
best overall response  
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
Clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
CPS 
Combined Positive Score 
CR 
complete response 
CLcr 
creatinine clearance 
CRS 
Cytokine Release Syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
CVA 
cerebrovascular accident 
D5W 
dextrose 5% in water for injection  


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Abbreviation or Term 
Definition 
DCI 
data collection instrument 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DOAC 
direct oral anticoagulation 
DOR 
duration of response 
DVT 
deep vein thrombosis 
DWI 
diffusion-weighted imaging 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCOA 
electronic clinical outcomes assessments 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EGFR 
epidermal growth factor receptor 
EOI 
End of Infusion 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCG 
human chorionic gonadotropin 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
Hgb 
Hemoglobin 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma  
Hr 
hour(s) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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Abbreviation or Term 
Definition 
IHC 
Immunohistochemistry 
IL-2 
interleukin-2 
IL2R 
IL-2 receptor alpha subunit  
IL2R 
IL-2 receptor beta subunit  
imAE 
immune-mediated adverse event 
IND 
Investigational New Drug application 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
Kg 
Kilogram 
LDH 
lactate dehydrogenase 
LMWH 
low molecular weight heparin 
LVEF 
left ventricular ejection fraction 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
minute(s) 
Mg 
Milligram 
mL 
Milliliter 
mmHg 
millimeters of mercury 
Mo 
month 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition  
N1 
sample size at Stage 1 
N2 
sample size at Stage 2 
NCI 
National Cancer Institute 
NE 
Inevaluable 
NK 
natural killer 
NKTR-214, bempeg, 
BEMPEG 
bempegaldesleukin (International Nonproprietary Name [INN] for NKTR-214) 


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Abbreviation or Term 
Definition 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate  
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PE 
pulmonary embolism 
PEG 
polyethylene glycol 
PFS 
progression-free survival 
PK 
Pharmacokinetic 
po 
Orally 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
q1h x 2 
every hour for 2 hours 
q1h x 3 
every hour for 3 hours 
q1h x 4 
every hour for 4 hours 
q1w 
every week 
q2w 
every 2 weeks  
q3w 
every 3 weeks 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cells 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin 2 
ROS1 
c-ros oncogene 1 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 


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Nektar Therapeutics 
 
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Abbreviation or Term 
Definition 
SAP 
statistical analysis plan  
SD 
stable disease 
SLD 
sum of the longest diameters 
SOP 
standard operating procedure 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
SWFI 
sterile water for injection 
t1/2 
half-life 
T3 
Triiodothyronine 
T4 
free thyroxine 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
TIL 
tumor infiltrating lymphocyte 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum concentration 
TP 
total protein 
TPS 
tumor proportion score 
Treg 
regulatory T cell 
TSH 
thyroid stimulating hormone 
TTR 
time to response 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
Vd 
volume of distribution 
WBC 
white blood cell 
WCBP 
women of childbearing potential 
 


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1.0 
STUDY SYNOPSIS  
Name of Sponsor:  
Nektar Therapeutics 
Name of Finished 
Products: 
Bempegaldesleukin (NKTR-214) Drug Product 
Keytruda® 
Name of Active 
Ingredients: 
Bempegaldesleukin (NKTR-214) Drug Substance 
Pembrolizumab (anti-PD-1) 
Title of Study: 
A Phase 1/2, Open-label, Multicenter Study to Investigate the Safety and Preliminary 
Efficacy of Combined Bempegaldesleukin (NKTR-214) and Pembrolizumab with or 
without Chemotherapy in Patients with Locally Advanced or Metastatic Solid 
Tumors 
Duration of Treatment:  
Patients will be treated until disease progression, death, unacceptable toxicity, 
symptomatic deterioration, lost to follow up, the Investigator decides to discontinue 
treatment, the patient decides to discontinue treatment or withdraw consent or Nektar 
Therapeutics decides to terminate the trial. Treatment may continue beyond 
progression if there is clinical benefit as determined by the Investigator. 
Phase of Development: 
Phase 1/2 
Objectives: 
Primary Objectives: Dose Optimization or Dose Expansion Cohorts 
The primary objectives in the dose optimization cohorts are: 
• 
To evaluate the safety and tolerability of NKTR-214 in combination with 
pembrolizumab. 
• 
To define the MTD/RP2D and optimal dosing schedule of NKTR-214 in 
combination with pembrolizumab. 
The primary objective in all the dose expansion cohorts is: 
• 
To determine the ORR per blinded independent central review (BICR) by 
RECIST 1.1 of NKTR-214 plus pembrolizumab with or without systemic 
chemotherapy in patients with untreated metastatic NSCLC. 
Secondary Objectives: Dose Optimization and/or Dose Expansion Cohorts 
The secondary objectives in the dose optimization and/or dose expansion cohorts are: 
• 
To evaluate safety and tolerability of NKTR-214 plus pembrolizumab with or 
without systemic chemotherapy in patients with untreated NSCLC (dose 
expansion only). 
• 
To assess the preliminary efficacy (per BICR) of NKTR-214 plus 
pembrolizumab with or without systemic chemotherapy: 
- 
objective response rate (ORR) by RECIST 1.1 (dose optimization only) 
- 
duration of response (DOR) by RECIST 1.1 
- 
clinical benefit rate (CBR) by RECIST 1.1 
- 
time to response (TTR) by RECIST 1.1 




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patients enrolled in the 3 + 3 dose optimization cohort and the dose optimization 
Cohort 1b will include patients enrolled in the step-up dose optimization cohort.  
The dose expansion cohorts will include first-line NSCLC patients (Cohorts 2, 3, 4, 
and 5). 
The original protocol and amendments (up to and including Amendment 4), 
evaluated atezolizumab in combination with NKTR-214 (0.006 mg/kg) for treatment 
of second-line NSCLC and first- and second- line urothelial carcinoma and 
pembrolizumab in combination with NKTR-214 (0.006 mg/kg) for treatment of 
first-line metastatic melanoma and first- and second-line NSCLC. Patients in the 
pembrolizumab first-line NSCLC cohort will continue on study in the dose 
expansion cohort of Amendment 5.0 or subsequent versions; however, the 
atezolizumab second-line NSCLC and first- or second-line urothelial carcinoma 
cohorts and the pembrolizumab first-line melanoma cohort have been closed to 
further enrollment. Patients on study who were enrolled in these cohorts under prior 
amendments will continue treatment as described in Amendment 5.0 and subsequent 
versions. Patients will be followed for efficacy and safety until the patient is lost to 
follow-up, withdraws consent, or patient death. 
Based on the findings from the NKTR-214 monotherapy study (EXCEL; 15-214-01) 
(see Section 2.1.4.1) and findings from the dose-escalation part of the PIVOT-02 
study (16-214-02) (see Section 2.1.4.2), the RP2D of NKTR-214 in combination 
with nivolumab 360 mg q3w was determined to be 0.006 mg/kg. 
Dose Optimization Cohorts (Cohorts 1a and 1b) 
Patients enrolled in the 3 + 3 dose optimization schema (Cohort 1a) will start 
NKTR-214 at a dose of 0.008 mg/kg q3w with pembrolizumab. Patients enrolled in 
the step-up dose optimization schema (Cohort 1b) will start NKTR-214 q3w with 
pembrolizumab at the previously tolerated dose established in the 3 + 3 dose 
optimization schema as determined by the SRC. Doses will be increased in 
0.002 mg/kg increments for the dose optimization cohorts (Figure 2).  
At the Investigator’s discretion, step-up dose increases may be delayed by 1 cycle. 
Moreover, the SRC or Sponsor may determine that inadequate information has been 
obtained in a cohort of 3 patients and may enroll additional patients to further assess 
the benefit/risk profile at a given dose level.  
For dose optimization cohorts, the SRC will decide the following: 
o Dose escalation to the next dose level. 
o Dose levels of NKTR-214 for a given cohort may be reduced depending on the 
severity, duration, and frequency of toxicities observed at the previous dose level 
tested. 
o Decision to evaluate NKTR-214 in combination with pembrolizumab at higher 
doses and different dose schedules to assess the benefit/risk profile within the 
anticipated total number of 40 patients. 
The dose-limiting toxicity (DLT) evaluation period for the 3 + 3 and step-up dose 
optimization cohorts will be 3 weeks (21 days) (Table 9). Any DLT past the DLT 
window is a delayed DLT.  
Dose Expansion Cohorts (Cohorts 2, 3, 4, and 5) 
Dose Expansion Cohort 2 (0.006 mg/kg of NKTR-214)  
The Dose Expansion Cohort 2 is currently enrolling first-line NSCLC patients at a 
dose of 0.006 mg/kg of NKTR-214 combined with pembrolizumab. 
Dose Expansion Cohort 3 (0.010 mg/kg of NKTR-214)  
Following review of safety and efficacy data from Cohort 2, approximately 
58 response-evaluable first-line NSCLC patients may be enrolled in Cohort 3, 
starting at a dose of 0.010 mg/kg of NKTR-214 combined with pembrolizumab. 
Following data review for safety and efficacy, dose adjustments may be made for 
subsequent patients within Cohort 3 in accordance with the findings from the dose 


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optimization cohorts. Enrollment may be stopped before 58 response-evaluable 
patients are enrolled. 
Dose Expansion Cohorts 4 and 5  
Following review of safety and efficacy data from Cohorts 2 and 3, a decision may 
be made on whether to initiate Cohorts 4 and 5. Approximately 63 response-
evaluable, first-line, nonsquamous NSCLC patients may be enrolled in Cohort 4, 
starting at a dose of either 0.006 mg/kg or 0.010 mg/kg of NKTR-214 (depending on 
available data from Cohorts 2 and 3) combined with pembrolizumab and 
platinum-based chemotherapy. Following data review for safety and efficacy, dose 
adjustments may be made for subsequent patients within Cohort 4 or Cohort 5 in 
accordance with the findings from the dose expansion cohorts.  
Key Eligibility Criteria: 
o Provide written, informed consent to participate in the study and follow the study 
procedures. 
o Age 18 years or older at the time of signing the informed consent form (ICF). 
o Life expectancy > 12 weeks from the time of enrollment as determined by the 
Investigator. 
o In the dose optimization cohorts, patients may have received no more than 
1 prior line of systemic therapy for metastatic cancer. A “line of therapy” is 
defined as any regimen – single-agent or combination therapy, cytotoxic therapy, 
immuno-oncology therapy separately or in combination – that is given in a non-
palliative setting and is stopped for progression of disease. 
o Patients must have a minimum of 6 months of response to any non-palliative 
cancer-directed treatment. 
o Prior IL-2 therapy is allowed for patients in the dose optimization cohorts who 
have completed therapy, and who have reported no severe ADRs or had all 
ADRs completely resolved. Prior IL-2 therapy is not allowed for patients in the 
dose expansion cohorts. 
o Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
o Measurable disease per RECIST 1.1. 
o A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 90 days 
prior to Cycle 1 Day 1 
o Oxygen saturation ≥ 90% on room air for all indications. 
o Patients with hypertension must be on ≤ 2 antihypertensive medications and 
without change for the 14 days prior to randomization. Screening blood pressure 
must be systolic < 150 mm Hg and < 90 mm Hg for diastolic blood pressure.  
o 
For France only: screening blood pressure must be systolic < 140 mm 
Hg and < 90 mm Hg for diastolic blood pressure. 
o A brain magnetic resonance image (MRI) at Screening is required for all patients 
with metastatic NSCLC, and for patients with other tumor types who have 
known brain metastasis.  
o Patients with brain metastases are eligible if all the criteria below are fulfilled:  
a. 
Brain metastases must be treated at least 2 weeks prior to study 
treatment initiation. 
b. Brain imaging after treatment and within the screening period must 
demonstrate no new or progressing brain metastases.  
c. 
No requirement for systemic corticosteroids >10 mg/day prednisone 
equivalents at therapy initiation. Stable doses of anticonvulsants are 
allowed. 
d. No clinically significant symptoms associated with brain metastases. 


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o Tumor tissue sample is required for all patients. Acceptable samples include 
archival tissue obtained no more than 12 months prior to enrollment if the patient 
has not received systemic treatment between the time of biopsy/resection and 
enrollment. Otherwise, a fresh tumor biopsy taken during screening is required.  
o For France only:  enrolled patients must be affiliated to a Social Security System. 
The following additional inclusion criteria are for the dose optimization cohorts (see 
Section 4.1.1) or dose expansion cohort (see Section 4.1.2). 
Dose Optimization Cohorts (Cohorts 1a and 1b) 
Tumor Types Included in Dose Optimization Cohorts  
(NKTR-214 and Pembrolizumab) 
Tumor Type 
Line of Treatment in 
Metastatic Setting 
PD-L1 Status 
Melanoma 
1st and 2nd 
Any 
Non-small cell lung 
cancer  
1st and 2nd  
Any 
Urothelial carcinoma 
1st and 2nd 
Any 
Head and neck 
squamous  
cell carcinoma 
1st and 2nd 
Any 
Hepatocellular 
carcinoma 
1st and 2nd 
Any 
1L and 2L Melanoma  
o 
Histologically confirmed Stage IV (metastatic) melanoma. 
1L and 2L Non-small Cell Lung Cancer  
o 
Histologically confirmed diagnosis of Stage IV NSCLC.  
o 
Patients with actionable mutations with approved targeted therapy in 
NSCLC are excluded. Testing for mutations should be performed per 
standard of care.  
1L and 2L Urothelial Carcinoma 
o 
Histologically confirmed diagnosis of metastatic urothelial carcinoma.  
1L and 2L Head and Neck Squamous Cell Carcinoma (HNSCC) 
o 
Histologically confirmed diagnosis of metastatic HNSCC.  
1L and 2L Hepatocellular Carcinoma (HCC) 
o 
Histologically confirmed diagnosis of metastatic HCC. 
Dose Expansion Cohorts  
1L Non- Small Cell Lung Cancer (Cohorts 2, 3, 4, and 5) 
o 
Histologically confirmed diagnosis of Stage IV NSCLC. 


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o 
Tumor tissue sample is required to be submitted to the central lab for all 
patients prior to enrollment. Acceptable samples include archival tissue 
obtained no more than 12 months prior to enrollment if the patient has not 
received systemic treatment between the time of biopsy/resection and 
enrollment. Otherwise, a fresh tumor biopsy taken during screening is 
required. A tracking number confirming shipment of the sample to the 
central laboratory must be supplied prior to Cycle 1 Day 1. Within each 
subgroup, this is:  
o 
PD-L1 negative (PD-L1 < 1%; Cohort 2.1): 20 response-evaluable 
patients  
o 
PD-L1 low/intermediate (PD-L1 1% to 49%; Cohort 2.2): 
18 response-evaluable patients  
o 
PD-L1 highly positive (PD-L1 ≥ 50%; Cohort 2.3): 
20 response-evaluable patients 
o 
For France only: patients in subgroup PD-L1 < 50% (Cohorts 2.1, 2.2) 
will be excluded. Eligibility for PD-L1 status can be determined with a 
local or central PD-L1 test. 
o 
If the decision is made to open Cohort 3, approximately 
58 response-evaluable patients may be enrolled. 
o 
If the decision is made to open Cohorts 4 and 5, approximately 
63 response-evaluable patients may be enrolled in each cohort. 
o 
Patients with actionable mutations with approved targeted therapy in 
NSCLC are excluded. Testing for mutations should be performed per 
standard of care.  
o 
Must not have received anti-cancer therapy for treatment of metastatic lung 
cancer. 
o 
Must not have received prior immunotherapy. 
Test Product, Dose and 
Mode of Administration:  
Each patient’s NKTR-214 dose will be determined by the NKTR-214 dose 
optimization or dose expansion schema and the patient’s weight in kilograms 
(Section 5.3.2). The patient’s weight in kilograms will be determined on Day 1 
before the start of each cycle; for weight changes of ± 10% from baseline, 
recalculation of dose is not required.  
Patients enrolled on previous amendments will follow dosing schedule of the 
amendment they were consented to. Pembrolizumab will be dosed as per the 
Pharmacy Manual.  
Dose Optimization Cohorts (Cohorts 1a and 1b) 
Study Drug Administration:  3 + 3 Dosing (Cohort 1a) Schema  
o 
NKTR-214 will be administered IV over 30 (± 5) minutes at a starting dose of 
0.008 mg/kg. Please refer to the Pharmacy Manual for additional details for 
study drug administration. 
 
Study Drug Administration:  Step-up Dosing (Cohort 1b) Schema  
o 
NKTR-214 will be administered IV over 30 (± 5) minutes starting at the 
previously tolerated dose established in the 3 + 3 dosing schema as determined 
by the Safety Review Committee (SRC) for the step-up dosing schema. This 
dose may increase at each cycle for individual patients at increments of 
0.002 mg/kg per the dose optimization schema in Figure 2. Please refer to the 
Pharmacy Manual for additional details for study drug administration. 
  
Dose Expansion Cohorts  
o 
Refer to the Pharmacy Manual for additional details related to study drug 
administration. 


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o 
Cohorts 4 and 5 may include: cisplatin, carboplatin, pemetrexed, nab-paclitaxel, 
and paclitaxel and will be dosed per local practice and label. 
o 
NKTR-214 will be administered q3w IV over 30 (± 5) minutes at the following 
doses: 
Cohort 2  
o Starting dose of NKTR-214: 0.006 mg/kg.  
Cohort 3  
o Starting dose of NKTR-214: 0.010 mg/kg.  
Cohort 4  
o Starting dose of NKTR-214: starting at a dose of either 0.006 mg/kg or 
0.010 mg/kg of NKTR-214 (depending on available data from Cohorts 2 
and 3). 
Cohort 5  
o Starting dose of NKTR-214: starting at a dose of either 0.006 mg/kg or 
0.010 mg/kg of NKTR-214 (depending on available data from Cohorts 2 
and 3). 
Safety: 
Safety will be assessed by an ongoing review of the following: 
• 
incidence of adverse events (AEs), including serious AEs (SAEs) 
• 
clinical laboratory tests (blood and urine sampling) 
• 
vital signs 
• 
physical examination 
Pharmacokinetics: 
Blood samples for PK analyses will be collected from all patients at multiple 
scheduled sampling times.  
Dose Optimization Cohorts (Cohorts 1a and 1b) 
For patients in 3 + 3 dose optimization cohort (Cohort 1a), blood for NKTR-214 PK 
determinations will be collected for Cycle 1 on Days 1, 3, 5, and 8 per the sampling 
scheme in Table 1. For Cycle 2 and every 3 cycles after Cycle 2 (ie, Cycles 5, 8, 11, 
etc.), blood will be collected predose on Day 1. For Cycles 2 and beyond, predose 
sampling assessments can be drawn within 72 hours prior to dosing. 
For patients in the step-up dose optimization cohort (Cohort 1b), blood for 
NKTR-214 PK determinations will be collected for Cycle 1 and only the first cycle 
of subsequent cycle(s) in which the patient is administered a step-up dose on Days 1, 
3, 5 and 8 per the sampling scheme in Table 1. With the exception of cycles in which 
the patient is administered a step-up dose, in Cycles ≥ 2, blood will be collected on 
predose on Day 1 on Cycle 2 and every 3 cycles after Cycle 2 (ie Cycles 5, 8, 11, 
etc.). For Cycles 2 and beyond, predose sampling assessments can be drawn within 
72 hours prior to dosing. 
Dose Expansion Cohorts (Cohorts 2, 3, 4, and 5):  
Blood for NKTR-214 PK determinations will be collected for Cycle 1 on Days 1, 3, 
5, and 8 per the sampling scheme in Table 2. Blood will be collected predose on 
Day 1 of Cycle 2 and every 3 cycles after Cycle 2. 
Plasma concentrations of NKTR-214 and its metabolites will be measured for each 
PK sample using validated or qualified method(s). Pharmacokinetic parameters such 
as maximum concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), 
clearance (CL), volume of distribution (Vd), and half-life (t½) will be estimated from 
plasma concentration-time data where feasible. 
Pharmacodynamics: 
Systemic and tumor tissue-based pharmacodynamic effects of NKTR-214 in 
combination with pembrolizumab will be examined. 
Blood samples (C1D1) and tumor tissue samples (screening) will be collected from 
all patients prior to their first dose of NKTR-214. Blood samples for 
pharmacodynamic analyses will be collected from all patients enrolled in the dose 




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Figure 1: 
Study Schematic 
 
 
 
 


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1.1 
Schedule of Events 
Table 1: 
Schedule of Events for Dose Optimization Cohorts 
Assessment Period 
Screening 
Cycle 1 (3 + 3) OR at the Start of Each Cycle 
a Patient is Administered a Step-up Dose 
Cycle 2 and 
Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 3 
Day 5 
(± 1 day) 
Day 8 
(± 1 day) 
Day 
15 to 21 
Day 1 
(± 3 days) 
EOTb 
30 (± 10) days 
Long-term 
Follow-up 
90 (± 10) daysc 
General Assessments 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
 
X 
 
X 
X 
 
Vital signse 
X 
X 
X 
 
X 
 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
 
X 
 
 
ECGf 
X 
 
 
 
 
 
 
 
 
ECHO/MUGAg 
X 
 
 
 
 
 
 
 
 
Oral hydration follow-uph 
 
 
X 
X 
 
 
X 
 
 
Adverse events review 
<----------------------------------------------------------------------------------------------------------------------------------> 
Concomitant 
medications/procedures review 
<----------------------------------------------------------------------------------------------------------------------------------> 
Quarterly follow-upc 
 
 
 
 
 
 
 
 
X 
Laboratory Tests and 
 Samples 
Pregnancy testi 
X 
X 
 
 
 
 
X 
X 
 
Hematologyj 
X 
X 
X 
X 
X 
 
X 
X 
 
Serum chemistryk 
X 
X 
 
X 
X 
 
X 
X 
 




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Footnotes: 
a. 
Study Days: Cycles are 21 days. Each cycle after Cycle 1 Day 1 must occur within 21 days (± 3 days) from the previous dose. Cycle intervals less than 21 
days should only occur if the Investigator believes there are no safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle. If scheduled visits 
or assessments coincide with a weekend or holiday, schedule at the next feasible date. Please contact the Medical Monitor to discuss any concerns about 
study visits or assessments that may fall out of the protocol-specified window because of unforeseen delays or other patient‑specific circumstances. All out 
of window visits and procedures will incur a protocol deviation. Study assessments, including imaging, may also be delayed or performed prior to the 
assessment window with permission from the medical monitor. All procedures and examinations should be performed before the administration of study 
drug(s), except as indicated.  
b. EOT Visit: The EOT visit should occur 30 (± 10) days after last dose of all study medications or before a new antineoplastic regimen (including 
commercially-sourced single-agent pembrolizumab) starts. EOT NKTR-214 immunogenicity sample must be drawn 30 (± 10) days after the last dose of 
NKTR-214. See Section 5.4. 
c. 
Long-Term Follow up: Long-term follow-up should continue until withdrawal of consent, death, or study termination by the Sponsor. Timing for long-term 
follow-up will be as follows: Upon discontinuation of all study treatment, the long-term follow-up visits should occur every 90 (± 10) days after the last dose 
of all study treatment and then every 90 (± 10) days for survival status. Per clinical judgment, the patient may come in earlier. If a patient did not experience 
PD by RECIST 1.1 when study drug treatment was discontinued, tumor assessments should continue every 90 (± 10) days until PD, consent withdrawal, 
start of new antineoplastic regimen, death, or study termination by Sponsor. Immunogenicity sample must be drawn 90 days (± 10) days after the last 
administered dose of NKTR-214. See Section 5.5. 
d. Physical Examination: Full physical examinations should be conducted at screening, and Days 1, 3 and 8 of Cycle 1. At Cycle 2 and beyond, full physical 
examinations are conducted on Day 1 of each cycle, and EOT. Other examinations may be focused, at the discretion of the Investigator, to identify changes 
from baseline or evaluate changes based on the patient’s clinical symptoms. Weight is to be reported at each dosing visit (for weight changes of ± 10% from 
baseline, recalculation of dose is not required), height at screening visit only. See Section 7.15. 
e. 
Vital Signs: Some clinic visits will have more frequent vital sign measurements. Vital signs include pulse rate, respiratory rate, systolic and diastolic blood 
pressure (supine position), oxygen saturation (on dosing days only), and temperature (oral preferred). On dosing days vital signs are to be taken and recorded 
prior to NKTR-214 dosing and monitored and recorded following completion of pembrolizumab administration. For the frequency (Cycle 1 Day 1, 3, 8 and 
Cycle ≥ 2 Day 1), see Sections 5.3.4.1 and 7.16.  
f. 
ECG: A screening 12-lead ECG must be done during the 28-day screening window prior to Cycle 1 Day 1. Patients must be resting quietly in the supine 
position for at least 5 minutes before the ECG collection. See Section 7.17. 
g. ECHO/MUGA: A standard echocardiogram (ECHO) or multigated acquisition (MUGA) will be performed for all patients within 90 days prior to dosing on 
Cycle 1 Day 1 to assess for cardiac function and left ventricular ejection fraction (LVEF). In the event of an abnormal ECHO, the Investigator may perform 
a stress ECHO (either exercise or nuclear). A MUGA scan can be performed to assess cardiac function and LVEF if a standard ECHO cannot be performed. 
See Section 7.18. 
h. Oral Hydration Follow-up: Patients will be asked about in-home hydration guideline compliance on Day 5 (see Section 5.3.4.2). In addition, between 2 and 
4 days (inclusive) following treatment with NKTR-214, site personnel must contact the patient (by telephone or clinic visit) to remind the patient of the oral 
hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and document the results of the discussion.  
i. 
Pregnancy Tests: Local serum pregnancy test required at screening (anytime during 28-day screening window; ICF signature not required), and urine 
pregnancy tests are required before dosing on Day 1 of each cycle and EOT for women of childbearing potential (WCBP). See Section 7.19. 




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s. 
Tumor Assessment: Tumor assessment at screening then every 9 weeks (± 7 days) from Cycle 1 Day 1, EOT (unless scan done within 4 weeks) and at the 
90-day long-term follow-up visits, (see Section 5.7). If a patient has an unconfirmed PR or CR, an early scan is recommended 4 weeks or later, and the next 
scheduled 9-week scan may be skipped if less than 4 weeks from the early scan. All subsequent tumor assessments must remain on the original 9-week 
assessment schedule. Patients with unconfirmed subsequent tumor assessments must remain on the original 9-week assessment schedule unless an early scan 
is clinically indicated. A brain MRI at screening is required for all patients with metastatic NSCLC, and for patients with other tumor types who have known 
brain metastasis only. Subsequent brain MRIs for all cohorts can be done at 9-week intervals as clinically indicated. Assessments will become less frequent 
during the long-term follow-up period. Changes in tumor assessments (either PR or CR) must be confirmed by repeat assessments that should be performed 
≥ 4 weeks after criteria for response are first met. See Section 8.2.2.3.  
t. 
Administer IV Fluids: Patients should receive administration of 1 liter of normal saline IV with study treatment infusion on Day 1 of each cycle. In 
addition, consider administering 1 liter of normal saline IV when the patients return for clinic visits (ex. if the patient returns for PK draws on Days 3 and 5 
of Cycle 1), anytime based on the patients need, or as clinically indicated. See Section 5.3.4.2. 
u. Prophylactic Acetaminophen/NSAIDS: Patients will be premedicated with acetaminophen (eg, 650 mg every 6 hours) or NSAIDs (eg, ibuprofen 400 mg 
every 6 hours) on Day 1 of each cycle. In addition, acetaminophen or NSAIDs will be administered on Day 2 to 5 of each cycle every 6 hours. See 
Section 5.3.4.3.  
v. Drug Administration: When administered on the same day, NKTR-214 will be administered first (30 ± 5 minutes) followed by pembrolizumab (30 ± 
5 minutes). See Section 5.3.1. After NKTR-214 administration, flush the intravenous line with an appropriate amount of the same diluent used for dose 
preparation to ensure that the total dose is completely administered over the appropriate time. No delay is necessary between drug administrations after 
checking for stable vitals. 
Abbreviations:  CVA = cerebrovascular event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiography; 
EOT = End of Treatment; IV = intravenous; MUGA = multigated acquisition; NSAIDS = nonsteroidal anti-inflammatory drugs; PK = pharmacokinetic. 
   


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Table 2: 
Schedule of Events for Dose Expansion Cohorts 2 and 3 
Assessment Period 
Screening 
Cycle 1 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 3 
Day 5 
(±1 day) 
Day 8 
(± 1 day) 
 
Day 1 
(±3 days) 
 
EOTb 
30 (± 10) days 
Long-term 
Follow up 
90 (± 10) daysc 
General Assessments 
Obtain informed consent 
X 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
 
X 
X  
X 
 
Vital signse 
X 
X 
X 
 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
ECGf 
X 
 
 
 
 
 
 
 
ECHO/MUGAg 
X 
 
 
 
 
 
 
 
Oral hydration follow-uph 
 
 
X 
X 
 
X 
 
 
Adverse events review 
<--------------------------------------------------------------------------------------------------------------------------------> 
Concomitant 
medications/procedures review 
<--------------------------------------------------------------------------------------------------------------------------------> 
Quarterly follow-upc 
 
 
 
 
 
 
 
X 
Laboratory Tests and 
 Samples 
Pregnancy testi 
X 
X 
 
 
 
X 
X 
 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryk 
X 
X 
 
X 
X 
X 
X 
 
Coagulationk 
X 
X 
 
X 
X 
X 
X 
 
Additional testsl 
X 
X 
 
 
X 
X 
X 
 




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Footnotes: 
a. 
Study Days: Cycles are 21 days. Each cycle after Cycle 1 Day 1 must occur within 21 days (± 3 days) from the previous dose. Cycle intervals less than 
21 days should only occur if the Investigator believes there are no safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle. If scheduled 
visits or assessments coincide with a weekend or holiday, schedule at the next feasible date. Please contact the Medical Monitor to discuss any concerns 
about study visits or assessments that may fall out of the protocol-specified window because of unforeseen delays or other patient‑specific circumstances. All 
out of window visits and procedures will incur a protocol deviation. Study assessments, including imaging, may also be delayed or performed prior to the 
assessment window with permission from the medical monitor. All procedures and examinations should be performed before the administration of study 
drug(s), except as indicated.  
b. EOT Visit: The EOT visit should occur 30 (± 10) days after the last dose of all study medications or before a new antineoplastic regimen (including 
commercially-sourced single-agent pembrolizumab) starts. EOT NKTR-214 immunogenicity sample must be drawn 30 (± 10 days) after the last dose of 
NKTR-214. See Section 5.4.  
c. 
Long-Term Follow up: Long-term follow-up should continue until withdrawal of consent, death, or study termination by the Sponsor. Timing for long-term 
follow-up will be as follows: Upon discontinuation of all study treatment, the long-term follow-up visits should occur every 90 (± 10) days for survival 
status. Per clinical judgment, the patient may come in earlier. If a patient did not experience PD by RECIST 1.1 when study drug treatment was 
discontinued, tumor assessments should continue every 90 (± 10) days until PD, consent withdrawal, start of new antineoplastic regimen, death, or study 
termination by Sponsor. See Section 5.5. Immunogenicity sample must be drawn 90 days (± 10 days) after the last administered dose of NKTR-214.  
d. Physical Examination: Full physical examinations should be conducted at screening, and Days 1, 3 and 8 of Cycle 1. In Cycle 2 and beyond, full physical 
examinations are conducted on Day 1 of each cycle, and EOT. Other examinations may be focused, at the discretion of the Investigator, to identify changes 
from baseline or evaluate changes based on the patient’s clinical symptoms. Weight is to be reported at each dosing visit, height at screening visit only. See 
Section 7.15. 
e. 
Vital Signs: Some clinic visits will have more frequent vital sign measurements. Vital signs include pulse rate, respiratory rate, systolic and diastolic blood 
pressure (supine position), oxygen saturation (on dosing days only), and temperature (oral preferred). On dosing days vital signs are to be taken and recorded 
prior to NKTR-214 dosing and monitored and recorded following completion of pembrolizumab administration. For the frequency (Cycle 1 Day 1, 3, 8 and  
Cycle ≥ 2 Day 1), see Sections 5.3.4.1 and 7.16.  
f. 
ECG: A screening 12 -lead ECG must be done during the 28-day screening window prior to Cycle 1 Day 1. Patients must be resting quietly in the supine 
position for at least 5 minutes before the ECG collection. On-treatment ECG monitoring may be initiated if clinically indicated. See Section 7.17. 
g. ECHO/MUGA: A standard echocardiogram (ECHO) or multigated acquisition (MUGA) will be performed for all patients within 90 days prior to dosing on 
Cycle 1 Day 1 to assess for cardiac function and left ventricular ejection fraction (LVEF). In the event of an abnormal ECHO, the Investigator may perform 
a stress ECHO (either exercise or nuclear). A MUGA scan can be performed to assess cardiac function and LVEF if a standard ECHO cannot be performed. 
See Section 7.18. 
h. Oral Hydration Follow-up: Patients will be asked about in-home hydration guideline compliance on Day 5 (see Section 5.3.4.2). In addition, between 2 and 
4 days (inclusive) following treatment with NKTR-214, site personnel must contact the patient (by telephone or clinic visit) to remind the patient of the oral 
hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and document the results of the discussion.  
i. 
Pregnancy Tests: A local serum pregnancy test is required at screening (anytime during 28-day screening window; ICF signature not required), and urine 
pregnancy tests are required before dosing on Day 1 of each cycle and EOT for women of childbearing potential (WCBP). See Section 7.19. 
j. 
Hematology: Local hematology assessments scheduled for the day of study drug(s) dosing must be available and assessed before dosing. The sampling for 
hematology assessments can be drawn within 72 hours prior to dosing. See Appendix 1. 




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v. Drug Administration: When administered on the same day, NKTR-214 will be administered first (30 ± 5 minutes) followed by pembrolizumab (30 ± 
5 minutes). See Section 5.3.1. After NKTR-214 administration, flush the intravenous line with an appropriate amount of the same diluent used for dose 
preparation to ensure that the total dose is completely administered over the appropriate time. No delay is necessary between drug administrations after 
checking for stable vitals. 
w. For Australia Only: Serum Cortisol Level: The Belberry HREC requires that all study Investigators in Australia follow the current NCCN guidelines 
relating to the management of immune checkpoint inhibitor-related toxicities, specifically related to serum cortisol monitoring. Please refer to the current 
version of the above-mentioned guidelines (Thompson 2020) and ensure that compliance with the guidelines is documented in the patient source 
documentation. Serum cortisol monitoring should be performed in Cycles 1, 2, 3, and 4 only. 
Abbreviations:  CVA = cerebrovascular event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiography; 
EOT = End of Treatment; IV = intravenous; MUGA = multigated acquisition; NSAIDS = nonsteroidal anti-inflammatory drugs; PK = pharmacokinetic 
 
 
 


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Table 3: 
Schedule of Events for Dose Expansion Cohort 4 
Assessment Period 
Screening 
Cycle 1 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 3 
Day 5 
(± 1 day) 
Day 8 
(± 1 day) 
 
Day 1 
(± 3 days) 
 
EOTb 
30 (± 10) days 
Long-term 
Follow up 
90 (± 10) daysc 
General Assessments 
Obtain informed consent 
X 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
 
X 
X  
X 
 
Vital signse 
X 
X 
X 
 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
ECGf 
X 
 
 
 
 
 
 
 
ECHO/MUGAg 
X 
 
 
 
 
 
 
 
Oral hydration follow-uph 
 
 
X 
X 
 
X 
 
 
Adverse events review 
<--------------------------------------------------------------------------------------------------------------------------------> 
Concomitant 
medications/procedures review 
<--------------------------------------------------------------------------------------------------------------------------------> 
Quarterly follow-upc 
 
 
 
 
 
 
 
X 
Laboratory Tests and
 Samples 
Pregnancy testi 
X 
X 
 
 
 
X 
X 
 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryk 
X 
X 
 
X 
X 
X 
X 
 
Coagulationk 
X 
X 
 
X 
X 
X 
X 
 
Additional testsl 
X 
X 
 
 
X 
X 
X 
 




Protocol No. 16-214-05 Amendment 7.0 
 
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Footnotes: 
a. 
Study Days: Cycles are 21 days. Each cycle after Cycle 1 Day 1 must occur within 21 days (± 3 days) from the previous dose. Cycle intervals less than 
21 days should only occur if the Investigator believes there are no safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle. If scheduled 
visits or assessments coincide with a weekend or holiday, schedule at the next feasible date. Please contact the Medical Monitor to discuss any concerns 
about study visits or assessments that may fall out of the protocol-specified window because of unforeseen delays or other patient‑specific circumstances. All 
out of window visits and procedures will incur a protocol deviation. Study assessments, including imaging, may also be delayed or performed prior to the 
assessment window with permission from the medical monitor. All procedures and examinations should be performed before the administration of study 
drug(s), except as indicated.  
b. EOT Visit: The EOT visit should occur 30 (± 10) days after the last dose of all study medications or before a new antineoplastic regimen (including 
commercially-sourced single-agent pembrolizumab) starts. EOT NKTR-214 immunogenicity sample must be drawn 30 (± 10 days) after the last dose of 
NKTR-214. See Section 5.4.  
c. 
Long-Term Follow up: Long-term follow-up should continue until withdrawal of consent, death, or study termination by the Sponsor. Timing for long-term 
follow-up will be as follows: Upon discontinuation of all study treatment, the long-term follow-up visits should occur every 90 (± 10) days for survival 
status. Per clinical judgment, the patient may come in earlier. If a patient did not experience PD by RECIST 1.1 when study drug treatment was 
discontinued, tumor assessments should continue every 90 (± 10) days until PD, consent withdrawal, start of new antineoplastic regimen, death, or study 
termination by Sponsor. See Section 5.5. Immunogenicity sample must be drawn 90 days (± 10 days) after the last administered dose of NKTR-214.  
d. Physical Examination: Full physical examinations should be conducted at screening, and Days 1, 3 and 8 of Cycle 1. In Cycle 2 and beyond, full physical 
examinations are conducted on Day 1 of each cycle, and EOT. Other examinations may be focused, at the discretion of the Investigator, to identify changes 
from baseline or evaluate changes based on the patient’s clinical symptoms. Weight is to be reported at each dosing visit, height at screening visit only. See 
Section 7.15. 
e. 
Vital Signs: Some clinic visits will have more frequent vital sign measurements. Vital signs include pulse rate, respiratory rate, systolic and diastolic blood 
pressure (supine position), oxygen saturation (on dosing days only), and temperature (oral preferred). On dosing days vital signs are to be taken and recorded 
prior to NKTR-214 dosing and monitored and recorded following completion of pembrolizumab administration. For the frequency (Cycle 1 Day 1, 3, 8 and  
Cycle ≥ 2 Day 1), see Sections 5.3.4.1 and 7.16.  
f. 
ECG: A screening 12 -lead ECG must be done during the 28-day screening window prior to Cycle 1 Day 1. Patients must be resting quietly in the supine 
position for at least 5 minutes before the ECG collection. On-treatment ECG monitoring may be initiated if clinically indicated. See Section 7.17. 
g. ECHO/MUGA: A standard echocardiogram (ECHO) or multigated acquisition (MUGA) will be performed for all patients within 90 days prior to dosing on 
Cycle 1 Day 1 to assess for cardiac function and left ventricular ejection fraction (LVEF). In the event of an abnormal ECHO, the Investigator may perform 
a stress ECHO (either exercise or nuclear). A MUGA scan can be performed to assess cardiac function and LVEF if a standard ECHO cannot be performed. 
See Section 7.18. 
h. Oral Hydration Follow-up: Patients will be asked about in-home hydration guideline compliance on Day 5 (see Section 5.3.4.2). In addition, between 2 and 
4 days (inclusive) following treatment with NKTR-214, site personnel must contact the patient (by telephone or clinic visit) to remind the patient of the oral 
hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and document the results of the discussion.  
i. 
Pregnancy Tests: A local serum pregnancy test is required at screening (anytime during 28-day screening window; ICF signature not required), and urine 
pregnancy tests are required before dosing on Day 1 of each cycle and EOT for women of childbearing potential (WCBP). See Section 7.19. 
j. 
Hematology: Local hematology assessments scheduled for the day of study drug(s) dosing must be available and assessed before dosing. The sampling for 
hematology assessments can be drawn within 72 hours prior to dosing. See Appendix 1. 




Protocol No. 16-214-05 Amendment 7.0 
 
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Nektar Therapeutics 
 
Page 40 of 138 
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23 December 2020 
v. Drug Administration: When administered on the same day, NKTR-214 will be administered first (30 ± 5 minutes) followed by pembrolizumab 
(30 ± 5 minutes). See Section 5.3.1. After NKTR-214 administration, flush the intravenous line with an appropriate amount of the same diluent used for dose 
preparation to ensure that the total dose is completely administered over the appropriate time. No delay is necessary between drug administrations after 
checking for stable vitals. Chemotherapy drugs will be administered after Pembrolizumab following local practice and labels.  
w. For Australia Only: Serum Cortisol Level: The Belberry HREC requires that all study Investigators in Australia follow the current NCCN guidelines 
relating to the management of immune checkpoint inhibitor-related toxicities, specifically related to serum cortisol monitoring. Please refer to the current 
version of the above-mentioned guidelines (Thompson 2020) and ensure that compliance with the guidelines is documented in the patient source 
documentation. Serum cortisol monitoring should be performed in Cycles 1, 2, 3, and 4 only. 
Abbreviations:  CVA = cerebrovascular event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiography; 
EOT = End of Treatment; IV = intravenous; MUGA = multigated acquisition; NSAIDS = nonsteroidal anti-inflammatory drugs; PK = pharmacokinetic 
 
 


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Table 4: 
Schedule of Events for Dose Expansion Cohort 5 
Assessment Period 
Screening 
Cycle 1 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 3 
Day 5 
(± 1 day) 
Day 8 
(± 1 day) 
 
Day 1 
(± 3 days) 
 
EOTb 
30 (± 10) days 
Long-term 
Follow up 
90 (± 10) daysc 
General Assessments 
Obtain informed consent 
X 
 
 
 
 
 
 
 
Physical examinationd 
X 
X 
X 
 
X 
X  
X 
 
Vital signse 
X 
X 
X 
 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
ECGf 
X 
 
 
 
 
 
 
 
ECHO/MUGAg 
X 
 
 
 
 
 
 
 
Oral hydration follow-uph 
 
 
X 
X 
 
X 
 
 
Adverse events review 
<--------------------------------------------------------------------------------------------------------------------------------> 
Concomitant 
medications/procedures review 
<--------------------------------------------------------------------------------------------------------------------------------> 
Quarterly follow-upc 
 
 
 
 
 
 
 
X 
Laboratory Tests and 
Samples 
Pregnancy testi 
X 
X 
 
 
 
X 
X 
 
Hematologyj 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryk 
X 
X 
 
X 
X 
X 
X 
 
Coagulationk 
X 
X 
 
X 
X 
X 
X 
 
Additional testsl 
X 
X 
 
 
X 
X 
X 
 




Protocol No. 16-214-05 Amendment 7.0 
 
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Footnotes: 
a. 
Study Days: Cycles are 21 days. Each cycle after Cycle 1 Day 1 must occur within 21 days (± 3 days) from the previous dose. Cycle intervals less than 
21 days should only occur if the Investigator believes there are no safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle. If scheduled 
visits or assessments coincide with a weekend or holiday, schedule at the next feasible date. Please contact the Medical Monitor to discuss any concerns 
about study visits or assessments that may fall out of the protocol-specified window because of unforeseen delays or other patient‑specific circumstances. All 
out of window visits and procedures will incur a protocol deviation. Study assessments, including imaging, may also be delayed or performed prior to the 
assessment window with permission from the medical monitor. All procedures and examinations should be performed before the administration of study 
drug(s), except as indicated.  
b. EOT Visit: The EOT visit should occur 30 (± 10) days after the last dose of all study medications or before a new antineoplastic regimen (including 
commercially-sourced single-agent pembrolizumab) starts. EOT NKTR-214 immunogenicity sample must be drawn 30 (± 10 days) after the last dose of 
NKTR-214. See Section 5.4.  
c. 
Long-Term Follow up: Long-term follow-up should continue until withdrawal of consent, death, or study termination by the Sponsor. Timing for long-term 
follow-up will be as follows: Upon discontinuation of all study treatment, the long-term follow-up visits should occur every 90 (± 10) days for survival 
status. Per clinical judgment, the patient may come in earlier. If a patient did not experience PD by RECIST 1.1 when study drug treatment was 
discontinued, tumor assessments should continue every 90 (± 10) days until PD, consent withdrawal, start of new antineoplastic regimen, death, or study 
termination by Sponsor. See Section 5.5. Immunogenicity sample must be drawn 90 days (± 10 days) after the last administered dose of NKTR-214.  
d. Physical Examination: Full physical examinations should be conducted at screening, and Days 1, 3 and 8 of Cycle 1. In Cycle 2 and beyond, full physical 
examinations are conducted on Day 1 of each cycle, and EOT. Other examinations may be focused, at the discretion of the Investigator, to identify changes 
from baseline or evaluate changes based on the patient’s clinical symptoms. Weight is to be reported at each dosing visit, height at screening visit only. See 
Section 7.15.  
e. 
Vital Signs: Some clinic visits will have more frequent vital sign measurements. Vital signs include pulse rate, respiratory rate, systolic and diastolic blood 
pressure (supine position), oxygen saturation (on dosing days only), and temperature (oral preferred). On dosing days vital signs are to be taken and recorded 
prior to NKTR-214 dosing and monitored and recorded following completion of pembrolizumab administration. For the frequency (Cycle 1 Day 1, 3, 8 and  
Cycle ≥ 2 Day 1), see Sections 5.3.4.1 and 7.16.  
f. 
ECG: A screening 12 -lead ECG must be done during the 28-day screening window prior to Cycle 1 Day 1. Patients must be resting quietly in the supine 
position for at least 5 minutes before the ECG collection. On-treatment ECG monitoring may be initiated if clinically indicated. See Section 7.17. 
g. ECHO/MUGA: A standard echocardiogram (ECHO) or multigated acquisition (MUGA) will be performed for all patients within 90 days prior to dosing on 
Cycle 1 Day 1 to assess for cardiac function and left ventricular ejection fraction (LVEF). In the event of an abnormal ECHO, the Investigator may perform 
a stress ECHO (either exercise or nuclear). A MUGA scan can be performed to assess cardiac function and LVEF if a standard ECHO cannot be performed. 
See Section 7.18. 
h. Oral Hydration Follow-up: Patients will be asked about in-home hydration guideline compliance on Day 5 (see Section 5.3.4.2). In addition, between 2 and 
4 days (inclusive) following treatment with NKTR-214, site personnel must contact the patient (by telephone or clinic visit) to remind the patient of the oral 
hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and document the results of the discussion.  
i. 
Pregnancy Tests: A local serum pregnancy test required at screening (anytime during 28-day screening window; ICF signature not required), and urine 
pregnancy tests are required before dosing on Day 1 of each cycle and EOT for women of childbearing potential (WCBP). See Section 7.19. 
j. 
Hematology: Local hematology assessments scheduled for the day of study drug(s) dosing must be available and assessed before dosing. The sampling for 
hematology assessments can be drawn within 72 hours prior to dosing. See Appendix 1. 




Protocol No. 16-214-05 Amendment 7.0 
 
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Nektar Therapeutics 
 
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v. Drug Administration: When administered on the same day, NKTR-214 will be administered first (30 ± 5 minutes) followed by pembrolizumab 
(30 ± 5 minutes). See Section 5.3.1. After NKTR-214 administration, flush the intravenous line with an appropriate amount of the same diluent used for dose 
preparation to ensure that the total dose is completely administered over the appropriate time. No delay is necessary between drug administrations after 
checking for stable vitals. Chemotherapy drugs will be administered after Pembrolizumab following local practice and labels. 
w. For Australia Only: Serum Cortisol Level: The Belberry HREC requires that all study Investigators in Australia follow the current NCCN guidelines 
relating to the management of immune checkpoint inhibitor-related toxicities, specifically related to serum cortisol monitoring. Please refer to the current 
version of the above-mentioned guidelines (Thompson 2020) and ensure that compliance with the guidelines is documented in the patient source 
documentation. Serum cortisol monitoring should be performed in Cycles 1, 2, 3, and 4 only. 
Abbreviations:  CVA = cerebrovascular event; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; ECHO = echocardiography; 
EOT = End of Treatment; IV = intravenous; MUGA = multigated acquisition; NSAIDS = nonsteroidal anti-inflammatory drugs; PK = pharmacokinetic 
 


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2.0 
INTRODUCTION 
2.1 
Background 
2.1.1 
NKTR-214 Mechanism of Action 
Bempegaldesleukin (NKTR-214) is a prodrug of a conjugated cancer immunotherapy cytokine 
that exerts its biological activity by binding to the IL-2 receptor and subsequent activation of 
effector T cells. As a PEGylated human recombinant IL-2 molecule of aldesleukin with an 
average of six releasable polyethylene glycol (PEG) chains, NKTR-214 can be administered 
conveniently in the outpatient setting using an antibody-like dosing regimen. The polymer 
conjugation renders the cytokine initially inactive. Upon intravenous administration, the PEG 
chains slowly release to generate the active cytokine species (mainly 2-PEG-IL-2 and 1-PEG-IL-
2) that have a peak plasma concentration 26 to 48 hours after infusion. The slow generation of 
the 2-PEG-IL-2 and 1 PEG-IL-2 significantly mitigates the rapid-onset, systemic cytokine-
related toxicities associated with high dose IL-2.  
The polymer conjugation of NKTR-214 promotes biased signaling through the IL-2 receptor beta 
gamma (IL-2Rβγ). Specifically, the location of the NKTR-214 PEG chains interferes with 
binding to the IL-2 alpha receptor subunit responsible for the undesirable effect of activating 
Tregs in the tumor while continuing to permit binding to the IL-2Rβγ (CD122) receptor. Upon 
infusion, NKTR-214 preferentially increases the proliferation, activation, and effector function 
of tumor antigen-specific CD8+ T cells and natural killer (NK) cells within the tumor 
microenvironment (TME) over expansion of unwanted intra-tumoral regulatory T cells (Tregs) 
that are activated through the IL-2 receptor alpha beta gamma (IL-2Rαβγ) (Charych 2016).  
NKTR-214 also correspondingly promotes expression of PD-1 on the surface of CD8+ T cells 
and induction of a Type II interferon gene signature in the TME, driving cell surface expression 
of programmed cell death ligand 1 (PD-L1) on tumor cells (Diab 2017). 
The immunological properties of NKTR-214 with the induction of tumor infiltrating 
lymphocytes and upregulation of the PD-1/PD-L1 axis makes NKTR-214 a potentially 
promising combination therapy for use with checkpoint inhibitors that target and inhibit the 
PD-1/PD-L1 pathway. Moreover, the safety profile of NKTR-214 does not overlap with that of 
checkpoint inhibitors, further supporting the use of NKTR-214 as a potentially complimentary 
combination partner with checkpoint inhibitors. 
2.1.2 
Rationale for the Combination of NKTR-214 and Immune Checkpoint 
Inhibitors 
Accumulating evidence suggests that patients with low baseline CD8+ T cells within the tumor 
microenvironment (tumor infiltrating lymphocytes [TILs]) predict poor response to checkpoint 
inhibitor immunotherapies (Daud 2016a, Daud 2016b); thus, agents designed to specifically 
activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. 
NKTR-214 targets the IL-2 pathway and is designed to provide biased sustained signaling 
through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand 


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NK and effector CD8+ T cells over Treg cells. Preliminary analyses of patients’ blood and tumor 
by flow cytometry and immunohistochemistry (IHC) demonstrate that NKTR-214, as a single 
agent, increases activated CD4+ and CD8+ T cells in peripheral blood, with an increase in T cell 
infiltrates within the tumor tissue after 1 dose of NKTR-214. In addition, there is an increase in 
programmed cell death receptor-1 (PD-1) expression on T cells in the blood and tumor after 
treatment with NKTR-214. The ability to alter the immune environment and increase PD-1 
expression on effector T cells may improve the effectiveness of anti-PD-1/anti-programmed cell 
death ligand 1 (PD-L1) blockade.  
2.1.3 
Clinical Experience with IL-2 and Checkpoint Inhibitors 
Simultaneous administration of IL-2 with immune checkpoint inhibitors directed against PD-1 
(nivolumab and pembrolizumab) or its ligand has not been reported as of the date of this 
protocol, although several studies are ongoing in which IL-2 and an anti-PD-1 antibody are 
co-administered following an infusion of either adoptive CD8+ T cells or tumor-infiltrating 
lymphocytes (NCT02757391, NCT02500576). 
Published data on the sequential administration of IL-2 with an anti-PD-1 inhibitor have been 
reported recently. A case report noted a near-complete response (near-CR) with extended 
duration of response when a patient with renal cell carcinoma (RCC; not responsive to 
nivolumab) was treated with high-dose IL-2 (Brayer 2014). A larger experience from an 
observational clinical trial reported that patients with metastatic melanoma who received  
high-dose IL-2 and received either ipilimumab or an anti-PD-1 inhibitor experienced a 
differential increase in median overall survival, 15.8 vs 28.7 months, respectively. The 12-month 
survival rate was 64% for patients receiving ipilimumab post high-dose IL-2 compared with 97% 
for patients receiving an anti-PD-1 inhibitor, suggesting that these two checkpoint inhibitors do 
not have overlapping mechanisms of action and that IL-2 may enhance the curative potential of 
the anti-PD-1 inhibitor (Wong 2015).  
In support of the hypothesis that IL-2 may have enhanced the curative potential of 
nivolumab/pembrolizumab, a recent report demonstrated that IL-12, which has been shown to 
induce tumor infiltrating lymphocytes and anti-tumor immunity similar to IL-2, appeared to 
prime response to anti-PD-1/PD-L1 inhibitors and demonstrated a clinical benefit rate of 75% 
(50% CR and 25% partial response [PR]) (Algazi 2016). 
Further support comes from clinical data from ongoing clinical trial 16-214-02 (PIVOT-02; 
NCT02983045), in which the combination of NKTR-214 and an anti-PD-1 (nivolumab) has 
shown rapid tumor response in patients. These data are discussed in Section 2.1.4, which 
describes overall clinical experience with NKTR-214, and in Section 5.3.3, which details the 
rationale for the dose of NKTR-214 used in the present study. 


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2.1.4 
Clinical Experience with NKTR-214 
As of the data cutoff date (29 October 2019) for the NKTR-214 Investigator’s Brochure, efficacy 
and safety data were available from two additional clinical studies of NKTR-214: 
• EXCEL Study 15-214-01 (NCT02869295) (complete):  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. This monotherapy study has 
completed enrollment and all patients have completed treatment.  
• PIVOT-02 Study 16-214-02 (ongoing):  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 Malignancies.  
Highlights of these studies are presented below; additional details on the clinical experience with 
NKTR-214 are provided in the NKTR-214 Investigator’s Brochure. 
2.1.4.1 
Study 15-214-01 (EXCEL) 
Study 15-214-01 (NCT02869295) was a Phase 1/2 open-label, multicenter, dose escalation and 
dose expansion monotherapy study of NKTR-214 in patients with locally advanced or metastatic 
solid tumors. The objectives of the EXCEL study (15-214-01) were to evaluate the safety and 
tolerability of NKTR-214 to determine the maximum tolerated dose (MTD) as well as to assess 
the objective response rate at or below the MTD, or to identify the recommended Phase 2 dose 
(RP2D). NKTR-214 was assessed in 28 patients across 5 dose cohorts in which NKTR-214 was 
administered at a dosing frequency of q3w at doses of 0.003, 0.006, 0.009, and 0.012 mg/kg, and 
at a dosing frequency of q2w at a dose of 0.006 mg/kg.  
Enrollment in EXCEL (15-214-01) was closed after 28 patients were exposed to NKTR-214 in 
the dose-escalation phase in order to allow continued development of NKTR-214 in combination 
through other studies (final database lock 29 March 2018). While no objective responses were 
observed, 9 patients experienced tumor shrinkage between 1% and 30% and two patients, after 
progressing on multiple prior therapies, had durable SD > 1 year. One patient with metastatic 
melanoma, who was previously treated with ipilimumab and a BRAF inhibitor received 
25 cycles of NKTR-214 and had durable SD for 18 months. A second patient with metastatic 
RCC, who had progressed on high dose IL-2 and was refractory to single agent OX40 and 
nivolumab, was treated with 19 cycles of NKTR-214 and had durable SD for 14 months. Given 
the biological properties of NKTR-214 and nivolumab these observations further supported the 
rationale for combining these two agents. 
NKTR-214 monotherapy was generally well tolerated. NKTR-214 at a dose of 0.009 mg/kg 
administered every 3 weeks (q3w) was deemed the MTD by predefined dose limiting toxicity 
(DLT) criteria. At the 0.012 mg/kg dose level, 1 patient experienced DLTs of Grade 3 
hypotension and syncope, which were rapidly reversed with intravenous fluids; this patient 


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continued on study and received 2 additional doses of NKTR-214 0.006 mg/kg and tolerated 
treatment well. Dosing of NKTR-214 at 0.006 mg/kg every 2 weeks (q2w) and q3w, as well as 
dosing at 0.003 and 0.009 mg/kg at q3w of NKTR-214 monotherapy were also deemed safe by 
the Safety Review Committee (SRC). One patient dosed at 0.009 mg/kg discontinued the study 
due to a serious adverse event (SAE) of Grade 3 infusion-related reaction (including diaphoresis, 
rash, shortness of breath, chest tightness, tingling in tongue, low blood pressure [47/44 mm Hg], 
and hyperglycemia). The reaction occurred following the first dose of NKTR-214 and resolved 
with treatment (oxygen, epinephrine, and antihistamines). This patient had a prior history of an 
infusion-related reaction to a previously administered immuno-oncology agent. 
The most common treatment-related AEs included 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 AEs as flu-like symptoms, rash and pruritus were 
generally mild to moderate in severity, monitorable, manageable, and transient. These low-grade 
cytokine-related AEs generally occurred 3 - 4 days after dosing and corresponded to the time of 
peak plasma concentration of the active cytokines. The flu-like symptoms were managed with 
acetaminophen and NSAIDs and the cases of rash/pruritus were either self-limiting or treated 
with antihistamines (steroids were administered for occasional patients who had severe 
rash/pruritus). Six of 28 patients reported Grade 3 treatment-related AEs, which included 
hypotension, abdominal pain, infusion-related reaction, headache, and syncope; Cases of Grade 3 
hypotension were rapidly reversed with IV fluids. To mitigate the risk of hypotension (a known 
adverse event (AE) associated with both IL-2 and engineered cytokines), management guidelines 
were implemented and included the following recommendations: 
• Withholding antihypertensive therapy and drugs with hypotensive properties, prior to 
administration of NKTR-214. 
• Administration of at least 1 L of IV fluids at the time of each NKTR-214 administration 
(Day 1). 
• Maintaining adequate oral fluid intake, particularly during the first 4 days postdose. 
• Avoiding activities that could lead to dehydration (eg, physically strenuous activity) or 
vasodilation (eg, hot showers, sauna). 
• Providing additional corticosteroid support for patients with adrenal insufficiency on 
corticosteroid replacement therapy.  
Since the implementation of these mitigation measures, the frequency of hypotension, 
particularly Grade 3 hypotension, has been successfully reduced. 
Hydration guidelines to help manage the risk of hypotension are provided in detail in 
Section 5.3.4.2. 
Other than one case of hypothyroidism reported in this monotherapy trial, no clinically 
confirmed cases of immune-mediated AEs (as seen with immune checkpoint inhibitors) or 


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capillary leak syndrome (as observed with other IL-2 therapy) have been reported in NKTR-214 
monotherapy study. No anti-drug antibodies (ADAs) to NKTR-214 or IL-2 were detected in any 
of the 28 treated patients. No Grade 4 treatment-related TEAEs or treatment-related deaths were 
reported on the study.  
2.1.4.2 
Study 16-214-02 (PIVOT-02) 
Study 16-214-02 is a Phase 1/2, open-label, multicenter study of the combination of NKTR-214 
with nivolumab or the combination of NKTR-214, nivolumab, and other anti-cancer therapies in 
patients with select locally advanced or metastatic solid tumor malignancies. Phase 1 (dose 
escalation cohort) enrolled patients with advanced or metastatic melanoma, RCC, or non-small 
cell lung cancer (NSCLC). In Phase 2 (dose expansion cohort), additional tumor types were 
added: breast cancer, urothelial carcinoma, and gastrointestinal malignancies. Part 3 (triplet dose 
escalation cohort) assesses schedules for NKTR-214 in combination with nivolumab and 
ipilimumab to establish RP2Ds for concurrent and staggered dosing schedules. Part 4 studies the 
RP2D for each respective tumor type. The objectives of the study are to evaluate the safety and 
tolerability of NKTR-214 to determine the MTD and/or the RP2D as well as to assess the ORR 
at the RP2D. 
The doses studied in the dose escalation part of the study were NKTR-214 0.003 or 0.006 mg/kg 
q2w with nivolumab 240 mg q2w; NKTR-214 0.006 mg/kg q3w with nivolumab either 240 mg 
q2w or 360 mg q3w; and NKTR-214 0.009 mg/kg q3w with nivolumab 360 mg q3w. The dose 
escalation portion of this study (Part 1) has been completed.  
Based on the findings from the NKTR-214 monotherapy study (EXCEL; 15-214-01; see 
Section 2.1.4.1) and findings from the dose-escalation part of the PIVOT-02 study, the RP2D of 
NKTR-214 in combination with nivolumab 360 mg q3w was determined to be 0.006 mg/kg. The 
rationale for this dose is further detailed in Section 5.3.3. 
The doses studied in the expansion portion part of the study have been NKTR-214 0.006 mg/kg 
q3w plus nivolumab 360 mg q3w plus ipilimumab 1 mg/kg q6w (RCC/NSCLC); 4 doses of 
NKTR-214 0.006 mg/kg q3w plus nivolumab 1 mg/kg q3w plus ipilimumab 3 mg/kg q3w; then 
continue with NKTR-214 0.006 mg/kg plus nivolumab 360 mg (urothelial 
carcinoma/melanoma); 4 doses of NKTR-214 0.006 mg/kg q3w plus nivolumab 3 mg/kg q3w 
plus ipilimumab 1 mg/kg q3w; then continue with NKTR-214 0.006 mg/kg plus nivolumab 
360 mg (RCC/melanoma). 
As of the data cutoff date (29 October 2019) for the NKTR-214 Investigator’s Brochure, tumor 
response data were available for 37 patients in the dose escalation phase of the study; among 
these patients 21 (56.8%) had CR or PR.  


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In the dose expansion phase of the study patients received treatment with the RP2D: 
• In 1L RCC patients who met the prespecified efficacy parameters a 46% (12 of 26 patients) 
objective response rate (ORR) was noted. Responses were seen in both PD-L1 positive (29%, 
2 of 7 patients) and PD-L1 negative (53%, 9 of 17 patients) (Diab 2018a; 29 May 2018 
cutoff). 
• In urothelial carcinoma patients, a 48% (13 of 27 patients) ORR was noted with a 19% 
complete response rate. Responses were seen in both PD-L1 positive and PD-L1 negative 
expression on tumor populations with an ORR of 50% in the PD-L1 positive population (6 of 
12 patients) and 43% in the PD-L1 negative population (5 of 11 patients) (Siefker-Radtke 
2019; 03 Dec 2018 data cutoff). 
• In 1L melanoma patients who met the prespecified efficacy parameters, a 53% (20 of 
38 patients) ORR was seen via independent central radiology review with a 34% (13 of 
38 patients) CR rate. Responses were seen in both the PD-L1 positive (defined as PD-L1 
expression ≥ 1% on tumor cells) and PD-L1 negative (defined as < 1% PD-L1 expression on 
tumor cells) populations with an ORR of 64% in the PD-L1 positive population (14 of 
22 patients) and 39% in the PD-L1 negative population (5 of 13 patients) (Diab 2019; 
25 Sep 2019 data cutoff). 
• In mTNBC patients who met the prespecified efficacy parameters, 13.2% (5 of 38 patients) 
ORR was noted. Responses were seen in both PD-L1 positive and PD-L1 negative 
populations with an ORR of 16.7% in the PD-L1 positive population (2 of 12 patients) and 
13.6% in the PD-L1 negative population (3 of 22 patients) (Tolaney 2019; 01 Jul 2019 data 
cutoff). 
The most frequently reported TEAEs were fatigue (294 of 541 patients, 54.3%), pyrexia (274 of 
541 patients, 50.6%), nausea (227 of 541 patients, 42.0%) pruritus (215 of 541 patients, 39.7%), 
decreased appetite (203 of 541 patients, 37.5%), diarrhoea (168 of 541 patients, 31.1%) and 
influenza-like illness (168 of 541 patients, 31.1%).  
The most frequently reported treatment-related TEAEs were fatigue (267 of 541 patients, 
49.4%), pyrexia (245 of 541 patients, 45.3%), pruritus (200 of 541 patients, 37.0%), nausea 
(178 of 541 patients, 32.9%) and influenza-like illness (165 of 541 patients, 30.5%). The most 
frequently reported TEAEs assessed as related in the 488 patient doublet group were fatigue 
(47.3%), pyrexia (44.3%), pruritus (35.7%), nausea (29.7%), influenza-like illness (26.8%), 
decreased appetite (26.4%), chills (26.0%), and rash (25.8%). For the 43 triplet patients, the most 
frequently reported TEAEs assessed as related were fatigue (79.1%), influenza-like illness 
(72.1%), nausea (60.5%), pruritus or diarrhoea (58.1%), pyrexia (55.8%), rash maculo-papular 
(53.5%), decreased appetite (46.5%), vomiting (39.5%), chills or hypothyroidism (37.2%), 
oedema peripheral (34.9%), arthralgia (32.6%), and cough (30.2%). Among the doublet plus 
other anti-cancer study drug patients, 7 of 10 experienced nausea assessed as related, 5 pyrexia, 
4 hypotension, and 3 alopecia, neutropenia, constipation, influenza-like illness, dizziness, 
vomiting, or decreased appetite.  


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As of the 28 October 2019 database cutoff date, 44.9% of patients reported SAEs. The most 
frequently experienced SAEs were pyrexia by 19 of 541 patients (3.5%), dyspnea and 
hypotension by 16 of 541 patients (each: 3.0%), and hyponatremia by 11 of 541 patients (2.0%). 
In the doublet (NKTR-214 plus nivolumab) cohort 218 of 488 patients (44.7%) experienced an 
SAE. The most frequently reported SAEs were pyrexia (18 patients of 488, 3.7%), dyspnea or 
hypotension (each: 14, 2.9%) and hyponatraemia (10, 2.0%). In the triplet cohort (NKTR-214 
plus nivolumab plus ipilimumab), 21 of 43 patients (48.8%) experienced SAEs. The most 
frequently reported were cerebrovascular accident in 3 patients (7.0%), acute kidney injury, 
embolism, adrenal insufficiency, or enterocolitis (each: 2 patients, 4.7%). Four of the 10 patients 
in the doublet plus other anti-cancer drug group experienced SAEs: 2 hypotension, and 1 each 
dyspnea, pneumonia, embolic stroke, or confusional state. 
A total of 102 patients of 541 (18.9%) reported SAEs that were considered related to any study 
treatment. In the doublet cohort, 84 of 488 patients (17.2%) experienced SAEs assessed as 
related. The most frequently reported were pyrexia (15 patients, 3.1%), hypotension (10, 2.0%), 
and pneumonitis (5, 1.0%). In the triplet cohort, 16 of 43 patients (37.2%) experienced SAEs 
assessed as related: cerebrovascular accident (3 patients of 43, 7.0%), acute kidney injury, 
adrenal insufficiency, or enterocolitis (each: 2 patients, 4.7%), and 1 patient each (2.3%) 
experienced thyroiditis, papilledema, influenza-like illness, hypothyroidism, hypophysitis, 
eosinophilia, diarrhoea, colitis, hyperthyroidism, hyponatraemia, atrial fibrillation, or 
pneumonitis. Two of the 10 patients in the doublet plus other anti-cancer drug cohort 
experienced an SAE of hypotension assessed as related. 
Twelve (2.2% of 541 patients) Grade 5 events have been reported. Nine patients in the doublet 
therapy regimen experienced Grade 5 events: 3 pneumonitis, 1 cardiac arrest, and 1 acute 
respiratory failure (assessed as related to one or both), and 1 cardio-respiratory arrest, 1 cardiac 
arrest, 1 large intestine perforation, and 1 respiratory failure (all unrelated). In the doublet plus 
other anti-cancer drug group 1 patient experienced embolic stroke (unrelated). In the triplet 
therapy regimen, 2 patients experienced Grade 5 events: adrenal insufficiency and 
cerebrovascular accident; both were assessed as related to all 3 drugs. 
Additional details on the clinical experience with NKTR-214 are provided in the NKTR-214 
Investigator’s Brochure. 
2.1.4.3 
Observed Events of Cerebrovascular Accident in Study 16-214-02 
Serious events of cerebrovascular accident (CVA), including 1 fatal event, were observed in 
patients who have received NKTR-214 in the triplet combination with nivolumab and 
ipilimumab and in the doublet combination with nivolumab. A comprehensive search (data 
cutoff 21 June 2019) found 3 of 43 patients (7%) who received triplet therapy in 
Study 16-214-02 (PIVOT-02) to have CVA events, all of which were considered by the 
Investigator to be related to treatment with NKTR-214, nivolumab, and ipilimumab. Eight of 
478 patients (1.7%) who received doublet immunotherapy (NKTR-214 and nivolumab) in Study 
16-214-02 were determined to have CVA events that were confirmed by the neurology 


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consultants. The incidence of CVA, combining all clinical trials in which the doublet of 
NKTR-214 plus nivolumab was administered was 8 out of 593 patients. (1.3%). Between 
21 June 2019 and 28 October 2019, a 71-year-old male with urothelial carcinoma on doublet 
therapy reported 1 Grade 2 SAE of cerebrovascular accident which resulted in dose delay and 
was reported as not related to study therapy due to the presence of multiple risk factors as 
confounders. One 66-year-old male patient with NSCLC on doublet therapy plus chemotherapy 
reported Grade 5 embolic stroke.  
In summary, a total of 9 patients out of 488 patients (1.8%) in NKTR-214 plus nivolumab 
doublet therapy reported a CVA event. One patient and 3 patients who received doublet therapy 
plus chemotherapy and triplet therapy, respectively, reported a CVA event.  
The relationship of these events to the triplet and doublet combinations is unclear. Based on 
these events and a comprehensive assessment of CVA across all NKTR-214 clinical studies, 
CVA has been escalated to an adverse event of special interest (AESI) and mitigations have been 
put in place to reduce the risk of CVA. These mitigations include implementation of a 
cerebrovascular accident adverse event management algorithm (Appendix 2) and updates to the 
exclusion criteria, renal function and hydration assessment, hydration guidelines, concomitant 
and prohibited medications, dose modification guidelines, and discontinuation criteria. 
Additional information on the clinical safety and risk of CVA is found in the NKTR-214 
Investigator’s Brochure. 
2.1.5 
Pembrolizumab Safety Summary 
See the pembrolizumab prescribing information. 
2.1.6 
Rationale for Dose Optimization Cohorts 
The dose optimization cohorts have been added to investigate the safety profile and MTD/RP2D 
of NKTR-214 in combination with pembrolizumab in locally advanced or metastatic solid 
tumors (see Section 5.3.2.1).  
2.1.7 
Rationale for Dose Expansion Cohorts 2, 3, 4, and 5 
For 1L NSCLC patients with a percentage of tumor cells expressing PD-L1 ≥ 1%, 
pembrolizumab has become a standard of care in the United States (US). In NSCLC patients 
with tumors that do not express PD-L1 (< 1%), pembrolizumab monotherapy data are limited. 
Given that treatment with NKTR-214 can increase PD-L1 expression on T cells in the blood and 
tumor, and increase the number of tumor-infiltrating lymphocytes, the addition of NKTR-214 is 
expected to improve the effectiveness of pembrolizumab in this population.  
Based on its mechanism of action, NKTR-214 in combination with pembrolizumab may improve 
response rates in first-line NSCLC patients, especially with low or negative PD-L1 expression. 
Thus, treatment with NKTR-214 at a dose of 0.006 mg/kg (Cohort 2) in combination with 
pembrolizumab was added to this protocol to evaluate efficacy in first-line NSCLC patients 


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regardless of PD-L1 expression. In Amendment 5, the dose of NKTR-214 at 0.010 mg/kg was 
tested in 7 patients in the dose optimization cohort. The first 6 patients were evaluated by the 
SRC for safety in this cohort. No DLTs were seen during the DLT period. The AEs that were 
related to NKTR-214 matched the expected toxicity profile. No dose delays or dose 
modifications were noted in the 6 patients during the DLT period.  
In patients with previously untreated metastatic, squamous cell lung cancer, the addition of 
pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in 
significantly longer overall survival and progression-free survival than chemotherapy alone 
(Paz-Ares 2018). In patients with previously untreated metastatic, nonsquamous NSCLC, the 
addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug 
resulted in significantly longer overall survival and progression-free survival than chemotherapy 
alone (Gandhi 2018). Given its mechanism of action, NKTR-214 in combination with 
pembrolizumab may improve response rates in both squamous cell lung cancer and 
nonsquamous NSCLC patients (Cohorts 4 and 5). 
2.2 
Overall Benefit/Risk 
NKTR-214 was designed to mitigate the serious toxicities associated with rapid systemic 
immune activation seen with administration of aldesleukin. The goal of engineering a PEGylated 
form of IL-2 that reduces the dose-limiting toxicities of aldesleukin, ie, those necessitating  
in-hospital administration, appears to have been realized with NKTR-214 at the doses tested. The 
safety profile of pembrolizumab is well characterized and manageable, including regimens where 
it is administered in combination with other immuno-oncology products. Clinical experience 
with the recommended phase 2 dose (RP2D) of NKTR-214 (0.006 mg/kg) in combination with 
nivolumab showed improvement in therapeutic response (ie, ORR and DCR) compared with 
either agent given alone. The conversion of PD-L1 (–) to PD-L1 (+) in tumor biopsies is 
associated with clinical benefit and rapid activation of the immune system (ie, increased 
lymphocyte proliferation in blood and increased CD8 T cells in tumors), which is consistent and 
maintained with successive treatment cycles has also been observed with NKTR-214 in 
combination with nivolumab. Furthermore, NKTR-214 in combination with nivolumab or 
pembrolizumab has so far demonstrated an acceptable safety profile in clinical studies. Thus, the 
potential benefit of combination therapy appears to outweigh the known risks of these agents and 
warrants continued clinical investigation. 
2.3 
Data Monitoring Committee 
The detailed and frequent safety monitoring that will be undertaken in this open-label study 
precludes the necessity for an independent Data Monitoring Committee.  


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objectives: Dose Optimization or Dose Expansion Cohorts 
The primary objectives in the dose optimization cohorts are: 
• 
To evaluate the safety and tolerability of NKTR-214 in combination with pembrolizumab. 
• 
To define the MTD/RP2D and optimal dosing schedule of NKTR-214 in combination with 
pembrolizumab. 
The primary objective in all the dose expansion cohorts is: 
• 
To determine the ORR per blinded independent central review (BICR) by RECIST 1.1 of 
NKTR-214 plus pembrolizumab with or without systemic chemotherapy in patients with 
untreated metastatic NSCLC. 
3.2 
Secondary Objectives: Dose Optimization and/or Dose Expansion Cohorts 
The secondary objectives in the dose optimization and/or dose expansion cohorts are: 
• 
To evaluate safety and tolerability of NKTR-214 plus pembrolizumab with or without 
systemic chemotherapy in patients with untreated NSCLC (dose expansion only). 
• 
To assess the preliminary efficacy (per BICR) of NKTR-214 plus pembrolizumab with or 
without systemic chemotherapy: 
o 
objective response rate (ORR) by RECIST 1.1 (dose optimization only) 
o 
duration of response (DOR) by RECIST 1.1 
o 
clinical benefit rate (CBR) by RECIST 1.1 
o 
time to response (TTR) by RECIST 1.1 
o 
progression-free survival (PFS) by RECIST 1.1 
o 
overall survival (OS) 
 
 
 
 
 
 
 
 
 
 
 
 
 




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4.0 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion Criteria 
A patient must meet all of the following criteria:  
1. Provide written, informed consent to participate in the study and follow the study 
procedures. 
2. Age 18 years or older at the time of signing the informed consent form (ICF). 
3. Life expectancy > 12 weeks from the time of enrollment as determined by the Investigator. 
4. In the dose optimization cohorts, patients may have received no more than 1 prior line of 
systemic therapy for metastatic cancer. A “line of therapy” is defined as any regimen – 
single-agent or combination therapy, cytotoxic therapy, immuno-oncology therapy 
separately or in combination – that is given in a non-palliative setting and is stopped for 
progression of disease. 
5. Patients must have a minimum of 6 months of response to any non-palliative cancer-
directed treatment. 
6. Prior IL-2 therapy is allowed for patients in the dose optimization cohorts who have 
completed therapy, and who have reported no severe ADRs or had all ADRs completely 
resolved. Prior IL-2 therapy is not allowed for patients in the dose expansion cohorts. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
8. Measurable disease per RECIST 1.1. 
9. Adequate organ function, as defined in Table 5, within 28 days of treatment initiation. 
Table 5: 
Definitions of Adequate Organ Function (Inclusion Criteria) 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥ 1500/μL (after at least 7 days without growth factor support). 
Platelet count 
≥ 100 × 103/μL (no transfusions allowed within 7 days of Day 1, Cycle 1) 
Hemoglobin 
≥ 9.0 g/dL (no transfusions allowed within 7 days of Day 1, Cycle 1) 
Renal 
Serum creatinine 
≤ 2 mg/dL 
Cohorts 4 and 5: creatinine clearance (CLcr) ≥ 45 mL/min 
 


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Table 5: 
Definitions of Adequate Organ Function (Inclusion Criteria) (Contd) 
System 
Laboratory Value 
 
Hepatic 
Aspartate 
aminotransferase 
(AST) and alanine 
transaminase (ALT) 
≤ 3 × upper limit of normal (ULN). 
 
Total bilirubin 
Cohorts 1, 2, 3:  Within normal limits (total bilirubin ≤ 2 × ULN if associated with 
hepatobiliary metastases or Gilbert’s syndrome). 
Cohorts 4, 5:  ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 x ULN 
Pancreatic 
Lipase and amylase 
≤ 1.5 × ULN. Patients with pancreatic metastases and lipase and/or amylase < 3 × ULN 
may enroll. Patients may not enroll if there are clinical or radiographic signs of 
pancreatitis. 
Coagulation (Cohorts 4 and 5) 
International 
Normalized Ratio 
(INR) or Prothrombin 
Time (PT) 
 
Activated Partial 
Thromboplastin Time 
(aPTT) or Partial 
Thromboplastin Time 
(PTT) 
≤1.5 x ULN unless the subject is receiving anticoagulant 
therapy 
 
≤1.5 x ULN unless the subject is receiving anticoagulant 
therapy 
 
10. A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 90 days prior to 
Cycle 1 Day 1.  
11. Oxygen saturation ≥ 90% on room air for all indications. 
12. Clinically significant toxic effect(s) of the most recent anti-cancer therapy must be Grade 1 
or resolved (except alopecia and sensory neuropathy); patients with Grade 2 adrenal 
insufficiency related to prior anti-cancer therapy (defined as requiring medical intervention, 
such as concomitant steroids) may be enrolled provided that clinical symptoms are 
adequately controlled and the daily dose is 10 mg or less of prednisone or equivalent. 
Patients with hypothyroidism that is stable on hormone replacement therapy may also be 
enrolled. If the patient received major surgery or radiation therapy of > 30 Gy, they must 
have recovered from the toxicity and/or complications from the intervention.  


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13. Women of childbearing potential (WCBP) must commit to the use of highly effective 
methods of birth control during study participation for 4 months following the last dose of 
all study drug(s). Acceptable methods are those that, alone or in combination, result in a low 
failure rate (< 1% per year), such as surgical sterilization, an intrauterine device, or 
hormonal contraception in combination with a barrier method. Abstinence is acceptable if 
this is the preferred contraception. Women of Childbearing Potential who are continuously 
not heterosexually active are exempt from contraceptive requirements, but still must 
undergo pregnancy testing as scheduled. Detail is provided in Appendix 3. 
14. Male patients who are sexually active with WCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study treatment(s) and 
3 months after NKTR-214 and/or pembrolizumab treatment completion. In addition, male 
patients must be willing to refrain from sperm donation during this time (Appendix 3). 
15. Patients with hypertension must be on ≤ 2 antihypertensive medications and without change 
for the 14 days prior to randomization. Screening blood pressure must be systolic 
< 150 mm Hg and < 90 mm Hg for diastolic blood pressure.  
• For France only: screening blood pressure must be systolic < 140 mm Hg and 
< 90 mm Hg for diastolic blood pressure. 
16. A brain MRI at Screening is required for all patients with metastatic NSCLC, and for 
patients with other tumor types who have known brain metastasis.  
17. Patients with brain metastases are eligible if all the criteria below are fulfilled: 
a. Brain metastases must be treated at least 2 weeks prior to enrollment.  
b. Brain imaging after treatment and within the screening period must demonstrate no new 
or progressing brain metastases.  
c. No requirement for systemic corticosteroids > 10 mg/day prednisone equivalents at 
therapy initiation. Stable doses of anticonvulsants are allowed.  
d. No clinically significant symptoms associated with brain metastases.  
18. A tumor tissue sample is required for all patients. Acceptable samples include archival 
tissue obtained no more than 12 months prior to enrollment if the patient has not received 
systemic treatment between the time of biopsy/resection and enrollment. Otherwise, a fresh 
tumor biopsy taken during screening is required.  
19. For France only: enrolled patients must be affiliated to a Social Security System. 
The following additional inclusion criteria are for the dose optimization cohorts (see 
Section 4.1.1) or dose expansion cohort (see Section 4.1.2) only. 


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4.1.1 
Dose Optimization Cohorts (Cohorts 1a and 1b) 
The tumor types included in the dose optimization cohorts of the study are shown in Table 6. 
Table 6: 
Tumor Types to be Included in Dose Optimization Cohorts 
(NKTR-214 and Pembrolizumab) 
Tumor Type 
Line of Treatment in Metastatic Setting 
PD-L1 Status 
Melanoma 
1st and 2nd 
Any 
Non-small cell lung cancer  
1st and 2nd  
Any 
Urothelial carcinoma 
1st and 2nd 
Any 
Head and neck squamous  
cell cancer 
1st and 2nd 
Any 
Hepatocellular carcinoma 
1st and 2nd 
Any 
 
20. 1L and 2L Melanoma  
a. Histologically confirmed diagnosis of Stage IV (metastatic) melanoma. 
21. 1L and 2L Non-small Cell Lung Cancer (NSCLC) 
a. Histologically confirmed diagnosis of Stage IV NSCLC. 
b. Patients with actionable mutations with approved targeted therapy in NSCLC are 
excluded. Testing for mutations should be performed per standard of care.  
22. 1L and 2L Urothelial Carcinoma 
a. Histologically confirmed diagnosis of metastatic urothelial carcinoma.  
23. 1L and 2L Head and Neck Squamous Cell Carcinoma (HNSCC) 
a. Histologically confirmed diagnosis of metastatic HNSCC  
24. 1L and 2L Hepatocellular Carcinoma (HCC) 
a. Histologically confirmed diagnosis of metastatic HCC.  
4.1.2 
Dose Expansion Cohorts (Cohorts 2, 3, 4, and 5) 
25. 1L Non-Small Cell Lung Cancer (Cohorts 2, 3, 4, and 5) 
• Histologically confirmed diagnosis of Stage IV NSCLC. 


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• Tumor tissue sample is required to be submitted to the central lab for all patients prior to 
enrollment. Acceptable samples include archival tissue obtained no more than 12 months 
prior to enrollment if the patient has not received systemic treatment between the time of 
biopsy/resection and enrollment. Otherwise, a fresh tumor biopsy taken during screening is 
required. A tracking number confirming shipment of the sample to the central laboratory 
must be supplied prior to Cycle 1 Day 1. Within each subgroup, this is:  
o PD-L1 negative (PD-L1 < 1%; Cohort 2.1): 20 response-evaluable patients  
o PD-L1 low/intermediate (PD-L1 1% to 49%; Cohort 2.2): 18 response-evaluable 
patients  
o PD-L1 highly positive (PD-L1 ≥ 50%; Cohort 2.3): 20 response-evaluable patients 
o For France only: patients in subgroup PD-L1 < 50% (Cohorts 2.1, 2.2) will be excluded. 
Eligibility for PD-L1 status can be determined with a local or central PD-L1 test. 
• Patients with actionable mutations with approved targeted therapy in NSCLC are excluded. 
Testing for mutations should be performed per standard of care 
• Must not have received anti-cancer therapy for treatment of metastatic lung cancer. 
• Must not have received prior immunotherapy. 
4.2 
Exclusion Criteria 
A patient will be excluded for any of the following criteria: 
1. Use of an investigational agent or an investigational device within 28 days prior to 
enrollment. 
2. Women who are pregnant or breastfeeding. 
3. Patients who have an active, autoimmune disease. Exceptions include patients with type I 
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders not 
requiring systemic treatment, or autoimmune conditions not expected to recur.  
4. History of allergy or hypersensitivity to study drug components. 
5. Prior malignancy within the previous 3 years. Exceptions include non-melanoma skin cancer 
and carcinoma in situ, treated with curative intent, with minimal risk of recurrence or 
requiring therapy during study participation. Patients with prostate cancer are allowed if one 
of the following criteria is met: Stage T2N0M0 or lower; Gleason score ≤ 3 + 4, and 
prostate-specific antigen (PSA) below lower limit of normal by local laboratory. 
6. Patients in the dose expansion cohorts must not have received prior immunotherapy or IL-2 
therapy. 


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7. Chronic systemic corticosteroid at > 10 mg prednisone or equivalent or other 
immunosuppressive agents. Patient on inhaled steroids for asthma or local steroid injections 
or topical steroids are allowed.  
8. Evidence of clinically significant interstitial lung disease or active, noninfectious 
pneumonitis.  
9. Surgery or radiotherapy within 14 days of enrollment. Patients who had surgery or 
radiotherapy outside of 14 days must have recovered from associated complications and 
toxicities.  
10. For Dose Optimization Cohort 1 only: Chemotherapy or biological therapy within 28 days of 
enrollment. Targeted therapy (eg, tyrosine kinase inhibitors) within 14 days of enrollment. 
Patients with ongoing AEs related to prior cancer therapies will be excluded. 
11. For Dose Expansion Cohorts: Patients with ongoing AEs related to prior cancer therapies 
will be excluded. 
12. Active infection requiring systemic therapy/ Active hepatitis B virus (HBV) infection 
(eg, positive hepatitis B surface antigen [HBsAg]) or hepatitis C virus (HCV) infection 
(eg, positive HCV ribonucleic acid [RNA]). 
13. Known immunodeficiency or active human immunodeficiency virus (HIV-1/2 antibodies). 
14. Known active SARS-CoV2 infection with confirmed test report. 
15. For France only: received a live vaccine within 30 days prior to the first dose of the study.  
16. For France only: known history of active tuberculosis (TB: Bacillus tuberculosis).  
17. Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for 
women at Screening. 
18. Known cardiovascular history, including cerebrovascular disease within 12 months of 
screening including but not limited to the following: 
a. Unstable angina or myocardial infarction. 
b. Congestive heart failure (New York Heart Association [NYHA] Class III or IV). 
c. Uncontrolled clinically significant arrhythmias. 
d. Cerebrovascular accident (CVA) or transient ischemic attack (TIA). 
e. History of pulmonary embolism (PE), deep vein thrombosis (DVT), or venous or 
non-CVA/TIA arterial thromboembolic event within 3 months prior to enrollment. 


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• Patients with a history of a venous or arterial thromboembolic event must be 
asymptomatic prior to enrollment and must be receiving a stable regimen of therapeutic 
anticoagulation (low molecular weight heparin [LMWH] or direct oral anticoagulation 
[DOAC]) or had received appropriate treatment as indicated by the regional clinical 
guidelines. Additionally: 
• Use of coumadin is permitted; however, therapeutic dosing should target a specific 
international normalized ratio (INR) stable for at least 4 weeks prior to enrollment. 
NKTR-214 has the potential to down-regulate metabolizing enzymes for coumadin for 
approximately 1 week after administration of each dose of NKTR-214. Due to the 
possibility of drug-drug interactions between coumadin and NKTR-214, frequent 
monitoring of INR and ongoing consideration of dose adjustments are warranted 
throughout the patient’s participation on study. 
19. Current alcohol abuse 
20. 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 of adverse events while participating in study.  


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5.0 
TREATMENT PLAN 
5.1 
Overview 
This is a Phase 1/2, open-label, multicenter, study of NKTR-214 in combination with 
pembrolizumab with or without systemic chemotherapy in patients with metastatic solid tumors. 
The dose optimization cohorts (Cohorts 1a and 1b) will include first- and second-line (1L and 
2L) melanoma, non-small cell lung carcinoma (NSCLC), urothelial carcinoma, head and neck 
squamous cell carcinoma (HNSCC), and hepatocellular carcinoma (HCC). The dose 
optimization Cohort 1a will include patients enrolled in the 3 + 3 dose optimization cohort and 
the dose optimization Cohort 1b will include patients enrolled in the step-up dose optimization 
cohort. The dose expansion cohorts (Cohorts 2, 3, 4, and 5) will include first-line NSCLC 
patients, first-line, nonsquamous NSCSC patients, and first-line squamous cell lung cancer 
patients.  
The original protocol and amendments (up to and including Amendment 4), evaluated 
atezolizumab in combination with NKTR-214 (0.006 mg/kg) for treatment of second-line 
NSCLC and first- and second- line urothelial carcinoma and pembrolizumab in combination with 
NKTR-214 (0.006 mg/kg) for treatment of first-line metastatic melanoma and first- and  
second-line NSCLC. Patients in the pembrolizumab first-line NSCLC cohort will continue on 
study in the dose expansion cohort of Amendment 5.0 or subsequent versions; however, the 
atezolizumab second-line NSCLC and first- or second-line urothelial carcinoma cohorts and the 
pembrolizumab first-line melanoma cohort have been closed to further enrollment. Patients on 
study who were enrolled in these cohorts under prior amendments will continue treatment as 
described in Amendment 5.0 and subsequent versions. Patients will be followed for efficacy and 
safety until the patient is lost to follow-up, withdraws consent or patient death. 
The study is divided into a Screening period, Treatment period, End of Treatment (EOT) and 
Long-Term Follow-up period. The treatment cycles are every 21 days (3 weeks). 
All procedures are outlined in the Schedule of Events (Section 1.1). 
5.2 
Screening Period 
The screening period is 28 days. Patients must provide written informed consent before starting 
screening and any protocol-specified procedures or evaluations not considered to be part of the 
patient’s standard care. The screening period ends on the day before Cycle 1 Day 1. Assessments 
done on Cycle 1 Day 1 prior to dosing are considered Cycle 1 Day 1 assessments and not 
screening assessments. Patients may be rescreened up to 1 time at the discretion of the 
Investigator. 
Dose Expansion Cohorts 2, 3, 4, and 5 only:  A tumor tissue sample is required to be submitted 
to the central lab for all patients prior to enrollment. Acceptable samples include archival tissue 
obtained no more than 12 months prior to enrollment if the patient has not received systemic 
treatment between the time of biopsy/resection and enrollment. Otherwise, a fresh tumor biopsy 


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taken during screening is required. A tracking number confirming shipment of the sample to the 
central laboratory must be supplied prior to Cycle 1 Day 1. This will allow for prompt PD-L1 
testing and results to ensure patient’s timely allocation to appropriate PD-L1 sub-cohort (Cohorts 
2.1, 2.2, 2.3, 3.1, 3.2, 3.3, 4.1, 4.2, 4.3, 5.1, 5.2, and 5.3). Sub-cohorts may be opened and closed 
to further accrual as determined by various factors, such as the number of response-evaluable 
patients enrolled within each sub-cohort.  
5.3 
Treatment Period  
Patients will be treated up to 2 years (or a maximum of 34 treatment cycles, whichever is sooner) 
until disease progression, death, unacceptable toxicity, symptomatic deterioration, lost to follow 
up, the Investigator decides to discontinue treatment, the patient decides to discontinue treatment 
or withdraw consent, or Nektar Therapeutics decides to terminate the trial.  
Patients with progressive disease (PD) per RECIST 1.1 may continue study treatment if the 
Investigator considers it safe and in the best interest of the patient. See Section 5.3.6 for 
treatment beyond progression. Patients with a PR or stable disease (SD) will continue to receive 
study treatment until, disease progression (by investigator), or intolerability to therapy. The 
Investigator may continue treating patients with a confirmed CR, for a maximum treatment of 
2 years from Cycle 1 Day 1.  
5.3.1 
Administration of Study Drug(s) 
Each patient’s NKTR-214 dose will be determined by the NKTR-214 dose optimization or dose 
expansion schema and the patient’s weight in kilograms (Section 5.3.2). The patient’s weight in 
kilograms will be determined on Day 1 before the start of each cycle; for weight changes of 
± 10% from baseline, recalculation of dose is not required. When administered on the same day, 
NKTR-214 will be administered first (30 ± 5 minutes) followed by pembrolizumab 
(30 ± 5 minutes). After NKTR-214 administration and before pembrolizumab administration, 
flush the intravenous line with an appropriate amount of the same diluent used for dose 
preparation to ensure that the total dose is completely administered over the appropriate time. No 
delay is necessary between the two drug administrations, after checking for stable vital signs. 
5.3.1.1 
Dose Optimization Cohorts (Cohorts 1a and 1b) 
Study Drug Administration - 3 + 3 Dosing (Cohort 1a) Schema  
• NKTR-214 will be administered IV over 30 (± 5) minutes at a starting dose of 0.008 mg/kg. 
Please refer to the Pharmacy Manual for additional details for study drug administration. 
• Pembrolizumab will be dosed as per the Pharmacy Manual. 


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Study Drug Administration - Step-up Dosing (Cohort 1b) Schema  
• NKTR-214 will be administered IV over 30 (± 5) minutes starting at the previously tolerated 
dose established in the 3 + 3 dosing schema as determined by the Safety Review Committee 
(SRC) for the step-up dosing schema. This dose may increase at each cycle for individual 
patients at increments of 0.002 mg/kg per the dose optimization schema in Figure 2. Please 
refer to the Pharmacy Manual for additional details for study drug administration. 
• Pembrolizumab will be dosed as per the Pharmacy Manual.  
5.3.1.2 
Dose Expansion Cohorts 2 and 3 
• NKTR-214 will be administered q3w IV over 30 (± 5) minutes at a starting dose of 
0.006 mg/kg in Cohort 2 (or 0.010 mg/kg in Cohort 3). Additional patients in the cohort may 
receive the dose as established by the dose optimization cohorts. Please refer to the Pharmacy 
Manual for additional details for study drug administration. 
• NKTR-214 will be dosed first, followed by pembrolizumab. 
• Pembrolizumab will be dosed as per the Pharmacy Manual. Pembrolizumab will be 
administered as a 30-minute IV infusion q3w. 
5.3.1.3 
Dose Expansion Cohort 4 
• Cohort 4 will use the NKTR-214 dose administered in Cohort 2 (or Cohort 3) following 
review of efficacy and safety data. Please refer to the Pharmacy Manual for additional details 
for study drug administration.  
• NKTR-214 will be dosed first, followed by pembrolizumab, followed by chemotherapy. 
• Pembrolizumab will be dosed as per the Pharmacy Manual. Pembrolizumab will be 
administered as a 30-minute IV infusion q3w. 
• In Cohort 4, NKTR-214 will be dosed in combination with pembrolizumab and either 
cisplatin, or carboplatin and pemetrexed, per investigator discretion. Cisplatin, 
carboplatin, and pemetrexed will be dosed per the Pharmacy Manual. Pemetrexed 
500 mg/m2 will be administered as an IV infusion for 4 cycles followed by maintenance 
dose given every 3 weeks per local practice and label. Five doses of folic acid (each 
ranging from 350 µg to 1000 µg) should be taken during the 7 days preceding the first 
dose of pemetrexed and folic acid must continue during the full course of chemotherapy 
and for 21 days after the last dose of pemetrexed. Vitamin B12 1000 µg IM injection 
must be given in the week preceding the first dose of pemetrexed and once every 3 cycles 
thereafter. Subsequent vitamin B-12 injections maybe given on the same day as 
pemetrexed administration. Dexamethasone prophylaxis 4 mg must be taken on the day 
before, day of, and the day after pemetrexed administration.  
• Cisplatin 75 mg/m2 will be administered as an IV infusion per local practice and labels 
for 4 cycles given every 3 weeks approximately 30 minutes after the pemetrexed 
infusion. It should be immediately preceded and followed by hydration procedures and 
administered according to local practice and labels.  


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• Carboplatin AUC 5 using Calvert formula will be administered as an IV infusion over 15 
to 60 minutes for 4 cycles given every 3 weeks immediately after pemetrexed as per local 
practice and label. All subjects should be premedicated according to the approved 
product label and/or standard practice. The estimated GFR used in the Calvert formula 
should not exceed 125 mL/min. Maximum carboplatin dose should not exceed 750 mg.  
• CALVERT formula: target AUC * (CLcr + 25)  
5.3.1.4 
Dose Expansion Cohort 5 
• Cohort 5 will use the NKTR-214 dose administered in Cohort 2 (or Cohort 3) following 
review of efficacy and safety data. Please refer to the Pharmacy Manual for additional details 
for study drug administration.  
• NKTR-214 will be dosed first, followed by pembrolizumab, followed by chemotherapy. 
• Pembrolizumab will be dosed as per the Pharmacy Manual. Pembrolizumab will be 
administered as a 30-minute IV infusion q3w. 
• In Cohort 5, NKTR-214 will be dosed in combination with pembrolizumab and 
carboplatin and either nab-paclitaxel or paclitaxel, per investigator discretion. 
Nab-paclitaxel and paclitaxel will be dosed per local practice and label. Paclitaxel 
200 mg/m2 will be administered as an IV infusion over 3 hours q3w for 4 cycles. All 
subjects should be premedicated with oral or intravenous steroid and antihistamines 
according to the approved product label and/or standard practice. 
• Additional premedications should be administered as per local practice and label. 
Nab-paclitaxel will be administered at 100 mg/m2 as an IV infusion over 30 minutes for 
4 cycles as per local practice and label. Subjects will be dosed on Day 1, 8, and 15 of 
each q3w cycle.  
• Paclitaxel and nab-paclitaxel should be completely administered before initiating 
carboplatin dose. Carboplatin AUC 5mg/ml/min will be administered as an IV infusion 
over 15 to 60 minutes for 4 cycles given every 3 weeks immediately after pemetrexed as 
per local practice and label. All subjects should be premedicated according to local 
practice and label.  
5.3.2 
Dosing Schema: Dose Optimization and Dose Expansion Cohorts 
5.3.2.1 
Dose Optimization Cohorts (Cohorts 1a and 1b) 
Patients enrolled in the 3 + 3 dose optimization schema (Cohort 1a) will start NKTR-214 at a 
dose of 0.008 mg/kg q3w with pembrolizumab. Patients enrolled in the step-up dose 
optimization schema (Cohort 1b) will start NKTR-214 q3w with pembrolizumab at the 
previously tolerated dose established in the 3 + 3 dose optimization schema as determined by the 
SRC. Doses will be increased in 0.002 mg/kg increments for the dose optimization cohorts. The 
risk mitigation measures for hypotension described in Section 5.3.4, such as hydration 
guidelines, have been found adequate to limit severity and frequency and have been implemented 
across the NKTR-214 studies following the EXCEL Study. Based on the adequacy of these 


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guidelines in managing hypotension, the Sponsor has moved forward with investigating doses of 
NKTR-214 higher than 0.009 mg/kg in the dose optimization scheme. 
For dose optimization cohorts, the SRC will decide the following: 
• Dose escalation to the next dose level. 
• Dose levels of NKTR-214 for a given cohort may be reduced depending on the severity, 
duration, and frequency of toxicities observed at the previous dose level tested. 
• Decision to evaluate NKTR-214 in combination with pembrolizumab at higher doses and 
different dose schedules to assess the benefit/risk profile within the anticipated total 
number of 40 patients. 
5.3.2.1.1 
Dose Optimization Cohorts (Cohorts 1a and 1b) Schema 
The dose optimization cohort schemas for the 3 + 3 and step-up doses are shown in Figure 2.  
Figure 2: 
Dose Optimization Cohorts Schema: 3 + 3 and Step-up Dosing 
 
 


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The dose optimization cohort decision guide for the 3 + 3 dose design is shown in Table 7.  
Table 7: 
Dose Optimization Cohort Decision Guide for the 3 + 3 Dose Design 
Number of Patients with DLT 
at a Given Dose Level 
Dose Optimization Cohort Decision Guide (3 + 3 Dose Design) 
0 out of 3 
Enter 3 patients at the next higher dose level (see Figure 2). 
1 out of 3 
If only 1 of 3 patients experiences a DLT, then 3 additional patients will be 
entered at the same dose level. If 1 of 6 patients experiences a DLT, the dose 
will be increased to the next higher dose (see Figure 2). 
≥ 2 
If 2 or more patients within a cohort experience DLTs, dose escalation will stop 
and the 3 + 3 dose optimization schema is complete (see Figure 2). 
Three new patients will be enrolled in the step-up dose optimization schema 
starting at the previously tolerated dose established in the 3 + 3 dose 
optimization schema as determined by the SRC; patients will individually step-
up dosing by increments of 0.002 mg/kg at each cycle. 
Abbreviations:  DLT = dose-limiting toxicity; SRC = Safety Review Committee.  
 
In the dose optimization step-up cohort, individual patients are allowed to step-up their dose at 
increments of 0.002 mg/kg. The dose optimization cohort decision guide for the step-up cohort 
(Cohort 1b) dose design is shown in Table 8. The decision to proceed to Cohort 1b will be the 
Sponsor’s and based on safety and tolerability data from Cohort 1a.  
Table 8: 
Dose Optimization Cohort Decision Guide for the Step-up Dose 
Design  
Number of Patients with DLT 
at a Given Dose Level 
Dose Optimization Cohort Decision Guide (Step-up Dose Design) 
0  
If 0 patients experience a DLT, patients continue to step-up their individual dose 
by increments of 0.002 mg/kg up to 0.012 mg/kg or patients can remain at their 
maximum tolerated step-up dose.  
Alternatively, the SRC may decide to enroll 3 new patients at the previously 
tolerated dose and step up dosing by increments of 0.002 mg/kg at each cycle. 
1  
If only 1 patient experiences a DLT, enroll 3 additional patients at the same dose 
schedule.  
Alternatively, the SRC may decide to enroll 3 new patients at 0.006 mg/kg and 
step up the individual patient dose by increments of 0.002 mg/kg at each cycle.  
≥ 2 
If 2 or more patients experience DLTs at a given dose level, dose escalation will 
be stopped; the MTD will be established in that cohort.  
Abbreviations:  DLT = dose-limiting toxicity. MTD = maximum tolerated dose; SRC = Safety Review Committee. 
 
The dose-limiting toxicity (DLT) evaluation period for the 3 + 3 and step-up dose optimization 
cohorts will be 3 weeks (21 days) (Table 9). Any DLT past the DLT window is a delayed DLT.  


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Table 9: 
Treatment Cycle Duration and DLT Window (3 + 3 and Step-up 
Cohorts) 
Dosing Schedule 
of NKTR-214 
Cycle Definition 
DLT Window 
3 + 3 dosing q3w 
21 days 
21 days from Cycle 1 
Step-up dosing q3w 
21 days 
21 days post administration, Cycle 1 
of highest NKTR-214 step-up dose  
Abbreviations:  DLT = dose-limiting toxicity; q3w = every 3 weeks. 
 
For the 3 + 3 dose optimization schema, patients will be enrolled in groups of at least 3 patients 
starting at a dose of NKTR-214 0.008 mg/kg unless unacceptable toxicity is observed. The first 
patient of each escalating dose cohort will be monitored for safety and tolerability on Cycle 1, 
Days 1 through 5 before additional patients are dosed within the same cohort. Enrollment into a 
new cohort with an escalating dose of NKTR-214 cannot begin until the DLT window has 
elapsed since the last patient’s first dose in the previous cohort. 
The definition of a DLT is provided in Section 5.11.1. For the 3 + 3 dose optimization cohort 
(Cohort 1a), if no DLTs occur in a cohort of at least 3 patients, a new cohort of 3 patients may be 
treated at the next higher dose level. If only 1 of 3 patients in a cohort experiences a DLT, that 
cohort will be expanded to 6 patients. If 3 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 in the cohort with Sponsor approval; however, these patients are not required to be 
included in the dose escalation decision for that cohort. If only 1 of the 6 patients experiences a 
DLT, then the next cohort of 3 patients may be treated at the next higher dose level. If 2 or more 
patients within a cohort experience DLTs, dose escalation will stop and the 3 + 3 dose 
optimization schema is complete (see Figure 2). Three new patients may be enrolled in the 
step-up dose optimization schema, starting at the previously tolerated dose as established in the 
3 + 3 dose optimization schema as determined by the SRC; patients will individually step-up 
dosing by increments of 0.002 mg/kg at each cycle. 
For the step-up dose optimization cohort (Cohort 1b), if a patient does not experience a DLT 
during the DLT evaluable period, he or she can continue to step-up their individual dose by 
increments of 0.002 mg/kg up to 0.012 mg/kg or a patient can remain at 1 dose level below his or 
her maximum tolerated step-up dose if a DLT is experienced. If only 1 patient experiences a 
DLT, 3 additional patients are enrolled at the same dose schedule. Alternatively, the SRC may 
decide to enroll 3 new patients at 0.006mg/kg and step up the individual patient dose by 
increments of 0.002 mg/kg at each cycle. If 2 or more patients experience DLTs, step-up dose 
escalation will be stopped and the MTD and an optimal dosing schedule will be established in 
this cohort.  
At the Investigator’s discretion, step-up dose increases may be delayed by 1 cycle. Moreover, the 
SRC or Sponsor may determine that inadequate information has been obtained in a cohort of 


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3 patients and may enroll additional patients to further assess the benefit/risk profile at a given 
dose level.  
All drug-related AEs after the DLT window will continue to be collected and evaluated by the 
Sponsor on an ongoing basis and may be taken into consideration in determining the MTD and 
further dose escalation. During dose escalation, patients who are withdrawn from the study 
during the DLT window for reasons other than occurrence of a DLT will be replaced. 
5.3.2.2 
Dose Expansion Cohorts 2 and 3 
Patients in the dose expansion cohorts will start at a dose of 0.006 mg/kg. Based on review of 
efficacy and safety data from Cohort 2, Cohort 3 may be opened for enrollment with dosing 
starting at 0.010 mg/kg. Following data review for safety and efficacy, additional patients in 
these cohorts may be dosed using the findings from the dose optimization cohorts.  
5.3.2.3 
Dose Expansion Cohorts 4 and 5 
Based on review of efficacy and safety data from Cohort 2 (and Cohort 3 if available), then 
Cohorts 4 and 5 may begin enrollment. Dosing will start at one of the doses identified in 
Cohort 2 or Cohort 3. 
Safety Run-in (Cohorts 4 and 5 Only) 
The treatment combinations planned for Cohorts 4 and 5 have not previously been evaluated in 
the planned patient populations. These cohorts will be dosed using a rolling 6-patient design to 
evaluate for toxicity and safety.  
Cohorts 4 and 5 will begin in parallel, and each cohort will undergo a run-in period, in which 
6 patients are planned to be enrolled to initially inform the safety profile and determine the 
RP2D; more or fewer patients may be enrolled depending on how many patients are 
response-evaluable based on the totality of the safety data for these initial patients.. A Safety 
Review Committee (SRC) will evaluate the safety, tolerability, and available PK of the treatment 
combination used in each of the 2 cohorts and may confirm the RP2D or recommend dose 
modification based on the first 6 evaluable patients who have completed the first treatment cycle 
or had a DLT during the first treatment cycle for each treatment arm. Patients participating in the 
safety-run in period who are not evaluable for DLTs may be replaced.  
If Cohorts 4 and 5 meet the safety evaluation criteria, each of these cohorts may be expanded to 
approximately 63 response-evaluable patients. 
5.3.3 
Rationale for Dose of NKTR-214  
Based on the findings from the NKTR-214 monotherapy study (EXCEL; 15-214-01) (see 
Section 2.1.4.1) and findings from the dose-escalation part of the PIVOT-02 study (16-214-02) 
(see Section 2.1.4.2), the RP2D of NKTR-214 in combination with nivolumab 360 mg q3w was 


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determined to be 0.006 mg/kg in the PIVOT-02 study (16-214-02), as described in more detail 
below.  
Two data analyses of patients receiving NKTR-214 and nivolumab in Study 16-214-02 are 
provided; first, the rationale for the RP2D of NKTR-214 0.006 mg/kg in combination with 
nivolumab 360 mg q3w based on a data cut of 05 October 2017, and second, safety and efficacy 
data. 
The safety of NKTR-214 as a single agent has been assessed in 5 monotherapy cohorts 
administered NKTR-214 q3w (22 patients) at doses ranging from 0.003 mg/kg to 0.012 mg/kg; a 
dosing frequency of q2w (6 patients) was further explored at 0.006 mg/kg (Table 10 and see 
Clinical Experience with NKTR-214 in Section 2.1.4). In the dose escalation phase of 
PIVOT- 02 (16-214-02), the safety of NKTR-214 in combination with nivolumab at doses shown 
in Table 10 was assessed in 38 patients.  
Additional rationale for dosing in Cohorts 3, 4, and 5 is provided in Section 2.1.7. 
Table 10: 
Patient Exposure Supporting the RP2D of NKTR-214 0.006 mg/kg in 
Combination with Nivolumab 360 mg q3w 
Study 
NKTR-214 
Dosing 
Frequency 
Nivolumab  
(Flat Dosea) Dosing 
Frequency 
NKTR-214 
Dose (mg/kg) 
No. Patients 
Examined for 
Safety 
Positive 
 Data 
and/or Evidence of 
Clinical Activity? 
NKTR-214 
Monotherapy 
(EXCEL; 
15-214-01) 
q3w 
n/a 
0.003, 0.006, 
0.009, 0.012 
22 
Yes 
q2w 
n/a 
0.006 
6 
Yes 
NKTR-214 + 
Nivolumab 
(PIVOT-02; 
16-214-02) 
q3w 
q2w 
0.006 
4 
Yes 
q2w 
0.006 
3 
Yes 
q3w 
0.006 
25 
Yes 
q2w 
0.003 
3 
Yes 
q3w 
0.009 
3 
Yes 
Abbreviations:  q2w = every 2 weeks; q3w = every 3 weeks; n/a = not applicable; RP2D = recommended Phase 2 
dose. 
a. 
Nivolumab q2w = 240 mg, q3w = 360 mg. 
The Safety Review Committee reviewed the totality of data and concluded the following for all 
5 combination dose cohorts with a data cut of 05 October 2017: 
• Two patients at the NKTR-214 0.009 mg/kg q3w + nivolumab 360 mg q3w dose level 
experienced dose limiting toxicities: Grade 3 hypotension and Grade 4 metabolic acidosis, 
each of which resolved within 5 days and the patients continued on treatment at a lower dose 
of NKTR-214. 


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• There were no Grade ≥ 3 treatment-related adverse events (TRAEs) at the RP2D of 
NKTR-214 0.006 mg/kg in combination with nivolumab 360 mg q3w. 
• TRAEs that occurred in ≥ 50% of the patients included fatigue, flu-like symptoms (combined 
MedDRA preferred terms of influenza-like illness, pyrexia, and chills), rash (combined 
MedDRA preferred terms of rash, rash erythematous, rash macular, rash maculopapular, and 
rash pruritic), and pruritus. 
• TRAEs were consistent across all five dose cohorts. 
• Management guidelines implemented in the combination program for hypotension were 
effective to mitigate the risk for Grade ≥ 3 hypotension. 
• No Grade ≥ 3 immune-mediated AEs were observed. 
• Cytokine-related AEs such as fever, chills, pruritus, fatigue, and rash are predictable based 
on the mechanism of action and were generally of mild severity and short duration. 
• The addition of NKTR-214 did not exacerbate nivolumab-related AEs that are commonly 
classified as immune-mediated AEs. 
• NKTR-214 alone or in combination with nivolumab did not produce capillary leak 
syndrome, which is commonly observed in patients treated with high-dose IL-2. 
Tumor response data were available as of 05 October 2017 for 34 patients, including 10 with 
metastatic melanoma, 19 with RCC, and 5 with NSCLC. Of the 34 response-evaluable patients, 
24 were treated at 0.006 mg/kg NKTR-214 with nivolumab 360 mg flat dose q3w; 17 patients 
had partial or complete responses and 13 had stable disease. Given the totality of data, including 
safety/tolerability, reproducible PK, dose-independent PD profile, immune cell activation, and 
promising efficacy data (see Clinical Experience with NKTR-214 in Section 2.1.4), the Safety 
Review Committee approved NKTR-214 0.006 mg/kg q3w plus nivolumab 360 mg q3w as the 
recommended dose to be administered in the expansion cohorts included in Part 2 of 
Study 16-214-02. 
5.3.3.1 
Update of Safety and Efficacy Data 
As of 28 October 2019, 541 patients have been dosed in Study 16-214-02: 488 patients on the 
“doublet treatment” of NKTR-214 plus nivolumab (64 patients are still on study treatment), 
43 patients on “triplet” treatment with NKTR-214 plus nivolumab plus ipilimumab (18 patients 
still on study), and 10 patients with NKTR-214 and nivolumab plus other anti-cancer study drugs 
excluding ipilimumab (5 patients still on study treatment). 
The most frequently reported TEAEs were fatigue (54.3%), pyrexia (50.6%), nausea (42.0%) 
pruritus (39.7%), decreased appetite (37.5%), diarrhoea (31.1%) and influenza-like illness 
(31.1%). The most frequently reported treatment-related TEAEs were fatigue (49.4%), pyrexia 
(45.3%), pruritus (37.0%), nausea (32.9%) and influenza-like illness (30.5%). Grade ≥ 3 adverse 
reactions most frequently reported in combination Study 16-214-02 were the following grouped 
terms: syncope in 18 patients (3.3%): 15 patients (3.1%) in the NKTR-214 plus nivolumab 


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doublet cohort and 3 patients (7.0%) in the NKTR-214 plus nivolumab plus ipilimumab triplet 
cohort; hypotension in 17 patients (3.1%): 13 (2.7%) in the doublet cohort, 2 (20%) in the 
doublet plus chemotherapy cohort, and 2 patients (4.7%) in the triplet cohort; fatigue in 15 
patients (2.8%): 12 (2.5) in the doublet cohort and 3 (7.0%) triplet; and rash in 12 (2.2%): 
10 (2.0%) in the doublet cohort and 2 (4.7%) in the triplet cohort. The most frequently reported 
serious adverse reactions were flu-like symptoms in 16 patients (3.0%): 15 (3.1%) in the doublet 
cohort, and 1 (2.3%) in the triplet cohort; and hypotension in 12 patients (2.2%), 10 (2.0%) in the 
doublet cohort, and 2 (20%) in the doublet cohort plus other anti-cancer study drug patients.  
See Section 2.1.4.2 for detail of AEs and SAEs by regimen in the expansion phase. 
As of the 29 October 2018 cutoff date, 37 patients (including 11 with metastatic melanoma, 
21 with RCC, and 5 with NSCLC) in the dose escalation phase of Study 16-214-02 had tumor 
response data (per RECIST 1.1) and were considered evaluable for efficacy. Of the 37 evaluable 
patients, 21 patients (56.8%) achieved a response (ORR) by RECIST 1.1; 4 patients (10.8%) had 
complete responses (Table 11). See Section 2.1.4.2 for additional data on current response rates 
and PD-1/PD-L1 status. 
Table 11: 
Overall Tumor Response by Cancer Type: PIVOT-02 Combination 
Therapy Study 16-214-02 (Dose Escalation Phase) 
  
Melanoma 
(1L) 
(N = 11) 
RCC (1L) 
(N = 14) 
RCC (2L) 
(N = 7) 
NSCLC 
(N = 5) 
Total 
(N = 37) 
ORR (CR + PR) 
7 (63.6%) 
10 (71.4%) 
1 (14.3%) 
3 (60.0%) 
21 (56.8%) 
CR 
2 (18.2%) 
1 (7.1%) 
0 
1 (20.0%) 
4 (10.8%) 
PR 
5 (45.5%) 
9 (64.3%) 
1 (14.3%) 
2 (40.0%) 
17 (45.9%) 
SD 
3 (27.3%) 
1 (7.1%) 
6 (85.7%) 
1 (20.0%) 
11 (29.7%) 
DCR (CR + PR + SD) 
10 (90.9%) 
11 (78.6%) 
7 (100.0%) 
4 (80.0%) 
32 (86.5%) 
PD 
1 (9.1%) 
3 (21.4% 
0 
1 (20.0%) 
5 (13.5%) 
Duration of Response (Month) 
n = 7 
n = 10 
n = 1 
n = 3 
n = 21 
Median 
NA 
NA 
NA 
NA 
NA 
Rangea 
4.5+, 12.0+ 
1.0+, 8.2+ 
10.0+, 10.0+ 
5.5+, 6.5+ 
1.0+, 12.0+ 
Time to Response (Month) 
 n = 7 
n = 10 
n = 1 
n = 3 
n = 21 
Median 
1.7 
3.5 
3.5 
1.7 
1.9 
Range 
1.4, 3.3 
1.3, 7.8 
3.5, 3.5 
1.3, 3.7 
1.3, 7.8 
CR = complete response; PR = partial response; SD = stable disease; DCR = disease control rate; PD = progressive 
disease; ORR = objective response rate, NA = not applicable; NSCLC = non-small cell lung cancer; RCC = 
renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended Phase 2 
dose. 
a. 
The “+” indicates the response is ongoing at the time of the data cutoff. 
 


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PIVOT-02 (16-214-02) is a 2-stage design and data for either the Stage 1 (N1) population alone 
or in combination with Stage 2 (N2; expansion) populations were presented depending on data 
maturity. Data was presented only in the response-evaluable population (defined as having 
received 1 dose of study treatment and having undergone at least 1 scheduled postbaseline scan). 
The 1L melanoma and 1L RCC indications include dose escalation and expansion patients, 
however, the 1L urothelial indication includes expansion patients only.  
As of the 29 May 2018 cutoff, in the dose expansion phase, 26 1L RCC patients and 10 1L 
urothelial cancer response-evaluable patients met the prespecified efficacy parameters. Twelve 
of 26 efficacy patients (46%) achieved a response (ORR). Responses were seen in both 
PD-L1 (+) (2 of 7 patients, 29%) and PD-L1 (–) (9 of 17 patients, 53%). Six of 10 urothelial 1L 
efficacy patients (60%) achieved a response (ORR). Responses were seen in both PD-L1 (+) 
(3 of 5 patients, 60%) and PD-L1 (–) patients (3 of 5 urothelial patients, 60%).  
As of the 11 October 2018 cutoff, 38 1L melanoma patients met prespecified efficacy 
parameters; 20 of 38 1L melanoma patients achieved a response (ORR). Nine of 38 patients 
(24%) had a complete response. Responses were seen in both the PD-L1 (+) (defined as PD-L1 
expression ≥ 1% on tumor cells) and PD-L1 (–) (defined as < 1% PD-L1 expression on tumor 
cells) populations with an ORR 13 of 19 patients (68%) in the PD-L1 (+) population and 6 of 
14 patients (43%) in the PD-L1 (–) population (Table 12). 


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Table 12: 
Overall Tumor Response by Cancer Type: PIVOT-02 Combination 
Therapy Study 16-214-02 - Patients who met Pre-specified Efficacy 
Parameters 
 
 
Melanoma (1L) 
RP2Da 
(N = 38) 
RCC (1L) 
RP2Da  
 (N = 26) 
Urothelial (IL)a 
(N = 10) 
Best Overall Response 
 
 
 
ORR (CR + PR) 
20 (53.0%) 
12 (46.0 %) 
6 (60.0%) 
CR 
9 (24%) 
NA 
NA 
PD-L1 Negativeb 
n = 14 
n = 17 
n = 5 
ORR (CR + PR) 
6 (43.0%) 
9 (53.0%) 
3 (60.0%) 
PD-L1 Positivec 
n = 19 
n = 7 
n = 5 
ORR (CR + PR) 
13 (68.0%) 
2 (29.0%) 
3 (60.0%) 
PD-L1 Unknown 
n = 5 
n = 2 
n = 0 
ORR (CR + PR) 
1 (20.0%) 
1 (50.0%) 
0 
Disease Control Rate 
 
 
 
DCR (CR + PR + SDd) 
29 (76.0%) 
20 (77.0%) 
7 (70.0%) 
Time on Study (Month) 
n = 41e 
n = 26 
n = 10 
Median 
5.8 
5.6 
3.9 
CR = complete response; DCR = disease control rate; IHC = immunohistochemistry; NA = not available; 
ORR = objective response rate, PD = progressive disease; PD-L1 = programmed cell death ligand 1; 
PR = partial response; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors; 
RP2D = recommended Phase 2 dose ; SD = stable disease; TEAE = treatment-emergent adverse event 
a. 
Melanoma 1L and RCC 1L include both escalation and expansion patients. Urothelial includes expansion 
patients only. 
b. PD-L1 negative tumors with < 1% of staining on tumor cell via IHC. 
c. 
PD-L1 positive tumor with ≥ 1% of staining on tumor cell via IHC. 
d. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study (RECIST 1.1). 
e. 
Includes 3 patients who were not considered response-evaluable in the Stage 1 (N1) and Stage 2 (N2) 
populations (all 3 patients discontinued prior to first scan due to an unrelated TEAE [n = 1] and Patient 
Decision [n = 2]). 
Source: Diab 2018b and Diab 2018a.  
 
 
5.3.3.2 
Rationale for NKTR-214 Doses in the Dose Optimization Cohorts  
While the RP2D of NKTR-214 in combination with nivolumab is 0.006 mg/kg, the MTD in 
combination with pembrolizumab has yet to be determined. In the 15-214-01 study, only 
1 patient who had a BMI > 30 received a monotherapy dose of NKTR-214 at 0.012 mg/kg. This 


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patient experienced DLTs of syncope and hypotension (a known adverse event (AE) associated 
with both IL-2 and engineered cytokines). These AEs resolved within 3 days.  
Hypotension is identified as an important risk in NKTR 214 monotherapy Study 15-214-01 as 
well as in other ongoing combination studies. To mitigate this risk, hypotension management 
guidelines were successfully implemented (See Section 2.1.4.1). Safety data with NKTR-214 
0.006 mg/kg in combination with nivolumab 360 mg q3w in the PIVOT-02 study (16-214-02) 
showed a lower incidence of treatment-related hypotension (59 of 358 patients, [16.5%]) with 
the implementation of hypotension management guidelines. The successful management of 
hypotension using the hypotension guidelines supports further exploration with higher doses of 
NKTR-214 than 0.006 mg/kg. 
Starting with Amendment 5.0 and subsequent amendments, to further investigate the MTD of 
NKTR-214 in combination with pembrolizumab in patients with locally advanced or metastatic 
solid tumors, NKTR-214 will be administered at a starting dose of 0.008 mg/kg in the 3 + 3 dose 
optimization schema and at the previously tolerated dose established in the 3 + 3 dose 
optimization schema as determined by the SRC in the step-up dose optimization schema. Details 
of the dose optimization schema are provided in Section 5.3.2.1. 
5.3.4 
Monitoring, Vital Signs, Hydration Guidelines, and Premedication for Flu-like 
Symptoms. 
The study site must be equipped for medical emergencies. 
5.3.4.1 
Frequent Vital Signs 
Vital signs (Section 7.16) are to be taken and recorded prior to NKTR-214 dosing and monitored 
and recorded following the completion time of the pembrolizumab administration. For Cycle 1 
only, monitoring windows will be as follows: 
During all cycles and beyond on dosing days monitor and record vital signs predose 
(NKTR-214) and approximately 1 hour after administration of pembrolizumab on Day 1. 
• Cycle 1 Day 3: monitor one time at 48 hr ± 3 hr from start of infusion of NKTR-214 
• Cycle 1 Day 8: monitor one time at 168 hr ± 24 hr from start of infusion of NKTR-214 
• EOT: monitor one time at 90 (± 10 days) 
If the patient experienced a Grade ≥ 2 infusion-related reaction or hypotension on the dosing day, 
the patient may be monitored overnight or for a longer period at the discretion of the 
Investigator.  


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5.3.4.2 
Hydration Guidelines 
Important safety information and hydration instructions are to be provided to patients. Details 
regarding intravenous and oral hydration will be captured in the EDC.  
Adequate hydration mitigates the development of hypotension associated with NKTR-214 
administration. Hydration and renal function must be assessed within 72 hours, or as soon as 
locally feasible, prior to NKTR-214 study drug administration see Appendix 1 for the list of 
analytes that require collection and evaluation prior to NKTR-214 study drug administration). 
For participants who must delay study treatment due to creatinine increase, see additional 
information regarding criteria to delay (Sections 5.13.1 and 5.13.2), resume (Section 5.13.6), or 
permanently discontinue study treatment (Section 5.15). Underlying reasons for decreased oral 
intake (eg, nausea) should be addressed and treatment (eg, IV hydration) should be provided. 
The Investigator may modify these recommendations based on the needs of the individual 
patient.  
Patients should be administered 1 liter of IV fluid on the day of each dosing of NKTR-214. In 
addition, consider administering 1 liter of normal saline IV when the patients return for clinic 
visits (eg, if the patient returns for PK draws on Days 3 and 5 of Cycle 1), anytime based on the 
patient’s need, or as clinically indicated. Patients are to be instructed that for the next 3 days after 
administration of NKTR-214, they should 1) drink at least 2 liters per day of self-administered 
oral hydration and 2), keep bedside drinking water at night and avoid posture change from sitting 
to standing without hand support and activity which may contribute to dehydration (including, 
but not limited to, strenuous activity, long hot showers, sunbathing, and saunas) for at least 
3 days following treatment with NKTR-214.  
Antihypertensive medications (including diuretics) should be withheld from Day 1 to Day 5 of 
each Cycle. Antihypertensive medications may be restarted on Day 6 or at any time as clinically 
indicated (eg, based on blood pressure measurements). 
Per clinical judgment, IV fluids may be administered at any time during any cycle. 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). Advise patients with orthostatic symptoms to call 
their treating oncologist and consider increasing oral hydration. 
Patients with pre-existing adrenal impairment requiring corticosteroid supplementation may be at 
increased risk for hypotensive episodes during treatment with NKTR-214. Co-management with 
an endocrinologist is recommended for patients with pre-existing adrenal insufficiency. 
Between 2 and 4 days (inclusive) following treatment with NKTR-214, site personnel must 
contact the patient (by telephone or clinic visit) to remind the patient of the oral hydration 
guidelines, to assess for any symptomatology and compliance with the guidelines and document 
the results of the discussion.  


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5.3.4.3 
Premedication for Flu-like Symptoms 
These recommendations have been developed to reduce the risk of flu-like symptoms during the 
first week of each treatment cycle. Investigator may modify these recommendations based on the 
needs of individual patient.  
• Administer acetaminophen (eg, 650 mg every 6 hours) or NSAIDs (eg, ibuprofen 400 mg 
every 6 hours) a minimum of 30 minutes prior to treatment on Day 1 of each cycle. 
• Administer acetaminophen or NSAIDs q6h on Day 2 to 5 of each cycle. For Cohort 4, 
premedication can only be done with acetaminophen.  
• Instruct patients on the signs and symptoms (fever over 100.4 °F or 38 °C, chills and 
sweats, muscle aches or join paint, fatigue and weakness), how to treat with 
acetaminophen or NSAIDs, and when to call their treating oncologist or present for 
medical care. 
5.3.5 
Duration of Treatment 
Patients will be treated until: 
• A maximum of 2 years (or a maximum of 34 cycles) of treatment have been completed 
• Disease progression 
• Death 
• Unacceptable toxicity 
• Symptomatic deterioration 
• Investigator’s decision to discontinue treatment 
• Patient decision to discontinue treatment 
• Patient withdraws consent  
• Lost to follow up 
• Nektar Therapeutics decides to terminate the study 
5.3.6 
Treatment Beyond Progression 
Accumulating evidence indicates that a minority of patients with solid tumors treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD (Wolchok 2009, 
Nishino 2015). 
Criteria:  Patients are permitted to continue study treatment beyond initial PD per RECIST 1.1 
as assessed by the Investigator if they meet the following criteria: 
• Investigator-assessed clinical benefit. 


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• All eligibility criteria, including ECOG performance status of 0 or 1 
• Absence of signs and symptoms indicating clinical disease progression (eg, increased 
pain or worsening laboratory values) 
• Absence of tumor progression at critical anatomical sites (eg, brain metastases or cord 
compression) requiring urgent intervention. 
• Provides written informed consent for treatment beyond progression. 
• Approval of Medical Monitor 
Assessments. Radiographic scans and other assessments should continue in accordance with the 
Schedule of Events (Section 1.1) for the duration of the treatment beyond progression. 
Discontinuation. Treatment beyond progression should be stopped when the Investigator 
assesses a loss of clinical benefit. The criteria may include clinical disease progression, second 
PD of target lesions per RECIST 1.1, radiographic progression of non-target lesions, or new 
lesions or high grade, unresolved treatment related toxicity. Discussion with the medical monitor 
is encouraged 
5.4 
End of Treatment (EOT) 
Patients may choose to discontinue the trial at any time and for any reason. Patients may 
discontinue treatment of all or one of the study drugs based on AEs. Reasons for permanent 
treatment discontinuation are detailed in Section 5.15. The EOT visit should occur 
30 (± 10) days after all study therapy is permanently discontinued or before a new antineoplastic 
regimen (including commercially-sourced single-agent pembrolizumab) starts. If the patient 
discontinues NKTR-214 but continues on pembrolizumab and/or chemotherapy, the NKTR-214 
immunogenicity EOT sample should be collected at 30 ((± 10) days after the last dose of 
NKTR-214. 
If a patient withdraws consent, the Investigator will promptly notify the Sponsor and make every 
effort to complete the End of Treatment procedures specified in the Schedule of Events 
(Section 1.1).  
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or Institutional Review Boards (IRBs)/ Independent Ethics Committees (IECs). 
5.5 
Long-term Follow-up 
Long-term follow-up should continue until withdrawal of consent, death, or study termination by 
the Sponsor. Timing for long-term follow-up will be as follows: 
• Upon discontinuation of all study treatment, the long-term follow-up visits should occur 
every 90 (± 10) days after the last dose of all study treatment and then every 90 (± 10) 
days for survival status. Per clinical judgment, the patient may come in earlier. 


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• If a patient did not experience PD per BICR by RECIST 1.1 when study drug treatment 
was discontinued, tumor assessments should continue every 90 (± 10) days until PD, 
consent withdrawal, start of new antineoplastic regime, death, or study termination by 
Sponsor. 
• A sample for immunogenicity testing for NKTR-214 will be collected at the first 90-day 
follow up visit.  
For AE and serious AE (SAE) reporting periods, please refer to Sections 7.5 and 7.6.  
5.6 
End of Study 
End of study is defined as no more than 3 years after the last patient received their first dose of 
NKTR-214 or Sponsor decision to terminate the study, whichever comes first.  
5.7 
Tumor and Radiographic Assessments 
Tumor assessments for all patients must be performed at Screening, every 9 weeks (± 7 days) 
from Cycle 1 Day 1, EOT, and at the 90-day long-term follow-up visits. If a patient has an 
unconfirmed PR or CR, an early scan is recommended 4 weeks or later, and the next scheduled 
9-week scan may be skipped if less than 4 weeks from the early scan. All subsequent tumor 
assessments must remain on the original 9-week assessment schedule based off Cycle 1 Day 1 
(ie, at Weeks 18, 27, 36, etc.). Patients with unconfirmed stable disease / progressive disease, 
subsequent tumor assessments must remain on the original 9-week assessment schedule unless 
an early scan is clinically indicated. Assessments will become less frequent during the long-term 
follow-up period (Section 5.5). Tumor response will be evaluated using RECIST 1.1 
(Section 8.0). If a patient does not experience PD by RECIST 1.1 when study drug treatment was 
discontinued, tumor assessments should continue every 90 (± 10) days until PD, consent 
withdrawal, start of new systemic therapy, death, or study termination by Sponsor. Confirmation 
of tumor response is discussed in Section 8.2.2.3. 
A brain MRI at Screening is required for all patients with metastatic NSCLC, and for patients 
with other tumor types who have known brain metastasis. Subsequent brain MRIs for all cohorts 
may be done at 9-week intervals if clinically indicated.  
Documented tumor assessments are required using CT scans, MRI, and/or physical examination, 
as appropriate. Radiographic assessments (chest/abdomen/pelvis) are required for all patients for 
tumor assessments. CT with intravenous contrast (at 5 mm thinness or less) is the preferred 
method. For patients with contrast allergies, chest CT without contrast and abdomen/pelvis MRI 
with gadolinium are alternatives. A CT portion of the PET-CT is acceptable if RECIST 1.1 
measurements can be performed. Note that for Germany only, pelvic radiographic assessment is 
not applicable.  
The same method of assessment (CT or MRI) and the same technique for acquisition of images 
must be used for all study assessments (contrast must be used unless medically contraindicated). 


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Baseline imaging must be done at the same institution/facility that will be used to measure 
response during the patient’s participation in the study. Radiographic assessments and efficacy 
analyses will be conducted by the Investigator site. 
5.8 
Pharmacokinetic Measurements 
Blood samples for PK analyses of NKTR-214 and its metabolites will be collected as described 
below.  
Dose Optimization 3 + 3 Cohort (Cohort 1a):  for Cycle 1 only, blood will be collected at 
predose on Day 1 and at the following times after the start of the NKTR-214 infusion:  
3 hr ± 30 min (Day 1), 48 hr ± 3 hr (Day 3), 96 hr ± 24 hr (Day 5), and 168 hr ± 24 hr (Day 8).  
For Cycle 2 and every 3 cycles after Cycle 2 (ie, Cycles 5, 8, 11, etc.), blood will be collected on 
predose on Day 1. For Cycles 2 and beyond, predose sampling assessments can be drawn within 
72 hours prior to dosing. 
Dose Optimization Step-up Cohort (Cohort 1b): for Cycle 1 and only in the first cycle of any 
subsequent cycle(s) in which the patient is administered a step-up dose, the PK sampling 
schedule is the same as shown above for Cycle 1 for Cohort 1a.  
With the exception of cycles in which the patient is administered a step-up dose, for Cycles 2 and 
every 3 cycles after Cycle 2 (ie, Cycles 5, 8, 11, etc.), blood will be collected on predose on 
Day 1. For Cycles 2 and beyond, predose sampling assessments can be drawn within 72 hours 
prior to dosing. 
Dose Expansion Cohorts (Cohorts 2, 3, 4, and 5): for Cycle 1, blood will be collected predose on 
Day 1 and at the following times after the start of the NKTR-214 infusion: 3 hr ± 30 min (Day 
1), 48 hr ± 3 hr (Day 3), 96 hr ± 24 hr (Day 5), and 168 hr ± 24 hr (Day 8).  
For Cycle 2 and every 3 cycles after Cycle 2 (ie, Cycles 5, 8, 11, etc.), blood will be collected 
predose on Day 1. For Cycles 2 and beyond, predose sampling assessments can be drawn within 
72 hours prior to dosing. 
If a possible study drug(s)-related SAE occurs on study, PK blood samples should be drawn as 
close to the event as possible to help characterize any possible relationships between drug 
exposure and the SAE. 
Blood samples for PK analysis will be collected and processed according to the Laboratory 
Manual provided to the site. All PK sample collections should align with days of study drug 
administration and adjusted for any dose delays. However, if a predose sample is collected but 
the dose is subsequently delayed, an additional predose sample should not be collected. For all 
PK blood samples, the date and actual time collected must be recorded.  


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5.9 
Immunogenicity Measurements 
Immunogenicity samples for NKTR-214 will be drawn at predose on Day 1 of Cycle 1, and 
Cycle 2, and predose on Day 1 of every 3 cycles after Cycle 2 (ie, Cycles 5, 8, 11, etc.), at the 
NKTR-214 EOT visit, and at 90 (± 10) days after the last administered dose of NKTR-214. If 
dosing occurs on a different day, the immunogenicity sampling should be adjusted accordingly. 
Serum samples will be collected and processed as outlined in the Laboratory Manual provided to 
the site.  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
 


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5.10.2 
Tumor Tissue Biopsy Collection Times and Analysis 
All patients must provide tumor tissue from resection or biopsy obtained within 12 months from 
screening as either formalin-fixed paraffin-embedded (FFPE) block or unstained slides (a 
minimum of 10 slides freshly-cut within 1 week of submission) (Table 13). Tissue obtained from 
fine needle aspiration, cytology specimen and bone lesion are NOT acceptable. A tracking 
number confirming shipment of the sample to the central lab must be supplied before Cycle 1 
Day 1. Unused portions of the block will be returned to the site. If archival tissue is not available, 
or if patient received systemic anticancer therapy between dates of tissue collection and 
screening, a fresh biopsy is required.  
Target lesions should not be biopsied.  
One on-treatment tumor biopsy (submitted as a block if possible) will be collected during 
Days 15-21 in Cycle 1 for the dose optimization cohorts only. No Day 15 to 21 on-treatment 
tumor biopsies will be collected for the dose expansion cohorts. If screening biopsies (fresh or 
archival) are not obtained, on-treatment biopsies should not be collected.  
Pretreatment and on-treatment biopsies should be taken from the same lesion, if feasible. 
Biopsies should only be performed on lesions that have not been exposed to prior radiation. 
Tumor tissue biopsies will be used for characterization of infiltrating immune cell populations 
using a panel of markers, using IHC, flow cytometry, mass spectroscopy, or other similar 
techniques. 


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Biopsy samples may also be used to investigate molecular signatures. DNA and/or RNA may be 
extracted from these samples for somatic mutation analysis and gene expression analysis. Genes 
to be assayed may include, but not be limited to, those with known driver mutations in solid 
tumors. These samples will be analyzed by the Sponsor or designee. 
Table 13: 
Tumor Biopsy Requirements (Dose Optimization and Dose 
Expansion) 
Requirementsa 
Visit 
Recommendation 
Specimen Type 
Screening 
All Patientsb 
Fresh biopsy or archival biopsy (block 
preferred, but slides [minimum of 10] 
acceptable) 
Week 3 (Days 15-21) 
Dose Optimization only 
Fresh biopsy 
a. 
Fine needle aspiration, cytology specimens, and bone lesions are not acceptable. Target lesions should not be 
biopsied unless there are no other lesions suitable for biopsy. Pretreatment and on-treatment biopsies should be 
taken from the same lesion, if feasible. 
b. Acceptable tissue specimens include archival tissue (10 slides) obtained no more than 12 months prior to 
enrollment if the patient has not received systemic treatment between the time of biopsy/resection and 
enrollment. Otherwise, a fresh tumor biopsy taken during screening is required. 
 
5.11 
Determination of Dose Limiting Toxicities (DLTs) 
Based on the nonclinical toxicology, safety data from the dose escalation study 
(Study 15-214-01) and PIVOT-02 (16-214-02) and the peak pharmacokinetic and 
pharmacodynamic profile of NKTR-214, drug-related toxicity is most likely to occur 1 to 5 days 
following treatment. Dose limiting toxicities will be assessed during the DLT window shown in 
Table 9. If DLTs are not observed, dose escalation will be permitted. Patients will continue to 
enroll until 40 patients have been evaluable for safety. Grading of AEs is described in 
Section 7.3. 
5.11.1 
DLTs Related to Study Drug(s) 
Examples of AEs related to study drug(s) that will be defined as a DLT include the following: 
• Any Grade ≥ 3 drug-related non-hematological AE that does not resolve to Grade 1 or 
baseline within 7 days except those listed in Section 5.11.2. 
• Any drug-related Grade ≥ 2 myocarditis, Grade ≥ 2 uveitis, Grade ≥ 3 pneumonitis, or 
Grade ≥ 3 neurotoxicity (encephalopathies, myasthenic syndromes, Guillain-Barre 
syndrome). 
• Any Grade 4 drug-related hematological AE that is clinically significant (neutropenia, 
leukopenia, thrombopenia) > 7 days and any Grade 4 anemia. 
• Any Grade 4 drug-related nausea or vomiting. 


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• Any Grade ≥ 3 drug-related hypotension lasting > 48 hours postdose, cytokine-release 
syndrome, capillary leak syndrome, pulmonary edema, or symptomatic hypereosinophilic 
syndrome. 
• Any case of Hy’s law (https://www.fda.gov/downloads/Guidances/UCM174090.pdf). 
All AEs that meet DLT criteria must be recorded in the electronic data capture system within 
approximately 24 hours of awareness. 
5.11.2 
Grade 3 or 4 AEs that Should Not be Considered a DLT 
The following Grade 3 or 4 AEs should not be considered a DLT: 
• Endocrinopathy AEs, such as adrenal insufficiency, adrenocorticotropic hormone 
(ACTH) deficiency, hyper- or hypothyroidism, that resolve or are adequately controlled 
with physiologic hormone replacement (corticosteroids, thyroid hormones) or glucose 
intolerance managed with glucose-controlling agents. 
• Asymptomatic amylase or lipase elevations. 
• Lymphopenia < 14 days in duration or not associated with clinical manifestations. 
• Electrolyte imbalances/abnormalities that are not associated with clinical sequelae and 
are corrected with supplementation/appropriate management within 72 hours of their 
onset. 
• Tumor flare defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor. 
• Grade 3 nausea or vomiting that can be medically managed to ≤ Grade 2 within 72 hours. 
• Grade 3 hypotension during Cycles 1 or 2 that lasts ≤ 48 hours postdose. 
• Fatigue that improves to ≤ Grade 2 within 7 days. 
• Amylase or lipase elevations that last ≤ 7 days and are not associated with symptoms or 
clinical manifestation of pancreatitis. 
5.12 
Delayed Dose-limiting Toxicities (DLTs) 
Delayed DLTs are AEs as defined in Section 5.11.1 that occur after the DLT window listed in 
Table 9. Delayed DLTs will not be used to determine the MTD for dose escalation. Delayed 
DLTs will be collected and evaluated by the Investigators and the Medical Monitor on an 
ongoing basis. 
All AEs that meet DLT criteria must be recorded in the electronic data capture (EDC) system 
within 24 hours of awareness. 


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5.13 
Dose Delay and Reduction Criteria 
Dose delays of more than one drug are allowed for management of treatment-related toxicities 
during a given treatment cycle for all cohorts. Any dose delays or reduction in all cohorts will 
require discussion and approval of the medical monitor. For dose delay and reduction criteria, 
see grading of AEs described in Section 7.3. Tumor assessments for all patients should continue 
as per protocol even if dosing is delayed.  
5.13.1 
Pembrolizumab and Chemotherapy Dose Delay and Reduction Criteria 
5.13.1.1 
Pembrolizumab (All Cohorts) 
Dose reductions for pembrolizumab are not permitted in this study. Pembrolizumab may be 
delayed based on drug-related toxicities and the medical monitor should be informed by the 
Investigator of any pembrolizumab dose delay. Refer to the Keytruda (pembrolizumab) full 
prescribing information for the conditions that warrant a delay in dosing. NKTR-214 
administration can continue independent of the pembrolizumab dose delay.  
5.13.1.2 
Chemotherapy (Cohorts 4 and 5 Only) 
For Cohorts 4 and 5:  Reduction of 1 chemotherapy agent and not the other agent is appropriate 
if, in the opinion of the Investigator, the toxicity is clearly related to one of the treatments. If, in 
the opinion of the Investigator, the toxicity is related to the combination of both chemotherapy 
agents, both drugs should be reduced according to recommended dose modifications. If the 
toxicity is related to the combination of three agents, all three agents should be reduced (if 
applicable), interrupted or discontinued according to the recommended dose modifications. 
Patients may continue on single study treatment drug if other study drug is discontinued for 
protocol defined reasons or at investigator’s medical judgement, example patient may continue 
receiving NKTR-214 if discontinued from pembrolizumab and/or chemotherapy. Subjects may 
also have chemotherapy discontinued and continue on pembrolizumab alone. Similarly, subjects 
may discontinue pembrolizumab and continue on chemotherapy alone during the first four 
cycles, if appropriate. 
Chemotherapy may be interrupted for a maximum of 6 weeks; pembrolizumab may be 
interrupted for a maximum of 12 weeks. Refer to approved product labels for dose modifications 
regarding paclitaxel and nab-paclitaxel. 
Pemetrexed, carboplatin, and cisplatin dose delay, reduction, and discontinuation criteria are 
shown below in Table 14. 


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Table 14: 
Pemetrexed, Carboplatin, and Cisplatin Dose Delay, Reduction, and 
Discontinuation Criteria 
Discontinuation Criteria: 
 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Cisplatin 
75 mg/m2 
56 mg/m2 
38 mg/m2 
Discontinue 
Carboplatin 
AUC 5 
Maximum dose 
750 mg 
AUC 3.75 
Maximum dose 
562.5 mg 
AUC 2.5 
Maximum dose 
375 mg 
Discontinue 
Pemetrexed 
500 mg/m2 
375 mg/m2 
250 mg/m2 
Discontinue 
Recommended Dose Modifications for Chemotherapy Non-hematological Toxicity: 
 
 
Pemetrexed 
Cisplatin 
Carboplatin 
Event 
CTC Grade 
Dose level (DL) 
Nausea or vomiting 
Grade 3 or 4 
DL 0 
DL 0 
DL 0 
Diarrhea 
Grade 3 or 4 
DL -1 
DL -1 
DL 0 
Mucositis 
Grade 3 or 4 
DL -2 
DL 0 
DL 0 
Neurotoxicity 
Grade 2 
DL 0 
DL -2 
DL 0 
Grade 3 or 4 
DL -1 
Discontinue 
DL -1 
Transaminase elevation 
Grade 3 
DL -1 
DL -1 
DL -1 
Grade 4 
Discontinue 
Discontinue 
Discontinue 
Other non-hematological 
toxicity 
Grade 3 or 4 
DL -1 
DL -1 
DL -1 
Recommended Dose Modifications for Chemotherapy Hematological Toxicity: 
 
 
Pemetrexed 
Cisplatin/Carboplatin 
Platelets 
ANC 
Dose level (DL) 
≥ 50 AND 
≥ 0.5 
DL 0 
DL 0 
≥ 50 AND 
< 0.5 
DL -1 
DL -1 
< 50 without bleeding 
AND 
ANY 
DL -1 
DL -1 
< 50 with 
Grade ≥ 2 bleeding AND 
ANY 
DL -2 
DL -2 
ANY AND 
< 1.0 + fever ≥ 38.5°C (101°F) 
DL -1 
DL -1 
Creatinine clearance (CLcr) will be calculated by the Cockcroft-Gault equation (Cockcroft 1976). CLcr must be 
≥ 45 mL/min prior to the administration of chemotherapy. Pemetrexed and/or platinum may be delayed for up 
to 42 days to allow the patient time to recover from the toxicity. If a patient’s CLcr value has not returned to 
≥ 45 mL/min within 42 days after the previous dose, platinum and/or pemetrexed must be discontinued. 
 
5.13.2 
NKTR-214 Dose Delay and Reduction Criteria 
With approval of the Sponsor’s Medical Monitor, the NKTR-214 dose may be delayed or 
reduced due to toxicities. Pembrolizumab administration can continue independent of the 
NKTR-214 dose reduction or delay. 


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NKTR-214 administration should be delayed for the following reasons: 
• For persistent Grade 2 related toxicity, at the discretion of the Investigator. 
• Grade ≥ 2 creatinine increase: 
o Treatment should be delayed. Participant may resume study drug when serum creatinine 
has returned to Grade ≤ 1, as assessed within 24 hours prior to redosing. 
• Grade ≥ 3 toxicity at least possibly related to NKTR-214: NKTR-214 dosing must be delayed 
until resolution to Grade 1 or baseline (unless otherwise requiring permanent discontinuation, 
per Section 5.15), with the following exceptions: 
o Grade ≥ 3 lymphopenia 
o Grade ≥ 3 asymptomatic amylase or lipase elevation 
• Patient has acute infection (eg, fever, upper or lower respiratory tract infection) requiring 
systemic antibiotic therapy. Patient may resume study treatment once free of signs or 
symptoms for 72 hours after completion of antibiotic therapy (See Section 5.13.6).  
• Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, warrants delaying the dose of study medication. 
NKTR-214 dosing may resume at the same or reduced NKTR-214 dose level depending on the 
toxicity resolution to Grade 1 or a return to baseline with adequate symptom management, 
except for instances where the potential recurrence of the event poses an undue risk for the 
participant. Medical Monitor consultation is required for dose reduction. 
5.13.3 Dose-Modification Criteria for NKTR-214 for Cycle 1 ALT/AST Elevations 
These recommendations are for Cycle 1 only and are not intended to serve as rigid guidelines or 
to replace clinical judgement. Subsequent cycles should follow standard Hepatic Adverse Event 
Management Algorithm (Pharmacy Manual). 
Rule out non-inflammatory etiologies. If non-inflammatory cause, treat accordingly and continue 
NKTR-214. Consider imaging for obstruction.  
If during monitoring ALT/AST increases, follow the guidance for the highest levels. 
ALT or AST > 3.0 to ≤ 5.0 × ULN (within first cycle of NKTR-214) 
Increase frequency of LFT monitoring to approximately every 3 days and delay treatment until 
lab abnormalities resolve to Grade 0-1. 
If no improvement within 7 days, treat with 0.5-1 mg/kg/day prednisone equivalents, and taper 
steroids over at least 1 month before resuming treatment 


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ALT or AST > 5.0 to ≤ 8.0 × ULN (within first cycle of NKTR-214) 
Increase frequency of monitoring to approximately every 3 days until lab abnormalities resolve 
to Grade 0-1. 
Treatment must be delayed until lab abnormalities resolve to Grade 0 to 1. 
If no improvement within 7 days (follow Hepatic Adverse Event Management Algorithm); 
• Discontinue NKTR-214  
• 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 
1 month 
• Consult gastroenterologist 
• Consider adding non-corticosteroid immunosuppressive medication if no improvement in 
> 3-5 days, worsens or rebounds while on steroids 
ALT or AST > 8.0 × ULN (follow Hepatic Adverse Event Management Algorithm) 
• Discontinue NKTR-214 
• Increase frequency of monitoring to approximately 1 to 2 days 
• 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 
1 month 
• Consult gastroenterologist 
• If no improvement in > 3 to 5 days, worsens or rebounds, add non-corticosteroid 
immunosuppressive medication 
Please refer to Section 5.15 for discontinuation criteria. 
5.13.4 
Monitoring and Management of Elevated Hepatic Transaminases 
Elevated hepatic transaminases are an overlapping toxicity that can occur for NKTR-214. The 
elevations in hepatic transaminases associated with NKTR-214 typically occur at the time of 
peak active cytokine concentration in the blood (Days 2-4) and are often accompanied by other 
cytokine-related toxicities such as flu-like symptoms, rash, or pruritus. The transient elevations 
in hepatic transaminases are usually mild or moderate in severity, not associated with increased 
total bilirubin, resolve spontaneously without treatment, and predominantly occur in Cycle 1 and 
Cycle 2. Grade 3 laboratory abnormalities with these characteristics have been observed in 
PIVOT-02 during Cycle 1, and patients were able to continue study treatment uninterrupted with 
close laboratory monitoring (Section 5.13.3). 
Hepatic events, including elevated liver function tests, have also been observed for 
pembrolizumab. Most cases were of low or moderate severity. Higher grade abnormalities are 


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concerning for immune-mediated hepatitis, and typically occur with a later onset (median time to 
onset of 3.3 months). Immune-mediated hepatitis generally results in a quick rise in liver 
function tests and responds to corticosteroids or immune-modulating agents. For transaminase 
elevations occurring in Cycle 2 onwards potentially involving an immune-mediated mechanism, 
follow the immune-mediated hepatic adverse event management guidelines in the product 
labeling for appropriate management.  
5.13.5 
Monitoring and Management of NKTR-214-Induced Eosinophilia 
Frequent and significant eosinophilia has been observed in patients receiving NKTR-214, 
primarily starting at Cycle 2 or later, consistent with the known effect of IL-2 therapy. Clinical 
data analysis demonstrated that frequency of selected AEs (primarily Grade 1 or 2 in severity) 
such as rash, pruritus, edema, nausea, vomiting, diarrhea, and dizziness increased with level of 
eosinophilia. Isolated cases of hypereosinophilic syndrome and other eosinophilic disorders have 
been reported. Eosinophilia and eosinophilic disorders have been reported with other 
immunotherapy like anti-PD-1/PDL-1 inhibitors as well. 
Absolute eosinophil count (AEC) should be closely monitored per protocol. If a study subject is 
suspected to have hypereosinophilic syndrome (symptoms may involve skin, lungs, digestive 
tract, heart, blood, and nervous systems) with AEC at or above 5000/µL (5 × 109/L) level, 
NKTR-214 treatment may need to be withheld, and the patient should be treated as clinically 
indicated. 
5.13.6 
Criteria to Resume NKTR-214 
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade  1 or baseline value, with the following exceptions: 
• Participants may resume treatment in the presence of Grade 2 fatigue 
• Participants who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity 
• For participants with AST or ALT > 3.0 to ≤ 5.0 × ULN, and/or total bilirubin 
abnormalities, dosing may resume when laboratory values return to baseline and 
management with corticosteroids, if needed, is complete. 
• Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion 
of a steroid taper over at least 1 month may be eligible for retreatment if discussed with 
and approved by Medical Monitor (or designee). 


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• For participants who must delay study treatment due to Grade ≥ 2 creatinine increase, the 
patient may resume study drug treatment when serum creatinine has returned to 
Grade ≤ 1 creatinine increase as assessed within 24 hours, or as soon as locally feasible, 
prior to redosing with study drug, except where permanent discontinuation of study drug 
is required (see Section 5.15). 
• Participants with drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement may resume treatment after consultation with the 
medical monitor (or designee). Withhold until clinically stable or permanently 
discontinue depending on severity for Grade ≥ 3 adrenal insufficiency or hypophysitis. 
Hospitalization for diagnostic workup of adrenal insufficiency without severe symptoms 
should not require discontinuation.  
5.14 
Management Algorithms for Immune-Mediated AEs and Cytokine Release 
Syndrome 
5.14.1 
Management Algorithms for Immune-Mediated AEs Associated with Immuno-
Oncology Agents  
Immune mediated adverse events (IMAEs) are well defined AEs associated with the use of 
Pembrolizumab. The management of these AEs should be according to pembrolizumab product 
labeling. Early recognition and management of AEs associated with immuno-oncology agents 
may mitigate severe toxicity. Management algorithms have been developed and are available as 
part of the pembrolizumab product labeling to assist Investigators in assessing and managing the 
following groups of AEs: 
• Pneumonitis 
• Colitis 
• Hepatitis 
• Endocrinopathies 
• Nephritis and renal dysfunction 
• Skin adverse reactions 
• Neurological  
• Other immune-related AEs  
The term immune-related adverse events (IrAEs) is interchangeable with immune-mediated 
adverse events (IMAEs).  
5.14.2 
Management Algorithm for Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is a clinical diagnosis of exclusion that usually presents with a 
constellation of symptoms associated with cytokine side effects such as persistent fever, 
hypotension, hypoxia in association with/without tachypnea, headache, rash, tachycardia, or 


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organ toxicity with varied manifestation. For confirmed cases of CRS or suspected CRS Grade 3 
or higher, the Investigator should contact the Medical Monitor regarding treatment modifications 
or dose changes. A general guidance with algorithm for CRS management and reportability is 
provided in Appendix 4.  
5.15 
Discontinuation from Study Treatment 
Patients MUST discontinue investigational product (and non-investigational product at the 
discretion of the Investigator) for any of the following reasons: 
• Patient’s request to stop study treatment. Patients who request to discontinue study treatment 
will remain in the study and must continue to be followed for protocol specified follow-up 
procedures. The only exception to this is when a patient specifically withdraws consent for 
further assessments or contact with him/her or persons previously authorized by patient to 
provide this information. 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the Investigator, indicates that continued participation in the study is not in the 
best interest of the patient. 
• Termination of the study by the Sponsor 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a patient who has been imprisoned may be permitted to continue as a 
patient. Strict conditions apply and Sponsor approval is required.) 
• Disease progression in the absence of clinical benefit as determined by the Investigator (see 
details regarding continuing treatment beyond initial assessment of progression per 
RECIST 1.1 in Section 5.3.6). 
• Occurrence of a clinically significant AE found to be unacceptable or nonresolution of a 
clinically significant AE for > 8 weeks. 
• Symptomatic deterioration in the absence of tumor progression per RECIST 1.1. 
• Noncompliance of the patient with protocol-mandated procedures based on the judgment and 
agreement of both the Investigator and Sponsor 
• If a patient has not progressed following discontinuation of study drug(s), every effort should 
be made to continue to obtain radiographic tumor assessments (until the patient has 
documented progression as per the BICR).  
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or Institutional Review Boards (IRBs)/ Independent Ethics Committees (IECs).  
Patients may choose to discontinue the study at any time, for any reason, and without prejudice 
to further treatment. Refer to the Schedule of Events for data to be collected at the time of 
treatment discontinuation and follow-up and for any further evaluations that can be completed. 


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If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately, and the Investigator must notify the Sponsor within 24 hours of awareness of the 
pregnancy. Refer to Section 7.12 (Pregnancy).  
All patients who discontinue study treatment should comply with protocol specified follow-up 
procedures. The only exception to this requirement is when a patient withdraws consent for all 
study procedures including post-treatment study follow-up or loses the ability to consent freely 
(ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness). 
If study treatment is discontinued prior to the patient’s completion of the study, the reason for the 
discontinuation must be documented in the patient’s medical records and entered on the 
appropriate case report form (CRF) page. 
Patients meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s); however, with Medical Monitor approval, NKTR-214 treatment may 
continue if the toxicities listed below are considered related to pembrolizumab only. For CVA 
events and suspected TIA events, follow the criteria described below (additional details are 
provided in the CVA management algorithm in Appendix 2). 
•
Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity
•
Grade 3 or 4 nephritis
•
AST or ALT greater than 5× ULN or total bilirubin greater than 3 × ULN
•
Grade 4 diarrhea or colitis
•
Grade 4 hypophysitis
•
Myasthenic syndrome/myasthenia gravis, Guillain-Barre, or meningoencephalitis (all
grades)
•
Grade 3 or 4 ocular inflammatory toxicity
•
Grade 4 pancreatitis, or any grade of recurrent pancreatitis or Grade 4 amylase or lipase
that does not return to baseline or Grade ≤ 1 within 7 days
•
Grade 3 or 4 infusion-related reactions
•
Grade 4 rash, severe skin reactions, or confirmed Stevens–Johnson syndrome or toxic
epidermal necrolysis
•
Any severe or Grade 3 treatment-related adverse reactions that recur
•
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation
except:
–
Grade 3 drug-related thrombocytopenia > 7 days or associated with clinically
significant bleeding requires discontinuation


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• Any Grade 4 drug-related AE or laboratory abnormality, except for the following events, 
which do not require discontinuation: 
– Grade 4 neutropenia  7 days 
– Grade 4 lymphopenia or leukopenia ≤ 14 days in duration 
– Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to Grade < 4 or 
return to baseline within 7 days 
– Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
– Grade 4 drug-related endocrinopathy AEs such as hyper- or hypothyroidism, or 
glucose intolerance, that resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids [10 mg or less of prednisone or equivalent per 
day], thyroid hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Medical Monitor 
• Any dosing delay lasting > 6 weeks after the last dose, with the following exceptions: 
– Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a patient with a dosing delay lasting 
> 6 weeks after the last dose and with no more than 3 missed doses, the Medical 
Monitor must be consulted. Tumor assessments should continue as per protocol even 
if dosing is delayed. 
– Dosing delays > 6 weeks after the last dose, which occur for nondrug-related reasons, 
may be allowed if approved by the Medical Monitor. Prior to re-initiating treatment in 
a patient with a dosing delay lasting > 6 weeks after the last dose and with no more 
than 3 missed doses, the Medical Monitor must be consulted. Tumor assessments 
should continue as per protocol even if dosing is delayed, and patients must otherwise 
meet the criteria for continued treatment at the time re-initiation of study therapy is 
considered.  
• Any new CVA event confirmed by imaging (diffusion-weighted imaging [DWI] MRI 
preferred unless contraindicated), regardless of neurological symptoms (see Appendix 2) 
• For a suspected TIA event without clear alternative etiology. For a suspected TIA event 
without clear alternative etiology, study treatment may be continued only after careful 
risk-benefit assessment by the Investigator (see Appendix 2) 
 
5.16 
Treatment of NKTR-214 and Pembrolizumab, Related Infusion Reactions  
Infusion reactions have been reported during infusion with NKTR-214 and pembrolizumab. If 
such a reaction were to occur with the NKTR-214 or pembrolizumab, it might manifest but not 


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limited to fever, chills, rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, 
bronchospasm, or other allergic-like reactions. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the study medical monitor and reported as an SAE if it meets the 
criteria. Infusion reactions should be graded as outlined below (consistent with 
CTCAE v5.0 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. The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg at least 30 minutes before subsequent infusions. 
For Grade 2 symptoms (moderate reaction; requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal 
anti-inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for  24 hours): 
• Stop the infusion, 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. If 
the infusion is interrupted, then restart the infusion at 50% of the original infusion rate 
when symptoms resolve; if no further complications ensue after 30 minutes, the rate may 
be increased to 100% of the original infusion rate. 
• For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg should be administered at least 30 minutes before the infusion. If necessary, 
corticosteroids (up to 25 mg of Solu-Cortef or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms (severe reaction, Grade 3:  prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]. Grade 4:  life-threatening; pressor or ventilatory 
support indicated): 


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• Immediately discontinue infusion of NKTR-214 or pembrolizumab. 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. 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). 
5.17 
Prior and Concomitant Medications 
Recording of prior medications should include prior cancer treatments:  previous 
immunotherapy, chemotherapy, targeted therapy, radiation, over-the-counter (OTC) medications, 
herbs, and dietary supplements. 
All medications (prescription and OTC), vitamin and mineral supplements, and/or herbs taken by 
the patient from Screening through the long-term follow-up visit will be recorded, including start 
and stop date, dose and route of administration, frequency, and indication. Medications taken for 
a procedure (eg, biopsy) should also be recorded.  
5.18 
Permitted Concomitant Medications/Treatment 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Patients with pre-existing adrenal 
impairment requiring corticosteroid supplementation may be at increased risk for hypotensive 
episodes during treatment with NKTR-214. For these patients, adrenal replacement steroid 
doses > 10 mg daily prednisone are permitted for the first 4 days after administration of study 
drug(s) based on assessment of the degree of adrenal impairment and the extent of existing 
corticosteroid supplementation. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions 
(eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
Prophylaxis for flu-like symptoms with either acetaminophen or NSAIDs are permitted on study 
per the Investigator’s discretion. Prophylaxis for flu-like symptoms is initiated on Day 1 of the 
dosing cycle and continued through Day 5 or longer as needed. Prophylaxis with only 
acetaminophen is permitted for Cohort 4.  


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Prophylaxis for rash and/or pruritus with antihistamines is permitted on study per the 
Investigator’s discretion. Prophylaxis for rash and/or pruritus can be initiated on either Day 1 or 
Day 2 of the dosing cycle and may continue through Day 5 or longer as needed. 
If a patient reports symptoms (such as nausea and/or vomiting), prophylactic use of anti-emetics 
may also be used.  
Concomitant palliative and supportive care for disease related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed. Prior palliative radiotherapy must have 
been completed > 14 days before administration of first dose of study drug. On-study palliative 
radiotherapy may occur only on non-target lesions and only after discussion with the Medical 
Monitor. On-study radiotherapy to target lesions is not permitted. If a patient receives 
radiotherapy or surgery on a target lesion, the patient  
1. Will be considered as having non-evaluable disease for ORR for all tumor assessments after 
the date of initiation of radiotherapy/surgery), and 
2. May be allowed to continue in the study (if written request is received from the study 
Investigator) and may remain on study treatment for as long as there is clinical benefit as 
assessed by the Investigator and in consultation with the medical monitor. 
5.18.1 
Thromboembolism Prophylaxis and Treatment 
Patients with a history of a venous or arterial thromboembolic event must be receiving or have 
received a stable regimen of therapeutic anticoagulation (LMWH or DOAC) as indicated by the 
regional clinical guidelines. Additionally: 
• Use of coumadin is permitted; however, therapeutic dosing should target a specific INR 
stable for at least 4 weeks prior to enrollment. NKTR-214 has the potential to 
down-regulate metabolizing enzymes for coumadin for approximately 1 week after 
administration of each dose of NKTR-214. Due to the possibility of drug-drug 
interactions between coumadin and NKTR-214, frequent monitoring of INR and ongoing 
consideration of dose adjustments are warranted throughout the patient’s participation on 
study. 
5.19 
Prohibited Concomitant Medications 
• Immunosuppressive agents (except for such agents used as supportive care for the 
treatment of potential autoimmune toxicities, for example anti-IL4-alpha antibody 
[dupilumab] for skin toxicity, anti-integrin α4β7 antibody [vedolizumab] or anti-TNF 
[infliximab] for colitis symptoms). 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.18), 
at a daily dose ≥10 mg prednisone equivalent. 


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• Any antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
investigational agent or extensive non-palliative radiation therapy (except as described in 
Section 5.18) is prohibited during the study.  
• Low-dose acetylsalicylic acid (approximately 81 mg/day) should not be combined with 
LMWH or DOAC due to an increased risk of hemorrhage (except as stated in 
Section 5.18.1). 
• Herbal remedies and supplements with an approved indication for cancer are not allowed 
while a patient is enrolled in the study 
• In addition, prohibited medications listed in the current pembrolizumab prescribing 
information are not allowed. 
5.20 
Effect of NKTR-214 on Concomitant Medication Metabolism 
NKTR-214 may have the potential to affect the clearance of co-administered drugs based on 
its ability to modulate immune function. NKTR-214 causes increases in circulating cytokines 
typical of those associated with an acute inflammatory response to infection or tissue injury. 
The increases in inflammatory cytokines induced by NKTR-214 are generally moderate, 
persist for about a week after NKTR-214 administration, and return to baseline levels prior to 
the next dose. Several of these cytokines (IFN-γ, IL-6, IL-10, etc.) have the potential to 
decrease the activity of multiple enzymes and drug transporters, and the suppressive effects 
can be additive (Haas 2005, Zídek 2009). Similar to changes that occur during a typical 
inflammatory response, NKTR-214 treatment may lead to downregulation of drug 
metabolizing enzymes, such as CYP enzymes, hepatic flavin monooxygenases, 
UDP-glucuronosyltransferases, sulfotransferases, and glutathione S-transferases. 
Consequently, treatment with NKTR-214 may lead to temporary decrease in clearance of 
drugs that are substrates of drug metabolizing enzymes or drug transporters. Investigators 
should carefully monitor patients receiving drugs with narrow therapeutic indices or drugs 
that are sensitive substrates of drug metabolizing enzymes or drug transporters for the 
occurrence of adverse effects and adjust the dose of these drugs if needed. 
5.20.1 
Interaction of NKTR-214 and Warfarin 
For patients receiving warfarin (coumadin), therapeutic dosing should target a specific INR that 
is stable for at least 4 weeks prior to NKTR-214 administration. NKTR-214 has the potential to 
down‑regulate metabolizing enzymes for warfarin for approximately 1 week after administration 
of each dose of NKTR-214. Due to the possibility of drug-drug interactions between warfarin 
and NKTR-214, frequent monitoring of INR and ongoing consideration of dose adjustments are 
warranted during NKTR-214 administration. 
5.21 
Adverse Events 
After initiation of study drug treatment, all adverse events (AEs), either reported by the patient or 
observed by the study Investigator/staff, will be reported from the time of first study drug(s) 






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6.4 
NKTR-214 Drug Reconstitution and Handling 
NKTR-214 will be administered first, before pembrolizumab. NKTR-214 is to be administered 
as an IV infusion over 30 (± 5) minutes. Patients should be carefully monitored for infusion 
reactions during NKTR-214 administration.  
 
 
 
 
 
 
 
  
 
 
Please refer to the Pharmacy Manual/current Investigator Brochure for detailed requirements 
regarding preparation and administration. 
6.5 
NKTR-214 Drug Storage 
 
 
6.6 
NKTR-214 Drug Shipment 
 
  
6.7 
Pembrolizumab, Pemetrexed, Cisplatin, Paclitaxel, Nab-paclitaxel, and Carboplatin 
Formulation, Reconstitution, Storage and Packaging 
Please refer to the Pharmacy Manual for details. 
6.8 
NKTR-214 Pembrolizumab, Pemetrexed, Cisplatin, Paclitaxel, Nab-paclitaxel, and 
Carboplatin Drug Accountability and Reconciliation  
Please refer to the Pharmacy Manual for details. 


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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 pre-existing 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). 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. 
An AE does not include: 
• A medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, or 
transfusion); an AE is the underlying condition that leads to the procedure.  
• 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).  
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization 
for elective surgery for a condition that has not worsened on study, social and/or 
convenience admissions to grant families a respite in caring for a patient).  
• 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 100 days after the last dose of all study drug(s). For treatment-related SAEs, 
additional reporting requirements also apply (Section 7.7).  
An event occurring after the patient has provided informed consent, but before the first dose of 
study treatment or confirmed screen failure, 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 


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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. 
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 will be assessed for severity using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 
guidelines. 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.  


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7.4 
Causality Relationship of AEs 
The relationship of each AE to each study drug (NKTR-214 and/or pembrolizumab) 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 pre-existing medical condition, underlying disease, concurrent 
illness, or concomitant medications/therapies.  
• Related:  There is a reasonable possibility that an 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 it follows a known response 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. 
7.5 
AE Reporting and Follow-up 
After initiation of study drug treatment, all AEs except for SAEs (Sections 7.7 and 7.8) will be 
reported from the time of first study drug(s) administration until 90 days after the last dose of all 
study drug(s).  
All ongoing non-serious AEs will be followed until resolution, the patient is lost to follow-up, 
patient death, or until the EOT visit, whichever is earlier. In case the AE has not completely 
resolved by the EOT visit, the final outcome of these ongoing AEs will be captured as “Not 
Recovered/Not Resolved” or “Recovering/Resolving”, whichever is applicable.  
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 places the patient at immediate 
risk of death from the event as it occurred; it does not include an AE 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, except for those due to the 
following: 
– A surgery or procedure that was planned before the patient entered the study and which is 
part of the planned study procedure. 


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– Nonmedical reasons (eg, elective hospitalizations for social reasons or due to long travel 
distances or for prophylactic patient observation), in the absence of an AE. 
• 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 
relationship to study drugs, that occur during the protocol-specified reporting period, must be 
reported with the exception of deaths attributed to disease progression (refer to Section 7.9). 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.  
7.7 
Serious AE Reporting 
Serious AEs occurring after the patient has provided informed consent, but before the first dose 
of study treatment or confirmed screen failure, 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. All SAEs, regardless of causality attribution (ie, related or not 
related), with an onset within 90 days of discontinuation of all study drug treatments or until a 
new antineoplastic regimen has been initiated will be reported to Nektar Therapeutics Drug 
Safety within 24 hours of when the site becomes aware of the event. SAEs must be reported to 
Nektar Therapeutics Drug Safety via email or fax as listed at the beginning of this protocol.  
In addition, all SAE’s that occur beyond 90 days after last dose of all study drug(s) that are 
assessed by the Investigator as related to study drug(s) will also be reported to Nektar 
Therapeutics Drug Safety within 24 hours of awareness of the event. 
SAEs must be reported to Nektar Therapeutics Drug Safety via email or Safety Fax as listed at 
the beginning of this protocol. Nektar Therapeutics may transition to reporting of SAEs via 
electronic data capture (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. 


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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 within 24 hours of receipt. 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 Institutional Review Board (IRB)/Independent Ethics Committee (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.  
7.8 
Serious AE Follow-up 
All study treatment-related SAEs that have not resolved by the EOT visit (Section 5.4) 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 assessed as “unrelated” to study drug(s) will be followed until resolution or 
until the EOT visit (Section 5.4), whichever is earlier. In the case where an unrelated SAE has 
not completely resolved by the EOT visit, the final outcome of these ongoing SAEs will be 
captured as “Not Recovered/Not Resolved” or “Recovering/Resolving”, whichever is applicable.  
7.9 
Disease Progression and Death Due to Disease Progression – Not Reportable as an 
AE/SAE 
It is anticipated that during this study a proportion of patients will experience disease progression 
prior to study discontinuation. Disease progression should not be reported as an AE or SAE. In 
some patients, disease progression may result in clinical manifestations (eg, pleural effusion) that 
meet “seriousness” criteria (eg, hospitalization). These clinical manifestations may be reported as 
non-fatal SAEs.  


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For all SAEs assessed as clinical manifestations associated with fatal disease progression, the 
following criteria will apply: 
•
Seriousness Criteria cannot equal Death
•
Severity cannot equal Grade 5
•
Outcome = Ongoing at time of Death
Deaths that are attributed solely to disease progression by the Investigator should not be reported 
as SAEs. 
7.10 
Immune-mediated AEs (IMAEs) and Other Monitored Events 
Immune-mediated AEs (imAEs) are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. imAEs can include events with an alternate etiology, which 
were exacerbated by the induction of autoimmunity. Investigators should use clinical judgment 
characterizing an AE as immune mediated, including the requirement for steroid treatment, and 
are encouraged to rule out neoplastic, infectious, metabolic, toxic, or other etiologies to the 
extent possible, before characterizing an event as immune mediated. Nektar will internally 
review imAEs to determine their association with NKTR-214 or pembrolizumab. 
See Section 5.14 for additional information on management algorithms for immune-mediated 
AEs. 
Management Algorithm for Cytokine Release Syndrome 
Cytokine release syndrome (CRS) is a clinical diagnosis of exclusion that usually presents with a 
constellation of symptoms associated with cytokine side effects such as persistent fever, 
hypotension, hypoxia in association with/without tachypnea, headache, rash, tachycardia, or 
organ toxicity with varied manifestation. For confirmed cases of CRS or suspected CRS Grade 3 
or higher, the Investigator should contact the Medical Monitor regarding treatment modifications 
or dose changes. A general guidance with algorithm for CRS management and reportability is 
provided in Appendix 4. 
7.11 
Adverse Events of Special Interest 
The AEs listed below are considered “adverse events of special interest” (AESI). Regardless of 
the assessment of whether the AESI is serious or nonserious, all AESIs are required to follow the 
timeline for SAE reporting (within 24 hours of awareness as described in Section 7.7.) from the 
sites to Nektar Drug Safety: pharmacovigilance@nektar.com. 
•
CVA events (any grade; CVA Management Guidelines are provided in Appendix 2)


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7.12 
Pregnancy 
The Sponsor must be notified within 24 hours of the initial report and any follow-up reports of a 
male patient’s female partner or a female patient becoming pregnant during the course of the 
study and for up to 4 months after the last dose of all study drugs for female patients or 4 months 
for female partners of male patients after the last dose of the study drug(s) via the Pregnancy 
form. Pregnancy, although reportable, is not considered an AE/SAE unless a female patient or 
male patient’s female partner 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 patients or female partner (s) of male 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.  
7.13 
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). 
Potential drug induced liver injury is defined as: 
1) Treatment-emergent ALT or AST > 3 times ULN, and 
2) Total bilirubin > 2 times ULN or clinical jaundice, without initial findings of cholestasis 
(elevated serum alkaline phosphatase), and 
3) No other immediately apparent possible causes of elevated liver enzymes and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
7.14 
Clinical Laboratory Tests 
Clinical laboratory tests will be conducted according to the Schedule of Events (Section 1.1). 
Clinical laboratory tests will be performed by local and central laboratories. Samples for clinical 
laboratory tests must be drawn within 72 hours prior to dosing. Clinical laboratory tests will be 
performed by a local laboratory and the data will be reviewed by the Investigator or a qualified 
Sub-Investigator. Additional clinical laboratory tests may be ordered and performed at the local 
laboratory at the Investigator’s or qualified Sub Investigator’s discretion. Testing for PK 
 
will be performed by a designated central laboratory.  


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The Investigator or qualified Sub-Investigator will review all clinical laboratory test 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.  
7.15 
Physical Examinations 
Physical examinations should be conducted according to the Schedule of Events (see  
Section 1.1). Full physical examinations (that 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) should be 
conducted at screening, and Days 1, 3 and 8 of Cycle 1. In Cycle 2 and beyond, full physical 
examinations are conducted on Day 1 of each cycle, and EOT. Other examinations may be 
focused, at the discretion of the Investigator, to identify changes from baseline or evaluate 
changes based on the patient’s clinical symptoms. Weight is to be reported at each dosing visit 
(for weight changes of ± 10% from baseline, recalculation of dose is not required), height at 
screening visit only. 
7.16 
Vital Signs 
Vital sign measurements will be recorded according to the Schedule of Events (Section 1.1). 
Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure (supine 
position), oxygen saturation (on dosing days only), and temperature (oral preferred). It is 
preferred that the same arm be used for all blood pressure readings, if possible. Instructions for 
more frequent vital sign monitoring after completion of study drug administration are provided 
in Section 5.3.4.1. 
7.17 
Electrocardiograms 
A screening 12-lead ECG must be done during the 28-day screening window prior to Cycle 1 
Day 1. Patients must be resting quietly in the supine position for at least 5 minutes before the 
ECG collection. Each ECG will be submitted to a local ECG laboratory for interpretation.  
The Investigator or qualified Sub-Investigator will review all ECG interpretations and interval 
duration measurements for clinical significance.  
7.18 
Echocardiograms 
Standard ECHOs will be performed at screening or within 90 days of Day 1 Cycle 1 to assess 
cardiac function and LVEF according to the Schedule of Events (Section 1.1). In the event of an 
abnormal ECHO, the Investigator may perform a stress ECHO (either exercise or nuclear). A 
MUGA scan can be performed to assess cardiac function and LVEF if a standard ECHO cannot 
be performed.  


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7.19 
Pregnancy Tests 
Serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) will be 
performed on women of childbearing potential during screening (anytime during 28-day 
screening window; ICF signature not required). Urine pregnancy tests will be performed on 
Day 1 of each cycle prior to dosing and at EOT. A negative pregnancy test result must be 
obtained before the administration of the study drug(s). 
A pregnancy test does not need to be performed on women who are postmenopausal for at least 
1 year or surgically sterile for at least 5 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 7.12. 


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8.0 
ASSESSMENT OF EFFICACY EVALUATIONS 
Response and progression will be determined using RECIST 1.1 (Eisenhauer 2009).  
8.1 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below.  
8.1.1 
Measurable Disease 
Target tumor lesions:  Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:   
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm).  
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness no 
greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed.  
8.1.2 
Non-measurable Disease 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes ≥ 10 to < 15 mm in short axis) as well as truly non-measurable lesions, are considered 
non-measurable disease. Lesions considered truly non-measurable include:  leptomeningeal 
disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung, or 
abdominal masses/abdominal organomegaly identified by physical examination that are not 
measurable by reproducible imaging techniques.  
8.2 
Specifications by Methods of Measurements 
The same method of assessment and the same technique must be used to characterize each lesion 
at baseline and during follow-up. Imaging-based evaluation must always be done rather than 
clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical examination.  
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). When lesions can be 
evaluated by both clinical examination and imaging, imaging evaluation must be undertaken 
since it is more objective and may also be reviewed at the end of the study. For cutaneous lesions 
that are included in target lesions, digital photographs must be obtained and utilized for 
measurement.  


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CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. MRI is also acceptable in certain situations (eg, for body 
scans). CT portion of PET-CT is acceptable if RECIST 1.1 measurements can be done.  
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the ULN, however, they must normalize for a patient to be considered 
in complete response.  
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare 
cases when the nature of a residual lesion is in question. The cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met criteria for response or SD in order to differentiate between 
response (or SD) and PD.  
8.2.1 
Tumor Response Evaluation 
8.2.1.1 
Assessment of Overall Tumor Burden at Baseline and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion.  
8.2.1.2 
Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
that in instances where patients have only 1 or 2 organ sites involved a maximum of 2 and 
4 lesions, respectively, will be recorded). Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  
Pathological nodes which are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.  


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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’.  
8.2.1.3 
Special Notes on the Assessment of Target Lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. For PR, SD, and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions.  
Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, if the lesion is believed to be 
present and is faintly seen but is too small to measure with any accuracy, a default value of 5 mm 
should be assigned.  
8.2.2 
Response Criteria using RECIST 1.1 
8.2.2.1 
Evaluation of Target Lesions 
Table 16 provides the definitions of the criteria used to determine objective tumor response for 
target lesions.  
Table 16: 
Criteria to Determine Objective Tumor Response for Target Lesions 
per RECIST 1.1 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, 
taking as reference the baseline SLD 
Progressive Disease (PD) 
At least a 20% increase in the SLD of target lesions, taking as reference the smallest 
SLD on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm relative to nadir. (Note: the appearance of one or more new 
lesions is considered progression.) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
8.2.2.2 
Evaluation of Non-target Lesions 
Table 17 provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. Although some non-target lesions may actually be measurable, they 


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need not be measured and instead should be assessed only qualitatively at the time points of 
radiographic assessments.  
Table 17: 
Criteria to Determine Tumor Response for Non-Target Lesions per 
RECIST 1.1 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. (Note: the appearance of one 
or more new lesions is also considered progression)a 
a. 
In this setting, when a patient has measurable disease, to achieve “unequivocal progression” on the basis of the 
non-target disease, there must be an overall level of substantial worsening in the non-target disease such that, 
even in the presence of SD or PR in the target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. A modest increase in size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare 
(from Section 4.3.4 of RECIST 1.1). 
 
NOTE: If tumor markers are assessed for a given patient and are initially above the ULN, they 
must normalize for a patient to be considered in complete CR.  
8.2.2.3 
Confirmatory Measurement/Duration of Response 
8.2.2.3.1 
Confirmation 
Confirmation of response (either PR or CR) is required. Changes in tumor assessments must be 
confirmed by repeat assessments that should be performed ≥ 4 weeks after the criteria for 
response are first met.  
8.2.2.4 
Evaluation of Overall Response Using RECIST 1.1 
Best overall response when confirmation of CR and PR is required is summarized in Table 18. 


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Table 18: 
Best Overall Response When Confirmation of CR and PR Required 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise. PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise. PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise. NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise. PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise. NE 
NE 
NE 
NE 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
a. 
If a CR is truly met at the first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared 
after CR). Best response would depend on whether minimum duration (8 weeks) for SD was met. However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in 
fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
Source: Eisenhauer 2009 
 


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9.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
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 dose cohort.  
For the 1L NSCLC dose expansion cohort (Cohorts 2 and 3), all efficacy endpoints except 
overall survival will be analyzed using the response evaluable population. Certain efficacy 
endpoints will also be summarized for all treated patients as sensitivity analyses. All safety 
endpoints will be summarized using the safety population.  
A description of analysis methods and detailed definitions for efficacy and safety endpoints will 
be provided in the statistical analysis plan.  
9.2 
Determination of Sample Size 
In Amendment 7.0 and subsequent versions, approximately 40 patients may be enrolled in Dose 
Optimization Cohorts 1a and 1b, approximately 58 response-evaluable patients may be enrolled 
in Dose Expansion Cohorts 2 and 3, and approximately 63 response-evaluable patients may be 
enrolled in Dose Expansion Cohorts 4 and 5. Patients who are not response-evaluable or who 
have insufficient biopsy material for PD-L1 assessment may be replaced. Up to 100 patients may 
be enrolled in each cohort to reach the number of responsible-evaluable patients. The sample size 
for Cohorts 1a and 1b is based on expected cohort number for dose optimization. The sample 
sizes for Cohorts 2, 3, 4, and 5 are based on the Fleming 2-stage design framework and historical 
comparators. 
For the dose optimization cohorts of NKTR-214 in combination with pembrolizumab for patients 
with locally advanced metastatic solid tumors, cohorts of at least 3 patients will be treated at 
each dose level. Additional patients will be added to each dose cohort based on the schema and 
rules outlined in Section 5.3 or Sponsor determination of the need for additional data to further 
evaluate the benefit/risk profile. It is estimated that approximately 40 patients will be enrolled 
into the dose optimization cohorts. 
For efficacy assessment of the dose expansion cohorts (first-line NSCLC patients), the sample 
size is strictly based on efficacy, specifically based on the target ORR relative to historic 
response rate per each PD-L1 categorization.  
The Fleming 2-stage design (Fleming, 1982) framework will be used as a guide for the 1L 
NSCLC Expansion Cohorts 2, 3, 4, and 5. The total sample size for each 1L NSCLC expansion 
cohort (TPS <1%, TPS 1% to 49%, and TPS ≥ 50%) will be calculated based on a one-sided 
Type 1 error of 10% and a power of 90%. The 2-stage design provides an option to stop early for 


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futility as well as allowing an expansion of enrollment if a strong antitumor activity signal is 
observed. However, the final decision will be based on the totality of overall treatment effect for 
multiple study endpoints and their associations with the tumor response rate. Enrollment may 
continue into Stage 2 while the planned number of patients for Stage 1 are followed for 
response-evaluable tumor assessments. There will be no stopping of enrollment to a tumor cohort 
for efficacy, although early planning for the next stage of clinical development may be initiated.  
Cohorts 2 and 3: 
Approximately 58 response-evaluable first-line NSCLC patients may be enrolled in Cohort 2 
(and in Cohort 3 if opened), including:  Cohort 2.1/3.1: minimum 20 PD-L1 < 1%, Cohort 
2.2/3.2: minimum 18 PD- L1 1% to 49%, and Cohort 2.3/3.3: minimum 20 PD-L1 ≥ 50%. 
Patients who are not response-evaluable and patients whose PDL-1 status is unable to be 
confirmed by central testing will be replaced (Table 19).  
Table 19: 
True (Target) and Historic Objective Response Rate for First-line 
NSCLC by PD-L1 Categorization (Cohorts 2 and 3) 
 
Objective 
Response Rate 
(ORR) (%) 
 Sample Sizea 
(Minimum Sample 
Size) 
Futility 
Efficacy 
Reference for 
Historical 
ORR 
Assumption 
Cohort 
Indication 
Historical 
Target  
N 1  
N2  
Total 
S1 
S2 
T1 
T2 
2.1 
NSCLC 1L  
(PD-L1 
< 1%)b 
8 
30 
12 
8 
20 
0 
≤ 3 
≥ 3 
≥ 4 
 
 
Carbone 2017 
Garon 2015 
2.2 
NSCLC 1L  
(PD-L1  
1% to 49 %)b 
14 
40 
8 
10 
18 
0 
≤ 4 
≥ 4 
≥ 5 
2.3 
NSCLC 1L  
(PD-L1 ≥ 
50%) 
25 
55 
11 
9 
20 
≤ 3 
≤ 7 
≥ 6 
≥ 8 
Abbreviations:  N1 = sample size at Stage 1; N2 = sample size at Stage 2; NSCLC = non-small cell lung cancer; 
ORR = objective response rate; PD-L1 = programmed cell death ligand 1; S1 = futility boundary at Stage 1; 
S2 = futility boundary at Stage 2; T1 = efficacy boundary at Stage 1; T2 = efficacy boundary at Stage 2.  
a. 
Sample size for each expansion cohort is calculated using a normal approximation to provide a reasonable false-
positive rate (FPR < 10%) and false-negative rate (FNR < 10%). This is the minimum-required sample size 
needed to achieve targeted number of response-evaluable patients. 
b. For France only: patients in first-line NSCLC dose expansion Cohorts 2.1/3.1 and 2.2/3.2 with PD-L1 status 
< 50% are excluded. 
 
Cohorts 4 and 5 
Based on safety and efficacy data from Cohorts 2 and 3, a decision may be made to open 
Cohorts 4 (1L nonsquamous NSCLC) and 5 (1L squamous NSCLC). Up to 63 response 


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evaluable patients may be enrolled in each of Cohorts 4 and 5, using a Fleming 2-stage design 
framework (see details in Statistical Analysis Plan). Patients who are not response-evaluable or 
who have insufficient biopsy material for PD-L1 assessment may be replaced. 
9.3 
Safety Monitoring 
In addition to routine safety monitoring on AEs, lab test findings, ECG and vital signs, a Safety 
Review Committee consisting of representatives from the Sponsor’s Clinical Development, Drug 
Safety, Biostatistics, other functional representatives, as needed, and at least one site Investigator 
will meet as per charter at least quarterly during the study to review safety data from the dose 
optimization and dose expansion cohorts for potential safety risks or more frequently if needed. 
The Safety Review Committee will be convened to make a recommendation on the continuation, 
modification, or discontinuation of the study. 
9.4 
Replacement of Patients 
In the dose optimization cohorts, patients who did not complete the DLT observation period for 
reasons other than a DLT will be replaced to provide the number of patients included for the 
dose escalation decision. In Dose Expansion Cohorts 2, 3, 4, and 5, patients who are not 
response-evaluable or who have insufficient biopsy material for PD-L1 assessment may be 
replaced. 
In Amendment 6.0 and subsequent versions, first-line NSCLC patients who enroll in the study, 
but do not meet the eligibility criteria will be replaced. 
9.5 
Analysis Sets 
Safety Population:  All patients who receive at least 1 dose (or partial dose) of study drug will be 
included in the analysis of safety.  
DLT Population:  All patients who complete at least the DLT observation period or discontinue 
from the study treatment due to DLT will be included.  
Pharmacokinetic Population:  All patients in the Safety Population who have evaluable analyte 
concentration-time profiles that allow for the computation of meaningful PK parameter values.  
Response-Evaluable Population:  Patients who have received at least 1 dose (or partial dose) of 
study drug, have measurable disease (per RECIST 1.1) at baseline, and have at least 1 scheduled 
postbaseline assessment of tumor response (earliest assessment at 9 weeks ± 1 week).  
9.6 
Planned Analyses 
9.6.1 
Demographics and Baseline Characteristics 
Demographic data (age, sex, ethnicity, body weight) and baseline disease characteristics will be 
tabulated and summarized by dose cohort and presented in data listings.  


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9.6.2 
Safety 
One of the primary endpoints of the study is to determine the MTD of NKTR214 in combination 
with pembrolizumab. AEs and toxicity for the dose optimization cohorts will be evaluated 
according to NCI CTCAE version 5.0. Adverse events and toxicity for the dose expansion 
cohorts will be evaluated according to NCI CTCAE version 5.0. Safety assessments will be 
performed by medical review of AEs and laboratory results.  
The incidence rate of DLTs will be evaluated by dose cohort for the DLT evaluable patients. 
Treatment emergent AEs (TEAEs) will be summarized by latest MedDRA preferred term, 
system organ class, NCI CTCAE version 5.0 grade of severity, and relationship to the study 
treatment.  
A TEAE is defined as: (regardless of intensity) 
• Any AE that happens after treatment initiation 
• AE that was present at time of treatment initiation but worsened after treatment initiation 
• AE that was present and resolved prior to treatment and reappeared after treatment 
initiation  
Vital signs (including change in weight) and clinical laboratory test results will be summarized 
descriptively by dose. Any significant physical examination findings will be listed. ECG data 
will be evaluated by central review and abnormalities, if present, will be listed. A separate listing 
and summary of all imAEs will be provided. A listing and summary of patients who discontinued 
study drug(s) due to an AE will be provided.  
A data listing for deaths will be provided.  
9.6.3 
Efficacy 
Efficacy analyses will be performed on data provided by the Investigator sites for the following 
efficacy outcomes: 
• Objective response rate (ORR) using RECIST 1.1  
• Duration of response (DOR) using RECIST 1.1 
• Clinical benefit rate (CBR) using RECIST 1.1 
• Time to response (TTR) using RECIST 1.1 
• Progression-free Survival (PFS) using RECIST 1.1 
• Overall Survival (OS) 


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The primary efficacy measurement is the confirmed ORR in the response-evaluable patients per 
BICR by RECIST 1.1 based on data provided by BICR. The secondary endpoint is ORR by the 
Investigator’s assessment using the response-evaluable population. The number and percentage 
of patients with CR or PR as their best overall response will be calculated. The 95% confidence 
interval (CI) will be calculated using the exact binomial method. In addition, the ORR analysis 
will be performed on the response evaluable population. All tumor assessments and response 
data will be listed. The best overall response (BOR) of CR, PR, SD and PD will be summarized 
similarly using the response evaluable population.  
The TTR will be defined for patients who had confirmed CR or confirmed PR as the time from 
the date of first dose to date of first documented CR or PR. TTR will be summarized using 
descriptive statistics.  
DOR will be defined for patients who have confirmed CR or confirmed PR as the date from first 
documented CR or PR to the date of the first objectively documented disease progression per 
RECIST 1.1 or death due to any cause, whichever is earlier. Patients who do not have disease 
progression per RECIST 1.1 will be censored on the date of last evaluable tumor assessment. 
Patients who started any subsequent antineoplastic regimen, including target-lesion 
tumor-directed radiotherapy and target-lesion tumor-directed surgery, without a prior reported 
progression will be censored at the last evaluable tumor assessment prior to initiation of the 
subsequent antineoplastic therapy. The DOR will be estimated using the Kaplan-Meier method. 
The 25%, median and 95% CI, and 75% quartiles will be summarized. 
CBR, defined as the number of patients with confirmed CR, confirmed PR, or SD (≥ 8 weeks), 
will be summarized similarly to ORR using the response evaluable population and all treated 
patients. Additionally, CBR at 18 weeks (CBR18) and CBR at 27 weeks (CBR27), defined as 
confirmed CR, confirmed PR, or SD for ≥ 18 weeks or ≥ 27 weeks, respectively, will be 
summarized. 
PFS is defined as the time from the date of first dose to the date of the first objectively 
documented progressive disease per RECIST 1.1 or death, whichever is first. For patients who 
do not have date of disease progression per RECIST 1.1 and date of death, patients will be 
censored on the date of last evaluable tumor assessment. For patients who started a new 
antineoplastic regimen or had surgery or radiotherapy to target lesion prior to disease progression 
per RECIST 1.1, patients will be censored on the date of last evaluable tumor assessment prior to 
receiving new treatment. For patients whose disease progression or death appears after missing 
two consecutive tumor assessments, patients will be censored on the date of last evaluable tumor 
assessment. Patients who are lost to follow up will be censored on the date of their last evaluable 
tumor assessment. Additional censoring rules will be discussed in the SAP. 
PFS will be estimated using the Kaplan-Meier method. The 25%, median and 95% CI, and 
75% quartiles will be summarized using all treated patients.  


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OS will be defined as the date of first dose to the date of death. Patients who do not have a date 
of death will be censored on the last date for which a patient was known to be alive. OS will be 
analyzed similarly to PFS.  
9.6.4 
Immunogenicity 
Validated methods to detect anti-NKTR-214, anti-IL-2, and anti-pembrolizumab ADA will be 
used to analyze the immunogenicity samples. Samples will be analyzed by multi-tiered ADA 
testing. Immunogenicity samples will be first tested with screening assays. Putative positive 
samples will then be analyzed in competition assays to confirm positivity. Confirmed 
anti-NKTR-214 ADA positive samples will be tested further in a PEG-immunocompetition assay 
to determine the antibody specificity of the reactivity to the PEG or non-PEG (IL-2, linker) 
moiety of NKTR-214. Confirmed positive samples from anti-pembrolizumab, anti-NKTR-214, 
and anti-IL-2 ADA assays will then be tested to obtain a titer. Samples confirmed to be positive 
for anti-pembrolizumab, anti-NKTR-214, and anti-IL-2 ADA may also be tested for neutralizing 
activity using validated assays. 
Blood samples designated for assessments (eg, immunogenicity, PK, 
) from the 
same collection time point may be used interchangeably for analyses, if required (eg, insufficient 
volume for complete assessment, to follow-up on suspected immunogenicity related AE, etc.). 
 
 
 
 
 
 
 
  
9.6.6 
Pharmacokinetics 
Plasma concentrations of NKTR-214 and its metabolites will be measured using validated or 
qualified method(s). Methods for calculating PK parameters will be described in a PK Analysis 
Plan. Pharmacokinetic parameters such as maximum concentration (Cmax), time to Cmax (Tmax), 
area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) will 
be estimated from concentration-time data where feasible. Plasma concentration-time data and 
PK parameters will be tabulated and summarized with descriptive statistics. Select PK parameter 
values may be evaluated for correlations with select safety and response measurements for 
assessment of exposure-response relationships. Pharmacokinetic data from this study may also 
be pooled with data from other clinical studies for the purpose of population PK modeling and/or 
exposure-response analyses, which would be prospectively described in one or more analysis 
plans and reported separately from the Study 16-214-05 clinical study report. 


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9.7 
Concomitant Medications 
All reported concomitant medications will be mapped using the World Health Organization Drug 
Dictionary. Concomitant medications will be tabulated in summary tables and data listings. 
9.8 
Missing Data 
Statistical considerations and methodology for handling missing data will be detailed in the 
Statistical Analysis Plan. 


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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 
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 a formal protocol amendment having 
been established and approved by an appropriate IRB/Independent Ethics Committee (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 unevaluable. 
All protocol deviations and the reasons for such deviations are to be reported to the Sponsor. 
Prior to formal protocol amendment, an administrative letter describing protocol changes may be 
used by the Sponsor where permitted. The administrative letter will include a commitment to 
amending the protocol within a specified time frame and, following approval by the IRB/IEC, 
will eliminate the requirement to document a protocol deviation for the described change. 
11.2 
Monitoring 
In accordance with Code of Federal Regulations 21 CFR 312.56, International Conference 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 


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local regulatory restrictions or institutional requirements, the Investigator must inform the 
Sponsor of these restrictions before initiation of the study.  
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 
ETHICS 
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 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.  
If a patient continues study treatment beyond disease progression, a separate ICF will be signed 
at that time.  


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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 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. 
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.  


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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.  


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14.0 
PUBLICATION POLICY 
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).  
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. 
Algazi A, Tsai KK, Takamura KT, et al. Intratumoral electroporation of plasmid IL-12 
can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a 
melanoma. Abstract CT134. Presented at the 2016 annual Meeting of the American 
Association for Cancer Research, 16-20 April 2016, New Orleans, LA. 
2. 
Brayer J, Fishman M. Regression of metastatic clear cell kidney cancer with interleukin-2 
treatment following nivolumab (anti-PD-1) treatment. J Immunother. 2014;37:187-191. 
3. 
Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent 
Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376:2415-2426. 
4. 
Charych DH, Hoch U, Langowski JL, et al. NKTR-214, an engineered cytokine with 
biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse 
tumor models. Clin Cancer Res. 2016;22(3):680-690. 
5. 
Cockcroft DW, Gault MH. Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron. 1976;16(1):31-41. 
6. 
Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to anti-PD-1 
therapy in human melanoma. J Clin Invest. 2016a;126:3447-3452. 
7. 
Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression and 
response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J Clin 
Oncol. 2016b;34:4102-4109. 
8. 
Diab A, Tannir NM, Bernatchez C, et al. A phase ½ study of a novel IL-2 cytokine, 
NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid 
tumors. J Clin Oncol. 2017;35:15_suppl, e14040-e14040. 
9. 
Diab A, Hurwitz M, Cho D, et al. NKTR-214 (CD-122-biased agonist) plus nivolumab in 
patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. Presented 
at Annual Meeting of the American Society of Clinical Oncology (ASCO); 2018a 
June 1-5; Chicago, IL 
10. 
Diab A, Tykodi S, Curti B, et al. NKTR- Immune Monitoring After NKTR‐214 plus 
Nivolumab (PIVOT‐02) in Previously Untreated Patients with Metastatic Stage IV 
Melanoma. Presented at Annual Meeting of the Society for Immunotherapy of Cancer 
(SITC); 2018b Nov 7-11; Washington, DC 
11. 
Diab A, Puzanov I, Maio M, et al. Clinical activity of BEMPEG Plus NIVO in previously 
untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-
02 study. J Immunother Cancer. 2019 Nov 6;7(suppl 1):O35. 
12. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
13. 
Fleming TR. One-sample multiple testing procedure for phase II clinical trials. 
Biometrics. 1982;38:143-151. 


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14. 
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in 
Metastatic Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378:2078-2092. 
15. 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non-small-cell 
Lung Cancer. N Engl J Med. 2015;372:2018-2028. 
16. 
Haas CE, Nelsen JL. Drug-cytokine interactions. In Piscitelli SC, Rodvold KA, editors. 
Drug Interactions in Infectious Diseases. Totowa NJ, USA: Human Press Inc., 2005. 
P. 431-461. 
17. 
Nishino M, Tirumani SH, Ramaiya NH, et al. Cancer immunotherapy and immune-
related response assessment: The role of radiologists in the new arena of cancer 
treatment. European journal of radiology. 2015;84(7):1259-1268. 
18. 
Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous 
Non–Small-Cell Lung Cancer. N Engl J Med 2018; 379:2040-2051. 
19. 
Siefker-Radtke A, Fishman M, Balar AV, et al. Bempegaldesleukin* (NKTR-214) + 
nivolumab in ﬁrst-line advanced/metastatic urothelial carcinoma: Updated results from 
PIVOT-02. Poster presented at ASCO GU, February 13-16, 2019, San Francisco, CA, 
USA. 
20. 
Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights. Management 
of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Netw. 
2020;18(3):230-241. 
21. 
Tolaney S, Baldini C, Spira A, et al. Clinical activity of BEMPEG plus NIVO observed 
in metastatic TNBC: preliminary results from the TNBC cohort of the Ph1/2 PIVOT-02 
study. Poster presented at the 2019 CRI-CIMT-EATI-AACR International Cancer 
Immunotherapy Conference 26 September 2019, Paris, France. 
22. 
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res. 
2009;15(23):7412-7420. 
23. 
Wong MKK, Morse MA, McDermott DF, et al. Overall survival of metastatic melanoma 
patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 
or the PD-1 pathways: analysis of data on the current use of HD IL-2. J Immunother 
Cancer. 2015;3(Suppl 2):P359. 
24. 
Zídek Z, Anzenbacher P, Kmoníčková E. Current status and challenges of cytokine 
pharmacology. Br J Pharmacol. 2009;157:342–361. 


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APPENDIX 1: 
CLINICAL LABORATORY TESTS 
Local Clinical Laboratory Tests Obtained Prior to NKTR-214 Study Drug Administration 
Laboratory Tests Required for Treatment Decisions 
• 
AST (SGOT) 
• 
ALT (SGPT) 
• 
Serum Creatinine 
• 
Blood urea nitrogen (BUN) or 
urea 
• 
Total bilirubin 
• 
Sodium 
• 
Potassium 
• 
Pregnancy test (for WCBP) 
• 
Any additional clinically-relevant test related 
to individual patient monitoringa 
a Particularly for patients with baseline comorbidities 
Laboratory tests must be assessed by a local laboratory within 24 hours, or as soon as locally feasible, prior to each 
NKTR-214 study drug administration. 
Clinical Laboratory Test Panel 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Serology (Screening Only) 
• 
Hemoglobin (Hgb) 
• 
Hematocrit (HCT) 
• 
Red blood cell (RBC) count 
• 
Platelet count 
• 
White blood cell (WBC) count 
• 
Neutrophils  
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
• 
Mean corpuscular volume (MCV) 
• 
Mean corpuscular hemoglobin 
(MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
AST (SGOT) 
• 
ALT (SGPT) 
• 
Alkaline phosphatase (ALP) 
• 
Gamma-glutamyl transferase (GGT) 
• 
Albumin 
• 
Creatinine 
• 
Calculated creatinine clearance 
• 
Calcium 
• 
Glucose 
• 
Total protein (TP) 
• 
Total bilirubin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
CO2 content or bicarbonate 
(optional) 
• 
Blood urea nitrogen (BUN) or urea 
• 
Lactate dehydrogenase (LDH) 
• 
Uric acid 
• 
Hepatitis B surface antigen 
(HBsAg) 
• 
Hepatitis C virus antibody 
(anti-HCV) 
• 
Human immunodeficiency 
virus (HIV) antibody 
Additional Labs 
• 
Creatine kinase 
• 
Serum or urine pregnancy 
(HCG) for WCBP 
• 
Thyroid stimulating 
hormone (TSH) 
• 
Free thyroxine (T4) 
• 
Free or total 
triiodothyronine (T3) 
• 
Lipase 
• 
Amylase 
Coagulation 
• 
Partial thromboplastin time (PTT) 
• 
Prothrombin time (PT) 
Urinalysis 
• 
Specific gravity 
• 
pH 
• 
Glucose 
• 
Protein 
• 
Bilirubin 
• 
Ketones 
• 
Leukocyte esterase 
• 
Blood 
For positive protein, white blood cell or blood, a microscopic examination including: 
• 
Red blood cells 
• 
White blood cells 
• 
Epithelial cells 
• 
Bacteria 
• 
Crystals 
• 
Casts 
 




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APPENDIX 3: 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
DEFINITIONS 
Woman of Childbearing Potential (WCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical records, 
medical examination, or medical history interview. 
• Postmenopausal female 
• A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle stimulating hormone level 
> 40 mIU/mL to confirm menopause.  
CONTRACEPTION GUIDANCE FOR FEMALE PATIENTS OF CHILDBEARING 
POTENTIAL 
At a minimum, patients must agree to use 2 effective methods of contraception, with 1 method 
being highly effective and another method from the list below during study duration for female 
patients and until the end of relevant systemic exposure, defined as 4 months following the last 
dose of study treatment. (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 
ovulation 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
oral 
• 
injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
• 
Hormonal methods of contraception including vaginal ring, injectables, implants and intrauterine hormone-
releasing system (IUS) 
• 
Intrauterine device (IUD) 
• 
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 WCBP 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. 
• 
WCBP patients who choose complete abstinence must continue to have pregnancy tests, as specified in 
Section 1.1. 
• 
Acceptable alternate methods of highly effective contraception must be discussed in the event that the WCBP 
patients chose to forego complete abstinence. 
NOTE: 
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. 
 
 


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Less Acceptable 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 
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 4 months after the end of study treatment for male patients 
treated with NKTR-214/pembrolizumab. 
• WCBP who are partners of males participating in the study to consider use of highly 
effective methods of contraception, listed in the table above, until the end of relevant 
systemic exposure, defined as 3 months after the end of treatment in male patients treated 
with NKTR-214/pembrolizumab. 
• 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 the treatment and until 4 months after the end of study treatment for male patients 
treated with NKTR-214/pembrolizumab. 
• Refrain from donating sperm for the duration of the study treatment and until 4 months after 
the end of study treatment for male patients treated with NKTR-214/pembrolizumab. 
Guidance for collection of Pregnancy Information is provided in Section 7.12. 


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APPENDIX 4: 
CYTOKINE RELEASE SYNDROME (CRS) MANAGEMENT 
ALGORITHM 
The following treatment management guidelines are provided for general guidance. These 
guidelines should not substitute for a more individualized, tailored approach to managing a 
patient experiencing CRS (see Section 5.14.2). 
CRS Management Measures/Algorithm 
As a general principle, differential diagnoses should be diligently evaluated according to standard medical practice. 
Non-inflammatory etiologies should be considered and appropriately treated.  
For patients with suspected CRS:   
- 
For Grade 1 or Grade 2 events, implement supportive care, including management of isolated symptoms 
based on institutional practices. 
- 
Consider admitting the patient for monitoring and providing supportive care, including management of 
isolated symptoms based on institutional practices and protocol management guidelines (eg, hydration 
management guidelines, Section 5.3.4.2). 
- 
For patients with a persistent or worsening clinical condition after initial treatment of CRS, reevaluate for 
other contributing conditions. It is particularly important to reassess the patient for coexisting infections, and 
cardiac, pulmonary, thromboembolic and other complications. 
Grading Assessment per CTCAE v.5.0 Treatment Measures Recommended 
Grade 3 CRS 
- 
Hypotension 
managed with 
one pressor 
- 
Hypoxia 
requiring 
> 40% O2 
- 
Vasopressin administration should be considered if the hypotensive 
event is refractory to >3L of fluid resuscitation 
- 
Oxygen therapy (nasal canula, non-invasive positive pressure 
ventilation, etc.) for respiratory symptoms with consideration of 
intubation for a patient with severe respiratory manifestations 
- 
Supportive care for renal, hepatic and other organ function 
deteriorations 
- 
Steroid therapy should be considered (eg, hydrocortisone 100 mg 
every 8 hours, dexamethasone 10 mg up to 4 times daily, 
1-2 mg/kg/day methylprednisone IV or PO equivalent) 
- 
High dose steroid (eg, solumedrol 2 mg/kg up to 1 gram daily for 
3 days) may be considered for severe CRS that failed to respond 
after repetitive steroid treatments 
- 
For severe CRS cases that require simultaneously aggressive 
management of hypotension, oxygenation, and cardiac telemetry, 
consult Intensivist for ICU evaluation 
Grade 4 CRS 
- 
Life-
threatening 
consequences 
- 
Pressor or 
ventilatory 
support 
indicated  
 
 

SAP_001.pdf: 
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    Statistical Analysis Plan 
Protocol 16-214-05 
 
 
 
 
 
      18-May-2022 
 
 
CONFIDENTIAL 
Page 1 of 25 
 
Statistical Analysis Plan 
Nektar Therapeutics 
Protocol 16-214-05 
A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY TO INVESTIGATE THE 
SAFETY AND PRELIMINARY EFFICACY OF COMBINED BEMPEGALDESLEUKIN 
(NKTR-214) AND PEMBROLIZUMAB WITH OR WITHOUT CHEMOTHERAPY IN 
PATIENTS WITH LOCALLY ADVANCED OR METASTATIC SOLID TUMORS  
 
Protocol Version: Amendment 7.0 (23 December 2020) 
  
Sponsor:  Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
  
Prepared by: 
 
 
  
Version: 1.0 
  
Version Date: 10 June 2022 
 


Nektar Therapeutics
    Statistical Analysis Plan
Protocol 16-214-05
      18-May-2022
CONFIDENTIAL
Page 2 of 25
Prepared by:


Nektar Therapeutics  
 
 
 
 
 
 
 
    Statistical Analysis Plan 
Protocol 16-214-05 
 
 
 
 
 
      18-May-2022 
 
 
CONFIDENTIAL 
Page 3 of 25 
TABLE OF CONTENTS 
1 
Introduction ...................................................................................................................6 
2 
Study Objectives ...........................................................................................................6 
2.1 
Primary Objectives: Dose Optimization or Dose Expansion Cohorts ........................... 6 
2.2 
Secondary Objectives: Dose Optimization and/or Dose Expansion Cohorts ................ 7 
 
 
3 
Endpoints ......................................................................................................................7 
3.1 
Primary Endpoints ......................................................................................................... 8 
3.2 
Secondary Endpoints ..................................................................................................... 8 
 
 
4 
Study Design and Plan ................................................................................................10 
5 
Determination of Sample Size ....................................................................................10 
6 
General Analysis Considerations and Definitions ......................................................13 
7 
Handling of Missing Data ...........................................................................................14 
8 
Analysis Populations ..................................................................................................16 
9 
Planned Analyses ........................................................................................................16 
9.1 
Subject Disposition ...................................................................................................... 16 
9.2 
Demographic and Baseline Characteristics ................................................................. 16 
9.3 
Cancer History ............................................................................................................. 17 
9.4 
Concomitant Medications ............................................................................................ 17 
9.5 
Study Exposure ............................................................................................................ 17 
9.6 
Efficacy Analysis ......................................................................................................... 19 
9.6.1 
Tumor Response (BOR, ORR, and CBR) ...................................................... 19 
9.6.2 
Time to Response ........................................................................................... 20 
9.6.3 
Duration of Response ..................................................................................... 20 
9.6.4 
Progression Free Survival ............................................................................... 20 
9.6.5 
Overall Survival .............................................................................................. 21 
9.7 
Safety Analyses ........................................................................................................... 21 
9.7.1 
Dose Limiting Toxicity .................................................................................. 21 
9.7.2 
Adverse Events ............................................................................................... 21 
9.7.3 
Adverse Events of Special Interest for Pembrolizumab ................................. 22 
9.7.4 
Adverse Events of Special Interest for Bempegaldesleukin ........................... 23 
9.7.5 
Clinical Laboratory, Vital Signs, Physical Examination and Electrocardiogram
 
23 
10 Immunogenicity ..........................................................................................................23 
11 Exploratory Analyses ..................................................................................................23 
12 Pharmacokinetics ........................................................................................................23 
13 References ...................................................................................................................24 
14 Appendices .................................................................................................................25 
14.1 Evaluation of Overall Response using RECIST 1.1 .................................................... 25 


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Protocol 16-214-05 
 
 
 
 
 
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CONFIDENTIAL 
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Abbreviation or Term Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BOR 
best overall response  
CBR 
clinical benefit rate 
CI 
confidence interval 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HR 
heart rate 
ICH 
International Council for Harmonisation 
IL-2 
interleukin-2 
irAE 
immune-related Adverse Events 
ICE 
ischemic cerebrovascular events 
Kg 
kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
minute(s) 
Mg 
milligram 
mL 
milliliter 
MTD 
maximum tolerated dose 
N1 
sample size at stage 1 
N2 
sample size at stage 2 
NCI 
National Cancer Institute 
NE 
inevaluable 
NKTR-214 
bempegaldesleukin (International Nonproprietary Name) 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate  
OS 
overall survival 
PD 
progressive disease 


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    Statistical Analysis Plan 
Protocol 16-214-05 
 
 
 
 
 
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CONFIDENTIAL 
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PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
q3w 
every 3 weeks 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SD 
stable disease 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TPS 
Tumor Proportion Score 
TTR 
time to response 


Nektar Therapeutics  
 
 
 
 
 
 
 
    Statistical Analysis Plan 
Protocol 16-214-05 
 
 
 
 
 
      18-May-2022 
 
 
CONFIDENTIAL 
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1 INTRODUCTION 
This statistical analysis plan (SAP) outlines the statistical methods to be implemented for the 
analyses of data collected within the scope of Nektar Therapeutics Protocol 16-214-05 (A Phase 
1/2, Open-label, Multicenter Study to Investigate the Safety and Preliminary Efficacy of 
Combined Bempegaldesleukin [NKTR-214] and Pembrolizumab with or without Chemotherapy 
in Patients with Locally Advanced or Metastatic Solid Tumors) dated 23 December 2020. The 
purpose of this SAP is to provide details on the analyses. Any deviations from the SAP will be 
documented in the clinical study report (CSR).  
This Phase 1/2 study is conducted in accordance with the protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements. 
On 14 April 2022, Nektar Therapeutics and Bristol-Myers Squibb jointly decided to end the global 
clinical development program for bempegaldesleukin. This study and all other ongoing studies in 
this program will be discontinued. 
2 STUDY OBJECTIVES 
This section shows the planned primary, secondary, and exploratory objectives from the study 
protocol. However, due to the closure of the bempegaldesleukin program, analyses and parameter 
calculations specified in the Protocol for pharmacokinetic (PK), immunogenicity, biomarker 
(except PD-L1), clinical laboratory, vital signs, physical examination, electrocardiogram (ECG), 
concomitant medications, clinical benefit rate at 18 weeks (CBR18), clinical benefit rate at 27 
weeks (CBR27) are no longer planned to be conducted. Other analyses no longer planned to be 
performed are other safety observations for NKTR-214, prior medications, prior therapy, medical 
history, and important protocol deviations. Analyses to address the exploratory objectives also will 
not be performed. 
2.1 
Primary Objectives: Dose Optimization or Dose Expansion Cohorts 
The primary objectives in the dose optimization cohorts are: 
x To evaluate the safety and tolerability of NKTR-214 in combination with pembrolizumab. 
x To define the MTD/RP2D and optimal dosing schedule of NKTR-214 in combination with 
pembrolizumab. 
The primary objective in all the dose expansion cohorts is: 
x To determine the ORR per blinded independent central review (BICR) by RECIST 1.1 of 
NKTR-214 plus pembrolizumab with or without systemic chemotherapy in patients with 
untreated metastatic NSCLC. 


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2.2 Secondary Objectives: Dose Optimization and/or Dose Expansion Cohorts 
The secondary objectives in the dose optimization and/or dose expansion cohorts are: 
x To evaluate safety and tolerability of NKTR-214 plus pembrolizumab with or without 
systemic chemotherapy in patients with untreated NSCLC (dose expansion only). 
x To assess the preliminary efficacy (per BICR) of NKTR-214 plus pembrolizumab with or 
without systemic chemotherapy: 
- Objective response rate (ORR) by RECIST 1.1 (dose optimization only) 
- Duration of response (DOR) by RECIST 1.1 
- Clinical benefit rate (CBR) by RECIST 1.1 
- Time to response (TTR) by RECIST 1.1 
- Progression-free survival (PFS) by RECIST 1.1 
- Overall survival (OS)  
x To assess the association between efficacy measures and PD-L1 expression in tumors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 STUDY ENDPOINTS 
This section shows the planned primary, secondary, 
endpoints from the study 
protocol. However, due to the closure of the bempegaldesleukin program, analyses and parameter 
calculations specified in the Protocol for PK, immunogenicity, biomarker (except PD-L1), clinical 
laboratory, vital signs, physical examination, electrocardiogram, concomitant medications, 
CBR18, and CBR27 are no longer planned to be conducted. Other analyses no longer planned to 
be performed are other safety observations for NKTR-214, prior medications, prior therapy, 
medical history, and important protocol deviations.
 
 


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3.1 Primary Endpoints 
Objective 
Endpoint 
Cohort 
x To evaluate the safety and 
tolerability of NKTR-214 in 
combination with 
pembrolizumab. 
x To define the MTD/RP2D 
and optimal dosing schedule 
of NKTR-214 in 
combination with 
pembrolizumab. 
x Incidence of dose limiting 
toxicity (DLT) 
x Incidence of 
treatment-emergent adverse 
events (TEAEs), serious 
TEAEs, Drug-related 
TEAEs, Grade 3 and above 
TEAEs, fatal TEAEs and 
TEAEs leading to treatment 
discontinuations, 
immune-related adverse 
events (irAEs), and ischemic 
cerebrovascular events 
(ICE)  
 
Dose 
Optimization 
x To determine the ORR per 
blinded independent central 
review (BICR) by RECIST 
1.1 of NKTR-214 plus 
pembrolizumab with or 
without systemic 
chemotherapy in patients 
with untreated metastatic 
NSCLC. 
x Objective response rate 
(ORR)  
Dose Expansion* 
* Efficacy endpoints for cohort 4 and 5 will be per Investigator’s assessments due to early 
termination of the study and incompleteness of BICR data for these cohorts; Efficacy endpoints for 
other dose expansion cohorts and dose optimization cohorts will be per BICR. 
3.2 Secondary Endpoints 
Objective 
Endpoint 
Cohort 
x To evaluate safety and 
tolerability of NKTR-214 
plus pembrolizumab with 
or without systemic 
chemotherapy in patients 
with untreated NSCLC 
(dose expansion only). 
x Incidence of TEAEs, serious 
TEAEs, Drug-related 
TEAEs, Grade 3 and above 
TEAEs, Fatal TEAEs and 
TEAEs leading to treatment 
discontinuations, 
immune-related adverse 
events (irAEs), and ischemic 
cerebrovascular events 
(ICE)  
Dose Expansion 
x To assess the preliminary 
x ORR 
Dose Optimization 


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efficacy (per BICR) of 
NKTR-214 plus 
pembrolizumab with or 
without systemic 
chemotherapy 
x To assess the association 
between efficacy measures 
and PD-L1 expression in 
tumors. 
x Duration of response (DOR)  
x Clinical benefit rate (CBR)  
x Time to response (TTR)  
x Progression-free survival 
(PFS) 
x Overall survival (OS) 
x Duration of response (DOR)  
x Clinical benefit rate (CBR)  
x Time to response (TTR)  
x Progression-free survival 
(PFS) 
x Overall survival (OS)  
Dose Expansion* 
* Efficacy endpoints for cohort 4 and 5 will be per Investigator’s assessments due to early 
termination of the study and incompleteness of BICR data for these cohorts; Efficacy endpoints for 
other dose expansion cohorts and dose optimization cohorts will be per BICR. 


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4 STUDY DESIGN AND PLAN 
This is a Phase 1/2, open-label, multicenter, study of NKTR-214 in combination with 
pembrolizumab with or without systemic chemotherapy in patients with metastatic solid tumors.  
The dose optimization cohorts (Cohorts 1a and 1b) will include first- and second-line (1L and 2L) 
melanoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous 
cell carcinoma (HNSCC), and hepatocellular carcinoma (HCC). The dose optimization Cohort 1a 
will include patients enrolled in the 3 + 3 dose optimization cohort and the dose optimization 
Cohort 1b will include patients enrolled in the step-up dose optimization cohort.   
The dose expansion cohorts (Cohorts 2, 3, 4, and 5) will include first-line NSCLC patients, 
first-line nonsquamous NSCSC patients, and first-line squamous cell lung cancer patients. 
The original protocol and amendments (up to and including Amendment 4), evaluated 
atezolizumab in combination with NKTR-214 (0.006 mg/kg) for treatment of second-line NSCLC 
and first- and second- line urothelial carcinoma and pembrolizumab in combination with 
NKTR-214 (0.006 mg/kg) for treatment of first-line metastatic melanoma and first- and 
second-line NSCLC.  Patients in the pembrolizumab first-line NSCLC cohort will continue on 
study in the dose expansion cohort of Amendment 5.0 or subsequent versions; however, the 
atezolizumab second-line NSCLC and first- or second-line urothelial carcinoma cohorts and the 
pembrolizumab first-line melanoma cohort have been closed to further enrollment.  Patients on 
study who were enrolled in these cohorts under prior amendments will continue treatment as 
described in Amendment 5.0 and subsequent versions. Patients will be followed for efficacy and 
safety until the patient is lost to follow-up, withdraws consent, or patient death.  
Analysis of subjects enrolled before Amendment 5.0 will be separate from the analysis of subjects 
enrolled under Amendment 5.0 and subsequent versions. 
The study is divided into a Screening period, Treatment period, End of Treatment (EOT) and 
Long-Term Follow-up period. The treatment cycles are every 21 days (3 weeks). 
5 DETERMINATION OF SAMPLE SIZE 
In Amendment 7.0 and subsequent versions, approximately 40 patients may be enrolled in Dose 
Optimization Cohorts 1a and 1b, approximately 58 response-evaluable patients may be enrolled in 
Dose Expansion Cohorts 2 and 3, and approximately 63 response-evaluable patients may be 
enrolled in Dose Expansion Cohorts 4 and 5. Patients who are not response-evaluable or who have 
insufficient biopsy material for PD-L1 assessment may be replaced. Up to 100 patients may be 
enrolled in each cohort to reach the number of responsible-evaluable patients. The sample size for 
Cohorts 1a and 1b is based on expected cohort number for dose optimization. The sample sizes for 
Cohorts 2, 3, 4, and 5 are based on the Fleming 2-stage design framework and historical 
comparators. 


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For the dose optimization cohorts of NKTR-214 in combination with pembrolizumab for patients 
with locally advanced metastatic solid tumors, cohorts of at least 3 patients will be treated at each 
dose level. Additional patients will be added to each dose cohort based on the schema and rules 
outlined in Section 5.3 in the protocol or Sponsor determination of the need for additional data to 
further evaluate the benefit/risk profile. It is estimated that approximately 40 patients will be 
enrolled into the dose optimization cohorts. 
For efficacy assessment of the dose expansion cohorts (first-line NSCLC patients), the sample size 
is strictly based on efficacy, specifically based on the target ORR relative to historic response rate 
per each PD-L1 categorization. 
The Fleming 2-stage design (Fleming 1982) framework will be used as a guide for the 1L NSCLC 
Expansion Cohorts 2, 3, 4, and 5.  The total sample size for each 1L NSCLC expansion cohort 
(TPS <1%, TPS 1% to 49%, and TPS ≥50%) will be calculated based on a one-sided Type 1 error 
of 10% and a power of 90%.  The 2-stage design provides an option to stop early for futility as well 
as allowing an expansion of enrollment if a strong antitumor activity signal is observed. However, 
the final decision will be based on the totality of overall treatment effect for multiple study 
endpoints and their associations with the tumor response rate.  Enrollment may continue into Stage 
2 while the planned number of patients for Stage 1 are followed for response-evaluable tumor 
assessments. There will be no stopping of enrollment to a tumor cohort for efficacy, although early 
planning for the next stage of clinical development may be initiated. 
Cohorts 2 and 3 
Approximately 58 response-evaluable first-line NSCLC patients may be enrolled in Cohort 2 (and 
in Cohort 3 if opened), including: Cohort 2.1/3.1: minimum 20 PD-L1 < 1%, Cohort 2.2/3.2: 
minimum 18 PD- L1 1% to 49%, and Cohort 2.3/3.3: minimum 20 PD-L1 ≥ 50%. Patients who are 
not response-evaluable and patients whose PD-L1 status is unable to be confirmed by central 
testing will be replaced (Table 1). 
Table 1 - True (Target) and Historic Objective Response Rate for First-line NSCLC by 
PD-L1 Categorization (Cohorts 2 and 3)  
 
Objective Response 
Rate (ORR) (%)a 
Sample Size (Minimum 
Sample Size)b 
Futility 
Efficacy 
Cohort 
Indication 
Historical 
Target 
N1 
N2 
Total 
S1 
S2 
T1 
T2 
2.1/3.1 
NSCLC 1L 
(PD-L1 <1 %)c 
8 
30 
12 
8 
20 
0 
≤ 3 
≥ 3 
≥ 4 
2.2/3.2 
NSCLC 1L 
(PD-L1 1% to 49 %)c 
14 
40 
8 
10 
18 
0 
≤ 4 
≥ 4 
≥ 5 
2.3/3.3 
NSCLC 1L 
(PD-L1 ≥ 50%) 
25 
55 
11 
9 
20 
≤ 3 
≤ 7 
≥ 6 
≥ 8 


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Abbreviations:  N1 = sample size at Stage 1; N2 = sample size at Stage 2; NSCLC = non-small cell lung cancer; ORR 
= objective response rate; PD-L1 = programmed cell death ligand 1; S1 = futility boundary at Stage 1; S2 = futility 
boundary at Stage 2; T1 = efficacy boundary at Stage 1; T2 = efficacy boundary at Stage 2.  
a. Reference for historical ORR assumption: Carbone 2017; Garon 2015.  
b. Sample size for each expansion cohort is calculated using a normal approximation to provide a reasonable 
false-positive rate (FPR < 10%) and false-negative rate (FNR < 10%). This is the minimum-required sample size 
needed to achieve targeted number of response-evaluable patients. 
c. For France only: patients in first-line NSCLC dose expansion Cohorts 2.1/3.1 and 2.2/3.2 with PD-L1 status < 50% 
are excluded. 
 
Cohorts 4 and 5  
Based on safety and efficacy data from Cohorts 2 and 3, a decision may be made to open Cohorts 4 
(1L nonsquamous NSCLC) and 5 (1L squamous NSCLC). Up to 63 response evaluable patients 
may be enrolled in each of Cohorts 4 and 5, using the Fleming 2-stage design framework. Patients 
who are not response-evaluable or who have insufficient biopsy material for PD-L1 assessment 
may be replaced. 
Approximately 61 response-evaluable first-line NSCLC patients may be enrolled in Cohort 4, 
including: Cohort 4.1: 21 PD-L1 <1%, Cohort 4.2: 21 PD- L1 1% to 49%, and Cohort 4.3: 19 
PD-L1 ≥50% (Table 2).  
Approximately 63 response-evaluable first-line NSCLC patients may be enrolled in Cohort 5, 
including: Cohort 5.1: 21 PD-L1 <1%, Cohort 5.2: 21 PD- L1 1% to 49%, and Cohort 5.3: 21 
PD-L1 ı50% (Table 2).  
Table 2 - True (Target) and Historic Objective Response Rate for First-line NSCLC by 
PD-L1 Categorization (Cohorts 4 and 5)  
 
Objective Response 
Rate (ORR) (%)a 
Sample Size (Minimum 
Sample Size)b 
Futility 
Efficacy 
Cohort 
Indication 
Historical 
Target 
N1 
N2 
Total 
S1 
S2 
T1 
T2 
4.1 
NSCLC 1L 
(PD-L1 <1 %)c 
32% 
60% 
13 
8 
21 
<= 4 
<= 9 
>= 8 
>= 10 
4.2 
NSCLC 1L 
(PD-L1 1% to 49 %)c 
49% 
77% 
9 
12 
21 
<= 4 
<= 13 
>= 8 
>= 14 
4.3 
NSCLC 1L 
(PD-L1 ≥ 50%) 
62% 
87% 
9 
10 
19 
<= 5 
<= 14 
>= 9 
>= 15 
5.1 
NSCLC 1L 
(PD-L1 <1 %)c 
63% 
88% 
11 
10 
21 
<= 7 
<= 16 
>= 10 
>= 17 
5.2 
NSCLC 1L 
(PD-L1 1% to 49 %)c 
50% 
77% 
9 
12 
21 
<= 4 
<= 13 
>= 8 
>= 14 


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Objective Response 
Rate (ORR) (%)a 
Sample Size (Minimum 
Sample Size)b 
Futility 
Efficacy 
Cohort 
Indication 
Historical 
Target 
N1 
N2 
Total 
S1 
S2 
T1 
T2 
4.1 
NSCLC 1L 
(PD-L1 <1 %)c 
32% 
60% 
13 
8 
21 
<= 4 
<= 9 
>= 8 
>= 10 
5.3 
NSCLC 1L 
(PD-L1 ≥ 50%) 
60% 
85% 
14 
7 
21 
<= 9 
<= 15 
>= 12 
>= 16 
Abbreviations:  N1 = sample size at Stage 1; N2 = sample size at Stage 2; NSCLC = non-small cell lung cancer; ORR 
= objective response rate; PD-L1 = programmed cell death ligand 1; S1 = futility boundary at Stage 1; S2 = futility 
boundary at Stage 2; T1 = efficacy boundary at Stage 1; T2 = efficacy boundary at Stage 2.  
a. Reference for historical ORR assumption: Gadgeel 2020 (Keynote-189), Paz-Ares 2020 (Keynote-407). 
b. Sample size for each expansion cohort is calculated using a normal approximation to provide a reasonable 
false-positive rate (FPR < 10%) and false-negative rate (FNR < 10%). This is the minimum-required sample size 
needed to achieve targeted number of response-evaluable patients. 
c. For France only: patients in first-line NSCLC dose expansion Cohorts 4.1/5.1 and 4.2/5.2 with PD-L1 status < 50% 
are excluded. 
 
6 GENERAL ANALYSIS CONSIDERATIONS AND DEFINITIONS 
The statistical analyses will be reported using summary tables, figures, and data listings. Unless 
otherwise specified, data collected during the dose escalation phase will be presented by dose 
cohort and overall. Data collected during the dose expansion phase will be presented by PD-L1 
level and overall. 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
minimum, and maximum. The mean will be presented to one decimal place beyond which the data 
were captured. The standard deviation will be presented to two decimal places beyond which the 
data were captured. The minimum and maximum will be presented to the precision with which the 
data were captured. 
Categorical variables will be presented as frequency counts and percentages. A row or column 
denoted ‘Missing’ will be included in count tabulations where necessary to account for dropouts 
and missing values. Percentages will be rounded to 1 decimal place and the percent will be 
suppressed when the count is zero. The denominator will be the number of subjects in that dose 
cohort within the population of interest unless otherwise noted.  
Time-to-event variables will be analyzed using the Kaplan-Meier method. The number and 
percentage of subjects with events or censored will be presented. The Kaplan-Meier estimates for 
quartiles (i.e., 25%, median, and 75%) and the 95% confidence interval (CI) for the median will be 
presented. Progression free survival and overall survival will be plotted using the Kaplan-Meier 
method. 


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All data, including data collected from the electronic case report form (eCRF) and derived for 
statistical analysis, will be listed.  
Baseline and Study Days 
Cycle 1 Day 1 (C1D1) is defined as the first day of study treatment administration. Other study 
days will be calculated as follows: 
x For any date post the date of  C1D1: 
Study day = visit date – date of C1D1 + 1  
x For any date prior to the date of C1D1: 
Study day = visit date – date of C1D1 
Unless otherwise specified, the baseline is defined as the last non-missing value on or prior to 
C1D1 date and time (or, if C1D1 time is not available, the last non-missing value on or prior to 
C1D1 date).  For vital signs the C1D1 pre-dose value will be used as baseline value unless 
otherwise specified. 
For post-baseline value, 
x The record closest to the day for visit will be chosen. 
x If there are 2 records equidistant from the target visit day, the later record will be chosen 
x If there is more than 1 record on the selected day, the latest will be taken, unless otherwise 
specified. If multiple measurements exist with the same collection date, then the last 
observation by sequence is used. 
7 HANDLING OF MISSING DATA 
No imputation will be considered for incomplete data except the following: 
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 initiation of the study, etc.  For partially missing start 
dates, missing day of the month will be imputed as the first day 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. 
x For prior radiotherapy and surgery, the relevant time to the initiation of the study, etc. will be 
calculated using the calculated study day corresponding to the date of radiotherapy or date of 
procedure for surgery. The imputation rules described for prior systemic cancer therapy will be 
applied to prior radiotherapy and surgery. 


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x For time from initial diagnosis to enrollment and time from diagnosis of metastatic disease to 
enrollment, partial dates for initial diagnosis and diagnosis of metastatic disease will be 
imputed as follows:  
– No imputation will be done if the year is missing. 
– If the year is before enrollment date then missing days will be imputed as the first day of 
the month and missing months will be imputed as July. 
– If the year is the current year of enrollment date then missing days will be imputed as the 
first day of the month and missing months will be imputed as January. 
x For duration of AEs, partial dates for start of AE will be imputed as follows:   
– Missing day, month, and year are not allowed and should be queried.  In case of 
non-resolution of missing month and/or year, no imputation will be performed.  
– Start day of AE is missing and the year is same as Cycle 1 Day 1 (C1D1) 
x 
If the reported month of occurrence of AE is after the month of C1D1 dose then 
missing day will be imputed as the first day of the month of occurrence of AE.  
x 
If the reported month of occurrence of AE is the month of C1D1 dose then the missing 
day will be imputed as the same day as C1D1. 
– Start day of AE is missing and the year is after the year of C1D1 
x 
 Missing day will be imputed as the first day of the month of occurrence of AE. 
x For duration of AEs, partial dates for stop of AE will be imputed as follows:   
– Missing day, month, and year are not allowed and should be queried.  In case of 
non-resolution of missing year, no imputation will be performed. 
– If only the day is missing, 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. 
– If month and day are missing, then December 31st, the date of discontinuation from the 
study, or the date of death, whichever is earlier, will be used as the stop date. 
x For determination of prior medication, any medication with a start date prior to C1D1 will be 
classified as prior medication regardless of when the stop date is.  Missing or partial dates will 
be handled as follows:  
– If missing day and/or month of the start date, the medication will be classified as prior 
unless the month and/or year of the start date is after C1D1. 
x For determination of concomitant medication, the following will be classified as concomitant 
medication: 
– Any medication with a start date prior to or on C1D1 and continued after C1D1. 
– Any medication with a start date after C1D1, and prior to or on 90 days after the last dose 
date. 


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x Missing or partial dates for concomitant medication will be handled as follows:  
– If missing day and/or month of the start date, the medication will be excluded from 
concomitant if the month and/or year of the start date is after the last dose date + 90 days. 
– If missing day and/or month of the stop date, the medication will be excluded from 
concomitant if the month and/or year of the stop date is prior to C1D1. 
– A medication with completely missing start and stop dates will be classified as 
concomitant. 
8 ANALYSIS POPULATIONS 
Safety Population: all subjects who receive at least one dose (or partial dose) of study treatment 
will be included in the analysis of safety. 
DLT Population: all subjects who complete at least the DLT observation period or discontinue 
from the study treatment due to DLT will be included. 
Response Evaluable Population: subjects who have received at least 1 dose (or partial dose) of 
study drug, have measurable disease (per RECIST 1.1) at baseline, and have at least one 
post-baseline assessment of tumor response. 
9 PLANNED ANALYSES 
All statistical summaries and analyses will be separated by dose level (3+3 cohort) and dose 
sequence (step-up cohort) in the dose optimization cohorts and by PD-L1 status in the dose 
expansion cohorts, unless specified otherwise.  
Subjects enrolled prior to Amendment 5.0 will be analyzed by drug combination (atezolizumab 
and pembrolizumab) unless otherwise specified. 
9.1 Subject Disposition 
The summary for subject disposition will include number of subjects enrolled, number of subjects 
in each study population, number of subjects who discontinue from study treatment and reasons 
for discontinuation, and number of subjects who discontinue from study and reasons for study 
discontinuation. 
All enrolled subjects will be included in the summary table. All disposition data will be provided 
in a listing. 
9.2 Demographic and Baseline Characteristics 
Demographic variables will include age, gender, ethnicity, and race. Baseline characteristics will 
include the Eastern Cooperative Oncology Group (ECOG) performance status, height, weight, and 


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calculated body mass index (BMI). All demographic and baseline characteristics will be 
summarized for the Safety Population. 
BMI will be calculated as: 
2
2
(m)]
[Height 
 
(kg)
Weight 
 
 )
(kg/m
BMI
 
. 
All demographic and baseline characteristics data will be provided in a listing. 
9.3 Cancer History 
The summary of cancer history will include type of primary cancer, stage at initial diagnosis, time 
since initial diagnosis of primary cancer to date of informed consent, time since diagnosis of 
metastatic disease or most recent local recurrence to date of informed consent, current status, stage 
at most recent recurrence, type of prior therapies, and time since the last prior systemic therapy to 
date of informed consent. Incomplete date of initial diagnosis of primary cancer, diagnosis of 
metastatic disease or most recent local recurrence, and last systemic therapy will be imputed using 
rules specified in Section 7.  
All cancer history data will be provided in a listing. 
9.4 Concomitant Medications  
Due to the early termination of this study as a consequence of the closure of the 
bempegaldesleukin clinical program, the planned analyses in the protocol will not be performed.  
9.5 Study Exposure 
For each cohort, the total number of infusions, total cumulative dose (mg), duration of exposure, 
and relative dose intensity will be summarized. The total cumulative dose is calculated as the sum 
of actual dose within each study cycle. The duration of exposure is calculated as the time between 
the date of first dose to the date of last dose. The relative dose intensity is calculated as the actual 
dose intensity divided by the planned dose intensity.  
Body Surface Area (BSA) will be calculated as (Mosteller 1987): 
BSA (m^2) = squared root of ((weight in kg * height in cm)/3600) 
Actual dose intensity for Carboplatin at cycle will be calculated using the Calvert formula: 
Actual Total Dose / (GFR+25), 
where the GFR will be calculated by the Cockcroft-Gault equation (Cockcroft 1976): 
GFR (male; mL/min) = (140 – age) × (weight in kg) / (72 × serum creatinine (mg/dL)) 
GFR (female; mL/min) = 0.85 × GFR (male) 


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For NKTR-214, the following parameters will be calculated:    
x Actual dose intensity (mg/kg/week): [Cumulative dose (mg/kg) / (Exposure duration in 
days + 20 days)] × 7 
x Expected dose intensity (mg/kg/week) = (Planned Dose at C1D1 / (3 weeks) = 0.002 
mg/kg/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For pembrolizumab, the following parameters will be calculated:    
x Actual dose intensity (mg/week): [Cumulative dose (mg) / (Exposure duration in days + 20 
days)] × 7 
x Expected dose intensity (mg/week) = (200 mg) / (3 weeks) = 67 mg/kg/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For cisplatin, the following parameters will be calculated:    
x Actual dose intensity (mg/m2/week): [Cumulative dose (mg/m2) / (Exposure duration in 
days + 20 days)] × 7 
x Expected dose intensity (mg/m2) = (75 mg/m2) / (3 weeks) = 25 mg/m2/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For carboplatin, the following parameters will be calculated:    
x Actual dose intensity (mg/(ml/min)/week): [Cumulative dose (mg/(ml/min)) / (Exposure 
duration in days + 20 days)] × 7 
x Expected dose intensity (mg/(ml/min)/week) = (5 mg/(ml/min)) / (3 weeks) = 1.67 
mg/(ml/min)/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For pemetrexed, the following parameters will be calculated:    
x Actual dose intensity (mg/m2/week): [Cumulative dose (mg/m2) / (Exposure duration in 
days + 20 days)] × 7 
x Expected dose intensity (mg/m2/week) = (500 mg/m2) / (3 weeks) = 167 mg/m2/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
For paclitaxel, the following parameters will be calculated:    
x Actual dose intensity (mg/m2/week): [Cumulative dose (mg/m2) / (Exposure duration in 
days + 20 days)] × 7 
x Expected dose intensity (mg/m2/week) = (200 mg/m2) / (3 weeks) = 67 mg/m2/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 


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For nab-paclitaxel, the following parameters will be calculated:    
x Actual dose intensity (mg/m2/week): [Cumulative dose (mg/m2) / (Exposure duration in 
days + 20 days)] × 7 
x Expected dose intensity (mg/m2/week) = (100 mg/m2) / (3 weeks) = 33 mg/m2/week 
x Relative dose intensity (%): (Actual dose intensity / Expected dose intensity) × 100 
Treatment exposure will be summarized for the safety population.  
All treatment exposure data will be listed by subject.  
9.6 Efficacy Analysis 
All tumor response and progression outcomes will be evaluated using RECIST 1.1 by Investigator 
assessment for Cohort 4 and 5 due to incompleteness of BICR data, and by BICR for other cohorts. 
x Best overall response (BOR) using RECIST 1.1 
x Objective response rate (ORR) using RECIST 1.1 
x Clinical benefit rate (CBR) using RECIST 1.1 
x Time to response (TTR) using RECIST 1.1 
x Duration of response (DOR) using RECIST 1.1 
x Progression-free survival (PFS) using RECIST 1.1 
x Overall survival (OS) 
Time to event variables (PFS and OS) will be plotted. All tumor response and time to event data 
will be listed by subject.  
Subjects enrolled prior to Amendment 5.0 will not be summarized. 
9.6.1 Tumor Response (BOR, ORR, and CBR) 
All lesions, including lymph nodes, will be categorized as target or non-target lesions at baseline 
and evaluated at each post-baseline tumor assessment to determine the overall response as one of 
the following: complete response (CR), partial response (PR), stable disease (SD), progressive 
disease (PD), and not evaluated (NE) based on RECIST 1.1. The BOR is determined based on the 
overall response from each post-baseline tumor assessment per RECIST 1.1 (Eisenhauer 2009; 
also see Section 14.1) in the following order: CR, PR, SD, PD, and NE.   
Tumor assessments after the first PD, new systemic anti-cancer therapy, irradiation or resection 
(i.e., surgical procedures or radiotherapy on target lesions) will not contribute to the BOR 
assessment.  For CR and PR, changes in tumor measurements must be confirmed by a repeat 
assessment at least 4 weeks after the time when criteria for CR or PR are first met. For the 
confirmation of CR or PR, there could be one (1) tumor assessment with overall response NE 


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between the first and the subsequent CR or PR. Additionally for the confirmation of PR, there 
could be one (1) SD between the first PR to the subsequent PR.  For SD, changes in tumor 
measurements must last for at least 56 days.  
The number and percentage of subjects in each BOR category will be summarized based on the 
response evaluable population.  
The ORR is defined as the proportion of subjects who have CR or PR as their BOR. The CBR is 
defined as the proportion of subjects who have CR, PR or SD (at least 8 weeks or longer from 
C1D1) as their BOR. The number and percentage of subjects who achieve objective response or 
clinical benefit will be summarized based on the response evaluable population. The 95% CI will 
be calculated using the exact binomial method. 
9.6.2 Time to Response  
For patients who achieved CR or PR, TTR is defined as the time from the date of first dose to the 
date of first response (i.e., CR or PR). TTR will be summarized for the response evaluable 
population using descriptive statistics. 
9.6.3 Duration of Response  
For patients who achieved CR or PR, DOR is defined as the time between the first response (i.e., 
CR or PR) to progressive disease per RECIST 1.1 or death due to any cause, whichever is earlier. 
DOR is subject to the PFS censoring rules as given in Table 3.   
DOR  will be listed but not summarized unless there is a sufficient number of subjects who achieve 
ORR. 
9.6.4 Progression Free Survival 
PFS is defined as the time between the date of first dose to the date of progressive disease per 
RECIST 1.1 or death due to any cause, whichever is earlier. PFS is subject to censoring rules as 
given in Table 3.  PFS will be summarized for the safety population using the Kaplan-Meier 
method. The summary will include number and percentage of subjects who have event or 
censored, the quartiles (25%, median, and 75%), and 95% CI for the median. In addition, the 
proportion of subjects who are alive at 6 months and 12 months and the 95% CI will be calculated 
using the Kaplan-Meier method.  
Table 3 - Censoring Rules for Progression Free Survival  
Situation 
Date of Disease Progression or Censoring 
Outcome 
No baseline assessments for tumor response 
Date of first dose 
Censored 
No post-baseline assessments for tumor 
response and no death 
Date of first dose 
Censored 


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Not known to have progressed or died 
according to data in the database as of 
data-cut-off 
Date of last evaluable tumor assessment 
showing no evidence of disease progression 
Censored 
Subsequent anti-cancer therapy / irradiation or 
resection started without death or progression 
per RECIST v1.1 reported prior to or on the 
same day observing PD or death 
Date of last evaluable tumor assessment prior 
to or on the date of initiation of the subsequent 
anti-cancer therapy 
Censored 
Documented progression per RECIST v1.1 
and no new anti-cancer therapy started before 
Date of the first documented progression per 
RECIST v1.1 
Progressed 
Death without progression per RECIST v1.1 
and no new anti-cancer therapy started before 
Date of death  
Progressed 
 
9.6.5 Overall Survival 
The overall survival (OS) is defined as the time between the date of first dose to the date of death 
from any cause. Subjects who do not have date of death will be censored on the last date known to 
be alive. OS will be summarized for the safety population using the Kaplan-Meier method. The 
summary will include number and percentage of subjects who have event or censored, the quartiles 
(25%, median, and 75%), and 95% CI for the median. In addition, the proportion of subjects who 
are alive at 6 months and 12 months and the 95% CI will be calculated using the Kaplan-Meier 
method.  
9.7 Safety Analyses 
All safety analyses will be based on the safety population unless otherwise specified. 
9.7.1 Dose Limiting Toxicity 
DLTs will be evaluated within the DLT evaluation window as specified in the protocol. Delayed 
DLTs are AEs that are defined in the protocol that occur after the DLT evaluation window. DLTs 
and delayed DLTs will be summarized separately by SOC and PT. All DLTs and delayed DLTs 
will be listed by patient. 
9.7.2 Adverse Events 
A treatment-emergent adverse event (TEAE) is:  
x Any AE that happens on or after treatment initiation 
x AE that was present at time of treatment initiation but worsened after treatment initiation 
x AE that was present and resolved prior to treatment and reappeared after treatment 
initiation. 
Incomplete start and end date for TEAEs will be imputed. Any AE will be considered as a TEAE if 
its status cannot be fully determined because of incomplete data. The treatment-emergent period 
will be defined as the period of time on or after the date/time of the first dose of study drug 


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administration (on or after the date of the first dose of study drug administration, if time is not 
available) until the earlier date of the two dates: 
x Date of initiation of new antineoplastic regimen  
x 30 days (90 days for SAEs) after the date of the last dose of all study drug 
Only TEAEs will be summarized in the table. All AEs including non-TEAEs will be listed by 
subject.  
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA. AE 
severity will be determined based on the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) Grade (version 5.0).  
A TEAE is considered as related to treatment if it is related or possible related to NKTR-214, 
pembrolizumab, atezolizumab or chemotherapy. A TEAE is considered as leading to treatment 
discontinuation if it is leading to discontinuation of NKTR-214, pembrolizumab, atezolizumab or 
chemotherapy.   
In each summary table, the number and percentage of subjects who have at least one event will be 
reported. For TEAE summaries by SOC and/or PT, a subject is counted only once within each 
summary level. For TEAE summary by CTCAE grade, a subject is counted only once using the 
highest grade. 
The following summaries will be provided for TEAEs (atezolizumab-related summaries will 
similarly be included where applicable for subjects enrolled under Amendment 4 or earlier): 
x Overall summary of TEAEs, 
x TEAEs by SOC and PT,  
x Serious TEAEs by SOC and PT,  
x Drug-related TEAEs by SOC and PT, 
x Fatal TEAEs by SOC and PT, 
x Grade 3 and above TEAEs by SOC and PT, 
x TEAEs leading to study drug discontinuation by SOC and PT.  
9.7.3 Adverse Events of Special Interest for Pembrolizumab 
Immune-related Adverse Events (irAEs)  
All potential non-endocrine or endocrine irAEs along with concomitant medication information 
will be reviewed by Clinical Development, and Clinical Development will manually determine 
and provide a final list of irAEs for the irAE summaries.  


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For irAE analysis, treatment-emergent period based on period of time from the date/time of the 
first dose of study drug until the earlier date of the following two dates will be used: 
x Date of initiation of new antineoplastic regimen  
x 90 days after the date of the last dose of all study drug. 
IrAEs will be summarized by safety population. The number and percentage of subjects who have 
at least one event will be reported.  
All irAEs will be listed by subject. 
9.7.4 Adverse Events of Special Interest for Bempegaldesleukin 
The AESI for bempegaldesleukin consist of ischemic cerebrovascular events (ICE). The ICE will 
be identified using the SMQ: Ischaemic central nervous system vascular conditions (SMQ) - 
Narrow Scope. 
All AESIs will be listed by subject. 
 
9.7.5 Clinical Laboratory, Vital Signs, Physical Examination and Electrocardiogram 
Due to the early termination of this study as a consequence of the closure of the 
bempegaldesleukin clinical program, the planned analyses in the protocol will not be performed.  
10 IMMUNOGENICITY 
Due to the early termination of this study as a consequence of the closure of the 
bempegaldesleukin clinical program, the planned analyses in the protocol will not be performed.  
12 PHARMACOKINETICS 
Due to the early termination of this study as a consequence of the closure of the 
bempegaldesleukin clinical program, the planned PK analyses in the protocol will not be 
performed.  


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13 REFERENCES 
Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent 
Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 376: 2415-2426. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228-47. 
Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982; 
38: 143-151. 
Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: 
pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic 
nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020; 38(14): 1505-1517. 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non-small-cell Lung 
Cancer. N Engl J Med. 2015; 372: 2018-2028. 
Mosteller RD. Simplified Calculation of Body Surface Area. N Engl J Med. 1987 Oct 
22;317(17):1098. 
Paz-Ares L, Vicente D, Tafreshi A, et al. A randomized, placebo-controlled trial of 
Pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC: 
protocol-specified final analysis of KEYNOTE-407. J Thorac Oncol. 2020; 15(10): 1657-1669. 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for evaluation for immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res. 2009; 15(23): 7412-20. 


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14 APPENDICES 
14.1 Evaluation of Overall Response using RECIST 1.1 
 
Overall response 
first time point 
Overall response 
subsequent time 
point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD. 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD. 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise, NE. 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD. 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise, NE. 
NE 
NE 
NE 
Abbreviations: CR, complete response; PR, partial response; SD, stable disease, PD, progressive disease; NE, 
unevaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the first 
time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.  
Source: Eisenhauer, 2009