An Open-Label, Multicenter, Dose Escalation And Expansion Study Of NKTR-214 In Subjects With Locally Advanced Or Metastatic Solid Tumor Malignancies
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Sponsor: Nektar Therapeutics

Protocol No. 15-214-01 Amendment 4.0 
NKTR-214 
Nektar Therapeutics 
Page 1 of 84 
Confidential and Proprietary 
24 Oct 2016 
Nektar Therapeutics 
CLINICAL STUDY PROTOCOL 
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 
Protocol Number: 15-214-01 
Protocol Amendment Date: 24 October 2016 
Protocol Amendment No. 4.0 
Supersedes: Protocol Amendment 3.1 dated 18 July 2016 
IND Number: 125,471 
Sponsor: Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
Sponsor’s Medical Contact and 
Study Medical Monitor: 
  
 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, 
your staff, and the applicable Institutional Review Board/Independent Ethics Committee and applicable Regulatory 
Authorities. Your acceptance of this document constitutes agreement that you will not disclose the information 
herein to others without written authorization from Nektar Therapeutics except to the extent necessary to obtain 
informed consent from persons who participate as subjects in this study. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 2 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
INVESTIGATOR SIGNATURE PAGE 
Nektar Therapeutics 
TITLE: 
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 
PROTOCOL NUMBER: 
15-214-01 
PHASE OF STUDY: 
Phase 1/2 
PROTOCOL DATE: 
12 August 2015 
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. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 4 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
LIST OF STUDY CONTACTS 
Study Contact 
Name 
Contact Information 
 
 
 
 
 
 
 
 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 5 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PRINCIPAL INVESTIGATOR COMMITMENT: ...................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................9 
LIST OF APPENDICES ...............................................................................................................9 
ABBREVIATIONS ......................................................................................................................10 
1.0 
STUDY SYNOPSIS .........................................................................................................14 
 
Study Schematic.....................................................................................................19 
1.1
 
Schedule of Assessments .......................................................................................22 
1.2
2.0 
INTRODUCTION............................................................................................................32 
 
Background ............................................................................................................32 
2.1
 
Pre-clinical Data.....................................................................................................32 
2.2
2.2.1 
Pharmacology ........................................................................................32 
2.2.2 
Pharmacokinetics ..................................................................................33 
2.2.3 
Toxicology ............................................................................................33 
 
Starting Dose Rationale .........................................................................................34 
2.3
3.0 
STUDY OBJECTIVES ....................................................................................................35 
 
Primary Objective ..................................................................................................35 
3.1
 
Secondary Objectives.............................................................................................35 
3.2
 
Exploratory Objectives ..........................................................................................35 
3.3
4.0 
STUDY DESIGN ..............................................................................................................36 
 
Summary of Study Design .....................................................................................36 
4.1
4.1.1 
Screening ...............................................................................................36 
4.1.2 
Open-label Treatment............................................................................36 
4.1.2.1 
Part 1:  Dose Escalation .................................................................36 
4.1.2.2 
Part 2:  Dose Expansion Scheme ...................................................39 
4.1.3 
Tumor Assessments ..............................................................................39 
4.1.4 
Post-treatment .......................................................................................39 
5.0 
SELECTION OF STUDY POPULATION ...................................................................40 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 6 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Inclusion Criteria ...................................................................................................40 
5.1
 
Exclusion Criteria ..................................................................................................42 
5.2
 
Removal of Subjects from Study Therapy or Assessment.....................................43 
5.3
6.0 
TREATMENT PLAN (DOSE ESCALATION AND DOSE EXPANSION) ..............45 
 
Overview ................................................................................................................45 
6.1
 
Screening Period ....................................................................................................45 
6.2
 
Treatment Period ....................................................................................................45 
6.3
 
Radiographic Assessments.....................................................................................46 
6.4
 
Post-treatment Period .............................................................................................47 
6.5
 
Pharmacokinetic Measurements ............................................................................47 
6.6
 
Immunogenicity Measurements .............................................................................48 
6.7
 
Biomarker Measurements ......................................................................................48 
6.8
6.8.1 
Biomarker Blood Collection Times and Assessments ..........................48 
6.8.2 
Tumor Tissue Biopsy Collection Times and Assessments ...................48 
6.8.3 
Stool Sample Collection Times and Assessments ................................49 
 
Determination of Dose-Limiting Toxicities...........................................................49 
6.9
 
Dose Modifications ................................................................................................50 
6.10
6.10.1 
Non-immune-related Adverse Events ...................................................50 
6.10.2 
Immune-related Adverse Events ...........................................................50 
 
Administration of NKTR-214 ................................................................................51 
6.11
 
Infusion Delays and Missed Doses ........................................................................51 
6.12
 
Prior and Concomitant Medications ......................................................................51 
6.13
 
Permitted Medications ...........................................................................................52 
6.14
 
Prohibited Medications ..........................................................................................52 
6.15
 
Adverse Events ......................................................................................................52 
6.16
 
Assigning Subject Numbers ...................................................................................52 
6.17
7.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ..............................................53 
 
Description and Formulation .................................................................................53 
7.1
 
Study Drug Packaging and Labeling .....................................................................53 
7.2
 
Study Drug Reconstitution and Handling ..............................................................53 
7.3
 
Study Drug Storage ................................................................................................53 
7.4
 
NKTR-214 Drug Shipment ....................................................................................53 
7.5
 
Study Drug Accountability and Reconciliation .....................................................54 
7.6

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 7 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
8.0 
ASSESSMENT OF SAFETY OR AES AND SERIOUS AES .....................................55 
 
AE Definition and Assessment ..............................................................................55 
8.1
 
Monitoring AEs .....................................................................................................55 
8.2
 
Grading of AEs ......................................................................................................56 
8.3
 
Causality Relationship of AEs ...............................................................................57 
8.4
 
AE Reporting and Follow-up .................................................................................57 
8.5
 
Serious AE Definition ............................................................................................57 
8.6
 
Serious AE Reporting ............................................................................................58 
8.7
 
Serious AE Follow-up............................................................................................59 
8.8
 
Immune-Related Adverse Event Reporting ...........................................................60 
8.9
 
Pregnancy ...............................................................................................................60 
8.10
 
Clinical Laboratory Tests .......................................................................................61 
8.11
 
Vital Signs ..............................................................................................................61 
8.12
 
Electrocardiograms ................................................................................................61 
8.13
 
Pregnancy Tests .....................................................................................................62 
8.14
9.0 
ASSESSMENT OF EFFICACY EVALUATIONS ......................................................63 
 
Definitions..............................................................................................................63 
9.1
9.1.1 
Measurable Disease ...............................................................................63 
9.1.2 
Non-measurable Disease .......................................................................64 
 
Specifications by Methods of Measurements ........................................................64 
9.2
9.2.1 
Tumor Response Evaluation .................................................................65 
9.2.1.1 
Assessment of Overall Tumor Burden at Baseline and 
Measurable Disease .......................................................................65 
9.2.1.2 
Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions ....65 
9.2.1.3 
Special Notes on the Assessment of Target Lesions .....................65 
9.2.2 
Response Criteria using RECIST v1.1 ..................................................66 
9.2.2.1 
Evaluation of Target Lesions .........................................................66 
9.2.2.2 
Evaluation of Non-target Lesions ..................................................66 
9.2.2.3 
Confirmatory Measurement/Duration of Response .......................67 
9.2.2.3.1 
Confirmation ..................................................................................67 
9.2.2.3.2 
Duration of Overall Response ........................................................67 
9.2.2.4 
Evaluation of Overall Response using RECIST v1.1 ....................67 
10.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE ......................................................................69 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 8 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
General Considerations ..........................................................................................69 
10.1
 
Determination of Sample Size ...............................................................................69 
10.2
10.2.1 
Expansion Cohorts Safety Monitoring ..................................................69 
 
Replacement of Subjects ........................................................................................71 
10.3
 
Analysis Sets ..........................................................................................................71 
10.4
 
Planned Analyses ...................................................................................................72 
10.5
10.5.1 
Demographics and Baseline Characteristics .........................................72 
10.5.2 
Safety.....................................................................................................72 
10.5.3 
Efficacy .................................................................................................73 
10.5.4 
Pharmacokinetics ..................................................................................74 
10.5.5 
Immunogenicity ....................................................................................74 
10.5.6 
Exploratory Analyses ............................................................................74 
 
Concomitant Medications ......................................................................................75 
10.6
 
Missing Data ..........................................................................................................75 
10.7
11.0 
STUDY OR STUDY SITE TERMINATION ................................................................76 
12.0 
QUALITY ASSURANCE ...............................................................................................77 
 
Changes to the Protocol .........................................................................................77 
12.1
 
Monitoring .............................................................................................................77 
12.2
 
Direct Access to Source Data/Documents for Audits and Inspections ..................78 
12.3
13.0 
ETHICS ............................................................................................................................79 
 
IRB/IEC Approval .................................................................................................79 
13.1
 
Written Informed Consent .....................................................................................79 
13.2
14.0 
DATA HANDLING AND RECORD KEEPING ..........................................................80 
 
Data Collection Instruments and Source Documents ............................................80 
14.1
14.1.1 
Study Records .......................................................................................80 
14.1.2 
Data Collection Instruments ..................................................................80 
 
Retention of Essential Documents .........................................................................80 
14.2
 
Confidentiality .......................................................................................................80 
14.3
15.0 
PUBLICATION POLICY ...............................................................................................81 
16.0 
REFERENCES .................................................................................................................82 
 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 9 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
LIST OF TABLES 
Table 1: 
Schedule of Visits and Procedures Dose Escalation (Phase 1) ........................22 
Table 2: 
Schedule of Visits and Procedures Dose Expansion (Phase 2)........................27 
Table 3: 
Safety Margins for the Proposed Clinical Dose of NKTR-214 .......................34 
Table 4: 
Part 1:  Sample Dose Escalation Scheme ........................................................37 
Table 5: 
Dose Escalation Rules......................................................................................38 
Table 6: 
Best Overall Response When Confirmation of CR and PR Required .............68 
Table 7: 
Suspension Boundaries for Toxicity During Expansion ..................................70 
Table 8: 
Operating Characteristics for Subject Accrual Suspension Rules ...................71 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic – Dose Escalation .................................................................19 
Figure 2: 
Study Schematic – Dose Expansion ................................................................20 
Figure 3: 
Study Schematic...............................................................................................21 
 
LIST OF APPENDICES 
Appendix 1: 
Clinical Laboratory Tests .................................................................................84 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 10 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ALP 
alkaline phosphatase 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
area under the curve 
BOR 
best overall response  
CBR 
clinical benefit rate 
CD8T  
tumor killing CD8+ T cell 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum concentration 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCI 
data collection instrument 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOA 
end of administration 
EOT 
end of treatment 
EMA 
European Medicines Agency 
ET 
early termination 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 11 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Abbreviation or Term 
Definition 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
hr 
hour(s) 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
IEC 
independent ethics committee 
IL-2 
interleukin-2 
IL2Rα 
IL-2 receptor alpha subunit  
IL2Rβ 
IL-2 receptor beta subunit  
IND 
Investigational New Drug 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IV 
intravenous 
kg 
Kilogram 
LDH 
lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MAD 
maximum administered dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 12 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Abbreviation or Term 
Definition 
min 
minute(s) 
mg 
milligram 
mL 
milliliter 
mmHg 
millimeters of mercury 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition  
NCI 
National Cancer Institute 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate  
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PEG 
polyethylene glycol 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
q14d 
every 14 days 
q21d 
every 21 days 
q28d 
every 28 days 
QTcF 
Fridericia’s corrected QT interval 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
Recombinant human interleukin 2 
RP2D 
recommended Phase 2 dose 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 13 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Abbreviation or Term 
Definition 
SAE 
serious adverse event 
SD 
stable disease 
SLD 
sum of the longest diameters 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination phase half-life 
TTE 
transthoracic echocardiogram 
Tmax 
time to maximum concentration 
Treg 
regulatory T cell 
TEAE 
treatment emergent adverse event 
TTR 
time to response 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
TIL 
tumor-infiltrating lymphocyte 
Vd 
volume of distribution 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 14 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
1.0 
STUDY SYNOPSIS 
Name of Sponsor:   
Nektar Therapeutics 
Name of Finished Product: NKTR-214 drug product 
Name of Active Ingredient: NKTR-214 drug substance 
Title of Study: 
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 
Duration of Treatment:   
Subjects will be treated until unacceptable toxicity, or disease progression per 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (treatment may 
continue if there is clinical benefit as determined by the Investigator). 
Phase of Development: 
Phase 1/2 
Objectives: 
The primary objectives are: 
 To evaluate the safety and tolerability, and define the maximum tolerated dose 
(MTD) of NKTR-214 
 To evaluate the efficacy of NKTR-214 by assessing the objective response rate 
(ORR) at the MTD or the dose below the MTD 
The secondary objectives are: 
 To evaluate the efficacy of NKTR-214 by assessing best overall response (BOR), 
 duration of response (DOR), clinical benefit rate 
(CBR), time to response (TTR), 
 
 To characterize the pharmacokinetic (PK) profile of NKTR-214 and relevant 
metabolites 
 To assess the immunogenicity of NKTR-214 
The exploratory objectives are: 
 To assess the immunologic effect of NKTR-214 in tumor tissue on tumor-
infiltrating lymphocytes (TIL) 
 To assess the immunologic effects of NKTR-214 in blood, including effects on 
cytokines, natural killer (NK) cells, T-cells, and other serum proteins and immune 
modulators 
Study Population 
Adults age 18 and older with histologically confirmed locally advanced or metastatic 
solid tumors in Part 1 (Dose Escalation) and renal cell carcinoma (RCC) in Part 2 
(Dose Expansion) who have measurable disease 
Number of Subjects 
(planned):   
Part 1:  Approximately 50 subjects will be enrolled into the dose escalation phase of 
the study. 
Part 2:  Approximately 50 subjects will be enrolled into the dose expansion phase of 
the study.  
Number of Study Sites: 
Approximately 3 clinical study sites for dose escalation cohorts; up to 15 additional 
sites may be added for the dose expansion cohort. 
Countries: 
USA  

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 15 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Study Design: 
This is a Phase 1/2, open-label, multicenter, dose escalation and dose expansion study 
of NKTR-214 in subjects with locally advanced or metastatic solid tumor 
malignancies.  The study will be conducted in 2 parts:  Part 1, Dose Escalation and 
Part 2, Dose Expansion.   
Part 1:  Sample Dose Escalation Scheme 
Cohort 
NKTR-214 Dose 
Cohort 1 
0.003 mg/kg 
Cohort 2 
0.006 mg/kg 
Cohort 3 
0.012 mg/kg 
 
 
 
 
 
 
 
The Sponsor and at least one Investigator will jointly decide the following: 
 Dose levels for a given cohort may be reduced by 25-50% depending on the 
severity, duration and frequency of toxicities observed at the previous dose level as 
well as the pharmacokinetic (PK) profile, if available. 
 In the event that MTD is not determined at the highest dose level listed in the table, 
dose escalation at no more than 100% higher than previous dose may continue. 
 The schedule of dosing can be modified to every 14 days or every 28 days based 
on a review of the safety data and available PK data. 
 Once the MAD has been reached, lower doses and different dose schedules may be 
assessed, within the anticipated total number of subjects of approximately 50. 
Dose escalation will proceed as follows for each dose level: 
Number of Subjects with 
a dose-limiting toxicity 
(DLT) at a Given Dose 
Level  
Dose Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next higher dose level. 
1 out of 3 
Enter at least 3 more subjects at the current dose level. 
If 0 of these 3 additional subjects experience DLT, 
proceed to the next higher dose level.  If 1 or more of 
this group suffers a DLT, then the dose escalation is 
stopped, and this dose is declared the maximum 
administered dose (MAD).  Three (3) additional 
subjects will be entered at a lower dose level if only 3 
subjects were treated previously at that dose. 
≥ 2 
Dose escalation will be stopped.  This dose level will be 
declared the MAD. Three (3) additional subjects will be 
entered at a lower dose level if only 3 subjects were 
treated previously at that dose. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 16 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
≤ 1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD. At least 6 subjects must be entered at 
this dose level before declaring it as the dose for part 2 
dose expansion.  
For each dose escalation cohort, the first subject enrolled to the cohort will be treated 
on Cycle 1 Day 1 and monitored for tolerance through Cycle 1 Day 5 prior to dosing 
of the additional subjects at that dose level.  Safety data from Cycle 1 will be utilized 
to assess dose escalation for each new cohort.   
A DLT is defined as a Grade 3 or higher study-drug-related or possibly related 
adverse event (AE) occurring within the first cycle of dosing (excluding Grade 3/4 
transient lymphopenia < 14 days in duration, tumor flare defined as local pain, 
irritation, or rash localized at sites of known or suspected tumor, a transient, 
reversible ≤ grade 3 infusion AE (< 24 hours), non-clinically significant laboratory 
abnormalities, or fatigue lasting less than 72 hours) using National Cancer Institute 
(NCI) Common Terminology Criteria for AEs (CTCAE) version 4.03.   
Part 2:  Dose Expansion 
Enrollment into the renal cell carcinoma cohort may commence once the MTD or 
RP2D has been determined. 
Subjects in the dose expansion cohort will be treated every 21 days (q21d), every 14 
days (q14d), or every 28 days (q28d) until tumor progression (treatment may 
continue if there is clinical benefit as determined by the Investigator), death, 
unacceptable toxicity, symptomatic deterioration, achievement of maximal response, 
subject’s choice, the Investigator’s decision to discontinue treatment, the subject 
withdraws consent or Nektar Therapeutics decides to terminate the trial.   
Key Inclusion Criteria:   
For Parts 1 and 2: 
 Willing and able to provide written informed consent. 
 Histologically confirmed diagnosis of a locally advanced (not amenable to curative 
therapy such as surgical resection) or metastatic solid tumor. 
 Male or female patients, age 18 years or older at the time of signing the informed 
consent form (ICF). 
 Life expectancy > 12 weeks. 
 Patients must not have received interleukin-2 [IL-2] therapy within 12 months of 
Cycle 1 Day 1. 
 Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. 
 Measurable disease per RECIST version 1.1. 
For Part 2 only: 
Renal Cell Carcinoma (RCC) 
a. 
Histologically confirmed diagnosis of unresectable or metastatic RCC with 
 
predominantly clear cell elements. 
b. 
Must have received only 1 prior line of anti-angiogenic therapy 
c. 
Must not have received prior immunotherapy with immune-modulators 
 
including but not limited to checkpoint inhibitors such as anti-PD-1, 
 
anti-PD-L1, anti-CTLA-4 antibody and any other antibody or drug 
 
specifically targeting T cell co-stimulation or checkpoint pathways, 
 
indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive 
 
cell therapies, and cytokine therapies. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 17 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Test Product, Dose and 
Mode of Administration:   
NKTR-214; Starting dose of 0.003 mg/kg intravenous (IV) infusion administered 
over 15 (± 5) minutes q21d 
Safety: 
Assessment of safety will be determined by an ongoing review of the following: 
 incidence of AEs, including serious AEs (SAEs) 
 clinical laboratory tests (blood and urine sampling) 
 vital signs 
 electrocardiograms (ECG) and echocardiograms 
 physical examination 
Pharmacokinetics: 
Blood samples for PK analyses will be collected from all subjects enrolled in the dose 
escalation and dose expansion phases.  Serial PK samples will be collected at 
multiple scheduled time points.  Plasma concentrations of NKTR-214 and its 
metabolites will be measured for each plasma PK sample using validated method(s).  
Pharmacokinetic parameters such as maximum concentration (Cmax), time to 
maximum concentration (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 possible.   
Pharmacodynamics: 
Systemic and tumor tissue based pharmacodynamic effects of NKTR-214 will be 
examined.   
Blood samples for systemic pharmacodynamic analyses will be collected pre- and 
post-NKTR-214 treatment from all subjects enrolled to assess the effects of 
NKTR-214 on markers of immune system activation, cytokines and immune cell 
populations.   
Fresh tumor tissue will be collected pre- and post-NKTR-214 treatment in consenting 
subjects for characterization of TILs, and immune system-related genes and proteins.   
In addition, archival tumor tissue samples will be collected from all subjects for 
analysis of immune system-related genes and proteins. 
Efficacy: 
Tumor measurements will be performed every 8 weeks ± 7 days.  The primary 
efficacy measurement will be objective response rate (ORR) by tumor type.  ORR by 
dose group will be descriptively presented. Other efficacy outcomes will include: 
 best overall response (BOR) 
 
 
 duration of response (DOR) 
 clinical benefit rate (CBR) 
  time to response (TTR) 
 
 
 tumor markers (e.g., LDH in melanoma) as an exploratory endpoint 
Statistical Methods: 
Safety: 
The primary safety analyses will include incidence of DLTs by dose cohort. Safety 
analyses will summarize the incidence, grade and duration of toxicities according to 
the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE), 
version 4.03.  All AEs will be listed and tabulated by system organ class, preferred 
term, and coded according to the Medical Dictionary for Regulatory Activities 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 18 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
(MedDRA).  The incidence of AEs will be tabulated and reviewed for potential 
significance and clinical importance.  Vital signs (including change in weight) and 
clinical laboratory test results will be listed and summarized descriptively by dose 
(for the dose escalation phase) and by tumor type (for the dose expansion phase).  
Any significant physical examination findings will be listed. ECG data will be 
evaluated by central review.  Abnormalities, if present, will be listed.  A separate 
listing and summary of all immune-related AEs (irAEs) will be provided.   
Efficacy: 
Efficacy assessments will be summarized separately for the dose escalation and dose 
expansion cohorts. In order to assess preliminary efficacy, the primary efficacy 
outcome measurement ORR, and the secondary efficacy outcomes, BOR, CBR, and 
TTR, will be tabulated by dose and tumor type. 
 
 Individual tumor measurements, tumor size 
and percent changes in tumor size will be listed.  Changes in tumor size will be 
presented graphically for each specific tumor type.  ORR and BOR will each be 
estimated based on the response evaluable population which is defined as subjects 
with measurable disease at baseline who receive the study drug and also have one 
post-baseline assessment of tumor response or are withdrawn due to progressive 
disease/death prior to first response assessment.  DOR will be estimated for subjects 
who achieve complete response (CR) or partial response (PR).  Other secondary 
efficacy analyses will be based on the all treated population and may be done for the 
response evaluable population as sensitivity analyses.  
Pharmacokinetic parameters will be tabulated and summarized with descriptive 
statistics by dose level.  Values for biomarker expression will be calculated at each 
observation time.  Changes in expression from screening to each observation time 
will be assessed. 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 21 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Figure 3: 
Study Schematic 
 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 22 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Schedule of Assessments 
1.2
Table 1: 
Schedule of Visits and Procedures Dose Escalation (Phase 1) 
Assessment Period 
Screening 
Cycle 1 and Cycle 2 
Cycle 3 and 
Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day
6 
Day
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
15 
Day 
22b 
Day 
1 
Day 
8 
Day 
22b 
End of 
Treatment 
(+10 days) 
Follow-
up 
3 mo 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/cancer historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Xg 
X 
X 
X 
X 
X 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
Xi 
Xi 
X 
Xi 
Xi 
X 
Xg 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECGj 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Xg 
X 
X 
X 
X 
X 
 
ECHOk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testl 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Hematologym 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Xg 
X 
X 
X 
X 
X 
 
Serum chemistryn 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
Xg 
X 
X 
X 
X 
X 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 23 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Table 1: 
Schedule of Visits and Procedures Dose Escalation (Phase 1) (Cont'd) 
Assessment Period 
Screening 
Cycle 1 and Cycle 2 
Cycle 3 and 
Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day
6 
Day
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
15 
Day 
22b 
Day 
1 
Day 
8 
Day 
22b 
End of 
Treatment 
(+10 days) 
Follow-
up 
3 mo 
Coagulationo 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
Xg 
X 
X 
X 
X 
X 
 
Additional labsp 
X 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
Xp 
 
 
X 
 
Urinalysis (dipstick)q 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Serologyr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissue 
collections 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy if accessiblet 
X t 
Xt 
 
 
 
 
 
 
 
 
 
 
 
 
Xt 
 
 
Xt 
 
Immunogenicity serum 
sample collection 
X 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
 
X 
X 
Tumor assessmentv 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Every 8 weeks 
(± 7d) 
X 
 
AEsw 
 
 
X 
 
Concomitant medications 
X 
 
X 
 
Biomarker blood sample 
collection 
 
Xx 
 
 
 
 
 
 
Xx 
 
 
 
 
 
Xx 
 
 
Xx 
 
PK blood sampley,z 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Xg 
 
X 
X 
 
X 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 24 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Table 1: 
Schedule of Visits and Procedures Dose Escalation (Phase 1) (Cont'd) 
Assessment Period 
Screening 
Cycle 1 and Cycle 2 
Cycle 3 and 
Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day
6 
Day
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
15 
Day 
22b 
Day 
1 
Day 
8 
Day 
22b 
End of 
Treatment 
(+10 days) 
Follow-
up 
3 mo 
Administer fluids and 
advise patientsaa 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Days 
1-5 
 
 
 
 
NKTR-214 
administrationbb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Quarterly follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Footnotes: 
a. 
The acceptable visit window is + 1 days for Day 11 and ±1 day for Day 8 and Day 15 and ± 7 days for the follow-up visit post-treatment.  Visits may be skipped or 
postponed if prospectively identified by the Investigator (e.g., national holidays, subject vacations).  If Day 4 visit is missed then Day 4 assessments must be done at 
the next in-clinic visit.  All procedures and examinations should be performed before the administration of study drug(s), except as indicated below. 
b. Assessments only applicable if dosing cycle is changed to 28-day cycle. 
c. 
The Institutional Review Board (IRB)-approved informed consent form (ICF) must be signed before any study-specific procedures or examinations are performed. 
d. An event occurring after the subject has provided informed consent, but before the first dose of study treatment, will be collected as medical history unless the event 
is either new and attributed to protocol-mandated procedures by the Investigator OR there is a significant change in the rate of occurrence or an increase in the 
severity of the pre-existing condition which is judged to be clinically important and attributed to the protocol-mandated procedures by the Investigator.  Any new or 
clinically significant changes in the subject’s medical and/or cancer history that occur immediately after the first dose of drug will be recorded as AEs. 
e. 
Include prior cancer treatments:  previous immunotherapy, chemotherapy, targeted therapy, radiation, OTC medications, herbs and dietary supplements. 
f. 
Physical examinations at screening/baseline, at day 1 of each cycle, and at end of treatment should be complete assessments (evaluate all major organ systems, 
including the following categories:  general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, extremities, integumentary, neurologic, 
and psychiatric).  Other examinations may be focused, at the discretion of the Investigator, to identify changes from baseline or evaluate changes based on the 
subject’s clinical symptoms.  Weight is to be reported at each visit, height at screening/baseline visit only. 
g. Assessments not applicable if dosing cycle is changed to 14-day cycle. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 25 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
h. Vital signs include temperature, pulse, respiration, systolic and diastolic blood pressure, and oxygen saturation.  On dosing days, monitor the subject for 1 hour 
postdosing and record vital signs at the end of the hour.  However, if the subject experienced a Grade ≥ 2 infusion-related reaction or hypotension during the study 
drug administration, the patient may be monitored for 24 hours per clinical judgment.  Per clinical judgment, additional monitoring might be implemented for 
subsequent cycles. 
i. 
Vital signs will be assessed on days 6, 7, 9, and 10 of Cycles 1 and 2 either in-clinic or using home health care visits. 
j. 
A 5-minute summary ECG will be performed for all subjects at screening and during the 5 minutes prior to the time points of predose, 0.5 hr ± 5 min, 3 hr ± 10 min, 
6 hr + 2 hr on Day 1 of Cycles 1 and 2 and on Days 2, 3, 4, 5, 8, 11, and 15 of Cycles 1 and 2.  A 5-minute summary ECG starting 5 minutes before the predose 
timepoint will be performed on Days 1 and 8 of Cycle 3 and beyond, including End of Treatment (EOT).  Frequency of ECGs may be increased if clinically 
indicated.  Prior to performing ECGs, subjects should rest in the supine position for at least 5 minutes.  All ECGs should be taken prior to the PK draw. 
k. Stress echocardiogram (either exercise or nuclear) will be performed for all subjects within 60 days prior to Cycle 1 Day 1 and at EOT to assess for cardiac function 
and left ventricular ejection fraction (LVEF).  At the discretion of the Investigator, patients who are unable to perform a stress echocardiogram may instead have a 
multigated acquisition (MUGA) scan or transthoracic echocardiogram (TTE).  The same assessment method should be used for the same subject throughout the 
study. 
l. 
For women of childbearing potential, serum β-HCG pregnancy test is required at screening.  Urine or serum pregnancy tests to be performed on Day 1 of each 
subsequent cycle and EOT.  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 
3 months before signing the ICF. 
m. Hematology performed at the indicated times by local laboratory:  red blood cell (RBC) count, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular volume 
(MCV), platelet count, white blood cell (WBC) count, and WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) (Appendix 1).  If hematology demonstrates CTCAE grade 3/4 cytopenias, increase 
frequency to daily monitoring as clinically appropriate.  Hematology assessments scheduled for the day of study drug dosing must be available and assessed for 
toxicity before dosing.  The sampling for hematology assessment can be drawn up to 24 hours prior to dosing. 
n. Serum chemistry performed at the indicated times by local laboratory:  sodium, potassium, calcium, chloride, creatinine, calculated creatinine clearance 
(Cockcroft-Gault), total bilirubin, albumin, alkaline phosphatase, CO2 or bicarbonate, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), glucose, blood urea nitrogen (BUN), total protein (TP), gamma-glutamyl transferase (GGT), and uric acid (Appendix 1). 
o. Coagulation performed at the indicated times by local laboratory:  partial thromboplastin time and prothrombin time (Appendix 1). 
p. Additional tests performed at Screening, on Day 15 of Cycle 1 and 2, and at End of Treatment:  thyroid stimulating hormone, lipase, amylase, free thyroxine (T4), 
creatine kinase, HLA typing (only at screening) and on Day 1 beginning from Cycle 4 (Appendix 1). 
q. Microscopy is required only to follow-up clinically significant urine dipstick findings.  List pH, specific gravity, protein, glucose, ketones, bilirubin, blood, and 
leukocyte esterase (Appendix 1). 
r. 
Serology tests include hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), and human immunodeficiency virus (HIV) antibody 
(Appendix 1). 
s. 
Unstained formalin-fixed, paraffin embedded, archival tumor tissue sections on slides are acceptable. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 26 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
t. 
One pre-treatment tumor tissue biopsy will be collected during screening (Cycle 1 Day 1 to 28 days).  If a pre-treatment biopsy was collected within 28 days, tumor 
sections can be provided.  One on-treatment tumor tissue biopsy will be collected at Week 3 (7 to 1 days prior to Cycle 2 Day 1).  An additional tumor tissue biopsy 
may be collected at the time of progression.  All tumor biopsies will be collected from the same non-target lesion, if feasible.  Exceptions will be made with Medical 
Monitor approval for tumors that are inaccessible. 
u. The screening immunogenicity sample should be drawn within 14 days prior to Day 1 Cycle 1.  No immunogenicity sample will be drawn at pre-dose on 
Cycle 1 Day 1.  Immunogenicity samples will be drawn at pre-dose on Cycle 2 Day 1, pre-dose on Day 1 of all odd-numbered cycles thereafter (e.g., Cycles 3, 5, 7, 
etc.), and at End-of-Treatment and Follow-up. 
v. Tumor assessment at screening then every 8 weeks (± 7 days) and End-of-Treatment (unless scan done within 4-weeks).  To ensure comparability, the baseline 
radiographs/scans and subsequent radiographs/scans to assess response should be performed using identical techniques.  In the event of a partial response (PR) or 
complete response (CR), confirmatory radiographic imaging should be completed at least 4 weeks from imaging showing a CR or PR.  If the subject discontinues 
treatment for a reason other than Progressive Disease, imaging will be conducted every 3 months until progressive disease is noted or start of new treatment. 
w. Any new or clinically significant changes in the subject’s medical and/or cancer history that occur immediately after the first dose of drug will be recorded as AEs.  
All AEs, including serious AEs (SAEs), will be recorded immediately after the first dose of study drug until 30 days after the last dose of study medication.  An SAE 
related to study procedures or study conduct must be reported to Nektar Therapeutics if it occurs prior to first dose of study drugs.  SAEs must be reported as 
described in Section 8.7 of the protocol.  Treatment-related AEs ongoing at the post-treatment visit should be followed to resolution or until the Investigator considers 
them “chronic” or “stable”.   
x. Biomarker sample will be drawn prior to dose on Day 1 and on Day 8 ± 3 days.  In addition, biomarker samples will be collected prior to dose on Day 1 of Cycle 3 
and all odd-numbered cycles thereafter (e.g., Cycles 3, 5, 7, etc.).  If the optional tumor biopsy at disease progression is collected, collect an additional biomarker 
sample at the same time.   
y. Blood samples (2 mL) for PK analyses will be collected in all cycles, with more intense sampling in Cycles 1 and 2.  PK sample times are as follows:  Cycle 1 and 
Cycle 2 Day 1:  predose, end of administration (EOA ± 2 min), 0.5 hr ± 5 min, 3 hr ± 10 min, 6 hr + 2 hr, and 2, 3, 4, 5, 8, 11, and 15 days postdose.  Cycle ≥3:  
predose, EOA (± 2 min), Day 8, and End of Treatment.  On Days 2 and 3 of Cycles 1 and 2, 4 mL of blood will be drawn instead of the usual 2 mL.  The blood draws 
should occur as close to 30 or 38 hours post dose as possible.   
z. 
In the event of a possible study-drug-related SAE throughout the study, additional PK blood samples may be drawn as close to the event as possible to help 
characterize any possible relationships between drug exposure and the clinical event.   
aa. Administer at least 2 liters of fluid (IV or self-administered orally [e.g., fluid containing electrolytes]) for Days 1 to 5 of every cycle.  Advise subjects to restrain from 
strenuous activity and avoid long hot showers and saunas for Days 1 to 5 of every cycle.  A Patient Wallet Card is available that contains important safety 
information. 
bb. Administer NKTR-214 at the subject’s assigned dose level as an intravenous infusion over 15 minutes ± 5 minutes. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 27 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Table 2: 
Schedule of Visits and Procedures Dose Expansion (Phase 2) 
Assessment Period 
Screening 
Cycle 1 and Cycle 2 
Cycle 3 and Beyond 
Post-Treatment 
Study Daysa 
Day 
 -28 to 1 
Day 1 Day 2 Day 3 Day 4 
Day 
5 
Day 
8 
Day 
11 
Day 
15 
Day 
22b 
Day 1 Day 8 
Day 
22b 
End of 
Treatment 
(+10 days) 
Follow-up 
3 mo 
Informed consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/cancer historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication historye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
 
 
 
 
X 
 
Xg 
X 
X 
X 
X 
X 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
ECGi 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
X 
X 
X 
X 
 
ECHOj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testk 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Hematologyl 
X 
X 
X 
X 
X 
X 
X 
 
Xg 
X 
X 
X 
X 
X 
 
Serum chemistrym 
X 
X 
 
 
X 
 
X 
 
Xg 
X 
X 
X 
X 
X 
 
Coagulationn 
X 
X 
 
 
X 
 
X 
 
Xg 
X 
X 
X 
X 
X 
 
Additional labso 
X 
 
 
 
 
 
 
 
Xg 
 
Xo 
 
 
X 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 28 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Table 2: 
Schedule of Visits and Procedures Dose Expansion (Phase 2) (Cont'd) 
Assessment Period 
Screening 
Cycle 1 and Cycle 2 
Cycle 3 and Beyond 
Post-Treatment 
Study Daysa 
Day 
-28 to 1 
Day 1 Day 2 Day 3 
Day 
4 
Day 
5 
Day 
8 
Day 
11 
Day 
15 
Day 
22b 
Day 1 Day 8 
Day 
22b 
End of 
Treatment 
(+10 days) 
Follow-up 
3 mo 
Urinalysis (dipstick)p 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Serologyq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissue 
collectionr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsy if accessibles 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Immunogenicity serum 
sample collection 
X 
Xt 
 
 
 
 
 
 
 
 
Xt 
 
 
X 
X 
Tumor assessmentu 
X 
 
 
 
 
 
 
 
 
 
Every 8 weeks (± 7d) 
X 
 
AEsv 
 
 
X 
 
Concomitant medications 
X 
 
X 
 
Biomarker blood sample 
collection 
 
Xw 
 
 
 
 
Xw 
 
 
 
Xw 
 
 
Xw 
 
Stool sample collection 
 
Xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood sampley,z 
 
X 
X 
X 
X 
X 
X 
X 
Xg 
 
X 
X 
 
X 
 
Administer fluids and advise 
patientsaa 
 
X 
X 
X 
X 
X 
 
 
 
 
Days 
1-5 
 
 
 
 
NKTR-214 administrationbb 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Quarterly follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 29 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Footnotes: 
a. 
The acceptable visit window is + 1 day for Day 11 and ±1 day for Day 8 and Day 15 and ± 7 days for the follow-up visit post-treatment.  Visits may be skipped or 
postponed if prospectively identified by the Investigator (e.g., national holidays, subject holidays).  If Day 4 visit is missed then Day 4 assessments must be done at 
the next in clinic visit.  All procedures and examinations should be performed before the administration of study drug(s), except as indicated below. 
b. Assessments only applicable if dosing cycle is changed to 28-day cycle. 
c. 
The Institutional Review Board (IRB)-approved informed consent form (ICF) must be signed before any study-specific procedures or examinations are performed. 
d. An event occurring after the subject has provided informed consent, but before the first dose of study treatment, will be collected as medical history unless the event 
is either new and attributed to protocol-mandated procedures by the Investigator OR there is a significant change in the rate of occurrence or an increase in the 
severity of the pre-existing condition which is judged to be clinically important and attributed to the protocol-mandated procedures by the Investigator.  Any new or 
clinically significant changes in the subject’s medical and/or cancer history that occur immediately after the first dose of drug will be recorded as AEs. 
e. 
Include prior cancer treatments:  previous immunotherapy, chemotherapy, targeted therapy, radiation, OTC medications, herbs and dietary supplements 
f. 
Physical examinations at screening/baseline, at day 1 of each cycle, and at end of treatment should be complete assessments (evaluate all major organ systems, 
including the following categories:  general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, extremities, integumentary, neurologic, 
and psychiatric).  Other examinations may be focused, at the discretion of the Investigator, to identify changes from baseline or evaluate changes based on the 
subject’s clinical symptoms. Weight is to be reported at each visit, height at screening/baseline visit only.   
g. Assessments not applicable if dosing cycle is changed to 14-day cycle. 
h. Vital signs include temperature, pulse, respiration, systolic and diastolic blood pressure, and oxygen saturation.  Monitor the subject for 1 hour postdosing and record 
vital signs at the end of the hour.  If a subject should experience a Grade ≥ 2 infusion reaction or hypotension during study visit subject may be monitored for 24 
hours. Per clinical judgment additional monitoring might be implemented. 
i. 
A 5-minute summary ECG will be performed for all subjects at screening and during the 5 minutes prior to the time points of predose, 0.5 hr ± 5 min., 3 hr ± 10 min, 
and 6 hr + 2 hr on Day 1 of Cycles 1 and 2 and on Days 2, 3, 4, 5, 8, 11, and 15 of Cycles 1 and 2.  A 5-minute summary ECG starting 5 minutes before the predose 
time point will be performed on Days 1 and 8 of Cycle 3 and beyond, including EOT.  Frequency of ECGs may be increased if clinically indicated.  Prior to 
performing ECGs, subjects should rest in the supine position for at least 5 minutes.  All ECGs should be taken prior to the PK draw. 
j. 
Stress echocardiogram (either exercise or nuclear) will be performed for all subjects within 60 days prior to Cycle 1 Day 1 and at End of Treatment to assess for 
cardiac function and left ventricular ejection fraction (LVEF).  At the discretion of the Investigator, patients who are unable to perform a stress echocardiogram may 
instead have a MUGA scan or TTE.  The same assessment method should be used for the same subject throughout the study. 
k. For women of childbearing potential, serum β-HCG pregnancy test is required at screening.  Urine or serum pregnancy tests to be performed on Day 1 of each 
subsequent cycle and EOT.  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 
3 months before signing the ICF. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 30 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
l. 
Hematology performed at the indicated times by a central laboratory:  red blood cell (RBC) count, hemoglobin (Hgb), hematocrit (Hct), mean corpuscular volume 
(MCV), platelet count, white blood cell (WBC) count, and WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) (Appendix 1).  If hematology demonstrates CTCAE grade 3/4 cytopenias, increase 
frequency to daily monitoring as clinically appropriate.  Hematology assessments scheduled for the day of study drug dosing must be available and assessed for 
toxicity before dosing.  The sampling for hematology assessment can be drawn up to 24 hours prior to dosing. 
m. Serum chemistry performed at the indicated times by a central laboratory:  sodium, potassium, calcium, chloride, creatinine, calculated creatinine clearance 
(Cockcroft-Gault), total bilirubin, albumin, alkaline phosphatase, CO2 or bicarbonate, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), glucose, blood urea nitrogen (BUN), total protein (TP), gamma-glutamyl transferase (GGT), and uric acid (Appendix 1). 
n. Coagulation performed at the indicated times by a central laboratory:  partial thromboplastin time and prothrombin time (Appendix 1). 
o. Additional tests performed at screening, on Day 15 of Cycle 1 and 2, and at End of Treatment:  thyroid stimulating hormone, lipase, amylase, free thyroxine (T4), 
creatine kinase, HLA typing (only at screening) and on Day 1 beginning from Cycle 4 (Appendix 1). 
p. Microscopy is required only to follow-up clinically significant urine dipstick findings. List pH, specific gravity, protein, glucose, ketones, bilirubin, blood, and 
leukocyte esterase (Appendix 1). 
q. Serology tests include hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), and human immunodeficiency virus (HIV) antibody 
(Appendix 1). 
r. 
Unstained formalin-fixed, paraffin embedded, archival tumor tissue sections on slides are acceptable. 
s. 
One pre-treatment tumor tissue biopsy will be collected during screening (Cycle 1 Day 1 − 28 days).  If a pre-treatment biopsy was collected within 28 days, tumor 
section can be provided.  One on-treatment tumor tissue biopsy will be collected at Week 3 (7 to 1 days prior to Cycle 2 Day 1).  An additional tumor tissue biopsy 
may be collected at the time of progression.  All tumor biopsies will be collected from the same non-target lesion, if feasible.  Twenty tumor biopsies will be 
collected. Exceptions will be made with Medical Monitor approval for tumors that are inaccessible. 
t. 
The screening immunogenicity sample should be drawn within 14 days prior to Cycle 1 Day 1.  No immunogenicity sample will be drawn at pre-dose on 
Cycle 1 Day 1.  Immunogenicity samples will be drawn at pre-dose on Cycle 2 Day 1, pre-dose on Day 1 of all odd-numbered cycles thereafter (e.g., Cycles 3, 5, 7, 
etc.), and at End-of-Treatment and Follow-up. 
u. Tumor assessment at screening then every 8 weeks (± 7 days) and End-of-Treatment (unless scan done within 4-weeks).  To ensure comparability, the baseline 
radiographs/scans and subsequent radiographs/scans to assess response should be performed using identical techniques.  In the event of a partial response (PR) or 
complete response (CR), confirmatory radiographic imaging should be completed at least 4 weeks from imaging showing a CR or PR.  If the subject discontinues 
treatment for a reason other than Progressive Disease, imaging will be conducted every 3 months until progressive disease is noted or start of new treatment. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 31 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
v. Any new or clinically significant changes in the subject’s medical and/or cancer history that occur immediately after the first dose of drug will be recorded as AEs.  
All AEs, including serious AEs (SAEs), will be recorded immediately after the first dose of study drug until 30 days after the last dose of study medication.  An SAE 
related to study procedures or study conduct must be reported to Nektar Therapeutics if it occurs prior to first dose of study drugs.  SAEs must be reported as 
described in Section 8.7 of the protocol.  Treatment-related AEs ongoing at the post-treatment visit should be followed to resolution or until the Investigator considers 
them “chronic” or “stable”.   
w. Biomarker sample drawn prior to dose on Day 1 and on Day 8 ± 3 days.  In addition, biomarker samples will be collected prior to dose on Day 1 of Cycle 3 and all 
odd-numbered cycles thereafter (e.g., Cycles 3, 5, 7, etc.).  If the optional tumor biopsy at disease progression is collected, collect an additional biomarker sample at 
the same time.   
x. Stool sample to be collected prior to Cycle 1 Day 1.   
y. Blood samples (2 mL) for PK analyses will be collected in all cycles, with more intense sampling in Cycles 1 and 2.  PK sample times are as follows:  Cycles 1 and 2 
Day 1:  predose, end of administration (EOA ± 2 min), 0.5 hr ± 5 min, 3 hr ± 10 min, 6 hr + 2 hr, and 2, 3, 4, 5, 8, 11, and 15 days postdose. Cycle ≥ 3:  predose, 
EOA ± 5 mins, Day 8 and End of Treatment.   
z. 
In the event of a possible study drug-related SAE throughout the study, additional PK blood samples will be drawn as close to the event as possible to help 
characterize any possible relationships between drug exposure and the clinical event.   
aa. Administer at least 2 liters of fluid (IV or self-administered orally [e.g., fluid containing electrolytes]) for Days 1 to 5 of every cycle.  Advise subjects to restrain from 
strenuous activity and avoid long hot showers and saunas for Days 1 to 5 of every cycle.  A Patient Wallet Card is available that contains important safety 
information.   
bb. Administer NKTR-214 at the subject’s assigned dose level as an intravenous infusion over 15 min ± 5 min. 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 32 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
2.0 
INTRODUCTION 
 
Background 
2.1
Activating the immune system has the potential to produce durable responses in human cancers 
(Hodi, 2010).  Recent attention in immunotherapy has focused on immune activation using 
checkpoint inhibitor antibodies (Topalian, 2014; Robert, 2014).  However, direct immune 
stimulation using cytokines can also drive immune-mediated cancer cures (Hanzly, 2014).  
Aldesleukin directly stimulates the immune system and has been shown to lead to durable 
responses in ~10% of people with metastatic melanoma and renal cancer (Payne, 2014).  
However, in addition to aldesleukin acting as a stimulator of the immune system by activating 
tumor killing CD8+ T cells (CD8T), it also suppresses the immune system by activating 
regulatory T (Treg) cells (Boyman, 2012).  Despite favorable clinical outcomes associated with 
aldesleukin, it has several therapeutic limitations including the need for inpatient hospital 
administration, 5 consecutive days of dosing, and the potential for serious toxicities, comprising 
capillary leak syndrome, hypotension and pulmonary edema requiring medical management in 
the intensive care unit.   
A novel cytokine with optimized immune system activation and the targeted profile of 
NKTR-214 (i.e., a superior safety profile allowing for outpatient administration and a longer 
duration of action requiring less frequent dosing) would potentially be an important advancement 
for the treatment of patients with cancer.  NKTR-214 consists of IL-2, which has the same amino 
acid sequence as aldesleukin, conjugated at a defined region within the protein to releasable 
polyethylene glycol (PEG) chains.  The PEG chains render the molecule inactive.  After 
administration in vivo, the PEG chains are slowly hydrolyzed to generate active cytokine 
conjugates.  The most active IL-2 conjugates are the 2-PEG-IL2 and 1-PEG-IL2.  Presumably, 
the location of the PEG chains on the active conjugated-IL-2 reduces the affinity to the IL2 
receptor alpha subunit (IL2Rα), responsible for activating the undesirable Treg cells to a greater 
extent than the affinity to the IL-2-receptor beta subunit (IL2Rβ) relative to aldesleukin.  In the 
tumor, NKTR-214 preferentially activates CD8+ T cells over Tregs.  In addition, NKTR-214 
provides sustained exposure to active 1-PEG and 2-PEG-IL2 in tumor. 
 
Pre-clinical Data 
2.2
2.2.1 
Pharmacology 
Pharmacology studies investigated the mechanism of action, as well as in vitro and in vivo 
activity of NKTR-214 using cell lines and syngeneic tumor models.  After administration in vivo, 
PEG is slowly hydrolyzed from NKTR-214 to generate active conjugated IL-2 forms, 
2-PEG-IL-2 and1-PEG-IL-2.  Presumably, the location of the PEG chains on IL-2 interferes with 
the interaction to the receptor that activates the undesirable Treg cells in the tumor 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 33 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
(Charych, 2013a).  As such, this receptor bias markedly increases the ratio of tumor killing CD8 
T cells to Treg cells in tumors (to > 400) (Charych, 2013b).  At the same time, the active 
conjugated IL-2 species released from NKTR-214 have different pharmacokinetic properties 
compared to aldesleukin, leading to a sustained and higher exposure in the tumor compared to an 
equivalent dose of aldesleukin (Hoch, 2013).  NKTR-214, as a single agent, showed marked 
tumor growth suppression in the B16F10 mouse melanoma model, requiring a 10-fold lower 
cytokine equivalent dose that is administered once every 9 days, compared to twice daily dosing 
required for aldesleukin.  The combinatorial immunity mediated by NKTR-214 induced 
CD8+ T cell activation and checkpoint blockade (anti-CTLA-4 and anti-PD-1) was synergistic, 
producing durable responses in multiple murine models of human cancer.  Rechallenge and 
immune cell depletion studies assessing the anti-tumor activity induced by NKTR-214 combined 
with anti-CTLA-4 in the EMT6 murine breast tumor model demonstrated synergistic efficacy 
that was specific, durable, and dependent on both CD8T and NK cells.  In all nonclinical species 
tested, NKTR-214 resulted in stimulation of several markers of immune system activation, in 
particular lymphocyte counts and sCD25.   
2.2.2 
Pharmacokinetics 
Pharmacokinetic data in mice, rats, and monkeys demonstrated that a single dose of NKTR-214 
provides sustained exposure to active conjugated IL-2 metabolites in both plasma and tumor. 
Exposure to NKTR-214 and active metabolites was consistent across nonclinical animal species.  
Active 2-PEG-IL-2 and 1-PEG-IL-2 are released gradually over 24 to 48 hours and decline in 
parallel to NKTR-214, at half-lives between 15-20 hours.  No differences were observed 
between male and female animals, and accumulation was less than 2-fold after repeat 
administrations every 14 days.  The NKTR-214 PK/ADME profile of gradual formation of and 
sustained tumor exposure to active 2-PEG-IL-2 and 1-PEG-IL-2 appears responsible for 
improved safety profile and antitumor activity in animals.   
2.2.3 
Toxicology 
The safety of NKTR-214 was evaluated in rats and cynomolgus monkeys for up to 6 weeks of 
every 14 day (q14d) administration (q14dx3).  A PEG control was included in the rat GLP 
toxicity study.  Biomarkers of NKTR-214 immune stimulation (peripheral lymphocyte counts 
and plasma sCD25 levels) were included in these studies.  In addition, cardiovascular safety was 
evaluated in a telemetry study in cynomolgus monkeys.  The monkey was identified as the most 
sensitive species (see Table 3).  In addition, NKTR-214 binding affinity to the IL-2 receptor and 
T-cell activation was comparable in vitro between human cell lines and the cynomolgus monkey 
cell lines.  Clinical observations in the monkey after each NKTR-214 dose included transient 
(and reversible) hypoactivity, decreased appetite, emesis, diarrhea, decreased fecal output, and 
hunched posture on Days 2-9 after each dose.  Findings consistent with systemic immune 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 34 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
stimulation included transient and dose-related increased white blood cell (WBC) counts, largely 
due to the increase in lymphocytes, and an increase in sCD25 that were observed 5 to 7 days post 
each NKTR-214 dose, all of which returned to baseline 14 days postdose.  Noteworthy 
histopathology findings in the monkey were minimal to mild inflammation in multiple organs 
(including liver, heart, and kidney), hematopoiesis in bone marrow, and hypercellularity in the 
thymus and spleen.  These histopathologic changes partially or in some cases completely 
resolved on recovery (6 weeks post last dose).  Of note, no evidence of cardiovascular effects 
such as ECG abnormalities, hypotension, pulmonary edema or vascular leak were found in the 
monkey at the NKTR-214 maximum tolerated dose (MTD) of 0.1 mg/kg in contrast to the 
reports of vascular leak at the MTD for aldesleukin (Anderson, 1993).  The MTD of NKTR-214 
was determined as 0.3 mg/kg in rats and 0.1 mg/kg in monkeys.  Detailed descriptions of these 
studies and their results can be found in the NKTR-214 Investigator’s Brochure.   
 
Starting Dose Rationale 
2.3
The planned Phase 1 NKTR-214 starting dose of 0.003 mg/kg is 1/10th of the cynomolgus 
monkey MTD (0.1 mg/kg) that has been corrected for body surface area.  A dose of 0.003 mg/kg 
is expected to be active in humans since it is the lowest dose tested in the monkey toxicology 
study at which increases in both sCD25 (10-fold) and lymphocyte counts (2-fold) were observed.  
A dosing schedule of q21d was chosen for the first in human study based on the histopathologic 
changes (inflammatory cell infiltrates) in monkeys 14 days after administration of the last q14d 
NKTR-214 dose that almost completely resolved with an additional 4 weeks of recovery 
(6 weeks following the last dose).  Table 3 shows the safety margins for the proposed clinical 
starting dose of NKTR-214. 
Table 3: 
Safety Margins for the Proposed Clinical Dose of NKTR-214 
Toxicity 
Study 
Animal MTD 
(mg/kg) 
HED 
(mg/kg)a 
Safety 
Margin 
Phase 1 Starting Dose 
(mg/kg) 
6-week Rat (q14dx3) 
0.3 
0.05 
17 
0.003 
6-week Monkey (q14dx3) 
0.1 
0.03 
10 
a. 
HED (Human Equivalent Dose) = (dose in animals)/(conversion factor). Conversion factor = 3.1 for monkeys 
and 6.2 for rats, based on body surface area differences per “FDA Guidance for Industry:  Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.” All 
NKTR-214 dose levels are expressed in IL-2 equivalents. 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 35 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
3.0 
STUDY OBJECTIVES 
 
Primary Objective 
3.1
The primary objectives are: 
 To evaluate the safety and tolerability, and define the MTD of NKTR-214. 
 To evaluate the efficacy of NKTR-214 by assessing the objective response rate (ORR) at the 
MTD or the dose below the MTD. 
 
Secondary Objectives 
3.2
The secondary objectives are: 
 To evaluate the efficacy of NKTR-214 by assessing best overall response (BOR), 
duration of response (DOR), clinical benefit rate (CBR), 
time to response (
 
 To characterize the pharmacokinetic (PK) profile of NKTR-214 and relevant metabolites. 
 To assess the immunogenicity of NKTR-214. 
 
Exploratory Objectives 
3.3
The exploratory objectives are: 
 To assess the immunologic effect of NKTR-214 in tumor tissue on tumor-infiltrating 
lymphocytes (TIL). 
 To assess the immunologic effects of NKTR-214 in blood, including effects on cytokines, 
NK cells, T-cells, and other serum proteins and immune modulators. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 36 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
4.0 
STUDY DESIGN 
 
Summary of Study Design 
4.1
This study is a multicenter Phase 1/2, open-label, dose escalation and dose expansion study of 
NKTR-214 in subjects with histologically confirmed locally advanced or metastatic solid tumors 
who have measurable disease.  The study will be conducted in 3 parts (Part 1 Dose Escalation 
followed by Part 2 Dose Expansion). 
4.1.1 
Screening 
Up to 28 days. 
4.1.2 
Open-label Treatment 
4.1.2.1 
Part 1:  Dose Escalation 
Subjects will be enrolled in groups of at least 3 subjects in each cohort during the dose escalation 
phase. 
The first dose to be studied will be 0.003 mg/kg administered as an IV infusion over 15 
(± 5) minutes every 21 days (q21d).  Dose escalation will be carried out as listed in Table 5.  
Dose levels for a given cohort, as listed in Table 4, may be reduced by 25-50% depending on the 
severity, duration and frequency of toxicities as well as the PK profile, if available, observed at 
the previous dose level.  A subject’s dose level may not be escalated once assigned. 
For each dose level, the first subject enrolled will be dosed on Cycle 1 Day 1 and monitored for 
safety and tolerability on Cycle 1, Days 1 through 5, before additional subjects are dosed. 
In situations where a cohort of 3 subjects has been enrolled and additional subjects in screening 
have been deemed eligible for the study, these additional eligible subjects may be enrolled to the 
cohort. In the event of more than 3 subjects being enrolled to a cohort, the dose escalation 
decision will be made when the first 3 subjects in the cohort have completed their first cycle 
(i.e. completion of cycle or occurrence of a dose-limiting toxicity [DLT]).  Moreover, the cohort 
safety review committee or Sponsor may determine that inadequate information has been 
obtained in a cohort of 3 subjects and to further understand the benefit/risk profile at a given 
dose level, additional subjects may be enrolled.   
Additional subjects may be enrolled at other doses and frequencies deemed to be safe to more 
fully explore the safety, tolerability, pharmacokinetics, biomarker assessments, and preliminary 
efficacy of NKTR-214.  These additional cohorts of up to 12 subjects may be enrolled to further 
evaluate NKTR-214 at the recommended phase 2 dose or at doses at or below the MTD.  

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 37 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
During dose escalation, subjects who are withdrawn from the study during Cycle 1 for reasons 
other than occurrence of a DLT will be replaced. 
A DLT is defined as a Grade 3 or higher study drug-related or possibly related AE occurring 
within the first cycle of dosing (excluding Grade 3/4 transient lymphopenia < 14 days in 
duration, tumor flare defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor, a transient, reversible ≤ grade 3 infusion AE [< 24 hours], non-clinically 
significant laboratory abnormalities, or fatigue lasting less than 72 hours) using National Cancer 
Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 4.03. 
All drug related AEs after Cycle 1 will continue to be collected and evaluated by the 
Investigators and the Sponsor on an ongoing basis and may be taken into consideration in 
determining the MTD. 
Dose Escalation Scheme 
For each dose level, the first subject enrolled to the dose cohort will be treated and monitored 
from Cycle 1, Day 1 through Cycle 1, Day 5 for tolerance prior to the dosing of additional 
subjects at that dose level.  The first subject enrolled to the study will be administered 
NKTR-214 at the first dose level of 0.003 mg/kg (Table 4).  Enrollment into the next cohort 
cannot begin until a full cycle has elapsed since the last subject’s first dose in the previous 
cohort. If no DLTs occur in a cohort of 3 subjects, a new cohort of 3 subjects will be treated at 
the next higher dose level (Table 5).  If only 1 of 3 subjects in a cohort experiences a DLT, that 
cohort will be expanded to 6 subjects.  If only 1 of the 6 subjects experiences a DLT, then the 
next cohort of 3 subjects will be treated at the next higher dose level.  If 2 or more subjects 
within a cohort experience DLTs, then that dose level will be above the MTD (the highest dose 
tested where no more than 1 of 6 subjects has experienced a DLT), and new subjects will be 
enrolled at the previous lower (tolerated) dose level until that cohort has 6 subjects.  A subject 
who is withdrawn from the study during Cycle 1 for reasons other than a DLT will be replaced.  
Approximately 50 subjects will be enrolled into the dose escalation phase of the study. 
Table 4: 
Part 1:  Sample Dose Escalation Scheme 
Cohort 
NKTR -214 Dose 
Cohort 1 
0.003 mg/kg 
Cohort 2 
0.006 mg/kg 
Cohort 3 
0.012 mg/kg 
 
 
 
 
 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 38 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
The Sponsor and at least one Investigator will jointly decide the following: 
 Dose levels for a given cohort, as listed in Table 4, may be reduced by 25-50% depending on 
the severity, duration, and frequency of toxicities observed at the previous dose level as well 
as the PK profile, if available. 
 In the event that MTD is not determined at the highest dose level listed in the table, dose 
escalation at no more than 100% higher than previous dose may continue. 
 The schedule of dosing can be modified to every 14 or 28 days based on a review of the 
safety data and available PK data. 
– Note, the first dose level for every 14-day cohort will be determined as follows: 
If MTD has been reached in the 21-day dosing cohort, the dosing level will be at least 
one dose lower than MTD.  If MTD has not been reached in the 21-day dosing cohort, the 
dosing level will be at least one dose lower than the highest dosing cohort tested in the 
21-day dosing cohort. 
– The first dose level for every 28-day cohort will be either the MTD using the 21-day 
dosing cohort (if determined) or the highest dosing cohort tested in the 21-day dosing 
cohort (if MTD not determined). 
 Once the MAD has been reached, lower doses and different dose schedules may be assessed, 
within the anticipated total number of subjects of approximately 50. 
Table 5: 
Dose Escalation Rules 
Number of Subjects with 
DLT at a Given Dose Level 
Dose Escalation Decision Rule 
0 out of 3 
Enter 3 subjects at the next higher dose level. 
1 out of 3 
Will enter at least 3 more subjects at this dose level.  If 0 of these additional 
3 subjects experience a DLT, will proceed to the next dose level.  If 1 or more of this 
group suffers a DLT, then the dose escalation is stopped, and this dose is declared 
the MAD.  Three (3) additional subjects will be entered at a lower dose level if only 
3 subjects were treated previously at that dose. 
≥ 2 
Dose escalation will be stopped.  This dose level will be declared the MAD (highest 
dose administered).  Three (3) additional subjects will be entered at a lower dose 
level if only 3 subjects were treated previously at that dose. 
≤ 1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD.  At least 6 subjects must be entered at the recommended dose for 
the phase 2 recommended dose.  

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 39 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
4.1.2.2 
Part 2:  Dose Expansion Scheme 
At least 1 study Investigator and the Sponsor Medical Monitor will meet and decide the dose to 
be studied in Part 2 before the initiation of the dose expansion cohort (either the MTD dose or 
dose lower than MTD).  This dose will be the recommended Phase 2 dose (RP2D), and all 
subjects in the expansion cohort will receive this dose.  The RP2D may also be determined based 
on a biological effect of the study drug as determined by anti-tumor activity and immune 
activation.  The RP2D for dose expansion will be communicated via an administrative dosing 
letter and enrollment in the expansion phase may begin without a protocol amendment. 
Approximately 50 subjects with renal cell carcinoma (RCC) will be enrolled into Part 2.  
Subjects in the expansion cohort will be treated until tumor progression (treatment may continue 
if there is clinical benefit), death, unacceptable toxicity, symptomatic deterioration, achievement 
of maximal response, subject choice, the Investigator’s decision to discontinue treatment, the 
subject withdraws consent, or Nektar Therapeutics decides to terminate the trial. 
Note:  The sponsor reserves the right to evaluate two doses or two dosing schedules in each 
expansion cohort if necessary based on the safety profile during the dose escalation portion. 
4.1.3 
Tumor Assessments 
Tumor response assessments for all subjects will occur every 8 weeks (± 7 days) (see 
Section 9.0).  Tumor response will be evaluated using Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1.  Subjects with progressive disease (PD) but with otherwise stable 
or improved performance and clinical status may continue to be treated with study drug in the 
event of a perceived benefit per Investigator (e.g., non-availability of alternate standard of care 
therapies).  Subjects with a partial response (PR) or stable disease (SD) will continue to receive 
NKTR-214 until achievement of a confirmed complete response (CR), disease progression, or 
intolerability to therapy.  It is at the discretion of the Investigator to continue treating subjects 
with a confirmed CR.   
4.1.4 
Post-treatment 
Subjects who discontinue NKTR-214 due to reasons other than radiographic disease progression 
will continue radiologic tumor assessments every 3 months until disease progression per 
RECIST v1.1 or start of subsequent anti-cancer therapy.  Subjects will also be contacted for 
survival every 3 months until death, withdrawal of consent, study termination by the Sponsor, 
lost to follow-up, or for a maximum of 3 years after Cycle 1 Day 1.   
A schematic of the study design is presented in Section 1.1 and the Schedule of Assessments for 
the Dose Escalation and Dose Expansion cohorts is in Section 1.2.   

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 40 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
5.0 
SELECTION OF STUDY POPULATION 
 
Inclusion Criteria 
5.1
For Parts 1 and 2 
1. Willing and able to provide written informed consent. 
2. Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy 
such as surgical resection) or metastatic solid tumor. 
3. Male or female patients, age 18 years or older at the time of signing the informed consent 
form (ICF) 
4. Life expectancy >12 weeks. 
5. Patients must not have received interleukin-2 [IL-2] therapy within 12 months of 
Cycle 1 Day 1. 
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. 
7. Measurable disease per RECIST v1.1 
8. Sample of archival tumor tissue and fresh baseline tumor biopsies (fresh baseline biopsy is 
defined as a biopsy specimen taken within 28 days prior to Cycle 1, Day 1) are required, 
except if inaccessible with Medical Monitor approval.  Subjects must consent to allow 
acquisition of existing formalin-fixed paraffin-embedded (FFPE) material, either a block or 
unstained slides for performance of correlative studies. 
9. Demonstrated adequate organ function, as defined below, within 14 days of treatment 
initiation: 
a. WBC count ≥ 2000/μL (after at least 7 days without growth factor support or transfusion) 
b. Absolute neutrophil count (ANC) ≥ 1500/μL (after at least 7 days without growth factor 
support or transfusion) 
c. Platelet count ≥ 100x 103/μL (transfusions allowed) 
d. Hemoglobin ≥ 9.0 g/dL (transfusions allowed) 
e. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 mL/min) 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 41 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
f. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3X upper limit of 
normal (ULN) 
g. Total bilirubin within normal limits unless associated with hepatobiliary metastases or 
Gilbert’s syndrome, in that case total bilirubin ≤ 2x ULN 
10. On stress echocardiogram, documented left ventricular ejection fraction >45% on cardiac 
stress test within 60 days prior to Cycle 1 Day 1.  At the discretion of the Investigator, 
patients who are unable to perform a stress echocardiogram may instead have a multigated 
acquisition (MUGA) scan or transthoracic echocardiogram (TTE). 
11. Oxygen saturation ≥ 92% on room air. NSCLC patients may use supplemental oxygen. 
12. Clinically significant toxic effect(s) of the most recent prior chemotherapy must be resolved 
to Grade 1 or less (except alopecia and sensory neuropathy).  Immune-related AEs from 
previous therapy must be resolved to Grade 0 (except for endocrinopathies, or rash, which 
can be Grade 1).  If the subject received major surgery or radiation therapy of > 30 Gy, they 
must have recovered from the toxicity and/or complications from the intervention. 
13. Women of childbearing potential must agree to use highly effective methods of birth control 
(defined as those, alone or in combination, that result in a low failure rate [i.e., < 1% per 
year] when used consistently and correctly, such as oral contraceptives, surgical sterilization, 
an intrauterine device, and/or 2-barrier methods [e.g., condom and cervical barrier such as a 
diaphragm]).  Protections against pregnancy must be continued for at least 3 months after the 
last dose of study drug.  All subjects must agree to use double-barrier contraception during 
participation in this study and for at least 3 months after the last dose of study drug.  This 
criterion may be waived for male subjects who have had a vasectomy > 6 months before 
signing ICF. 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 42 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
e. Clinically asymptomatic in screening. 
15. For expansion cohort only: 
Renal Cell Carcinoma (RCC) 
a. Histologically confirmed diagnosis of unresectable or metastatic RCC with 
predominantly clear cell elements 
b. Must have received only 1 prior line of anti-angiogenic therapy.   
c. Must not have received prior immunotherapy with immune-modulators including but not 
limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody 
and any other antibody or drug specifically targeting T cell co-stimulation or checkpoint 
pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive 
cell therapies, and cytokine therapies. 
 
Exclusion Criteria 
5.2
1. Use of an investigational agent or an investigational device within 28 days before 
administration of first dose of NKTR-214. 
2. Females who are pregnant or breastfeeding. 
3. Subjects who have an active autoimmune disease requiring systemic treatment within the 
past 3 months or a documented history of clinically severe autoimmune disease that requires 
systemic steroids or immunosuppressive agents.  (Exceptions include any subject on 10 mg 
or less of prednisone or equivalent, subjects with vitiligo, hypothyroidism stable on hormone 
replacement, Type I diabetes, Graves' disease, Hashimoto's disease, alopecia areata, eczema, 
or with Medical Monitor approval.) 
4. History of organ transplant that requires use of immune suppressive agents. 
5. Use of warfarin within 14 days of initiating NKTR-214. (Note:  Low molecular weight 
heparin is allowed on the study). 
6. Evidence of clinically significant interstitial lung disease or active, noninfectious 
pneumonitis. 
7. Active central nervous system (CNS) metastases. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 43 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
8. Prior surgery or radiotherapy within 14 days of therapy.  Subjects must have recovered from 
all radiation-related toxicities, not required corticosteroids and have not had radiation 
pneumonitis. 
9. Subjects who have had < 28 days since the last chemotherapy, immunotherapy, biological 
therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, 
sorafenib, vemurafenib, dabrafenib, cobimetinib), or systemic or inhaled steroid therapy at 
doses greater than 10mg of prednisone or equivalent before administration of the first dose of 
study medication. 
10. Active infection requiring systemic therapy. 
11. Has known hepatitis B virus (HBV) infection (e.g. HBsAg reactive) or hepatitis C virus 
(HCV) e.g., HCV RNA qualitative is detected). 
12. Has known immunodeficiency or active human immunodeficiency virus (HIV 1/2 
antibodies). 
13. Prolonged QTcF >450 milliseconds (ms) for men and >470 ms for women at Screening 
14. History of unstable or deteriorating cardiac disease within the previous 6 months prior to 
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 
15. Need for > 2 antihypertensive medications for management of hypertension. 
16. Known current drug or alcohol abuse. 
17. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of 
the Investigator, would preclude the subject from adhering to the protocol. 
 
Removal of Subjects from Study Therapy or Assessment 
5.3
Subjects may choose to discontinue the trial at any time, for any reason, and without prejudice to 
further treatment. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 44 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Subjects may stop participating in or be withdrawn from the study for any of the following 
reasons, but are to be followed according to the procedures section for progression of disease and 
for safety until resolution or permanent sequelae of all toxicities attributable to the study drug. 
 Subject has progressive disease, 
 Occurrence of a clinically significant AE found to be unacceptable by the Investigator; 
 Subjects who need more than 6 weeks to recover from treatment-related toxicities; 
 Symptomatic deterioration, 
 Achievement of maximal response, 
 Noncompliance of the subject with protocol-mandated procedures based on agreement of 
both the Investigator and Sponsor; 
 Continued participation is no longer in the subject’s best interest in the opinion of the 
Investigator; 
 If a female subject becomes pregnant, administration of the study drug must be discontinued 
immediately; 
 Withdrawal of Consent; 
 The study is terminated by the Sponsor. 
In the event of a subject’s withdrawal, the Investigator will promptly notify the Sponsor and 
make every effort to complete the Early Termination assessments specified in the Schedule of 
Assessments (Section 1.2). 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 45 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
6.0 
TREATMENT PLAN (DOSE ESCALATION AND DOSE EXPANSION) 
 
Overview 
6.1
The study has a screening period, treatment period and post-treatment period.  All procedures are 
outlined in the Schedule of Assessments (Section 1.2). 
 
Screening Period 
6.2
Subjects will provide written informed consent to participate in the study before completing any 
protocol-specified procedures or evaluations not considered to part of the subject’s normal care.  
After signing the ICF subjects will be evaluated for entry criteria during the Screening period 
within 28 days before administration of study drug. 
 
Treatment Period 
6.3
Subjects who meet the selection criteria may start NKTR-214 treatment within 28 days following 
the Screening visit.  The treatment period of the study is divided into multiple 21-day cycles with 
associated evaluations and procedures.  Results of the assessments must be reviewed and 
documented before administering the first dose of the next cycle.  No subject will be permitted 
escalation of dose level after assignment to a specific NKTR-214 dose level.  Dose reductions 
after Cycle 1 due to AEs may occur following a discussion with the site Investigator and Medical 
Monitor.  Every effort should be made to schedule visits within the protocol-specified windows. 
For each dose level in Part 1, the first subject enrolled into a given dose cohort will be treated 
and monitored from Cycle 1, Day 1 through Cycle 1, Day 5 for safety and tolerability prior to 
dosing of additional subjects at that dose level. 
Cycle 1, Day 1 will be the first day of treatment with NKTR-214 and Cycle 2, Day 1 will be the 
first day of the second dose of NKTR-214. Results from Day 1 laboratory evaluations must meet 
eligibility criteria prior to Cycle 1, Day 1 dosing. 
During dose escalation, subjects who drop out prior to completion of Cycle 1 will be replaced 
unless the subject discontinued due to a DLT.  During dose expansion, subjects will not be 
replaced. 
Subjects will be treated until unacceptable toxicity, or disease progression per RECIST 
version 1.1.  In the presence of disease progression, treatment may continue if there is clinical 
benefit as determined by the Investigator based on a reduction of symptoms related to cancer and 
absence of clinical deterioration or decline in ECOG performance status. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 46 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Note:  Dosing may change to q14d or q28d following review and agreement by the Sponsor and 
Investigators.  The change in cycle length will be determined by review of safety data and PK 
review of study drug. 
After completing the pre-dosing procedures, administer NKTR-214 as an IV infusion over 
15 ± 5 minutes (Section 6.11). 
Postdosing: 
 The study site must be equipped for medical emergencies and have access to an intensive 
care unit. 
 During dosing days, subject will stay in clinic for observation approximately 1 hour after 
dosing. 
 Administer at least 2 liters of fluid (IV or self-administered orally [e.g., fluid containing 
electrolytes]) during Days 1 to 5 of every cycle. 
 Advise subjects to restrain from strenuous activity and avoid long hot showers and saunas for 
Days 1 to 5 of every cycle (Parts 1 and 2, dose escalation and expansion). 
 Should a subject experience hypotension at any time during a cycle, IV fluid administration 
has been effective.  Subjects with adrenal insufficiency requiring corticosteroid 
supplementation may benefit from additional short term corticosteroid use of up to 5mg/day 
of prednisone for the management of hypotension.  Vasopressors may also be used for 
hypotension. 
 A Patient Wallet Card is available that contains important safety information. 
Vital Signs 
Vital signs (temperature, pulse, respiration, systolic and diastolic blood pressure, and oxygen 
saturation), concomitant medications, and potential AEs will be assessed either at the study site 
or as a Home Health visit as needed.  Qualified home health personnel may visit the subject to 
take vital sign measurements.  The results of these measurements will be provided to the 
Investigator or designee.  The Investigator will be responsible for assessing any adverse events 
and for following up with the subject.   
 
Radiographic Assessments 
6.4
Radiographic assessments (chest/abdomen/pelvis) by computed tomography (CT) scan or 
magnetic resonance imaging (MRI) are required for all subjects for tumor measurements. CT 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 47 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
scans or MRIs will be performed, target lesions measured, and tumor response evaluation 
completed at Screening (within 28 days prior to Cycle 1 Day 1) and every 8 weeks (± 7 days) 
from Cycle 1 Day 1 while on study treatment, until PD is noted (even if subject has stopped 
treatment with study drug) or the subject withdraws consent. 
The same method of assessment (CT or MRI) and the same technique for acquisition of images 
must be used for all study assessments.  Baseline imaging should be done at the same 
institution/facility which will be used to measure response during the subject’s participation in 
the study.  Radiographic assessments will also be conducted by an independent central imaging 
core laboratory for all dose escalation and dose expansion cohorts.  There must at least one 
measurable solid tumor by RECIST version 1.1 present on the Screening scan. 
 
Post-treatment Period 
6.5
The EOT/Early Termination visit is to occur within 30 days (+ 10 days) after last dose of study 
drug. 
Subjects who reach the EOT visit without radiographic disease progression must continue to 
undergo immunogenicity testing and radiological assessment at the interval of every 3 months 
(±7 days) until either disease progression per RECIST version 1.1 or the start of a new 
anti-cancer therapy.  Subjects will also be followed every 3 months (±7 days) for survival until 
death, lost to follow-up, study termination by Sponsor, or 3 years have passed since the subject’s 
first dose. 
For any toxicity the Investigator attributed to study drug, the Investigator will assess the subject 
to determine whether the toxicity resolved or worsened.  Information on whether the toxicity 
resolved or worsened must be entered into the eCRF. 
 
Pharmacokinetic Measurements 
6.6
Blood samples for pharmacokinetic analysis will be collected and processed as outlined in a 
Laboratory Manual that will be provided to the site.  Briefly, at each designated sampling time, 
using Sponsor-provided kits, collect 2 mL or 4 mL whole blood into tubes; centrifuge to obtain 
plasma. Aliquot plasma in plasma storage tubes, freeze, and ship as outlined in the Laboratory 
Manual. 
For all PK blood samples, the date and actual time collected must be recorded. For subjects 
whose only peripheral access is via a venous access device or peripherally inserted central 
catheter, refer to the Laboratory Manual for the proper technique to ensure undiluted whole 
blood for PK assessments. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 48 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Immunogenicity Measurements 
6.7
Serum samples will be collected and processed as outlined in the Laboratory Manual that will be 
provided to the site.  Briefly, at each designated time point, collect 5-10 mL of blood into serum 
collection tube, harvest serum, freeze, and ship as outlined in the Laboratory Manual. 
 
Biomarker Measurements 
6.8
Blood and tumor tissue biopsies will be collected and processed as outlined in the Laboratory 
Manual that will be provided to the site.  Briefly, for blood biopsies, at each designated time 
point, collect 4x10 mL of blood into green-topped blood collection tubes and 1x10 mL of blood 
into red-topped blood collection tubes.  For optional blood biopsies at time of optional tumor 
biopsies, collect 1x10 mL of blood into green-topped blood collection tube.  For tumor biopsies, 
collect core biopsies or biopsies with a volume ≥ 100 mm3, and divide into 3 portions.  One 
portion will be FFPE for immunohistochemistry (IHC) analysis, one portion will be used for 
RNA isolation and molecular characterization, and one portion will be used to analyze TILs 
using flow cytometry.  Refer to the Laboratory Manual for specific instructions on sample 
processing, storage, and shipping. 
6.8.1 
Biomarker Blood Collection Times and Assessments 
Blood for biomarker analysis will be collected as described in the Schedule of Assessments 
(Section 1.2).  The whole blood correlative pharmacodynamic samples will be analyzed by flow 
cytometry for changes in markers of immune cell populations, including, but not limited to, 
markers for immune cell populations (T lymphocytes, B lymphocytes, natural killer cells, 
monocytes, memory T cell subsets, Tregs, and T-cell activation).  In addition, whole blood 
samples will be obtained for evaluation in assays of immune function such as stimulated cell 
activation (assessed by marker expression, cytokine secretion, proliferation, etc.), isolation of 
peripheral blood mononuclear cells to assess immunodiversity, and miRNA/mRNA analysis, and 
genetic profiling. 
6.8.2 
Tumor Tissue Biopsy Collection Times and Assessments 
Archival tumor samples and fresh tumor biopsies (defined as a biopsy specimen taken within 
28 days prior to the first dose of study treatment) will be required at baseline.  For archival 
unstained tumor samples, a minimum of 10 slides must be submitted (no more than 30 days after 
first dose).  Exceptions may be made with Medical Monitor approval in cases where fresh tumor 
tissue and/or archival tumor samples are inaccessible.  A biopsy specimen from a sample taken 
since completion of the most recent prior systemic treatment may be acceptable in lieu of a fresh 
biopsy with medical monitor approval.  Tumor biopsy collection is described in the Schedule of 
Assessments (Section 1.2).  Exceptions will be made with Medical Monitor approval in cases 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 49 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
where tumor tissue is inaccessible.  Only 20 tumor biopsies will be collected in Part 2.  Biopsies 
should be performed on lesions that have not been exposed to prior radiation.  Tumor lesions 
used for biopsy should not be lesions used as target lesions, unless there are no other lesions 
suitable for biopsy.  If a target lesion is used for biopsy, the lesion must be ≥ 2 cm in the longest 
diameter.  Pre- and post-treatment tumor tissue biopsies should be taken from the same lesion, if 
feasible.  Tumor tissue biopsies will be used for characterization of infiltrating immune cell 
populations using a panel of markers (including, but not limited to CD3, CD4, CD8, CD25, 
FoxP3, CD68, CD56, CD20, CD45RO, PD-1, CTLA-4, and granzyme B), using IHC, flow 
cytometry, mass spectroscopy, or other similar techniques.  Biopsy samples may also be used to 
investigate molecular signatures.  DNA and/or RNA may be extracted from these samples to do 
somatic mutation analysis and gene expression analysis.  Genes to be assayed may include, but 
not be limited by those with known driver mutations in solid tumors.  These samples will be 
analyzed by the sponsor or designee. 
6.8.3 
Stool Sample Collection Times and Assessments 
A stool sample from a single bowel movement will be collected by subjects participating in the 
expansion phase of the study prior to administration of the first dose.  Subjects will be provided 
with a materials kit and instructions for collecting the stool sample.  Stool samples will be 
processed to extract and sequence microbial DNA and RNA as outlined in a Laboratory Manual. 
 
Determination of Dose-Limiting Toxicities 
6.9
Based on the preclinical toxicology data and the anticipated half-life of NKTR-214 
(15-20 hours), drug-related toxicity is most likely to occur during treatment or within 10 days 
following treatment.  Based on this, dose-limiting toxicities (DLTs) will be assessed in the first 
cycle for all subjects enrolled to a specific cohort (same dose level).  If DLTs are not observed, 
dose escalation will be permitted and enrollment will begin at the next successive ascending dose 
cohort. Intra-subject dose escalation will not be permitted.  Dose reduction is allowed in subjects 
based on toxicity with approval from the Medical Monitor. 
Unless otherwise suggested by clinical data, a dose-limiting toxicity (DLT) is defined as a 
Grade 3 or higher study drug-related or possibly related AE occurring within the first cycle of 
dosing (excluding Grade 3/4 transient lymphopenia < 14 days in duration, tumor flare defined as 
local pain, irritation, or rash localized at sites of known or suspected tumor, a transient, 
reversible ≤ grade 3 infusion AE, non-clinically significant laboratory abnormalities, or fatigue 
lasting less than 72 hours) using NCI CTCAE version 4.03.   

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 50 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Delayed DLTs are drug-related adverse events that occur after Cycle 1. 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 Sponsor on an ongoing basis. 
All drug related adverse events after Cycle 1 will continue to be collected and evaluated by the 
Investigators and the Sponsor on an ongoing basis and will be taken into consideration in 
determining the MTD. 
All AEs that meet DLT criteria, as well as any ≥ Grade 3 immune-related adverse event 
(regardless of attribution), must be reported to the Sponsor, within 24 hours using the same rapid 
notification procedures that are used for serious AEs (Section 8.7). 
 
Dose Modifications 
6.10
6.10.1 
Non-immune-related Adverse Events 
 Grade 1 or 2 toxicity:  No requirement for dose delay or dose reduction. If the toxicity 
persists at Grade 2 following completion of Cycle 1, a dose reduction to the next lower 
NKTR-214 dose level (for dose escalation) or 50% of the assigned dose (dose escalation or 
dose expansion) may be implemented at the discretion of the Investigator with the approval 
of the Medical Monitor. 
 Grade 3 toxicity:  NKTR-214 may be withheld if toxicity cannot be managed by adequate 
medical intervention. NKTR-214 dosing may resume at the same dose or the next lower 
NKTR-214 dose level (for dose escalation) or 50% of the assigned dose (dose escalation or 
dose expansion) when toxicity resolves to Grade 1 or returns to baseline, except for instances 
consistent with clinically significant capillary leak syndrome or where the potential 
recurrence of the event poses an undue risk for the subject.  
 Grade 4 toxicity (excluding Grade 4 transient lymphopenia < 14 days in duration):  Dosing 
should be permanently discontinued. 
6.10.2 
Immune-related Adverse Events 
Permanently discontinue NKTR-214 for: 
 Grade 2 or 3 immune-related AEs (irAEs) that do not improve to Grade 0 or 1, except 
endocrinopathies managed with replacement hormones 
 Grade 3 irAEs that recur at ≥ Grade 3 
 Grade 3 immune-related pneumonitis, colitis, hepatitis, pancreatitis 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 51 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 Grade 4 irAEs, except endocrinopathies managed with replacement hormones 
 Any uveitis event 
Subjects who need more than 6 weeks to recover from treatment-related toxicities should be 
removed from study treatment. 
 
Administration of NKTR-214 
6.11
The subject’s weight in kilograms will be determined before the start of each cycle.  Each 
subject’s NKTR-214 dose will be determined by the dose escalation scheme and the subject’s 
weight in kilograms.  NKTR-214 will be administered as an intravenous (IV) infusion over 
15 ± 5 minutes. 
Pre-medications should not be administered prior to the initial administration of NKTR-214, but 
if a subject reports symptoms (such as nausea and/or vomiting), prophylactic use of anti-emetics 
may be used. 
The administration of NKTR-214 will be captured in the source documents and recorded on the 
electronic case report form (eCRF).  The lot number for the NKTR-214 vials will be captured on 
Drug Accountability Log. 
Refer to the Pharmacy Binder for further information. 
 
Infusion Delays and Missed Doses 
6.12
In exceptional circumstances, NKTR-214 administration may be delayed.  NKTR-214 
administrations that cannot be done within 7 days will be considered a missed dose, and the 
subject should come in for their next, regularly scheduled visit.  The next scheduled visit should 
occur according to the subject’s next regularly scheduled visit relative to Day 1.  The Medical 
Monitor should be notified if a subject misses 3 consecutive doses.  If a subject misses multiple 
consecutive doses of study drug, the subject may be considered discontinued with Medical 
Monitor approval. 
 
Prior and Concomitant Medications 
6.13
All medications (prescription and over-the-counter [OTC]), vitamin and mineral supplements, 
and/or herbs taken by the subject from Screening through the EOT visit will be documented, and 
recorded on the concomitant medication eCRF and will include start and stop date, dose and 
route of administration, frequency and indication.  Medications taken for a procedure (e.g., 
biopsy) should also be included. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 52 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Permitted Medications 
6.14
Throughout the study, Investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care (including flu vaccines).  All concomitant 
medications administered to study subjects will be captured in source documents and recorded 
on the eCRF.   
 
Prohibited Medications 
6.15
Any anti-cancer therapy (other than NKTR-214), investigational agent, or radiation therapy is 
prohibited during the study.  Palliative radiation is permitted to 1 non-target lesion at a time, 
provided it is completed 14 days before dosing of NKTR-214.  Subjects with pre-existing 
adrenal impairment requiring corticosteroid supplementation may be at increased risk for 
hypotensive episodes during treatment with NKTR-214.  For these subjects, their existing 
corticosteroid dose may be increased by an additional supplementation of up to 5 mg/day of 
prednisone, or equivalent, for the first 4 days after administration of NKTR-214 based on an 
assessment of the degree of adrenal impairment and the extent of existing corticosteroid 
supplementation. 
Consideration should be given to discontinuing antihypertensive medications including diuretics, 
as well as other drugs with hypotensive properties (e.g., alpha blockers for BPH), prior to each 
dose of NKTR-214, particularly when therapy involves multiple antihypertensive drugs and 
classes other than thiazide diuretics.  Antihypertensive medications should be discontinued no 
less than 12 hours and no more than 48 hours prior to each dose of NKTR-214.  
Antihypertensive medications may be reinstituted in between doses of NKTR-214 if the diastolic 
pressure exceeds 90 mmHg and/or the systolic pressure exceeds 160 mmHg. 
 
Adverse Events 
6.16
All AEs, either reported by the subject or observed by study staff, will be recorded in the source 
documents and in the eCRF.  This trial will use the Medical Dictionary for Regulatory Activities 
(MedDRA 18.1 or later) for coding all AEs.  AEs within each system will be summarized by 
preferred term, system organ class, NCI-CTCAE version 4.03 grade of severity, and relationship 
to the study drug. 
 
Assigning Subject Numbers 
6.17
Each subject will be assigned a unique subject number after signing the ICF.  This subject 
number will be used on all subjects’ study information.  Subject numbers will not be reassigned. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 53 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
7.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS 
 
Description and Formulation 
7.1
The investigational drug product, NKTR-214, is formulated as a sterile lyophilized powder for 
reconstitution in single-use glass vials.  Lyophilized NKTR-214 drug product will be diluted 
with commercially available Dextrose 5% in water for injection (D5W).  Each 5 mL, clear glass, 
single-use vial contains 1.1 mg of recombinant human interleukin 2 (rhIL-2) equivalence 
(including 0.1 mg of overage).  NKTR-214 is formulated in 10 mM citrate buffer, 7% (w/v) 
trehalose, pH 4.0. 
 
Study Drug Packaging and Labeling 
7.2
The study drug will be packaged and labeled according to current good manufacturing practices 
(cGMP).  The lyophilized drug product is packaged in a Schott 5 mL, 13 mm opening, USP 
Type I glass serum lyophilization vial with 13 mm Westar® coated gray rubber stoppers and 
aluminum crimps with flip cap.  Secondary packaging will be cardboard box with foam inserts 
holding up to 10 vials. 
Each vial will be labeled with the study drug number/name, strength, name of the Sponsor, 
storage condition, lot number and the required cautionary statement. 
 
Study Drug Reconstitution and Handling 
7.3
The instructions for reconstitution and administration of NKTR-214 drug product are described 
in the Pharmacy Manual. 
 
Study Drug Storage 
7.4
NKTR-214 drug product should be stored in a secure, locked area with temperature at -
20C (± 5°C), as specified on the drug label. 
 
NKTR-214 Drug Shipment 
7.5
Supply of NKTR-214 drug product will be shipped frozen (-20C) to the site pharmacy upon 
completion of the site activation process. 
Please refer to the Pharmacy Manual for additional details for ordering drug supply. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 54 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Study Drug Accountability and Reconciliation 
7.6
All study drug will be supplied to the Investigator by Nektar Therapeutics or its designee.  Study 
drug supplies must be kept in an appropriate, secure locked area and stored in accordance with 
the conditions specified on the labels. 
The Investigator, pharmacist, or designee must maintain an accurate record of dispensing the 
study drug in a Drug Accountability Log, a copy of which must be given to Nektar Therapeutics 
at the end of the study. 
The Drug Accountability Log may record specifics to study drug dispensation such as: 
 Records of product delivery, inventory, temperature monitoring, destruction, and return as 
per Sponsor’s instructions 
 Dosages prepared, time prepared, doses dispensed 
 Doses and/or vials destroyed 
The Drug Accountability Log will be reviewed by the field monitor during site visits and at the 
completion of the study. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 55 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
8.0 
ASSESSMENT OF SAFETY OR AES AND SERIOUS AES 
 
AE Definition and Assessment 
8.1
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product, at any dose, not necessarily related to the treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can also arise from any use of the drug and from any route of 
administration, formulation, dose, or overdose.  This definition includes intercurrent illnesses or 
injuries, and exacerbation of preexisting conditions.  Clinical laboratory abnormalities will only 
be reported as AEs if they are deemed clinically significant by the Investigator and/or are 
associated with signs and symptoms, require treatment, or require follow-up. 
An AE does not include: 
 A medical or surgical procedure (e.g., 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 medication 
administration which do not worsen or increase in severity or frequency after the 
administration of study medication 
 Situations where an untoward medical occurrence has not occurred (e.g., 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 subject) 
 Overdose of either study medication or concomitant medication without any signs or 
symptoms 
 
Monitoring AEs 
8.2
All AEs will be assessed by the Investigator and recorded on the appropriate eCRF including but 
not limited to, the following:  the event term, the date of onset and resolution, seriousness, 
severity, relationship to study drug, outcome, treatment of the event, and action taken with the 
study drug.  AEs will be reported starting immediately after the subject has been administered 
the first dose of study medication through 30 days after the last dose of NKTR-214. 
An event occurring after the subject has provided informed consent, but before the first dose of 
study treatment, will be collected as medical history unless the event is either new and attributed 
to protocol-mandated procedures by the Investigator OR there is a significant change in the rate 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 56 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
of occurrence or an increase in the severity of the pre-existing condition which is judged to be 
clinically important and attributed to the protocol-mandated procedures by the Investigator.  
Under the latter two circumstances, the event will be considered an AE and will be captured as 
such on the eCRF. 
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 on the eCRF page, and it will be documented 
as being “unrelated” to study drug as applicable. 
Example 2: 
An ankle sprain following an unexpected fall from a flight of stairs while at home, after the 
subject has provided informed consent, but before the first dose of study drug, is clearly 
unrelated to any protocol-mandated procedures and would therefore be captured as medical 
history in the medical history section of the eCRF. 
 
Grading of AEs 
8.3
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 subject/event 
outcome or action criteria.  All AEs will be assessed for severity using the NCI-CTCAE 
version 4.03.  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 
(e.g., insomnia, mild headache) 
 Grade 2 = Moderate (event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment (e.g., fever requiring antipyretic medication) 
 Grade 3 = Severe (event results in significant symptoms that prevents normal daily activities; 
may require hospitalization or invasive intervention). 
 Grade 4 = Life threatening or disabling 
 Grade 5 = Death 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 57 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
AEs will be reported with an individual start and stop date for each level of severity. 
 
Causality Relationship of AEs 
8.4
The relationship of each AE to the study treatment (NKTR-214) as applicable will be evaluated 
by the Investigator using the following definitions: 
 Not related:  The AE is clearly not related to the investigational agent(s).  The AE can be 
explained to be likely related to other factors such as concomitant medications or the 
subject’s clinical state. 
 Possibly related:  The AE may be related to the investigational agent(s).  A plausible 
temporal sequence exists between the time of administration of the investigational product 
and the development of the AE and it follows a known response pattern to the investigational 
product.  The reaction may have been produced by the subject’s clinical state or other 
concomitant therapies or interventions. 
 Related:  The AE is clearly related to the investigational agent(s).  A plausible temporal 
sequence exists between the time of administration of the investigational product and the 
development of the AE and it follows a known response pattern to the investigational 
product.  The occurrence of this AE can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
The causality criteria of related and possibly related will be considered “related” to the study 
medication for regulatory reporting requirements.   
 
AE Reporting and Follow-up 
8.5
Adverse events will be reported from the time of first study drug administration until 30 days 
after the last dose of study drug.  All ongoing AEs will be followed until resolution, the subject is 
lost to follow-up, subject death, or until 30 days after last dose of study treatment, whichever is 
earlier.  In case the AE has not completely resolved up to 30 days after last dose of study 
treatment, the final outcome of these ongoing AEs will be captured as “Not Recovered/Not 
Resolved” or “Recovering/Resolving”, whichever is applicable.  Any new AEs occurring more 
than 30 days after last dose of study treatment will not be captured unless related to study drug. 
For specific instructions on identifying and reporting SAEs, see Sections 8.6 and 8.7. 
 
Serious AE Definition 
8.6
An SAE is defined as any untoward medical occurrence that at any dose: 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 58 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 Results in death 
 Is life threatening, i.e., in the opinion of the Investigator, the AE places the subject at 
immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
 Requires inpatient- hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a subject’s participation in a clinical study, except for those due to the 
following: 
– A surgery or procedure that was planned before the subject entered the study and which 
is part of the planned study procedure. 
– Nonmedical reasons, 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 subject 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 deaths regardless of causality must be 
reported.  An efficacy failure is not considered an SAE.  “Life-threatening” means that the 
subject 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 subject 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. 
 
Serious AE Reporting 
8.7
SAEs with an onset within 30 days after the subject’s last dose of study treatment, but before 
initiation of a new antineoplastic treatment, will be reported to Nektar Therapeutics Drug Safety 
within 24 hours of when the site becomes aware of the event.  It is anticipated that some patients 
will experience disease progression before study discontinuation, and the disease progression 
may result in hospitalization or death.  Adverse events leading to hospitalization or death 
typically are considered serious and require reporting on a serious adverse event form. In 
addition, disease progression per se is already captured as an efficacy endpoint. Where possible, 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 59 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
the specific event defining the disease progression should be reported, such as pleural effusion, 
intestinal obstruction or cardiac failure.  Only if it is not possible to discern the specific event 
leading to disease progression, should “disease progression” be reported as the event.  In 
addition, SAEs that are assessed by the Investigator as possibly or related to study medication 
and occurring > 30 days after last dose of study treatment will also be reported to Nektar 
Therapeutics Drug Safety within 24 hours or when the site becomes aware of the event. 
 
 
 
 
 
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 8.8. 
Reporting of SAEs to the Institutional Review Board (IRB) will be done in accordance with the 
standard operating procedures (SOPs) and policies of the IRB.  Adequate documentation must be 
provided to Nektar Therapeutics, showing that the IRB was properly notified.  Serious AEs will 
be reported by Nektar Therapeutics or designee to the Regulatory Authorities, per local 
regulations. 
 
Serious AE Follow-up 
8.8
All study treatment-related SAEs that have not resolved within 30 days of last dose of study 
treatment as applicable, 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 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 60 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 It is unlikely that any additional information can be obtained (e.g., subject or health care 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
  The subject dies or is lost to follow-up. 
All ongoing SAEs assessed as “unrelated” to study medication will be followed until resolution 
or until 30 days after last dose of study medication, whichever is earlier.  In the case where an 
unrelated SAE has not completely resolved up to 30 days after last dose of study treatment, the 
final outcome of these ongoing SAEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable. 
 
Immune-Related Adverse Event Reporting 
8.9
Immune-related adverse events (irAE) are considered adverse events of special interest due to 
their potential clinical significance.  Investigators should use clinical judgment to determine that 
an adverse event is immune related, and are encouraged to rule out neoplastic, infectious, 
metabolic, toxic or other etiologies, to the extent possible, before characterizing an event as 
immune related. 
Grade 3 or higher immune-related adverse events, with an onset within 30 days after the 
subject’s last dose of study treatment, must be reported to Nektar Therapeutics Drug Safety or its 
designee within 24 hours of when the site becomes aware of the event. 
 
 
 
 
 
 
The Investigator must complete the SAE Form, mark the report as an immune related adverse 
event and send the completed form via email or fax to Nektar Therapeutics Drug Safety.  Any 
medication or other therapeutic measures used to treat the event will be recorded.  A follow-up 
report will be emailed or faxed to Nektar Therapeutics Drug Safety as soon as additional details 
become available. 
 
Pregnancy 
8.10
The sponsor must be notified within 24 hours of the initial report and any follow-up reports of a 
male subject’s female partner or a female subject becoming pregnant during the course of the 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 61 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
study and for 3 months after the last dose of the study drug.  Pregnancy, although reportable, is 
not considered an AE/SAE unless a female subject or male subject’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 8.7.  Females who become 
pregnant will be followed every trimester 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 subject becomes pregnant, administration of the study drug must be discontinued 
immediately. 
 
Clinical Laboratory Tests 
8.11
Clinical laboratory tests will be conducted according to the Schedule of Assessments 
(Section 1.2).  Clinical laboratory tests will be performed by the local laboratory for the Dose 
Escalation phase and central laboratory for the Dose Expansion phase.  Clinical laboratory test 
data will be reviewed by the Investigator or qualified Sub-investigator.  Additional clinical 
laboratory tests may be ordered at the Investigator’s or qualified Sub-investigator’s discretion. 
Additional testing for PK and biomarkers will be performed by the designated central laboratory. 
The Investigator or qualified Sub-investigator will review all laboratory results for clinical 
significance.  Any laboratory result deemed clinically significant (i.e., are associated with signs 
and symptoms, require treatment or require follow-up) will be recorded as an AE as described in 
Section 8.1. 
 
Vital Signs 
8.12
Vital sign measurement will be recorded at every visit.  Vital signs include pulse rate, respiratory 
rate, systolic and diastolic blood pressure, and temperature (oral). 
 
Electrocardiograms 
8.13
Five-minute summary ECGs will be performed on a calibrated 12-lead machine according to the 
Schedule of Assessments (Section 1.2).  Subjects must be resting quietly in the supine position 
for at least 5 minutes before the ECG. ECG recordings will start at 5 minutes before the time 
point and end at the time point.  All ECGs should be recorded before any corresponding 
PK samples are obtained.  Interpretation of ECGs and interval duration measurements will be 
performed by a designated ECG laboratory.  Interpretation of ECGs and interval duration 
measurements will be provided to the site. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 62 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
At each time point, 5 minutes of ECG data will be recorded.  The 5 minutes of ECG data is 
converted into a Summary ECG (simulated 10-second ECG) for each subject.  The Summary 
ECG is then submitted to CalECG (version 3.3.0) and the Glasgow algorithm (version 27.0.2) for 
measurements and diagnoses, and to the Cardiologist over-reader for confirmation, as though it 
were a standard 10-second ECG. 
The Investigator or qualified Sub-investigator will review all ECG interpretations and interval 
duration measurements for clinical significance.  Any ECG interpretation deemed to be clinically 
significant will be reported as an AE as described in Section 8.1.  Subjects who are discontinued 
will be required to complete the ET visit and all safety follow-up procedures. 
 
Pregnancy Tests 
8.14
Serum pregnancy tests will be performed on women of childbearing potential during screening. 
Urine or serum pregnancy tests will be performed on women on Day 1 of each cycle prior to 
dosing.  A negative pregnancy test result must be obtained before the administration of the study 
drug. 
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 3 months before signing the ICF. 
If a female subject becomes pregnant, administration of the study drug must be discontinued 
immediately. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 63 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
9.0 
ASSESSMENT OF EFFICACY EVALUATIONS 
Documented tumor measurements are required using CT scans or MRI, as appropriate and are to 
be performed every 8 weeks (± 7 days) and in line with standard of care.  The same method of 
assessment (CT or MRI) and the same technique for acquisition of data must be used to 
characterize each identified and reported lesion at baseline, during the treatment period, and at 
the EOT visit (if previous assessment was not completed within 4 weeks). 
Radiological imaging must include the pelvis, abdomen, and chest. 
All subjects must have tumor measurements performed at the participating study center. 
Efficacy analyses will be on data provided by the investigator site as well as an independent 
central imaging core laboratory.  Site training, data collection, and analysis of all scans acquired 
during the study as per schedule of assessments will be detailed in a study manual and imaging 
charter. 
Response and progression will be determined using the RECIST guidelines (version 1.1) 
(Eisenhauer, 2009) 
 
Definitions 
9.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
described below. 
9.1.1 
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); when CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. 
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 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 64 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
9.1.2 
Non-measurable Disease 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes ≥ 10 to < 15 mm 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, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
 
Specifications by Methods of Measurements 
9.2
The same method of assessment and the same technique should be used to characterize each 
lesion at baseline and during follow-up.  Imaging-based evaluation should always be done rather 
than clinical examination unless the lesion(s) being followed cannot be imaged but are assessable 
by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  When lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should 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 should be obtained and utilized for measurement. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  If a slice thickness > 5 mm is used for CT scanning, then the 
minimum longest diameter for a target lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g., for body scans). 
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 subject 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. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 65 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
9.2.1 
Tumor Response Evaluation 
9.2.1.1 
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. 
9.2.1.2 
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 
in instances where subjects have only one or two 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. 
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’. 
9.2.1.3 
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), 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 66 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm.  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 (e.g., 2 mm).  However, if the lesion is believed to 
be present and is faintly seen but too small to measure with any accuracy, a default value of 
5 mm should be assigned. 
9.2.2 
Response Criteria using RECIST v1.1 
9.2.2.1 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions.  
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of 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.  
(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. 
 
9.2.2.2 
Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points of 
radiographic assessments.  

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 67 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
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). 
 
NOTE:  If tumor markers are assessed for a given subject and are initially above the ULN, they 
must normalize for a subject to be considered in complete CR. 
9.2.2.3 
Confirmatory Measurement/Duration of Response 
9.2.2.3.1 
Confirmation 
Confirmation of response (either PR or CR) is required.  Changes in tumor measurements must 
be confirmed by repeat assessments that should be performed ≥ 4 weeks after the criteria for 
response are first met. 
9.2.2.3.2 
Duration of Overall Response 
DOR is measured from the time that measurement criteria are met for CR or PR (whichever is 
first recorded) until a documented PD per RECIST 1.1 or death. 
9.2.2.4 
Evaluation of Overall Response using RECIST v1.1 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 68 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Table 6: 
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; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable 
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 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 69 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
10.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
 
General Considerations 
10.1
All analyses will be descriptive in nature and subject data will be listed.  Descriptive statistics 
will be presented by dose level and for all subjects, and further summarized by tumor type. 
All subjects that received at least 1 dose (or partial dose) of NKTR-214 will be considered 
evaluable for safety analysis.  Safety will be assessed by the tabulation of AEs and review of 
laboratory evaluations. AEs, hematological and biochemical toxicity will be classified according 
to MedDRA 18.1 or later.  All demographics, laboratory values, and vital signs will be 
summarized using descriptive statistics. 
 
Determination of Sample Size 
10.2
This is a Phase 1/2 dose escalation and dose expansion study.  Cohorts of at least 3 subjects will 
be treated at each dose level during dose escalation and additional subjects will be added to each 
dose cohort based on the dose assignment action (escalate to a higher dose, stay at the same dose, 
or de-escalate to a lower dose) listed in Table 4 or Sponsor determination of the need for 
additional data to further evaluate the benefit/risk profile.  It is estimated that approximately 
50 subjects will be enrolled into the dose escalation phase. 
Dose Expansion will enroll approximately 50 subjects with RCC.  Ongoing safety monitoring 
will be performed as detailed in Section 10.2.1. 
10.2.1 
Expansion Cohorts Safety Monitoring 
Bayesian sequential monitoring will be employed to perform ongoing safety monitoring 
targeting a toxicity rate of not more than 30% (where toxicity follows the same definition as a 
DLT defined in Section 4.1.2.1) for the first 80 subjects enrolled in the dose expansion phase. 
Subjects will be monitored across tumor-specific cohorts after a minimum of 6 subjects treated at 
the selected dose for the dose expansion phase.  The criteria for suspending enrollment due to 
safety are included in Table 7 based on Bayesian sequential monitoring designs by 
Thall et al. (1995).  The determination of the criteria is when: 
Pr [prob(toxicity) > 0.30 | data] > 0.95. 
If there is a greater than 95% chance that the toxicity rate is greater than 30%, then accrual will 
be suspended and the safety review committee will meet to review safety data including 
aggregated safety summaries.  We assume a beta (0.6, 1.4) prior distribution for the toxicity rate, 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 70 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
which has a mean of 0.3 corresponding to the 30% target toxicity rate.  A constant 30% rate was 
chosen for the standard treatment rate. 
Table 7: 
Suspension Boundaries for Toxicity During Expansion 
Total Number of Treated Subjects 
Suspending Accrual if ≥ Number of Subjects  
with Toxicity 
1-5 
Not Applicable 
6-8 
5 
9-10 
6 
11-12 
7 
13-15 
8 
16-18 
9 
19-20 
10 
21-23 
11 
24-25 
12 
26-28 
13 
29-31 
14 
32-34 
15 
35-36 
16 
37-39 
17 
40-42 
18 
43-45 
19 
46-48 
20 
49-50 
21 
51-53 
22 
54-56 
23 
57-59 
24 
60-62 
25 
63-65 
26 
66-68 
27 
69-71 
28 
72-73 
29 
74-76 
30 
77-79 
31 
80 
Maximum enrollment for safety monitoring 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 71 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
Table 8: 
Operating Characteristics for Subject Accrual Suspension Rules 
True Toxicity Rate 
Accrual Suspension 
Probability 
Achieved Sample Size 
25th 
50th 
75th percentiles 
0.1 
0.001 
80 
80 
80 
0.2 
0.018 
80 
80 
80 
0.3 
 0.202 
80 
80 
80 
0.4 
 0.759 
14 
34 
80 
0.5 
0.991 
7 
14 
25 
0.6 
1.000 
6 
8 
14 
 
An internal safety review committee consisting of representatives from Clinical Development, 
Drug Safety,  Biostatistics, other functional representatives, as needed, and at least one Principal 
Investigator will meet at least quarterly to review safety data for potential safety risks or more 
frequently if needed.  If it is determined there is a high probability of observing more than 30% 
toxicities, enrollment will be suspended and the safety review committee will be convened to 
make a recommendation on the continuation, modification, or discontinuation of the study. 
 
Replacement of Subjects 
10.3
Subjects in the dose escalation phase who do not complete Cycle 1 of treatment for reasons other 
than a DLT will be replaced to provide sufficient number of subjects included for the dose 
escalation decision. During dose expansion, subjects will not be replaced. 
 
Analysis Sets 
10.4
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 one cycle of treatment or discontinue from 
the study treatment due to DLT will be included. 
Pharmacokinetic Population:  All subjects in the Safety Population who have relatively complete 
individual analyte concentration-time profiles that allow for the computation of meaningful PK 
parameter values. 
Response Evaluable Population:  Subjects who have measurable disease (per RECIST 1.1) at 
baseline and also have one post-baseline assessment of tumor response or are withdrawn due to 
progressive disease/death prior to first response assessment. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 72 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Planned Analyses 
10.5
10.5.1 
Demographics and Baseline Characteristics 
Demographic data (age, sex, ethnicity, body weight) and baseline disease characteristics will be 
tabulated and summarized by dose cohort (for the dose escalation phase) and by tumor type (for 
the dose expansion phase) and presented in data listings. 
10.5.2 
Safety 
The primary endpoints of the study are to determine the MTD with NKTR-214.  Adverse events 
and toxicity will be evaluated according to NCI CTCAE version 4.03.  Safety assessments will 
be performed by medical review of AEs and laboratory results. 
Incidence rate of DLT will be tabulated by dose cohort for the DLT population. 
Treatment emergent AEs (TEAEs) within each system will be summarized by preferred term, 
system organ class, NCI-CTCAE grade of severity, and relationship to the study treatment. 
Serious AEs and AEs leading to study drug discontinuation will also be summarized. 
A TEAE is defined as an AE that was not present prior to treatment with study treatment, but 
appeared following treatment or was present at treatment initiation, but worsened during 
treatment.  An AE that was present at treatment initiation, but resolved and then reappeared 
while the subject was on treatment, is a TEAE (regardless of the intensity of the AE when the 
treatment was initiated). 
Vital signs (including change in weight) and clinical laboratory test results will be summarized 
descriptively by dose (for the dose escalation phase) and by tumor type (for the dose expansion 
phase).  Any significant physical examination findings will be listed. ECG and echocardiogram 
data will be evaluated by central review and abnormalities, if present, will be listed.  A separate 
listing and summary of all immune-related AEs (irAEs) will be provided.  A listing and summary 
of subjects who discontinued study drug due to an adverse event will be provided. 
A data listing for deaths will be provided. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 73 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
10.5.3 
Efficacy 
The efficacy outcomes will include: 
1. objective response rate (ORR) 
2. best overall response (BOR) 
 
 
4. duration of response (DOR) 
5. clinical benefit rate (CBR) 
6. time to response (TTR) 
 
 
The primary efficacy measurement will be ORR per RECIST v1.1 based on the Response 
Evaluable population by tumor type.  The number and proportion of subjects with objective 
tumor response (CR and PR) will be calculated based on number of subjects with measurable 
disease at baseline.  Ninety-five percent (95%) confidence interval (CI) will also be calculated 
using exact binomial method.  Data listing for tumor assessments and tumor response will be 
provided. 
A secondary measurement will be BOR per RECIST v1.1 based on the Response Evaluable 
population by tumor type.  The number and proportion of subjects with a best overall response of 
CR or PR will be calculated based on number of subjects with measurable disease at baseline. 
Ninety-five percent (95%) CI will also be calculated using exact binomial method. 
DOR will be defined as the time from first documented CR or PR until the earliest evidence of 
disease progression, new subsequent anti-cancer therapy, or death from any cause.  DOR will be 
estimated using Kaplan-Meier method for those subjects who have a CR or PR. 
Clinical benefit rate will be calculated as the number of subjects with confirmed CR, PR, or SD 
(where the duration of SD should be ≥ 3 months) divided by the total number of subjects in the 
Response Evaluable Population.  The number and proportion of subjects with clinical benefit 
will be summarized. 
The time to response will be summarized descriptively for subjects who have a CR or PR. 
 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 74 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
 
 
 
 
 
 
10.5.4 
Pharmacokinetics 
Plasma concentrations of NKTR-214 and its metabolites will be measured using validated 
method(s).  Before analysis of samples, assay sensitivity, specificity, linearity, and 
reproducibility will be determined.  Pharmacokinetic parameters such as Cmax, time to Cmax 
(Tmax), AUC, CL, Vd, and t½ will be estimated from plasma concentration-time data where 
possible.  Pharmacokinetic data from this study may also be pooled with data from other clinical 
studies for the purpose of pharmacokinetic modeling.  Pharmacokinetic parameters will be 
tabulated and summarized with descriptive statistics.  Data from subjects prematurely ending 
participation in the study may be excluded from the PK data evaluation. 
A detailed description of the planned PK analyses will be provided in the PK Analysis Plan. 
10.5.5 
Immunogenicity 
Validated assays will be used for the determination of anti-drug antibodies to NKTR-214 in 
human serum.  Only subjects who receive at least 1 dose of NKTR-214 and provide at least 
1 post-treatment sample will be evaluated.  Immunogenicity results will be analyzed 
descriptively by summarizing the number and percentage of subjects who develop detectable 
anti-NKTR-214 antibodies.  Samples confirmed positive may also be evaluated for neutralizing 
antibody activity. 
10.5.6 
Exploratory Analyses 
In addition, characterization of immune system biomarkers (e.g., LDH in melanoma) in predose 
blood and tumor biopsies, as well as changes in immune system biomarkers after treatment with 
NKTR-214, and their relationship with efficacy will be exploratory endpoints.  Samples may be 
used for additional research purposes related to the development of NKTR-214. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 75 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Concomitant Medications 
10.6
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. 
 
Missing Data 
10.7
Statistical considerations and methodology for handling missing data will be detailed in the 
Statistical Analysis Plan. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 76 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
11.0 
STUDY OR STUDY SITE TERMINATION 
The sponsor has the right to suspend or terminate the study at any time.  The study may be 
suspended or terminated for any reason. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 77 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
12.0 
QUALITY ASSURANCE 
Nektar Therapeutics will implement and maintain quality control and quality assurance 
procedures with written standard operating procedures to ensure that the study is conducted and 
data are generated, documented, and reported in compliance with the protocol, GCP, and 
applicable regulatory requirements. 
 
Changes to the Protocol 
12.1
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 subject or when the change(s) 
involve only logistical or administrative aspects of the study. 
A protocol amendment will be submitted if the sample size will be increased above what is 
currently specified (or if new cohorts will be added in order to investigate any new dosing 
schedules, doses, or forms of administration not currently specified in the protocol).  All protocol 
deviations are to be documented and reported to Nektar or its designee. 
 
Monitoring 
12.2
In accordance with 21 CFR § 312.56, ICH GCP and local regulations, the clinical monitor will 
periodically inspect 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 
subjects in this trial.  The names and identities of all research subjects 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 regulations also require the Investigator to allow 
authorized representatives of the FDA and European Union Regulatory Authorities to inspect 
and make copies of the same records.  The names and identities of the subjects need not be 
divulged to the Sponsor; however, the records must nevertheless be inspected.  This can be 
accomplished by blacking out the subject’s name and replacing the name with the subject’s study 
identification number.  If these requirements are in conflict with local regulatory restrictions or 
institutional requirements, the Investigator must inform the Sponsor of these restrictions prior to 
initiation of the study. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 78 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
 
Direct Access to Source Data/Documents for Audits and Inspections 
12.3
Members of the Sponsor’s GCP Quality Assurance Department or designees may conduct an 
audit of a clinical site at any time during or after completion of the study.  The Investigator will 
be informed if an audit is to take place and advised as to the scope of the audit.  Inspections and 
audits are typically carried out during the clinical and reporting phases of this study to ensure 
that the study is conducted and data are generated, documented, and reported in compliance with 
the protocol, GCP, written SOPs and applicable laws, rules, and regulations. 
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives may 
also conduct an audit of the study.  If informed of such an inspection, the Investigator should 
notify the Sponsor immediately.  The Investigator will ensure that the auditors have access to the 
clinical supplies, study site facilities; laboratory and that all data (including original source 
documentation) and all study files are available, if requested. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 79 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
13.0 
ETHICS 
This trial will be conducted according to the provisions of the Declaration of Helsinki (October 
2008) and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, and 312), with the ICH 
guidelines on Good Clinical Practice (ICH E6), as well as with any and all applicable federal, 
state and/or local laws and regulations. 
 
IRB/IEC Approval 
13.1
Prior to enrollment of subjects into the study, as required by United States Federal regulations 
(21 CFR § 56), ICH GCP and local regulations, the protocol and informed consent form 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 prior to the initiation of the study.  Amendments to the 
protocol will be subject to the same requirements as the original protocol. 
The Investigator, the Sponsor, or designee will submit a progress report at least once yearly to 
the IRB or IEC and Regulatory Authorities.  The frequency of these reports will depend on local 
regulations.  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’s requirements. 
The Investigator, the Sponsor or designee shall promptly notify the IRB or IEC of any SUSARs 
or any other information that may affect the safe use of the study drug during the course of the 
trial, per the IRB or IEC’s requirements. 
 
Written Informed Consent 
13.2
Written informed consent must be obtained from each subject or legal guardian before entering 
the study. Subjects will be informed of the nature of the study, and the ICF must be presented to 
each subject in the language in which the subject is fluent. 
Informed consent will be obtained and documented from each subject prior to any protocol-
specific procedures.  Signed and dated ICFs will be retained by the Investigator with the study 
records. Each subject will be given a copy of the signed consent form.   

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 80 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
14.0 
DATA HANDLING AND RECORD KEEPING 
 
Data Collection Instruments and Source Documents 
14.1
14.1.1 
Study Records 
During the study, the Investigator will maintain adequate records for the study, including 
medical records, records detailing the progress of the study for each subject, laboratory reports, 
eCRFs, signed ICFs, drug accountability records, correspondence with the IRB or IEC and 
regulatory agencies’ AE reports, and information regarding subject discontinuation and 
completion of the study.   
14.1.2 
Data Collection Instruments 
Data collection instruments (DCIs) (e.g., 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. 
 
Retention of Essential Documents 
14.2
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/European 
Medicines Agency (EMA) approval of the drug or at least 2 years after withdrawal of the IND 
under which this study was conducted, whichever is longer.  In countries outside the United 
States, at a minimum, records must be kept for the period of time required by the US FDA, and 
must also comply with the local country regulatory requirements, if longer retention times are 
required than in the United States.  In order to avoid 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. 
 
Confidentiality 
14.3
Subject confidentiality will be maintained according to local legal and regulatory requirements 
and applicable US federal regulations and ICH GCP guidelines.  In order to comply with GCP 
guidelines and requirements, subject 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 subject 
identifying information, as confidential as possible as required by law. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 81 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
15.0 
PUBLICATION POLICY 
All data are the property of the Sponsor.  The Sponsor intends that the results of the study will be 
published and/or presented at scientific meetings.  Any formal presentation or publication of data 
from this trial will be considered as a joint publication by the Investigator(s) and appropriate 
Sponsor personnel.  In addition, the Sponsor intends to distribute a study report to each Principal 
Investigator.  The Investigator may share this report with subjects who have expressed an interest 
in knowing the study results. 
The Sponsor must receive copies of any intended communication in advance of submission for 
publication (at least 14 days for an abstract or oral presentation and 30 days for a journal 
submission).  The Sponsor will review the communications for accuracy (thus avoiding potential 
discrepancies with submissions to health authorities), verify that confidential information is not 
being inadvertently divulged, and provide any relevant supplementary information. 
An 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.   

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 82 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
16.0 
REFERENCES 
1. 
Anderson TD, Hayes TJ, Powers GD, Gately MK, Tudor R, Rushton A. Comparative 
toxicity and pathology associated with administration of recombinant IL-2 to animals. 
Int Rev Exp Path. 1993;34A:57-77. 
2. 
Boyman O and Sprent J, The role of interleukin-2 during homeostasis and activation of 
the immune system. Nat Rev Immunol. 2012;12(3):180-190. 
3. 
Charych D, et al., Tipping the balance in the tumor microenvironment:  An engineered 
cytokine (NKTR-214) with altered IL2 receptor binding selectivity and improved 
efficacy. AACR 2013a, Abstract 482. 
4. 
Charych D. An engineered immunotherapy (NKTR-214) with altered selectivity toward 
the IL2 receptor:  Efficacy and tolerability in a murine tumor model. J Clin Oncol. 
2013b;31(15_Suppl.):Abstract 3060. 
5. 
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. 
6. 
Hanzly M, et al., High-dose interleukin-2 therapy for metastatic renal cell carcinoma:  a 
contemporary experience. Urology. 2014;83(5):1129-1134. 
7. 
Hoch U, et al, NKTR-214:  An immunotherapy with altered selectivity at the IL2 
receptor; pharmacokinetics (PK) and pharmacodynamics (PD) in animal models. Mol 
Cancer Ther. 2013;12(11 Suppl):Abstract B296. 
8. 
Hodi FS, et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. N Engl J Med. 2010;363(8):711-723. 
9. 
Payne R, et al., Durable responses and reversible toxicity of high-dose interleukin-2 
treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program. 
J Immunother Cancer. 2014;2:13. 
10. 
Robert C, et al., Anti-programmed-death-receptor-1 treatment with pembrolizumab in 
ipilimumab-refractory advanced melanoma:  a randomised dose-comparison cohort of a 
phase 1 trial. Lancet. 2014;384(9948):1109-1117. 
11. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med. 1995;14(4):357-379. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 83 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
12. 
Topalian SL, et al., Survival, durable tumor remission, and long-term safety in patients 
with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030. 

Protocol No. 15-214-01 Amendment 4.0 
 
NKTR-214 
Nektar Therapeutics 
 
Page 84 of 84 
Confidential and Proprietary 
 
24 Oct 2016 
APPENDIX 1: 
CLINICAL LABORATORY TESTS 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Serology 
 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 
 Blood urea nitrogen (BUN) 
 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 
 Thyroid stimulating hormone 
 Free thyroxine (T4) 
 Lipase 
 Amylase 
 HLA typing (screening only) 
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 
Local laboratory will be used for Part 1; central laboratory will be used for Part 2.