A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and Immunotherapy Combinations for the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer
Phase: PHASE1
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Parker Institute for Cancer Immunotherapy

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Protocol Title:  A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers 
and Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-
resistant Prostate Cancer 
Appendix Cohort A 
Protocol Number:  PICI0033 
Amendment Number:  Not applicable 
Compound Number:  NKTR-214, Nivolumab 
Short Title:  Platform Study for Prostate Researching Translational Endpoints Correlated to 
Response to Inform Use of Novel Combinations (PORTER) 
Sponsor Name and Legal Registered Address:   
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 415-985-7311 
Fax: 415-872-5305 
Regulatory Agency Identifying Number(s):  
IND NUMBER: 139269 
EudraCT NUMBER:  Not applicable 
Approval Date:  Final Protocol: 07 December 2018 
 
Amendment 1: 24 January 2019 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to Parker Institute for Cancer 
Immunotherapy. Any unauthorized copying or use of this document is prohibited. 
 
 

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Institutional Review Board or Independent Ethics Committee except where necessary to 
eliminate an immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described 
in this cohort appendix and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure(s). 
• 
That I am aware of, and will comply with, the International Conference on 
Harmonisation for Good Clinical Practice (GCP) and all applicable regulatory 
requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about the 
study drugs, the Parker Institute for Cancer Immunotherapy study protocol, and of their 
study-related duties and functions as described in the protocol. 
• 
That I agree that persons debarred from conducting or working on clinical studies by any 
court or regulatory agency will not be allowed to conduct or work on studies for the 
Parker Institute for Cancer Immunotherapy or for a partnership in which the Parker 
Institute for Cancer Immunotherapy is involved, and that I will immediately disclose in 
writing to the Parker Institute for Cancer Immunotherapy if any person who is involved 
in the study is debarred, or if any proceeding for debarment is pending. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 
 
  
 

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Amendment(s) to Appendix Cohort A 
Text revisions resulting from the amendment(s) are incorporated in the synopsis and body of the 
Appendix Cohort Amendment. Major changes to the appendix cohort are summarized below. 
Key Revisions in Amendment 1 (24 January 2019) 
Section # and Name 
Description of Change 
Eligibility Criteria 
5.1 Inclusion Criteria 
Combined previous inclusion criteria #6 and #10 into a single inclusion 
criterion #6. 
Study Design 
1.3 Schema, Figure 1 
Modified to improve identification of key research procedure time points. 
Study Intervention 
6.6.1 Dose Modifications for the 
Combination of Nivolumab and 
NKTR-214 
Added text related to written approval from the Medical Monitor to 
clarify that participants with toxicity that does not resolve or met 
retreatment criteria within 6 weeks of the last dose, must be discontinued 
from the combination therapy, unless written approval to restart therapy 
is provided by the Medical Monitor. 
6.6.2 Dose Modifications Nivolumab 
Added text related to written approval from the Medical Monitor to 
clarify that participants with toxicity that does not resolve or met 
retreatment criteria within 6 weeks of the last dose, must discontinue 
study intervention, unless written approval to restart therapy is provided 
by the Medical Monitor. 
Clarification of Document 
General Revisions 
Document updated to address minor typographical errors and editorial 
changes for clarity. 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
1 
PROTOCOL SUMMARY ...................................................................................................9 
1.1 
SYNOPSIS ...............................................................................................................9 
1.2 
SCHEMA ...............................................................................................................10 
1.3 
SCHEDULE OF ACTIVITIES..............................................................................12 
2 
INTRODUCTION .............................................................................................................17 
2.1 
STUDY RATIONALE ..........................................................................................17 
2.2 
BACKGROUND ...................................................................................................17 
2.2.1 
Background on Nivolumab (Bristol-Myers Squibb Company) ...............18 
2.2.2 
Background on NKTR-214 (Nektar Therapeutics) .................................18 
2.2.3 
Rationale for NKRT-214 + Nivolumab Immunotherapy Combination ..20 
2.3 
BENEFIT/RISK ASSESSMENT ..........................................................................24 
3 
OBJECTIVES AND ENDPOINTS ...................................................................................25 
4 
STUDY DESIGN...............................................................................................................26 
4.1 
OVERALL DESIGN .............................................................................................26 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ...........................................27 
4.3 
JUSTIFICATION FOR DOSE ..............................................................................27 
4.3.1 
Rationale for Nivolumab Dose and Schedule .........................................27 
4.3.1.1 
Nivolumab 360 mg Q3W Dosing Regimen ..........................28 
4.3.2 
Rationale for NKTR-214 Dose and Schedule .........................................28 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION ........................................29 
4.5 
END OF STUDY DEFINITION ...........................................................................29 
5 
STUDY POPULATION ....................................................................................................29 
5.1 
INCLUSION CRITERIA.......................................................................................29 
5.1.1 
Common Inclusion Criteria .....................................................................29 
5.1.2 
Combination-specific Inclusion Criteria .................................................32 
5.2 
EXCLUSION CRITERIA .....................................................................................32 
5.2.1 
Common Exclusion Criteria ....................................................................32 

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5.2.2 
Combination-specific Exclusion Criteria ................................................33 
5.3 
LIFESTYLE CONSIDERATIONS .......................................................................34 
5.3.1 
Meals and Dietary Restrictions ...............................................................34 
5.3.2 
Activity ....................................................................................................34 
5.4 
SCREEN FAILURES ............................................................................................34 
6 
STUDY INTERVENTION ................................................................................................34 
6.1 
STUDY INTERVENTION(S) ADMINISTERED ................................................34 
6.1.1 
Hydration Guidelines for NKTR-214 ......................................................35 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................36 
6.3 
RANDOMIZATION AND BLINDING................................................................36 
6.4 
STUDY INTERVENTION COMPLIANCE .........................................................36 
6.5 
CONCOMITANT THERAPY...............................................................................36 
6.5.1 
Permitted Therapy ...................................................................................36 
6.5.2 
Prohibited Therapy ..................................................................................36 
6.6 
DOSE MODIFICATIONs .....................................................................................36 
6.6.1 
Dose Modifications for the Combination of Nivolumab and NKTR-214
 .................................................................................................................36 
6.6.1.1 
Potential for Overlapping Toxicities with Nivolumab and 
NKTR-214 .............................................................................38 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse 
Events Associated with Nivolumab and NKTR-214 .............39 
6.6.1.3 
Dose Modifications and Toxicity Management for Infusion-
related Reactions Associated with the Administration of 
NKTR-214 and/or Nivolumab ...............................................40 
6.6.1.4 
Dose Delays and Interruptions of NKTR-214 + Nivolumab 
Combination Immunotherapy ................................................42 
6.6.2 
Dose Modifications for Nivolumab .........................................................42 
6.6.3 
Dose Modifications for NKTR-214 .........................................................44 
6.6.3.1 
Permanent Treatment Discontinuation Criteria .....................46 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................48 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ........................................48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........48 
7.3 
LOST TO FOLLOW-UP .......................................................................................48 
8 
STUDY ASSESSMENTS AND PROCEDURES .............................................................48 

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8.1 
EFFICACY ASSESSMENTS ...............................................................................48 
8.1.1 
Laboratory Assessments of Clinical Activity ..........................................48 
8.2 
SAFETY ASSESSMENTS ....................................................................................49 
8.2.1 
Increased Monitoring and Vital Sign Guidelines for Infusion-related 
Reaction or Hypotension .........................................................................49 
8.2.2 
Echocardiograms .....................................................................................49 
8.2.3 
Clinical Safety Laboratory Assessments .................................................49 
8.2.3.1 
Local Laboratory Assessments ..............................................49 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..............................50 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................50 
8.3.7 
Adverse Events of Special Interest ..........................................................51 
8.4 
TREATMENT OF OVERDOSE ...........................................................................51 
8.5 
PHARMACOKINETICS .......................................................................................51 
8.6 
ANTI-DRUG ANTIBODIES ................................................................................51 
8.7 
BIOMARKERS .....................................................................................................51 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ..........51 
9 
STATISTICAL CONSIDERATIONS...............................................................................51 
9.5.1 
Interim Safety Monitoring .......................................................................51 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ....52 
10.1 
APPENDIX A-1: MANAGEMENT ALGORITHMS ..........................................53 
10.2 
APPENDIX A-2: LISTS OF TERMINOLOGY AND ABBREVIATIONS ........61 
10.2.1 
List of Terminology .................................................................................61 
10.2.2 
List of Abbreviations ...............................................................................61 
10.3 
APPENDIX A-3: APPENDIX COHORT A AMENDMENT HISTORY ............65 
11 
REFERENCES ..................................................................................................................66 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities ............................................................................................13 
Table 2: 
Overall Tumor Response by Cancer Type: PIVOT-02 Dose-escalation Phase .....21 
Table 3: 
Overall Tumor Response by Cancer Type: PIVOT-02 Expansion at 
Recommended Phase 2 Dose .................................................................................22 
Table 4: 
Safety: PIVOT-02 Expansion at Recommended Phase 2 Dose .............................23 
Table 5: 
Cohort-Specific Objectives and Corresponding Endpoints ...................................26 
Table 6: 
Study Intervention ..................................................................................................34 
Table 7: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation ......................38 
Table 8:  
Dose Modification and Toxicity Management Guidelines for Infusion-related 
Reactions Associated with the administration of NKTR-214 and/or Nivolumab .41 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab ...................................................................................43 
Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints ......................................................................................49 
Table 11: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of Safety
................................................................................................................................50 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schema.........................................................................................................11 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol Title: 
A Multicenter, Open-Label, Exploratory Platform Study to Evaluate Biomarkers and 
Immunotherapy Combinations for the Treatment of Patients with Metastatic Castration-resistant 
Prostate Cancer 
Appendix Cohort A 
Short Title: 
Platform Study for Prostate Researching Translational Endpoints Correlated to Response to 
Inform Use of Novel Combinations (PORTER) 
Note to Investigators:  This cohort appendix is intended to supplement the core protocol, and as 
such, will focus on combination-specific (ie, NKTR-214 and nivolumab) information that is not 
already available in the core protocol. 
Rationale: 
This study cohort is designed to explore the immune activation properties of NKTR-214 by 
induction of tumor infiltrating T and natural killer (NK) lymphocytes when used in combination 
with anti-programmed cell death 1 (PD-1) therapy in metastatic castration-resistant prostate 
cancer (mCRPC). 
Objectives and Endpoints: 
Refer to the core protocol. 
Combination-specific exploratory objectives include: 
Combination-specific Exploratory Objectives 
Endpoints 
• To evaluate the PK of NKTR-214 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
NKTR-214 and/or nivolumab. 
• Sparse PK analysis 
• Presence of ADA against NKTR-214 and/or 
nivolumab. 
ADA = anti-drug antibodies; PK = pharmacokinetics 
 
Overall Design, Number of Participants, Follow-up, and Data Monitoring Committee: 
Refer to the core protocol. 

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Intervention Groups and Duration: 
Participants will be assigned to receive one of the enrolling immunotherapy combination study 
interventions. In this cohort, participants will receive NKTR-214 and nivolumab as follows: 
Intervention 
Dose 
Frequency 
Route 
Schedule 
NKTR-214 
0.006 mg/kg 
Q3W 
IV over 30 (± 5) minutes 
Starting Day 1 
Nivolumab 
360 mg 
Q3W 
IV over 30 minutes 
Starting Day 1 
IV = intravenous(ly); Q3W = every 3 weeks 
 
Participants will be administered intravenous (IV) fluid and provided guidelines for self-
administered oral hydration following administration of NKTR-214. 
NKTR-214 and nivolumab will be administered for up to 2 years, unless the participant: is no 
longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression 
and/or clinical deterioration); experiences any toxicity meeting specified discontinuation criteria 
(see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician 
(ie, Investigator discretion); reaches the maximum duration of study intervention; or withdraws 
consent. In this cohort, a cycle is defined as 3 calendar weeks. 
1.2 
SCHEMA 
The study schema is depicted in Figure 1. 

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Figure 1: 
Study Schema 
 
IV = intravenously; mCRPC = metastatic castration-resistant prostate cancer; Q3W = every 3 weeks; S = screening 
NKTR-214 and nivolumab will be administered for up to 2 years, unless the participant: is no longer clinically benefiting (as evidenced by symptomatic or 
radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see Section 6.6) or 
unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or withdraws consent. A cycle 
is defined as 3 calendar weeks. Participants will be followed for up to 2.5 years from the time of the initiation of study intervention. 
This study design is applicable to Stage 1, as well as Stage 2 if the cohort is expanded. 

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1.3 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SOA) shown in Table 1 is specific for this combination and 
supersedes the SOA provided in the core protocol. 

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Table 1: 
Schedule of Activities 
Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: NKTR-214 + Nivolumab 
End of 
Treatmentb 
Follow-up 
Cycle 1 (Q3W) 
Cycles 2, 3, and 4 
Cycle 5 Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 1 
Day 8 
Day 1 
Day 
8 
14 – 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 1 
± 1 
± 1 
± 3 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Review of I/E criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
ECOG performance 
status 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Vital signs (see Core 
Protocol Section 8.2.3) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Body weight 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Hematology (see Table 
11) 
X 
Xe 
X 
X 
X 
Xe 
X 
Xe 
X 
X 
X 
 
Clinical chemistry (see 
Table 11) 
X 
Xe 
 
 
X 
Xe 
X 
Xe 
X 
X 
X 
 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Prostate-specific antigen 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Testosterone level 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Circulating tumor cellsf 
 
Xe 
 
 
 
Xe 
 
Xe 
 
X 
 
 
cfDNA (blood)g 
X 
 
 
 
 
Xe (Cycles 
2 and 4) 
 
 
 
X 
 
 
Circulating soluble 
analytes/PK/ADAh 
X 
Xe 
X 
 
X 
Xe (Cycles 
2, 3, and 4) 
 
 
 
X 
 
 

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Tests & Procedures 
Screening/ 
Enrollmenta 
On-Treatment: NKTR-214 + Nivolumab 
End of 
Treatmentb 
Follow-up 
Cycle 1 (Q3W) 
Cycles 2, 3, and 4 
Cycle 5 Onward 
Day 
Day -28 to 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 1 
Day 8 
Day 1 
Day 
8 
14 – 28 
days after 
last dose 
110 days 
after last 
dose 
Q3Mc 
Window (days) 
-28 
 
± 1 
± 1 
± 1 
± 3 
± 1 
± 3 
± 3 
± 7 
± 10 
± 14 
NKTR-214 PKi 
X 
Xe 
X 
 
X 
Xe (Cycles 
2, 3, and 4) 
 
 
 
X 
 
 
Blood immune 
biomarkersh 
X 
Xe 
 
 
X 
Xe 
(Cycles 2, 
3, and 4) 
 
 
 
X 
 
 
Archival tumor tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyj 
X 
 
 
 
 
X 
(Cycle 2) 
 
 
 
X (at PD 
[optional])j 
 
 
Stool collectionk 
X 
 
 
 
 
X 
(Cycle 2)k 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
All AEs and SAEs will be collected for at least 100 days after the last dose of study intervention.l 
 
NKTR-214 
administrationm 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Administer IV fluidsn 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Nivolumab 
administrationo 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Radiographic disease 
assessment 
X 
At Week 9 (± 1 week), repeat every 9 weeks (± 1 week) for the first 27 weeks, and every 12 weeks (± 1 week) 
thereafter until radiographic PD or start of subsequent therapy 
Review of alternate 
anticancer therapyp 
 
 
 
 
 
 
 
 
 
 
X 
X 
Follow up for overall 
survival 
 
 
 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibodies; AE(s) = adverse event(s); cfDNA = cell-free deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; I/E =  inclusion/exclusion; IV = intravenously; MUGA = multigated acquisition; PD = progressive disease; 
PK = pharmacokinetics; Q3M = every 3 months; Q3W = every 3 weeks; SAE(s) = serious adverse event(s) 

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a Tests/procedures performed as standard of care prior to obtaining informed consent and within 28 days prior to the first dose of study intervention do not have to be repeated at 
screening. 
b The End of Treatment Visit will be completed following the last dose of study intervention, either at the completion of the on-treatment phase or at early discontinuation. 
c For up to 2.5 years from the initiation of study intervention, participants in the follow up phase will be contacted by the site to collect alternate anticancer therapy information 
and determine survival status. 
d Informed consent must be obtained prior to any study-specific procedures and may be obtained prior to the 28-day screening window. 
e Blood samples should be collected prior to administration of any study intervention. 
f Circulating tumor cells will be collected at baseline (ie, Day 1 of Cycle 1 prior to study intervention administration), Day 1 of each cycle (prior to study intervention 
administration), and EOT. 
g cfDNA (blood) will be collected at baseline (ie, screening visit prior to study intervention administration), Day 1 of Cycle 2 and Cycle 4, and EOT. 
h Circulating soluble analytes, PK (nivolumab) and ADA blood sample, and/or blood immune biomarkers will be collected at baseline (ie, screening and/or Day 1 of Cycle 1 prior 
to study intervention administration), Day 2 of Cycle 1 (circulating soluble analytes), Day 8 of Cycle 1 (circulating soluble analytes, and blood immune biomarkers), prior to 
study intervention administration on Day 1 of Cycles 2-4, and at EOT. 
i Pre-infusion blood samples will be collected to allow for PK evaluation of NKTR-214. PK blood samples will also be collected immediately post-infusion of NKTR-214 (prior 
to nivolumab administration) on Day 1 of Cycles 1-4. Additionally, PK blood samples will be collected on Day 2 and Day 8 of Cycle 1. 
j Participants will undergo 2-3 tumor biopsies: prior to beginning study intervention (ie, baseline biopsy, mandatory for all participants, including those with bone only disease if 
medically feasible), and during treatment (ie, on-treatment biopsy during Cycle 2, if medically feasible). On- treatment biopsy should occur as early as possible after the second 
dose (Day 2 – Day 10 of Cycle 2); however, any on treatment biopsy after Day 1 of Cycle 2 will be accepted. An optional biopsy may be obtained at the time of disease 
progression, including from participants who respond and subsequently progress. Every attempt should be made for the on-treatment biopsies to be taken from the same lesion as 
the pre-treatment biopsy when feasible. 
k Stool will be collected at screening and during Cycle 2, if possible. Otherwise, any on-treatment stool sample will be acceptable. The stool sample may be collected at the clinic 
or at the participant’s home. 
l All SAEs will be collected from the time the participant signs informed consent. Prior to initiation of study intervention, only SAEs that are related to a protocol-mandated 
intervention, including those that occur prior to the assignment of study procedures should be reported. All AEs will be collected from the start of study intervention. All AEs 
and SAEs will be collected for at least 100 days after the last dose of study intervention. Refer to Section 8.3 of the core protocol for details regarding safety reporting for this 
study. 
m NKTR-214 will be administered at a dose of 0.006 mg/kg IV over 30 minutes Q3W on the same day as nivolumab and will continue for up to 2 years, unless the participant: is 
no longer clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified 
discontinuation criteria (see Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or 
withdraws consent. A cycle is defined as 3 calendar weeks. 
n At least 1 liter of IV fluid will be administered prior to NKTR-214 administration on the day of each NKTR-214 dose. For the next 3 days after administration (ie, Days 2-4 of 
each cycle), participants are required to drink at least 2 liters per day of self-administered oral hydration (note: alcohol and caffeine intake should not be counted toward the daily 
hydration requirements). Advise participants to restrain from strenuous activity and avoid long hot showers and saunas for Days 1 to 5 of each cycle. Per clinical discretion, IV 
fluids may be administered at any time. The Investigator may decide to forego administering IV fluids to a participant if this is deemed in the best interest of the participant (eg, 
evidence of fluid overload). Advise participants with orthostatic symptoms to call their treating oncologist and consider increasing oral hydration (see Section 6.1.1). 
o Nivolumab will be administered at a dose of 360 mg IV over 30 minutes Q3W and will continue for up to 2 years, unless the participant: is no longer clinically benefiting (as 
evidenced by symptomatic or radiographic disease progression and/or clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see Section 6.6) 
or unacceptable toxicity in the best clinical discretion of the treating physician; reaches the maximum duration of study intervention; or withdraws consent. A cycle is defined as 
3 calendar weeks. The time between nivolumab doses should not be less than 18 days. 

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p Collection of information related to any post-study intervention alternate anticancer therapy. 
 

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2 
INTRODUCTION 
Refer to the core protocol. 
2.1 
STUDY RATIONALE 
Refer to the core protocol. 
2.2 
BACKGROUND 
Immunotherapy has changed the landscape of treatments for a number of malignancies, resulting 
in marked clinical benefit for patients with cancers including metastatic melanoma, non-small 
cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Studies of immunotherapy in patients 
with advanced prostate cancer have failed to yield similar results. A phase 3 randomized, 
controlled trial of ipilimumab after docetaxel in patients with metastatic castration-resistant 
prostate cancer (mCRPC) failed to meet its primary endpoint of overall survival (OS; Kwon et 
al., 2014), and early phase studies of programmed cell death 1 (PD-1) blockade in advanced 
malignancies did not demonstrate clinical activity in advanced prostate cancer (Topalian et al., 
2012). However, emerging data suggest subsets of patients with prostate cancer, such as those 
with microsatellite instable tumors, which are enriched for neoantigens for T cells to respond to, 
may respond to anti-PD-1 immunotherapy (Graff et al., 2016). 
The prostate has historically been thought to be an immune-privileged site, with disease evidence 
of intratumoral natural killer (NK) cells, macrophages, and ‘low levels’ of both CD4+ and CD8+ 
T cells in prostate tumor tissue (Flammiger et al., 2012; Sfanos et al, 2009; De Marzo et al., 
2007; Massari et al., 2016). As a ‘cold’ tumor, the immunosuppressive microenvironment may 
contribute to the lack of clinical benefit to immunotherapy in prostate cancer, including low 
programmed cell death ligand 1 (PD-L1) expression (Martin et al., 2015), low mutational burden 
(Alexandrov et al., 2013), low abundance of intratumoral T cells (Flammiger et al., 2012), low 
cytolytic activity of NK cells (Pasero et al., 2016), and accumulation of regulatory T cells 
(Tregs) and myeloid-derived suppressor cells (MDSCs) in tumor bed (Miller et al., 2006; Lopez-
Bujanda and Drake, 2017). Treatment-based approaches that address these mechanisms of 
immune evasion or identify immune-responsive patient subsets may allow for more successful 
immunotherapy treatment approaches for this patient population with high unmet medical need.  
The T cell cytokine interleukin 2 (IL-2) is a potent antitumor cytokine, with a long clinical 
history as one of the first immunotherapeutic agents for the treatment of cancer. Aldesleukin 
(Proleukin®), which is approved by the United States (US) Food and Drug Administration 
(FDA) for metastatic melanoma and metastatic renal cell carcinoma, 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 et al., 2014). However, in addition to acting as a 

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stimulator of the immune system by activating tumor killing CD8+ T cells, aldesleukin also 
suppresses the immune system by activating Tregs (Boyman and Sprent, 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, including capillary leak syndrome, hypotension, 
and pulmonary edema requiring medical management in the intensive care unit.  Nevertheless, a 
continued role for IL-2 in cancer immunotherapy exists, as patients treated with high dose IL-2 
have long lasting durable responses, including patients considered non-responders with stable 
disease (SD) (McDermott et al., 2015). These data underscore the relevance of cytokines and the 
need for improved cytokine therapies in the era of immune checkpoint inhibitors. 
2.2.1 
Background on Nivolumab (Bristol-Myers Squibb Company) 
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 
receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the antitumor immune response. Opdivo® 
(nivolumab) is approved in the US for the treatment of several cancer types, including 
unresectable or metastatic melanoma (as monotherapy or in combination with ipilimumab) and 
as monotherapy in previously-treated metastatic NSCLC, advanced RCC, relapsed or refractory 
classical Hodgkin lymphoma (cHL), locally advanced or metastatic urothelial carcinoma (UC); 
recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), microsatellite 
instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer 
(CRC), and hepatocellular carcinoma (HCC). In phase 1 investigation, nivolumab did not 
demonstrate clinical activity in 17 participants with mCRPC. This is consistent with mCRPC 
having a low level of immune cell infiltrate and tumor mutational burden (TMB). Treatment 
strategies to increase antigen presentation and immune infiltration and activation may improve 
the immune responsiveness of mCRPC to nivolumab. 
Refer to the Investigator’s Brochure (IB; Nivolumab Investigator’s Brochure, 2018) and 
approved US prescribing information (Opdivo [nivolumab] US Prescribing Information [USPI], 
2018) for detailed background information on nivolumab. 
2.2.2 
Background on NKTR-214 (Nektar Therapeutics) 
NKTR-214 is a novel cytokine with enhanced immune system activation. NKTR-214 consists of 
IL-2, which has the same amino acid sequence as aldesleukin (recombinant human IL-2 [rhIL-
2]), conjugated at a defined region within the protein to releasable polyethylene glycol (PEG) 
chains. In contrast to high-dose aldesleukin, which requires patients to be hospitalized for 
administration, NKTR-214 was designed as an outpatient therapy. In addition, NKTR-214 was 

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designed to mitigate the serious toxicities associated with rapid systemic immune activation seen 
with administration of high-dose IL-2 (NKTR-214 Investigator’s Brochure, 2018). 
NKTR-214 is a prodrug of a conjugated cancer immunotherapy cytokine that exerts its biological 
activity by binding to the IL-2 receptor and subsequent activation of effector T cells. The PEG 
chains of NKTR-214 render the molecule inactive. Upon intravenous (IV) administration, the 
PEG chains slowly release via hydrolysis to generate the active cytokine species (2-PEG-IL-2 
and 1-PEG-IL-2) that have a peak plasma concentration 26 to 30 hours after infusion. The slow 
generation of the 2-PEG-IL-2 and 1 PEG-IL-2 significantly mitigates the rapid-onset, systemic 
cytokine-related toxicities associated with high dose IL-2. Furthermore, the prodrug design of 
NKTR-214 with its antibody-like dosing, and the long half-life (13 to 19 hours) and sustained 
CD122 signaling of the active NKTR-214 moiety, obviate the need for 5-day courses of thrice 
daily infusions, or of daily subcutaneous injections. 
The polymer conjugation of NKTR-214 promotes biased signaling through the IL-2 receptor beta 
gamma (IL-2Rβγ). This unique feature preferentially increases the proliferation, activation and 
effector function of tumor antigen-specific CD8+ T cells and NK cells within the tumor 
microenvironment without expanding unwanted intra-tumoral Tregs that are activated through 
the IL-2 receptor alpha beta gamma (IL-2Rαβγ) (Charych et al., 2016a; Charych et al., 2016b). 
Specifically, the location of the NKTR-214 PEG chains interferes with the IL-2 alpha subunit 
responsible for the undesirable effect of activating Tregs in the tumor while continuing to permit 
binding to the IL-2Rβγ (CD122) receptor. 
NKTR-214 also correspondingly promotes expression of PD-1 on the surface of CD8+ T cells 
and induction of a Type II interferon gene signature in the tumor microenvironment, driving cell 
surface expression of PD-L1 on tumor cells (Diab et al., 2017a). The immunogenic properties of 
NKTR-214 with the induction of tumor infiltrating lymphocytes and upregulation of the 
PD-1/PD-L1 axis makes NKTR-214 a potentially promising combination therapy for use with 
checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway. 
Multiple phase 1/2 clinical trials are currently underway in which NKTR-214 is administered 
either as monotherapy or in combination with immune checkpoint inhibitors, such as nivolumab, 
once every 2 or 3 weeks for the treatment of solid tumors (Charych et al., 2017). NKTR-214 has 
been generally well-tolerated in the clinical studies to date, with promising evidence of clinical 
efficacy in cancer patients, indicating a favorable benefit-risk profile. While no objective 
responses were observed in the single-agent study of NKTR-214 (Study 15-214-01 [EXCEL]), 9 
patients experienced tumor shrinkage between 1% and 30%, and 2 patients, after progressing on 
multiple prior therapies, had durable SD > 1 year. One patient with metastatic melanoma, who 
was previously treated with ipilimumab and a BRAF inhibitor, received 25 cycles of NKTR-214 
and had durable SD for 18 months. A second patient with metastatic RCC, who had progressed 

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on high dose IL-2 and was refractory to single-agent OX40 and nivolumab, was treated with 19 
cycles of NKTR-214 and had durable SD for 14 months. Given the biological properties of 
NKTR-214 and nivolumab these observations further supported the rationale for combining 
these two agents. 
NKTR-214 has been safely administered in an out-patient setting supported by appropriate 
clinical monitoring. Hypotension is the most clinical significant adverse effect can be effectively 
mitigated by prevention and hydration guidelines. Hypotension due to capillary leak syndrome as 
has been observed with the use of IL-2 has not been observed in the hypotension associated with 
NKTR-214, which appears to be due to a vasodilatory effect of the cytokines released in 
response to NKTR-214. Other common adverse events (AEs) associated with NKTR-214 appear 
to be largely cytokine-driven, are generally mild or moderate in severity and self-limiting. 
Refer to the IB (NKTR-214 Investigator’s Brochure, 2018 and Addendum 1 to NKTR-214 
Investigator’s Brochure, 2018) for detailed background information on NKTR-214. 
2.2.3 
Rationale for NKRT-214 + Nivolumab Immunotherapy 
Combination 
Given the safety profile, modest antitumor activity, and observed pharmacodynamic effects of 
NKTR-214 on increasing PD-L1 expression and induction of interferon gene signature and T and 
NK lymphocytes in the tumor, a major focus of the development of NKTR-214 treatment is in 
combination with PD-1 checkpoint inhibitors. In an ongoing phase 1/2 study of NKTR-214 and 
nivolumab in immuno-oncology naive patients with locally advanced or metastatic solid tumor 
malignancies (Study 16-214-02 [PIVOT-02 study]), a total of 38 patients with melanoma, 
NSCLC, RCC were enrolled in the phase 1b dose-escalation cohort. Among these patients, 
clinical activity was observed in both PD-L1 negative and positive patients (Table 2). The 
recommended phase 2 dose for the combination is 0.006 mg/kg NKTR-214 and 360 mg 
nivolumab administered on the same day every 3 weeks (Q3W). 

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Table 2: 
Overall Tumor Response by Cancer Type: PIVOT-02 Dose-escalation Phase 
 
Melanoma 
(1L) 
(N = 11) 
RCC (1L) 
(N = 14) 
NSCLC (2L) 
(N = 4) 
NSCLC 
(1/2L) 
(N = 5) 
Best Overall Response (RECIST) 
 
 
 
 
ORR (CR + PR) 
  7 (64%) 
10 (71%) 
3 (75%) 
3 (60%) 
DCR (CR + PR + SD) 
10 (91%) 
11 (79%) 
3 (75%) 
4 (80%) 
ORR by PD-L1 Status 
 
 
 
 
PD-L1 (-) 
3/5 (60%) 
5/8 (63%) 
3/4 (75%) 
3/5 (60%) 
PD-L1 (+) 
4/6 (67%) 
4/5 (80%) 
0 
0 
PD-L1 Unknown 
0 
1/1 
0 
0 
Source: Diab et al., 2018 
1L = first-line; 2L = second-line; CR = complete response; DCR = disease control rate; NSCLC = non-small cell 
lung cancer; ORR = objective response rate; PD-L1 = programmed cell death ligand-1; PR = partial response; 
Q3W = every 3 weeks; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors; 
SD = stable disease 
Data included for the following doses studied:  NKTR-214 0.006 mg/kg Q3W + nivoloumab 240 mg QW; NKTR-
214 0.003 mg/kg Q2W + nivolumab 240 mg Q2W; 0.006 mg/kg Q2W + nivolumab 240 mg Q2W; 0.006 mg/kg 
Q3W + nivolumab 360 mg Q3W 
Data cut: 29 May 2018 
 
In the expansion cohort, 283 patients with melanoma, NSCLC, RCC, UC, or triple-negative 
breast cancer (TNBC) have been treated at the recommended phase 2 dose, including 18 first-
line (1L) patients from the dose-escalation cohort (7 melanoma and 11 RCC; Diab et al., 2018). 
Three of the phase 2 expansion cohorts have met the prespecified efficacy criteria as of the 29 
May 2018 data cutoff, supporting the evaluation of NKTR-214 and nivolumab in registrational 
trials (Table 3). Enrollment is ongoing for additional tumor types in immuno-oncology naive and 
refractory settings. 

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Table 3: 
Overall Tumor Response by Cancer Type: PIVOT-02 Expansion at 
Recommended Phase 2 Dose 
 
Melanoma Stage IV 
Naive 1L 
(N = 28) 
RCC Stage IV 
Naive 1L 
(N = 26) 
UC Stage IV 
Naive 1L 
(Cisplatin-
ineligible) 
(N = 10) 
Best Overall Response (RECIST) 
 
 
 
ORR (CR + PR) 
14 (50%) 
12 (46%) 
6 (60%) 
DCR (CR + PR + SD) 
20 (71%) 
20 (77%) 
7 (70%) 
ORR by PD-L1 Status 
 
 
 
PD-L1 (-) 
5/12 (42%) 
9/17 (53%) 
3/5 (60%) 
PD-L1 (+) 
8/13 (62%) 
2/7   (29%) 
3/5 (60%) 
PD-L1 Unknown 
1/3   (33%) 
1/5   (50%) 
0 
Source: Diab et al., 2018 
CR = complete response; DCR = disease control rate; 1L = first-line; ORR = objective response rate; 
PD-L1 = programmed cell death ligand-1; PR = partial response; RCC = renal cell carcinoma; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease; UC = urothelial carcinoma 
Recommended phase 2 dose: NKTR-214 0.006 mg/kg in combination with nivolumab 360 mg every 3 weeks 
Data cut: 29 May 2018 
 
The combination is safe and well-tolerated at the recommended phase 2 dose, with a low rate of 
≥ Grade 3 treatment-related AEs, including immune-mediated AEs (imAEs; Table 4). 
Cytokine-related toxicity is the most common toxicity observed in patients treated with 
NKTR-214 in combination with nivolumab. These toxicities, reported either as stand-alone 
clinical diagnoses or as the associated individual signs and symptoms, including flu-like 
symptoms, rash, pruritus, cytokine release syndrome, fatigue, and elevated hepatic 
transaminases, are generally mild or moderate in severity and are generally self-limiting. 

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Table 4: 
Safety: PIVOT-02 Expansion at Recommended Phase 2 Dose 
Preferred Term 
NKTR-214 0.006 mg/kg + 
Nivo 360 Q3W 
(N=283) 
Treatment-Related AE Grade 1-2 in > 15% 
 
Flu-like symptomsa 
166 (58.7%) 
Rashb 
126 (44.5%) 
Fatigue 
119 (42.0%) 
Pruritus 
89 (31.4%) 
Nausea 
62 (21.9%) 
Decreased appetite 
54 (19.1%) 
Diarrhea 
43 (15.2%) 
Treatment-Related AE Grade 3 or higher (≥ 1% listed below) 
40 (14.1%) 
Hypotension 
5 (1.8%) 
Syncope 
5 (1.8%) 
Increased lipase 
4 (1.4%) 
Rashb 
4 (1.4%) 
Dehydration 
3 (1.1%) 
Patients who discontinued due to a TRAE 
6 (2.1%) 
Any Immune-Mediated AE (≥ Grade 3) 
10 (3.5%) 
≥ Grade 3 Immune-Mediated AE Treated with Steroid / 
Immunomodulating Medication 
7 (2.5%) 
Pneumonitisc/dyspnea 
2 (0.7%) 
Skin adverse event 
2 (0.7%) 
Hepatitis 
1 (0.4%) 
Colitis 
1 (0.4%) 
Elevated lipase 
1 (0.4%) 
≥ Grade 3 Endocrinopathy 
3 (1.1%) 
Diabetes mellitus treated with insulin 
1 (0.4%) 
Hyperglycemia treated with insulin 
2 (0.7%) 
Source: Diab et al., 2018 
AE(s) = adverse event(s); MedDRA = Medical Dictionary for Regulatory Activities; Q3W = every 3 weeks; 
TRAE(s) = treatment-related adverse event(s) 
Data cut: 07 May 2018 
Patients are only counted once under each preferred term using highest grade 
a Flu-like symptoms includes the following MedDRA preferred terms: chills; influenza; influenza-like illness; 
pyrexia. 
b Rash includes the following MedDRA preferred terms: rash; rash erythematous; rash maculo-papular; rash 
pruritic; erythema; rash generalized; rash popular; rash pustular; rash macular 
c One treatment-related Grade 5 pneumonitis related to nivolumab in a patient with NSCLC pretreated with 
carboplatin/pemetrexed and history of brain metastases 
 

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Translational data from the PIVOT-02 study confirm the rationale for activation of the immune 
system in the tumor microenvironment, with a conversion of PD-L1 negative tumors to PD-L1 
positive on treatment in 9/17 (53%) of patients (Diab et al., 2018). 
Given that NKTR-214 administration results in increasing PD-L1 expression and induction of 
interferon gene signature and T and NK lymphocytes in the tumor, it may overcome some of the 
immune evasion mechanisms identified in mCRPC. NKTR-214 is a potentially promising 
immune-activating agent in combination therapy with checkpoint inhibitors targeting the 
PD-1/PD-L1 pathway, such as nivolumab. Moreover, the side effect profile of NKTR-214 does 
not overlap with that of checkpoint inhibitors, further supporting the use of NKTR-214 as a 
potentially complimentary combination partner with nivolumab. 
2.3 
BENEFIT/RISK ASSESSMENT 
Nivolumab 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including NSCLC, melanoma, RCC, and SCCHN. In confirmatory trials, 
nivolumab demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. 
For monotherapy, the safety profile is similar across tumor types. Most AEs were low-grade 
(Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There is no pattern in 
the incidence, severity, or causality of AEs to nivolumab dose level. Clinically-relevant AEs 
typical of stimulation of the immune system were infrequent and manageable by delaying or 
stopping nivolumab treatment and timely immunosuppressive therapy or other supportive care 
(Nivolumab Investigator’s Brochure, 2018).  
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. 
Overall, these findings support a favorable benefit-risk profile for nivolumab across various 
tumor types. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of nivolumab may be found in the prescribing information (Opdivo 
USPI, 2018). 

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NKTR-214 
NKTR-214 has been generally well-tolerated in the clinical studies to date, both as monotherapy 
as well as in combination with immune checkpoint inhibitors, such as nivolumab, with promising 
evidence of clinical efficacy indicating a favorable benefit-risk profile (NKTR-214 Investigator’s 
Brochure, 2018). NKTR-214 has been safely administered in an out-patient setting supported by 
appropriate clinical monitoring. 
The most clinically important risk, hypotension, can be effectively mitigated by prevention and 
hydration guidelines. Other common AEs associated with NKTR-214 appear to be largely 
cytokine-driven, are generally mild or moderate in severity and self-limiting. Importantly, 
although cases of hypothyroidism, thyroiditis, and vitiligo/hypopigmentation consistent with 
immune-mediated mechanism have been observed in participants receiving NKTR-214 plus 
nivolumab, there is no evidence that NKTR-214 increases the frequency or severity of imAEs 
associated with immune checkpoint inhibitors. The risk mitigation strategy and measures 
described for this immunotherapy combination are considered robust and adequate to safe guard 
participants from clinically significant toxicities. 
NKTR-214 and Nivolumab 
The safety profile of nivolumab is well characterized and manageable when administered alone 
or in combination, including regimens where it is administered in combination with additional 
immuno-oncology products. The risk of hypotension with NKTR-214 seen in the monotherapy 
study was mitigated by the implementation of a hydration protocol in the PIVOT-02 study and 
these guidelines will be used in the current study. The current aggregate safety data for patients 
treated with the combination appears similar to nivolumab monotherapy. Nonclinical data, as 
well as clinical experience with high dose IL-2 and checkpoint inhibitor combinations, indicate 
the potential for improvement in therapeutic response compared with either agent given alone. 
Thus, the potential benefit of this immunotherapy combination appears to outweigh the known 
risks of these agents and warrants clinical investigation. 
3 
OBJECTIVES AND ENDPOINTS 
The cohort-specific objectives and endpoints are listed in Table 5. 

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Table 5: 
Cohort-Specific Objectives and Corresponding Endpoints 
Objectives 
Endpoints 
Primary 
 
• To determine the safety of NKTR-214 + nivolumab 
in participants with mCRPC. 
Refer to the core protocol. 
Secondary 
 
• To determine the ORR of NKTR-214 + nivolumab 
in participants with measurable mCRPC. 
• To determine the DCR ≥ 9 months of NKTR-214 + 
nivolumab in participants with measurable mCRPC. 
• To evaluate the rPFS of NKTR-214 + nivolumab in 
participants with mCRPC. 
• To estimate the OS of NKTR-214 + nivolumab in 
participants with mCRPC. 
Refer to the core protocol. 
Exploratory 
 
• To evaluate the PK of NKTR-214 and/or nivolumab. 
• To evaluate the immunogenicity (ADA) of 
NKTR-214 and/or nivolumab. 
 
Refer to the core protocol for overall exploratory 
objective(s). 
• Sparse PK analysis. 
• Presence of ADA against NKTR-214 and/or 
nivolumab. 
 
Refer to the core protocol for overall exploratory 
endpoint(s). 
ADA = anti-drug antibodies; DCR = disease control rate; mCRPC = metastatic castration-resistant prostate cancer; 
ORR = objective response rate; OS = overall survival; PK = pharmacokinetics; rPFS = radiographic progression-free 
survival 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
In this study intervention cohort, NKTR-214 and nivolumab will be administered Q3W for up to 
2 years (Figure 1), unless the participant: is no longer clinically benefiting (as evidenced by 
symptomatic or radiographic disease progression and/or clinical deterioration); experiences any 
toxicity meeting specified discontinuation criteria (see Section 6.6) or unacceptable toxicity in 
the best clinical discretion of the treating physician; reaches the maximum duration of study 
intervention; or withdraws consent. 
Participants will be monitored for safety and response and will be followed on-study for up to 
2.5 years from the time of the initiation of study intervention. All participants will be followed 
for safety for at least 100 days after discontinuation of study intervention. Approximately 15 
participants, including a minimum of 7 with a non-bone metastatic lesion that can be biopsied, 
will be enrolled in Stage 1. An additional approximately 15 participants, including a minimum of 
7 with a non-bone metastatic lesion, will be enrolled in Stage 2, if the cohort is expanded. 

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A pre-treatment biopsy of a metastatic lesion is required for all participants, including those with 
bone only disease, if medically feasible. Participants must provide also consent for archival 
tissue from a prior biopsy or surgery for prostate cancer. An on-treatment biopsy is required, 
when medically feasible, usually after the second dose of study intervention. An optional biopsy 
may be obtained at the time of disease progression, including from participants who respond and 
subsequently progress following a response to treatment. The on-treatment biopsies should be 
taken from the same lesion as the pre-treatment biopsy when feasible. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The scientific rationale for this combination is provided in Section 2.2.3. 
4.3 
JUSTIFICATION FOR DOSE 
The doses of NKTR-214 and nivolumab proposed for this study have been established as being 
safe, resulting in pharmacodynamic activity and having antitumor activity in previous and 
ongoing clinical trials (Section 4.3.2 and Section 4.3.1.1, respectively). Further, the proposed 
doses are those currently under study as the recommended phase 2 dose in Study 16-214-02, the 
ongoing phase 1/2 study in subjects with locally advanced or metastatic solid tumor 
malignancies (Study 16-214-02 [PIVOT-02 study]; Diab et al., 2017b; Diab et al., 2018). 
Based on the safety profiles of the individual components, as well as the safety data from the use 
of the combination of NKTR-214 and nivolumab in other disease populations, there does not 
appear to be overlapping toxicities. Therefore, this combination at the doses proposed is 
considered warranted for the evaluation of safety and efficacy in this population. 
4.3.1 
Rationale for Nivolumab Dose and Schedule 
In the US, single-agent nivolumab was approved in 2014 at a dose of 3 mg/kg every 2 weeks 
(Q2W). Subsequently, population pharmacokinetics (PPK) and exposure response analyses were 
performed to support use of flat dosing regimens (ie, nivolumab 240 mg Q2W, 360 mg Q3W, 
and 480 mg every 4 weeks [Q4W]) in participants with cancer. A flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg for participants weighing 80 kg, the 
observed median body weight in nivolumab-treated cancer patients, while the nivolumab 360 mg 
Q3W and 480 mg Q4W regimens allow flexibility of dosing with less frequent visits and in 
combination with other agents using alternative dosing schedules to Q2W, such as ipilimumab. 
Using a PPK model, the overall distributions of nivolumab exposures (average steady-state 
concentration [Cavgss], minimum steady-state plasma concentration [Cminss], maximum steady-
state plasma concentration [Cmaxss], and trough concentration after the first dose [Cmin1]) are 
comparable after treatment with either nivolumab 3 mg/kg or 240 mg Q2W (Nivolumab 
Investigator’s Brochure, 2018). The 240 mg Q2W dose was approved in the USPI in September 
2016 for use in metastatic melanoma, NSCLC, and RCC indications. In March 2018, the 480 mg 

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Q4W dose was approved in the USPI for use in metastatic melanoma, NSCLC, RCC, cHL, 
SCCHN, UC, and HCC indications (Opdivo USPI, 2018). 
4.3.1.1 
Nivolumab 360 mg Q3W Dosing Regimen 
Although not approved in the US, available data support the use of 360 mg Q3W. Following 
nivolumab 360 mg Q3W, Cavgss are expected to be similar to those following nivolumab 
3 mg/kg or 240 mg Q2W, while Cminss are predicted to be 6% lower and are not considered to 
be clinically relevant. Cmaxss are predicted to be approximately ~23% greater relative to that 
following nivolumab 3 mg/kg Q2W dosing. However, the range of nivolumab exposures 
(median and 90% prediction intervals) following administration of 240 mg flat Q2W, 360 mg 
Q3W, and 480 mg Q4W regimens across the 35 to 160 kg weight range are predicted to be 
maintained well below the corresponding exposures observed with the well tolerated 10 mg/kg 
nivolumab Q2W dosing regimen. This less frequent dosing regimen (ie, Q3W vs Q2W) is 
designed to afford greater convenience to the target patient population and allow combination of 
nivolumab with other agents (Nivolumab Investigator’s Brochure, 2018). 
4.3.2 
Rationale for NKTR-214 Dose and Schedule 
The clinical pharmacology profile of single-agent NKTR-214 was assessed in Study 15-214-01 
(Study 15-214-01 [EXCEL]). NKTR-214 was administered as a 15-minute intravenous infusion 
at dose levels of 0.003, 0.006, 0.009, and 0.012 mg/kg every 2 weeks (Q2W) or Q3W. The 
maximum tolerated dose (MTD) of NKTR-214, based on pre-defined dose limiting toxicity 
(DLT) criteria, was 0.009 mg/kg administered Q3W. Blood samples were analyzed for NKTR-
214 related cytokines (NKTR-214-RC), NKTR-214 active cytokines (NKTR-214-AC), 
unconjugated IL-2, and PEG to characterize the pharmacokinetics (PK) and metabolism of 
NKTR-214 (NKTR-214 Investigator’s Brochure, 2018). 
Maximal concentrations of NKTR-214-RC were achieved shortly after the end of the first 
infusion of NKTR-214 and declined monoexponentially thereafter, remaining detectable for 8 to 
11 days postdose and resulting in mean half-life values between 13 and 19 hours across dose 
levels. NKTR-214-RC maximum plasma concentrations (Cmax) and area under the curve (AUC) 
increased linearly with dose.  
NKTR-214-AC concentrations increased gradually after dosing, achieving a mean time to Cmax 
(Tmax) between 26 and 30 hours postdose. After reaching Cmax, NKTR-214-AC declined 
monoexponentially in parallel to the decline in NKTR-214-RC, and remained detectable for 8 
days postdose, resulting in mean half-life values between 13 and 23 hours.   
NKTR-214-RC and NKTR-214-AC exposure were similar across participants within a dose 
cohort and between cycles, without indication of accumulation with either the Q3W or Q2W 

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administration schedules, as expected based on the half-life. NKTR-214-AC and NKTR-214-RC 
exposure increased linearly with dose over the dose range studied. 
Unconjugated IL-2 was only sporadically detected, and when detected, was present only at low 
concentrations (0.5 to 7.1 ng/mL, with the majority near the quantitation limit of 0.5 ng/mL) 
indicating that unconjugated IL-2 does not contribute to plasma NKTR-214 exposure. Analysis 
of PEG is ongoing. 
The effect of nivolumab on NKTR-214 PK was assessed in Study 16-214-02 (PIVOT-02), based 
on NKTR-214-RC exposure. Pharmacokinetics of NKTR-214-RC in combination with 
nivolumab appear similar to those after NKTR-214 monotherapy, suggesting no drug-drug 
interaction between NKTR-214 and nivolumab (NKTR-214 Investigator’s Brochure, 2018). 
4.4 
TREATMENT BEYOND DISEASE PROGRESSION 
Refer to the core protocol. 
4.5 
END OF STUDY DEFINITION 
Refer to the core protocol for the end of study definition. 
The total length of this study cohort, from screening of the first participant to the end of the 
cohort, is expected to be approximately 3 years, 9 months. 
5 
STUDY POPULATION 
Prospective requests for approval of protocol deviations to recruitment and enrollment criteria, 
also known as waivers or exemptions, is not allowed. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all the following criteria apply: 
5.1.1 
Common Inclusion Criteria 
1. Participant must be ≥ 18 years of age at the time the informed consent is signed. 
2. Participants must agree to use an adequate method of contraception as outlined in 
Appendix 6 of the core protocol starting with the first dose of study intervention and for 
at least 7 months after the last dose of study intervention and refrain from donating sperm 
during this period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
3. Participants must be able and willing to comply with the study visit schedule and study 
procedures. 
4. Histologically documented adenocarcinoma of the prostate. 

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5. Metastatic castration resistant prostate cancer with castrate-level testosterone 
(< 50 ng/dL) at screening. 
6. Have received and progressed on prior secondary androgen receptor signaling inhibitor 
therapy (eg, abiraterone, enzalutamide, apalutamide). Progression is defined by one or 
more of the following 3 criteria: 
a. Prostate-specific antigen (PSA) ≥ 1.0 ng/mL and rising PSA by at least 2 
consecutive measurements a minimum of 1-week apart. 
b. Soft tissue progression as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 (Eisenhauer et al., 2009). 
c. Bone disease progression as defined by 2 new bone lesions (as per Prostate 
Cancer Clinical Trials Working Group 3 [PCWG3; Scher et al., 2016]).  
7. Have measurable disease or non-measurable disease based on PCWG3-modified 
RECIST 1.1. 
8. Provide fresh pre-treatment core needle or incisional biopsy of a metastatic tumor lesion 
not previously irradiated. Fine needle aspiration is not acceptable. 
a. Additionally, if a pre-treatment biopsy is not medically feasible for participants 
with bone only disease, formalin-fixed paraffin-embedded (FFPE) tumor 
specimen in a paraffin block (preferred) or at least 10 slides containing unstained, 
freshly cut, serial sections must be provided. 
b. For all participants, in addition to fresh pre-treatment biopsy, consent for archival 
tissue is required. 
9. Must be willing to undergo tumor biopsy(ies) on treatment, if medically feasible. 
10. Participants must discontinue antiandrogen therapy (ie, bicalutamide, flutamide, 
nilutamide) at least 4-6 weeks prior to registration with no evidence of PSA decline after 
washout. 
a. Bicalutamide: Washout period at least 6 weeks 
b. Flutamide and nilutamide: Washout period at least 4 weeks 
11. Participants must discontinue therapies for mCRPC for 5 half-lives or 28 days, whichever 
is shorter. 
a. Participants will remain on gonadotropin-releasing hormone (GnRH) agents 
throughout this study. 
b. Prior chemotherapy is allowed if no progression of disease on chemotherapy as 
defined by PCWG3-modified RECIST 1.1.  
c. Prior treatment with sipuleucel-T, radium-223, or poly adenosine diphosphate 
(ADP)-ribose polymerase (PARP) inhibitor (eg, olaparib) is allowed. 
d. Tissue biopsy may be performed during washout period. 
12. Participants with prior or concurrent malignancies are permitted if any one of the 
following applies: 

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a. Previously treated malignancy for which all treatment of that malignancy was 
completed at least 2 years before enrollment and no evidence of disease exists, or 
b. With agreement from the Medical Monitor and Principal Investigator (PI), 
participants who have a concurrent malignancy that is clinically stable and does 
not require tumor-directed treatment are eligible to participate if the risk of the 
prior malignancy interfering with either safety or efficacy endpoints is very low, 
or 
c. With agreement from the Medical Monitor and PI, other malignancies may be 
permitted if the risk of the prior malignancy interfering with either safety or 
efficacy end points is very low. 
13. Have a performance status of 0 or 1 according to the Eastern Cooperative Oncology 
Group (ECOG) scale. 
14. Demonstrate adequate organ function on screening laboratory tests performed within 
14 days of treatment initiation and as evidenced by: 
a. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin 
(EPO) dependency (within ≤ 7 days of assessment) 
b. Absolute neutrophil count ≥ 1,500/mm3 without growth factor support (within 
< 28 days of assessment) 
c. Platelet count ≥ 100,000/mm3 
d. Estimated glomerular filtration rate (GFR) ≥ 45 mL/min using the Cockcroft-
Gault formula 
e. Serum total bilirubin < 1.5 x upper limit of normal (ULN) or ≤ 2.0 x ULN for 
participants with liver metastases 
i. Participants with Gilbert's syndrome must have ≤ 3 x ULN and no liver 
lesions 
f. Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) 
(SGPT) ≤ 3.0 x ULN or ≤ 5.0 x ULN for participants with liver metastases. 
g. Albumin ≥ 2.5 mg/dL. 
h. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN 
unless participant is receiving anticoagulant therapy, as long as PT is within 
therapeutic range of intended use of anticoagulants. 
i. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is 
receiving anticoagulant therapy, as long as PTT is within therapeutic range of 
intended use of anticoagulants. 

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15. Willing and capable of giving signed informed consent as described in Appendix 1 of the 
core protocol, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
 
5.1.2 
Combination-specific Inclusion Criteria 
1. A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram (ECHO) or multigated acquisition (MUGA) scan test within 60 days 
prior to Cycle 1 Day 1. 
2. Oxygen saturation ≥ 92% on room air. 
 
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1 
Common Exclusion Criteria 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment. 
a. Recent or concurrent non-therapeutic investigational agents that are not 
anticipated to interfere with study intervention, such as certain investigational 
imaging tracers, may be permitted with written agreement from the Medical 
Monitor. 
2. Has a diagnosis of immunodeficiency or conditions that need systemic corticosteroid 
replacement therapy > 10 mg/day prednisone (or equivalent) or other immunosuppressive 
medications within 28 days prior to the first dose of study intervention. Inhaled steroids 
are permitted if necessary. 
3. Has any active known or suspected autoimmune disease. Participants with vitiligo, type I 
diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis not requiring 
systemic treatment, or other conditions under control are permitted to enroll. 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy ≤ 10 mg of prednisone/day for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.  
4. Has a known history of active TB (Bacillus Tuberculosis). 
5. Has known history of, or any evidence of active, non-infectious pneumonitis. 
6. Has an active infection requiring systemic therapy. 
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating Investigator. 

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8. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
9. Is expecting to father children within the projected duration of the trial, starting with the 
pre-screening or screening visit through 7 months after the last dose of study intervention. 
10. Known history of testing positive for human immunodeficiency virus (HIV), known 
acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or 
hepatitis C virus representing acute or chronic disease. 
11. Has received a live vaccine within 30 days of planned start of study intervention. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
12. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least 4 weeks prior to 
the first dose of study intervention and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study intervention.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
13. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier. 
a. Participants with controlled autoimmune disease as described in exclusion 
criterion #3 are permitted to enroll. 
14. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
AEs due to a previously administered agent. 
a. Note:  Participants with ≤ Grade 2 neuropathy and/or hearing loss are an 
exception to this criterion and may qualify for the study. 
b. Note:  If a participant received major surgery, he must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
15. History of allergy to any of the study intervention components. 
 
5.2.2 
Combination-specific Exclusion Criteria 
1. Participants must not have received prior IL-2 therapy. 
2. Has had prior therapy with any anti-PD-1 or anti-PD-L1 antibody (prior therapy with an 
anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] antibody is permitted). 
3. Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms at screening. 

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4. 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 
5. Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics). 
 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 
Meals and Dietary Restrictions 
Complete hydration guidelines are provided in Section 6.1.1. For all cycles, at least 2 liters per 
day of self-administered oral hydration on Days 2 to 5 are recommended. 
5.3.2 
Activity 
As part of the protocol hydration guidelines, participants should be advised to restrain from 
strenuous activity and avoid long hot showers and saunas for Days 1 to 5 of every cycle.   
5.4 
SCREEN FAILURES 
Refer to the core protocol. 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
The study interventions to be administered in this study are summarized in Table 6. 
Table 6: 
Study Intervention 
Study 
Intervention 
Name 
Dosage Formulation 
Unit Dose 
Strength(s) 
Dosage 
Level(s) 
Route of 
Administration 
Sourcing 
NKTR-214 
Sterile lyophilized powder to be 
reconstituted with sterile water 
for injection and diluted with 
commercially available dextrose 
5% or normal saline 
1.0 mg/mL 
of IL-2 
0.006 mg/kg 
IV infusion 
Nektar 
Therapeutics 
Nivolumab 
Aqueous solution 
10 mg/mL 
360 mg 
IV infusion 
Bristol-Myers 
Squibb 
IV = intravenous 
 

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NKTR-214 0.006 mg/kg will be administered as an IV infusion over approximately 30 minutes 
(± 5 minutes) (see Section 4.3.2), followed approximately 30 minutes later by nivolumab 360 
mg, administered as an IV infusion over approximately 30 minutes (see Section 4.3.1.1). Study 
intervention will be administered Q3W for up to 2 years, unless the participant: is no longer 
clinically benefiting (as evidenced by symptomatic or radiographic disease progression and/or 
clinical deterioration); experiences any toxicity meeting specified discontinuation criteria (see 
Section 6.6) or unacceptable toxicity in the best clinical discretion of the treating physician; 
reaches the maximum duration of study intervention; or withdraws consent. A cycle is defined as 
3 calendar weeks. 
The NKTR-214 dose will be determined by the participant’s weight in kilograms, which will be 
determined before the start of each 3-week cycle. If the participant’s weight is within 10% of the 
participant’s weight on Day 1 of Cycle 1, the study drug dose does not need to be recalculated, 
depending on institutional guidelines/preference. 
Administration of study intervention will be performed in a monitored setting in which there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions. 
6.1.1 
Hydration Guidelines for NKTR-214 
Important safety information and hydration instructions are to be provided to participants. 
For those participants enrolled in this cohort, at least 1 liter of IV fluid on will be administered 
prior to NKTR-214 administration on the day of each NKTR-214 dose. For the next 3 days after 
administration (ie, Days 2 – 4 of each cycle), participants should be instructed that they are 
required to drink at least 2 liters per day of self-administered oral hydration (note: alcohol and 
caffeine intake should not be counted toward the daily hydration requirements). Participants 
should be advised to restrain from strenuous activity and avoid long hot showers and saunas for 
Day 1 to Day 5 of each cycle of NKTR-214 administration. Per clinical discretion, IV fluids may 
be administered at any time. The Investigator may decide to forego administering IV fluids to a 
participant if this is deemed to be in the best interest of the participant (eg, evidence of fluid 
overload). 
Participants should be advised to call their treating oncologist if they experience orthostatic 
symptoms and consider increasing oral hydration. 
To mitigate the event of hypotension, consideration should be given to withholding 
antihypertensive medications, including diuretics, as well as other drugs with hypotensive 
properties as described Section 6.5.2. 

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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Refer to the core protocol for general guidance on handling, storage, and accountability. 
NKTR-214 drug product should be stored in a secure, locked area with temperature at monitored 
-20 °C (± 5 °C), as specified on the drug label. 
Nivolumab must be stored at 2°-8°C and protected from light and freezing.  
The instructions for reconstitution and administration of the study intervention are described in 
the Pharmacy Manual(s). 
6.3 
RANDOMIZATION AND BLINDING 
This is not a randomized study, and study intervention will be administered in an open-label 
fashion. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study intervention will be administered by authorized site personnel and tracked using drug 
accountability records. No additional measures of compliance will be instituted. 
6.5 
CONCOMITANT THERAPY 
Refer to the core protocol. 
6.5.1 
Permitted Therapy 
Refer to the core protocol. 
6.5.2 
Prohibited Therapy 
Refer to the core protocol. 
In addition to the prohibited therapy described in the core protocol, based on clinical evidence, 
the Investigator may decide to withhold antihypertensive medications, including diuretics, as 
well as other drugs with hypotensive properties (eg, alpha blockers for benign prostatic 
hypertrophy) prior to each dose of NKTR-214, particularly when therapy involves multiple anti-
hypertensive drugs and classes other than thiazide diuretics. If discontinuing antihypertensive 
medications, discontinue 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 mm Hg and/or the systolic pressure exceeds 160 mm Hg. 
6.6 
DOSE MODIFICATIONS 
6.6.1 
Dose Modifications for the Combination of Nivolumab and 
NKTR-214 
Study participants may not have any dose escalation or dose reduction of nivolumab in this 
study; dose reduction, but not dose escalation, of NKTR-214 is allowed. 

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Participants who experience an AE described in Table 7 will be permanently discontinued from 
all study intervention and should continue follow-up assessments as outlined in the SOA 
(Section 1.3). 
Grade 3 and 4 toxicities are observed in all trials of nivolumab in multiple tumor types. As such 
toxicities are anticipated; however, given the unique nature of this protocol, monitoring for AEs 
described in Table 7 will continue throughout the study. 
The Investigator may attribute each AE to the combination or any individual component of the 
study intervention. Holding of 1 agent and not the other agents is appropriate if, in the opinion of 
the Investigator, the toxicity is clearly related to 1 of the study interventions. If an Investigator 
believes a toxicity is uniquely related to one agent, then appropriate documentation is required 
regarding the drug to which the Investigator is attributing the AE. If, in the opinion of the 
Investigator, the toxicity is related to the combination of nivolumab and NKTR-214 then all 
drugs should be held according to recommended dose modifications. If toxicity does not resolve 
or the criteria for resuming study intervention are not met within 6 weeks after the last dose, the 
participant must be discontinued from the combination therapy, unless written approval to restart 
therapy is provided by the Medical Monitor. 
The anticipated important safety risks associated with the administration of nivolumab and 
NKTR-214, as well as the measures to be taken, are outlined in the following sections. The 
combined effect of NKTR-214 and nivolumab on the AE or immune-related AE (irAE) profiles 
of these agents continues to evolve. Guidance with respect to the individual agents is provided in 
Section 6.6.2 and Section 6.6.3. Refer to the USPI for nivolumab (Opdivo USPI, 2018) and the 
Investigator’s Brochures for nivolumab and NKTR-214 for complete summaries of safety 
information. 

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Table 7: 
Toxicity Criteria Requiring Permanent Treatment Discontinuation 
Participants should be monitored for the occurrence of any of the following AEs that are considered by the 
Investigator to be possibly, probably, or definitely related to nivolumab, NKTR-214, or the immunotherapy 
combination. Treatment with all study intervention should be permanently discontinued for the following: 
• 
Grade 4 non-hematological toxicity (not laboratory) 
• 
Grade 4 hematologic toxicity lasting ≥ 7 days or that is clinically significant 
• 
Grade 3 thrombocytopenia in the presence of clinically significant active bleeding (eg, requiring 
transfusion or hospitalization) 
• 
Any non-hematologic toxicity ≥ Grade 3 in severity, with the following exceptions: 
o 
Endocrinopathy AEs, such as adrenal insufficiency, adrenocorticotropic hormone (ACTH) deficiency, 
hyper- or hypothyroidism, that resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose intolerance managed with glucose-
controlling agents 
o 
Amylase or lipase elevations that last ≤ 7 days 
o 
Electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected 
with supplementation/appropriate management within 72 hours of their onset 
o 
Tumor flare defined as local pain, irritation, or rash localized at sites of known or suspected tumor 
o 
Grade 3 nausea, vomiting, or diarrhea that can be medically managed to ≤ Grade 2 within 72 hours 
o 
Grade 3 hypotension during Cycles 1 or 2 that lasts ≤ 48 hours post-dose 
o 
Fatigue that improves to ≤ Grade 2 with 7 days 
o 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care 
• 
Any new Grade 3 or Grade 4 non-hematologic laboratory abnormality, if 
o 
the abnormality leads to hospitalization, or 
o 
the abnormality persists for > 1 week and is believed to be clinically significant. For example, 
exceptions would include asymptomatic pancreatitis. 
• 
Febrile neutropenia Grade 3 or Grade 4 
• 
Any elevated AST or ALT laboratory value that is ≥ 3 × ULN and an elevated total bilirubin lab value that 
is ≥ 2 × ULN and an alkaline phosphatase lab value that is < 2 × ULN, in which no alternative reasons can 
be found to explain the combination of increased AST/ALT and total bilirubin, such as viral hepatitis A, B 
or C, preexisting or acute liver diseases, pre-existing known liver metastases, or another drug capable of 
causing the observed injury 
• 
Grade 5 toxicity 
ACTH = adrenocorticotropic hormone; AE(s) = adverse event(s); ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; ULN = upper limit of normal 
 
 
6.6.1.1 
Potential for Overlapping Toxicities with Nivolumab and 
NKTR-214 
Based on the safety profile observed with ongoing use of this combination, the toxicities 
associated with the monotherapy administration of nivolumab and NKTR-214 do not overlap 
when administered in combination. 
The safety data for nivolumab are described in the USPI (Opdivo USPI, 2018). Nivolumab 
therapy is associated with immune-mediated adverse reactions, which can be severe and fatal in 
some cases. With appropriate medical therapy, immune-related adverse reactions resolved in 
most cases. Immune-mediated adverse reactions may involve any organ system; however, the 

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most common severe immune-mediated adverse reactions are enterocolitis, endocrinopathies, 
hepatitis, dermatitis (including toxic epidermal necrolysis and Stevens-Johnson syndrome), and 
neuropathy. The safety profile of nivolumab combination therapy varies with the agent combined 
with nivolumab but is generally consistent with the safety profiles observed with either agent 
alone and, in some cases, both frequency and severity of AEs were greater than that observed 
with either agent alone. 
Cytokine-related toxicity is the most common toxicity observed in patients treated with 
NKTR-214 monotherapy and NKTR-214 in combination with nivolumab. These toxicities, 
reported either as stand-alone clinical diagnoses or as the associated individual signs and 
symptoms, including flu-like symptoms, rash, pruritus, cytokine release syndrome, fatigue, and 
elevated hepatic transaminases are generally mild or moderate in severity, and are self-limiting. 
Thyroid dysfunction, reported as hypothyroidism, thyroiditis (may be characterized by initial 
hyperthyroidism followed by hypothyroidism), or hyperthyroidism, occurred primarily in 
patients receiving combination therapy with NKTR-214 and nivolumab. Most of the cases were 
mild or moderate in severity, asymptomatic, and managed by hormone replacement therapy 
without corticosteroids. 
Frequent and significant eosinophilia has been observed in patients receiving both single agent 
NKTR-214 and NKTR-214 plus nivolumab, primarily starting at Cycle 2 or later, consistent with 
a known effect of IL-2 therapy. The frequency of selected AEs (primarily Grade 1 or 2 in 
severity) such as rash, pruritus, edema, nausea, vomiting, diarrhea and dizziness increased with 
level of eosinophilia. Isolated cases of suspected hypereosinophilic syndrome have been 
reported. Absolute eosinophil count should be closely monitored per protocol. 
6.6.1.2 
Dose Modifications and Toxicity Management for Adverse Events 
Associated with Nivolumab and NKTR-214 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms (Appendix 
A-1) have been developed to assist Investigators in assessing and managing the following drug-
related AEs. 
• Immune-mediated colitis 
• Immune-mediated nephritis and renal dysfunction 
• Immune-mediated pneumonitis 
• Immune-mediated hepatitis 

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• Immune-mediated endocrinopathies (hypophysitis, adrenal insufficiency, hypothyroidism 
and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse reactions 
• Immune-mediated encephalitis 
 
6.6.1.3 
Dose Modifications and Toxicity Management for Infusion-
related Reactions Associated with the Administration of 
NKTR-214 and/or Nivolumab 
Interrupt or slow the rate of infusion in participants with mild or moderate infusion reactions. 
Discontinue the immunotherapy combination in participants with severe or life-threatening 
infusion reactions. 
All Grade 3 or 4 infusion reactions should be reported within 24 hours to the study Medical 
Monitor and reported as a serious adverse event (SAE) if it meets the criteria. Infusion reactions 
should be graded as described in Section 10.5.3 of the core protocol. 
Dose modification and toxicity management guidelines for infusion-related reactions are 
provided in Table 8.  
 

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Table 8:  
Dose Modification and Toxicity Management Guidelines for Infusion-related Reactions Associated with the 
administration of NKTR-214 and/or Nivolumab 
Grade 
(NCI CTCAE v 5.0) 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
None 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤ 24 hours 
Stop Infusion 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/h to 50 mL/h).  
Otherwise dosing will be held until symptoms resolve and the participant should 
be premedicated for the next scheduled dose 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study intervention 
Participant may be premedicated 
according to local treatment 
guidelines 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory support indicated 
Stop Infusion 
Administer urgent medical therapy as appropriate/clinically indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the Investigator 
Hospitalization may be indicated 
**In cases of anaphylaxis, epinephrine should be used immediately 
Participant is permanently discontinued from further study intervention 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; IV = intravenous 
 

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6.6.1.4 
Dose Delays and Interruptions of NKTR-214 + Nivolumab 
Combination Immunotherapy 
Dose delays and interruptions are permitted for toxicity reasons (see Section 6.6.2 and 
Section 6.6.3). 
The Investigator may attribute each AE to the combination or to either individual intervention. 
• If, in the opinion of the Investigator, the toxicity is related to the combination of the 
agents, then all drugs should be held according to recommended dose modifications. 
• If the toxicity is considered clearly related to 1 agent, but not the others, then the other 
agents can continue unless toxicity related to that study intervention would warrant a 
dose delay. 
 
Appropriate documentation is required regarding the drug to which the Investigator is attributing 
the AE. If toxicity does not resolve or the criteria for resuming study intervention are not met 
within 6 weeks after the last dose, the participant must be discontinued from the combination 
therapy. 
Dose delays and interruptions for reasons other than toxicity, such as surgical procedures, may 
be allowed with Medical Monitor approval. The acceptable length of interruption will depend on 
agreement between Investigator and Medical Monitor. 
6.6.2 
Dose Modifications for Nivolumab 
This study will include set dosing for nivolumab (360 mg Q3W). Dose escalation or reduction of 
nivolumab will not be allowed. If toxicity does not resolve or the criteria for resuming study 
intervention are not met within 6 weeks after the last dose, the participant must discontinue study 
intervention, unless written approval to restart therapy is provided by the Medical Monitor. 
Specific anticipated or potential toxicities associated with the administration of nivolumab, as 
well as the measures to be taken to avoid or minimize such toxicity in this trial, are described in 
Table 9. 
AEs associated with nivolumab exposure may represent an immunologic etiology. These irAEs 
may occur shortly after the first dose or several months after the last dose of treatment and may 
affect more than one body system simultaneously. Therefore, early recognition and initiation of 
treatment is critical to reduce complications. Based on existing clinical study data, drug-related 
AEs have included pulmonary toxicity, renal toxicity (including acute renal failure), endocrine 
abnormalities, gastrointestinal toxicity, dermatologic toxicity (including rash), and 
hepatotoxicity. For nivolumab monotherapy, as well as when administered in combination, the 
majority of these AEs have been managed successfully with supportive care and, in more severe 
cases, a combination of dose delay, permanent discontinuation, and/or use of corticosteroids or 

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hormone replacement therapy (endocrinopathies). For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, and skin biopsy may be included as part of the evaluation. 
Dose modification and toxicity management guidelines for irAEs associated with nivolumab are 
provided in Table 9. 
Table 9: 
Dose Modification and Toxicity Management Guidelines for Adverse Events 
Associated with Nivolumab 
Adverse Reaction 
Severitya 
Dose Modifications 
Colitis 
Grade 2 diarrhea or colitis 
Withhold doseb 
Grade 3 diarrhea or colitis 
Withhold doseb  
Grade 4 diarrhea or colitis 
Permanently discontinue 
Pneumonitis 
Grade 2 pneumonitis 
Withhold doseb 
Grade 3 or 4 pneumonitis 
Permanently discontinue 
Hepatitis/non-HCC 
Aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) more than 3 and up 
to 5 times the upper limit of normal (ULN) 
or total bilirubin more than 1.5 and up to 3 
times the ULN 
Withhold doseb 
AST or ALT more than 5 times the ULN or 
total bilirubin more than 3 times the ULN 
Permanently discontinue 
Hepatitis/HCC 
• If AST/ALT is within normal limits at 
baseline and increases to more than 3 and 
up to 5 times the ULN 
• If AST/ALT is more than 1 and up to 3 
times ULN at baseline and increases to 
more than 5 and up to 10 times the ULN 
• If AST/ALT is more than 3 and up to 5 
times ULN at baseline and increases to 
more than 8 and up to 10 times the ULN 
Withhold dosec 
If AST or ALT increases to more than 10 
times the ULN or total bilirubin increases to 
more than 3 times the ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 hypophysitis 
Withhold doseb 
Grade 4 hypophysitis 
Permanently discontinue 
Adrenal insufficiency 
Grade 2 adrenal insufficiency 
Withhold doseb 
Grade 3 or 4 adrenal insufficiency 
Permanently discontinue 
Type 1 diabetes mellitus 
Grade 3 hyperglycemia 
Withhold doseb 
Grade 4 hyperglycemia 
Permanently discontinue 
Nephritis and renal 
dysfunction 
Serum creatinine more than 1.5 and up to 6 
times the ULN 
Withhold doseb 
Serum creatinine more than 6 times the 
ULN 
Permanently discontinue 

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Adverse Reaction 
Severitya 
Dose Modifications 
Skin 
Grade 3 rash or suspected Stevens-Johnson 
syndrome (SJS) or toxic epidermal 
necrolysis (TEN) 
Withhold doseb 
Grade 4 rash or confirmed SJS or TEN 
Permanently discontinue 
Encephalitis 
New onset moderate or severe neurologic 
signs or symptoms 
Withhold doseb 
Immune-mediated encephalitis 
Permanently discontinue 
Other 
Other Grade 3 adverse reaction 
• First occurrence 
• Recurrence of the same Grade 3 adverse 
reaction 
 
Withhold doseb 
Permanently discontinue 
Life-threatening or Grade 4 adverse reaction 
Permanently discontinue 
Grade 3 myocarditis 
Permanently discontinue 
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks 
Permanently discontinue 
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer 
Permanently discontinue 
Source: Opdivo USPI, 2018  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCC = hepatocellular carcinoma; 
SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 
a Guidelines based on toxicity graded per National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), where applicable. 
b Resume treatment when adverse reaction improves to Grade 0 or 1. 
c Resume treatment when AST/ALT return(s) to baseline. 
 
6.6.3 
Dose Modifications for NKTR-214 
Dose delays and reductions are permitted for NKTR-214. Per recommendation of the 
Investigator and approval of the Sponsor’s Medical Monitor, NKTR-214 dose may be delayed or 
reduced to 0.003 mg/kg based on observed drug-related toxicities. If the NKTR-214 dose is 
reduced to 0.003 mg/kg, the dose should remain at this level throughout the remainder of the 
study.  
NKTR-214 may be delayed or reduced for the following reasons (considered to be related to 
NKTR-214): 
• 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 delay or dose reduction may 
be implemented at the discretion of the Investigator with the approval of the Medical 
Monitor. 

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• 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 NKTR-214 dose or at a 
lower NKTR-214 dose level when toxicity resolves to Grade 1 or returns to baseline, 
except for instances where the potential recurrence of the event poses an undue risk for 
the participant. 
If NKTR-214 is delayed, nivolumab administration can continue unless toxicity related to 
nivolumab would warrant a dose delay.   
Participants will be permitted to resume study drug(s) at the same dose level(s) following 
resolution of an AE to ≤ Grade 1 or to baseline within 6 weeks after the last dose, with the 
exception of participants who meet criteria for permanent discontinuation as specified in 
Section 6.6.3.1. Participants who meet criteria for permanent discontinuation of NKTR-214 must 
permanently discontinue all study intervention. 
If the decision is made to resume study drug(s) dosing, the participant should restart treatment on 
the next regularly scheduled study drug(s) dosing visit.  Skipped doses are not to be replaced. 
Participants may resume treatment when the drug-related AE(s) resolve(s) to ≤ Grade 1 or 
baseline, with the following exceptions: 
• Participants may resume treatment in the presence of Grade 2 fatigue. 
• Participants with baseline Grade 1 AST/ALT or total bilirubin who require dose delays 
for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT or total bilirubin. 
• Participants with combined Grade 2 AST/ALT and total bilirubin values meeting 
discontinuation parameters (see Section 6.6.3.1) should have treatment permanently 
discontinued. 
• Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline 
before treatment is resumed. Participants with persistent Grade 1 pneumonitis after 
completion of a steroid taper over at least 1 month may be eligible to resume study 
drug(s) treatment if discussed with and approved by the Medical Monitor. 
• Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the Medical Monitor. 
 
Dose delay of NKTR-214 that results in treatment delay of > 6 weeks requires treatment 
discontinuation, with exceptions as noted in Section 6.6.3.1. However, if the toxicity resolves to 
≤ Grade 1 or baseline > 6 weeks after the last dose, but the participant does not otherwise meet 

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the criteria for permanent discontinuation (see Section 6.6.3.1), and the Investigator believes that 
the participant is deriving clinical benefit, then the participant may be eligible to resume 
treatment with NKTR-214.  
6.6.3.1 
Permanent Treatment Discontinuation Criteria 
Participants meeting any of the following criteria attributed to NKTR-214 will be required to 
permanently discontinue all treatment with NKTR-214. However, with Medical Monitor 
approval, NKTR-214 treatment may continue if the toxicities listed below are considered related 
to nivolumab only, provided the event does not meet criteria for delaying or discontinuation of 
nivolumab (see Section 6.6.2).  
• Disease progression in the absence of clinical benefit (see details regarding continuing 
treatment beyond initial assessment of progression per PCWG3-modified RECIST 1.1 in 
Section 4.4 of the core protocol). 
• Clinical deterioration, as assessed by the Investigator. 
• Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within 6 weeks or requires 
systemic treatment. 
• Any ≥ Grade 2 drug-related pneumonitis or interstitial lung disease that does not resolve 
following dose delay and systemic steroids (also see Pulmonary Adverse Event 
Management Algorithm in Appendix A-1). 
• Any Grade 3 nonskin, drug-related AE lasting > 7 days, with the following exceptions for 
uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, 
hypersensitivity reactions, infusion reactions, endocrinopathies, and laboratory 
abnormalities: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation. 
o Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except: 
 Grade 3 drug-related thrombocytopenia > 7 days associated with clinically 
significant bleeding requires discontinuation. 

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 Any drug-related liver function test abnormality that meets the following criteria 
require discontinuation (also see Hepatic Adverse Event Management Algorithm 
in Appendix A-1): 
­ AST or ALT > 5 × to 10 × ULN for > 2 weeks 
­ AST or ALT > 10 × ULN 
­ Total bilirubin > 5 × ULN 
­ Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN 
• Any Grade 4 drug-related AE or laboratory abnormality, except for the following events, 
which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia ≤ 14 days in duration 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 or 
return to baseline within 7 days. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
o Grade 4 drug-related endocrinopathy AEs such as adrenal insufficiency, 
adrenocorticotropic hormone deficiency, hyper- or hypothyroidism, or glucose 
intolerance, that resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids at ≤ 10 mg of prednisone or equivalent per day, thyroid 
hormones) or glucose-controlling agents, respectively, may not require 
discontinuation after discussion with and approval from the Medical Monitor. 
• Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued 
treatment. 
• Any dosing delay lasting > 6 weeks after the last dose, with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a participant with a dosing delay lasting 
> 6 weeks after the last dose and with no more than 3 missed doses, the Medical 
Monitor must be consulted.  Tumor assessments should continue as per protocol even 
if dosing is delayed. 

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o Dosing delays > 6 weeks after the last dose that occur for nondrug-related reasons, 
may be allowed if approved by the Medical Monitor. Prior to re-initiating treatment in 
a participant with a dosing delay lasting > 6 weeks after the last dose and with no 
more than 3 missed doses, the Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed, and 
participants must otherwise meet the criteria for continued treatment at the time re-
initiation of study intervention is considered. 
 
7 
DISCONTINUATIONS OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Refer to the core protocol. 
In addition to the discontinuation criteria described in the core protocol, refer to Table 7, 
Section 6.6.2, and Section 6.6.3 for toxicities requiring permanent discontinuation of nivolumab 
and/or NKTR-214. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Refer to the core protocol. 
7.3 
LOST TO FOLLOW-UP 
Refer to the core protocol. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Refer to the core protocol. Any combination-specific supplementary information or 
modifications from the core protocol are described in the following sections. 
In this study cohort, the time between doses must not be less than 18 days. 
8.1 
EFFICACY ASSESSMENTS 
Refer to the core protocol. 
8.1.1 
Laboratory Assessments of Clinical Activity 
Samples for the laboratory assessments of clinical activity and hormone levels in Table 10 will 
be sent to the study site’s local laboratory for analysis: 

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Table 10: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Disease-related Endpoints 
Profile 
Laboratory Test 
Clinical activity 
PSA 
Hormone levels 
testosterone 
PSA = prostate-specific antigen 
 
 
8.2 
SAFETY ASSESSMENTS 
Refer to the core protocol for a description of the assessments for medical history and 
demographic data, physical examinations, vital signs, and electrocardiograms. 
Descriptions of additional combination-specific assessments are provided in the following 
sections.  
8.2.1 
Increased Monitoring and Vital Sign Guidelines for Infusion-
related Reaction or Hypotension 
If the participant experiences a ≥ Grade 2 infusion-related reaction or hypotension during the 
days after NKTR-214 and/or nivolumab administration, the participant may be monitored 
overnight at the discretion of the Investigator. Longer periods of monitoring may be 
implemented at the discretion of the Investigator. 
8.2.2 
Echocardiograms 
Standard ECHO will be performed to assess cardiac function and LVEF according to the SOA 
(Section 1.3). In the event of an abnormal ECHO, the Investigator may perform a stress ECHO 
(either exercise or nuclear). A MUGA scan can be performed to assess cardiac function and 
LVEF if a standard echocardiogram cannot be performed. The same assessment method should 
be used for the same participant throughout the study. 
8.2.3 
Clinical Safety Laboratory Assessments 
8.2.3.1 
Local Laboratory Assessments 
Samples for the laboratory tests in Table 11 will be sent to the study site’s local laboratory for 
analysis: 

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Table 11: 
Laboratory Tests Sent to the Study Site’s Local Laboratory for Analysis of 
Safety 
Profile 
Laboratory Test 
Hematology 
RBC count 
hemoglobin 
hematocrit 
WBC count with automated differential (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells) 
platelet count 
manual differential, if clinically indicated 
Clinical Chemistry 
(Serum or Plasma) 
sodium 
potassium 
chloride 
bicarbonate 
glucose 
BUN or urea 
creatinine 
total protein 
albumin 
calcium 
total bilirubin 
alkaline phosphatase 
ALT 
AST 
LDH 
TSH (T3 and FT4 should be checked if TSH is outside the normal range) 
coagulation assessments (PT, PTT, INR)a 
Urinalysis 
 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
INR = international normalized ratio; LDH = lactate dehydrogenase; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell; TSH = thyroid stimulating hormone; WBC = white blood cell 
a Coagulation assessment not required during treatment phase unless indicated 
 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Refer to the core protocol for the SAE and AE collection periods and for details regarding safety 
reporting. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Refer to the core protocol for the regulatory reporting requirements for SAEs. 
For this cohort, the Parker Institute for Cancer Immunotherapy Pharmacovigilance Group will 
report SAEs to regulatory authorities, the overall PI, Bristol-Myers Squibb, Nektar Therapeutics, 
and the Institutional Review Board/Independent Ethics Committee (IRB/IEC), as appropriate. 

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The process for such reporting, including contact information and specific instructions for 
reporting to each of these organizations, is described in the Safety Monitoring Plan. 
8.3.7 
Adverse Events of Special Interest 
There are no identified adverse events of special interest for this immunotherapy combination. 
8.4 
TREATMENT OF OVERDOSE 
Refer to the core protocol. 
8.5 
PHARMACOKINETICS 
Sparse PK blood sampling will be collected according to the SOA to assess the PK of 
NKTR-214 and/or nivolumab. 
PK profiles for NKTR-214 and/or nivolumab may be performed using a validated assay method 
under the supervision of the Sponsor’s designee. 
8.6 
ANTI-DRUG ANTIBODIES 
Immunogenicity samples will be collected according to the SOA to enable evaluation of anti-
drug antibodies (ADA) to either NKTR-214 and/or nivolumab. Additionally, blood samples 
should also be collected at the final visit from participants who discontinued study intervention 
or were withdrawn from the study. These samples may be tested by the Sponsor's designee. 
The detection and characterization of antibodies to NKTR-214 and/or nivolumab may be 
performed using a validated assay method under the supervision of the Sponsor’s designee. 
8.7 
BIOMARKERS 
Refer to the core protocol. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Refer to the core protocol. 
9 
STATISTICAL CONSIDERATIONS 
Refer to the core protocol. 
9.5.1 
Interim Safety Monitoring 
Refer to the core protocol for details related to the Safety Assessment Committee (SAC), the 
committee charged with safety review for this study. 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
Refer to the core protocol for the following appendices: 
Appendix 1: Regulatory, Ethical and Study Oversight Considerations 
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Appendix 3: RECIST Criteria (Version 1.1) with Modifications as Recommended by 
PCWG3 
Appendix 4: Clinical Laboratory Tests 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information 
Appendix 7: Genetics 

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10.1 
APPENDIX A-1: MANAGEMENT ALGORITHMS 
Management algorithms have been developed to provide guidance for Investigators in assessing 
and managing immune-mediated events in participants receiving nivolumab. Section 6.6.2 
describes the criteria for dose delay and discontinuation to be followed for nivolumab in this 
cohort. These algorithms are intended to provide clinical recommendations. In cases in which the 
modification criteria in Section 6.6.2 and the algorithms differ, the criteria in Section 6.6.2 
should take precedence. 
The management algorithms are provided for the following groups of drug-related AEs: 
• Immune-mediated gastrointestinal adverse events (diarrhea, colitis) 
• Immune-mediated renal adverse events (nephritis and renal dysfunction) 
• Immune-mediated pulmonary adverse events (pneumonitis) 
• Immune-mediated hepatic adverse events (hepatitis) 
• Immune-mediated endocrinopathy adverse events (hypophysitis, adrenal insufficiency, 
hypothyroidism and hyperthyroidism, Type 1 diabetes mellitus) 
• Immune-mediated skin adverse events 
• Immune-mediated neurologic adverse events (encephalitis) 
 
 

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10.2 
APPENDIX A-2: LISTS OF TERMINOLOGY AND 
ABBREVIATIONS 
10.2.1 
List of Terminology 
Terminology 
Description 
Cohort 
A group of participants receiving the same immunotherapy 
combination. 
Cohort appendix 
A document that guides the treatment of participants in a given 
cohort. The cohort appendices are identified using a letter 
designation (eg, Appendix Cohort A).  
Core protocol 
The master document that provides the elements common 
across the study and among all cohorts, unless otherwise 
specified. 
Immunotherapy combination 
Two or more study interventions administered to a cohort of 
participants. 
 
10.2.2 
List of Abbreviations 
Abbreviation 
Definition 
1L 
first-line 
2L 
second-line 
ACTH 
adrenocorticotropic hormone 
ADA 
anti-drug antibody(ies) 
ADP 
adenosine diphosphate 
AE(s) 
adverse event(s) 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BUN 
blood urea nitrogen 
C 
cycle 
Cavgss 
average steady-state concentration 
cfDNA 
cell-free deoxyribonucleic acid 
cHL 
classical Hodgkin lymphoma 
Cmax 
maximum observed drug concentration 
Cmaxss 
maximum steady-state plasma concentration 
Cminss 
minimum steady-state plasma concentration 
Cmin1 
trough concentration after the first dose 
CNS 
central nervous system 

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Abbreviation 
Definition 
CR 
complete response 
CRC 
colorectal cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
dMMR 
mismatch repair deficient 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
EPO 
erythropoietin 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GnRH 
gonadotropin-releasing hormone 
HCC 
hepatocellular carcinoma 
HIV 
human immunodeficiency virus 
I/E 
inclusion/exclusion 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IgG4 
immunoglobulin G4 
IL-2 
interleukin 2 
IL-2Rαβγ 
IL-2 receptor alpha beta gamma 
IL-2Rβγ 
IL-2 receptor beta gamma 
imAE(s) 
immune-mediated AE(s) 
INR 
international normalized ratio 
irAE(s) 
immune-related AE(s) 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
mCRPC 
metastatic castration-resistant prostate cancer 
MDSC(s) 
myeloid-derived suppressor cell(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI-H 
microsatellite instability-high 

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Abbreviation 
Definition 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NK 
natural killer 
NKTR-214-AC 
NKTR-214 active cytokines 
NKTR-214-RC 
NKTR-214 related cytokines 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non–small-cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly ADP ribose polymerase 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programed cell death ligand 1 
PEG 
polyethylene glycol 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PORTER 
Prostate Researching Translational Endpoints Correlated to Response 
PPK 
population pharmacokinetics 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q2W 
every 2 weeks 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q4W 
every 4 weeks 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin-2 
rPFS 
radiographic progression-free survival 
S 
screening 
SAC 
Safety Assessment Committee 
SAE(s) 
serious adverse event(s) 

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Abbreviation 
Definition 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
SJS 
Stevens-Johnson syndrome 
SOA 
Schedule of Activities 
TB 
tuberculosis 
TEN 
toxic epidermal necrolysis 
Tmax 
mean time to maximum serum concentration 
TMB 
tumor mutational burden 
TNBC 
triple-negative breast cancer 
TRAE(s) 
treatment-related adverse event(s) 
Treg(s) 
regulatory tumor cell(s) 
TSH 
thyroid stimulating hormone 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
US 
United States 
USPI 
US Prescribing Information 
WBC 
white blood cell 
 

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10.3 
APPENDIX A-3: APPENDIX COHORT A AMENDMENT 
HISTORY 
 
DOCUMENT HISTORY 
Documents 
Date of Issue 
Amendment 1 
24 Jan 2019 
Original Appendix Cohort A 
07 Dec 2018 
 
 
 

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11 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
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