Conditions: Melanoma Renal Cell Carcinoma Non Small Cell Lung Cancer Urothelial Carcinoma Triple Negative Breast Cancer HR+/HER2- Breast Cancer Gastric Cancer
Keywords: NKTR-214 Bempegaldesleukin Nivolumab Paclitaxel Carboplatin Cisplatin Pemetrexed Melanoma Renal Cell Carcinoma Non Small Cell Lung Cancer Urothelial Carcinoma Triple Negative Breast Cancer HR+/HER2- Breast Cancer Gastric Cancer Colorectal Cancer Metastatic Advanced Immunotherapy Anti-PD-1 anti-CTLA-4
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 557
Healthy volunteers: no

Brief summary:
In this four-part study, NKTR-214 was administered in combination with nivolumab and with/without other anticancer therapies. Part 1 considered escalating doublet (NKTR 214 + nivolumab) doses to determine the RP2D. Part 2 considered dose expansion cohorts for the doublet (NKTR 214 + nivolumab ± chemotherapy). Part 3 was schedule-finding for a triplet therapy (NKTR 214 + nivolumab + ipilimumab). Part 4 dose expansion for the triplet (NKTR 214 + nivolumab + ipilimumab) was planned to further assess the efficacy of the RP2D triplet combination at dosing schedules from Part 3.

Detailed description:
Part 1 enrolled patients with advanced or metastatic melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), urothelial carcinoma, or triple negative breast cancer (TNBC) to determine the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD) of NKTR 214 + nivolumab doublet therapy.

Part 2 enrolled patients with advanced or metastatic solid tumor malignancies (including 9 tumor types consisting of the same 5 tumor types as in Part 1, plus hormone receptor positive human epidermal growth factor receptor 2 \[HER 2\] negative breast cancer \[HR+ HER2- BC\], gastric cancer, colorectal carcinoma, and small cell lung cancer \[SCLC\]) to assess the efficacy of the RP2D.

Part 3 enrolled patients with advanced or metastatic melanoma, RCC, NSCLC, or urothelial carcinoma (UCC) in a first-line setting (1L) to assess the safety and tolerability of NKTR 214 + nivolumab + ipilimumab triplet therapy Three dosing schedules were evaluated to establish RP2D dosing schedules for Part 4 of the study.

Part 4 planned to enroll patients with advanced or metastatic melanoma, RCC, NSCLC, or UCC to further assess the efficacy of the RP2D triplet combination at the 3 dosing schedules from Part 3. Patients were enrolled simultaneously to each tumor cohort.

All patients enrolled in the study were closely monitored for safety, tolerability and response per RECIST criteria. The primary efficacy endpoint was objective response rate (ORR) using RECIST 1.1 at the RP2D doublet.

Arms:
arm 1: NKTR 214 + nivolumab at 5 dosage levels to determine the RP2D Part 1 of RP2D in patients with advanced or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, or TNBC. arm 2: NKTR-214+nivolumab in patients with advanced or metastatic solid tumor malignancies to assess the efficacy of the RP2D. arm 3: To assess the safety and tolerability of NKTR 214 + nivolumab + ipilimumab triplet therapy and establish RP2D dosing schedules for Part 4 in patients with advanced or metastatic melanoma, RCC, NSCLC, or UCC in a first-line setting (1L). arm 4: To further assess the RP2D triplet combination dosing schedules from Part 3 in 1L NSCLC and 1L RCC patients.

Interventions: intervention 1: Dose Escalation Doublet: Combination of NKTR-214 + nivolumab intervention 2: Dose Expansion Doublet: Combination of NKTR-214 + nivolumab intervention 3: Schedule Finding Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab intervention 4: Dose Expansion Triplet: Combination of NKTR-214+ nivolumab+ ipilimumab
Intervention descriptions: intervention 1: NKTR 214 + nivolumab at 5 dosage levels. intervention 2: Select patient cohorts with select tumor types will be dosed with NKTR-214 + nivolumab at the RP2D + other anti-cancer therapies per institution standard. intervention 3: 1L patients with RCC, NSCLC, UCC, and melanoma received NKTR-214 0.006 mg/kg q3w in combination with nivolumab and ipilimumab according to 3 dosing schedules. intervention 4: Combination of NKTR-214 + nivolumab + ipilimumab was administered at RP2D dose/schedules in select tumor types

Protocol document:
Prot_000.pdf: 
Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 1 of 178 
Confidential and Proprietary 
 
11 February 2020 
 
 
Nektar Therapeutics 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY OF THE COMBINATION OF 
NKTR-214 AND NIVOLUMAB OR THE COMBINATION OF NKTR-214, NIVOLUMAB, AND 
OTHER ANTI-CANCER THERAPIES IN PATIENTS WITH SELECT LOCALLY ADVANCED 
OR METASTATIC SOLID TUMOR MALIGNANCIES 
Protocol Number: 
16-214-02 
Protocol Amendment Date: 
11 February 2020  
Protocol Amendment No.  
7.0 
Supersedes: 
Amendment 6.0 dated 18 June 2018 
Amendment 5.1 dated 09 January 2018  
Amendment 5.0 dated 05 December 2017 (US) 
Amendment 4.0 dated 22 June 2017 (Canada, Belgium, Ukraine, US) 
Amendment 3.2 dated 07 August 2017 (France) 
US IND Number: 
125471 
EudraCT Number: 
2016-003543-11 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
Sponsor’s Medical Contact 
and Study Medical Monitor: 
 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or consultant for review by 
you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee and applicable 
Regulatory Authorities.  Your acceptance of this document constitutes agreement that you will not disclose the 
information herein to others without written authorization from Nektar Therapeutics except to the extent necessary 
to obtain informed consent from persons who participate as patients in this study. 


Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 2 of 178 
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INVESTIGATOR SIGNATURE PAGE 
Nektar Therapeutics 
TITLE: 
A Phase 1/2, Open-label, Multicenter Study of the Combination 
of NKTR-214 and Nivolumab or the Combination of NKTR-214, 
Nivolumab, and Other Anti-Cancer Therapies in Patients with 
Select Locally Advanced or Metastatic Solid Tumor Malignancies 
PROTOCOL NUMBER: 
16-214-02 
PHASE OF STUDY: 
Phase 1/2 
PROTOCOL DATE: 
11 February 2020 
STUDY SPONSOR: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to the Code of Federal Regulations (21 CFR § 312) and 
ICH E6 Good Clinical Practice guidelines, as well as with any and all applicable federal, state 
and/or local laws and regulations, and agree to conduct the study in accordance with the protocol 
referenced herein. 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date 
 




Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 4 of 178 
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LIST OF STUDY CONTACTS 
Study Contact 
Name 
Contact Information 
Nektar Medical Monitor 
 
Email: 
 
  
 
NKTR-214 Development Program 
Lead 
 
 
Email:  
 
  
 
Serious AE,  
AEs of Special Interest, and 
Pregnancy Reporting 
 
Email: 
 
 
  
 
 


Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 5 of 178 
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11 February 2020 
TABLE OF CONTENTS  
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PRINCIPAL INVESTIGATOR COMMITMENT: ...................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .......................................................................................................................10 
LIST OF FIGURES .....................................................................................................................11 
LIST OF APPENDICES .............................................................................................................11 
ABBREVIATIONS ......................................................................................................................12 
1.0 
STUDY SYNOPSIS .........................................................................................................17 
1.1 
Study Schematics ...................................................................................................37 
1.2 
Schedule of Events .................................................................................................39 
2.0 
INTRODUCTION............................................................................................................48 
2.1 
Background ............................................................................................................48 
2.1.1 
NKTR-214 Mechanism of Action .........................................................48 
2.1.2 
Rationale for the Combination of NKTR-214 and Immune 
Checkpoint Inhibitors ............................................................................48 
2.1.3 
Clinical Experience with IL-2 and Checkpoint Inhibitors ....................49 
2.1.4 
Clinical Experience with NKTR-214 ....................................................49 
2.1.4.1 
Observed Events of Cerebrovascular Accident in Study 16-
214-02 ............................................................................................50 
2.1.4.1.1 
Observed Events of Cerebrovascular Accident Following 
Triplet Immunotherapy ..................................................................51 
2.1.4.1.2 
Observed Events of Cerebrovascular Accident Following 
Doublet Immunotherapy ................................................................52 
2.1.4.2 
Mitigation Measures ......................................................................53 
2.1.5 
Flat Dose Regimens with Nivolumab (360 mg q3w and 480 mg 
q4w) ......................................................................................................53 
2.1.6 
Nivolumab Shorter Infusion Duration ..................................................54 
2.1.7 
Nivolumab Safety Summary .................................................................54 
2.1.8 
Ipilimumab Shorter Infusion Duration ..................................................55 
2.1.9 
Ipilimumab Safety Summary ................................................................55 
2.1.10 
Safety Summary of Study Regimen in Patients with 1L 
Nonsquamous NSCLC ..........................................................................55 
2.1.11 
Safety Summary of Paclitaxel Formulations in Patients with 1L 
NSCLC ..................................................................................................56 
2.1.12 
Safety Summary of Nab-Paclitaxel in Patients with TNBC .................56 


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Nektar Therapeutics 
 
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2.1.13 
Safety Summary of Eribulin in Patients with TNBC ............................57 
2.2 
Overall Benefit/Risk ..............................................................................................57 
2.3 
Data Monitoring Committee ..................................................................................57 
3.0 
STUDY OBJECTIVES ....................................................................................................58 
3.1 
Primary Objectives .................................................................................................58 
3.2 
Secondary Objectives .............................................................................................58 
 
 
4.0 
SELECTION OF STUDY POPULATION ...................................................................59 
4.1 
Inclusion Criteria ...................................................................................................59 
4.2 
Exclusion Criteria ..................................................................................................78 
5.0 
TREATMENT PLAN ......................................................................................................81 
5.1 
Overview ................................................................................................................81 
5.2 
Screening Period ....................................................................................................81 
5.3 
Treatment Period ....................................................................................................82 
5.3.1 
Administration of Study Drug ...............................................................82 
5.3.2 
Part 1:  Dose Escalation ........................................................................83 
5.3.3 
Rationale for Recommended Phase 2 Dose for Part 2 ..........................86 
5.3.3.1 
Update of Safety and Efficacy Data for Protocol Amendment 6 
(dated 18 June 2018) ......................................................................88 
5.3.4 
Part 2:  Dose Expansion ........................................................................89 
5.3.4.1 
Other Anti-Cancer Study Drugs Administered in Part 2 ...............91 
5.3.4.1.1 
Cohorts 3d.1 and 3d.2:  NSCLC (1L nonsquamous) .....................91 
5.3.4.1.2 
Cohort 3e:  NSCLC (1L squamous)...............................................92 
5.3.4.1.3 
Cohort 5b:  TNBC in Combination with Nab-Paclitaxel ...............92 
5.3.4.1.4 
Cohort 5c:  TNBC in Combination with Eribulin ..........................92 
5.3.5 
Part 3: Schedule Finding for Triplet (NKTR-214, Nivolumab, and 
Ipilimumab) ...........................................................................................92 
5.3.6 
Part 4:  Dose Expansion of Triplet (NKTR-214 plus Nivolumab 
plus Ipilimumab) ...................................................................................95 
5.3.7 
Monitoring, Vital Signs, and Hydration Guidelines .............................95 
5.3.7.1 
Frequent Vital Signs ......................................................................96 
5.3.7.2 
Hydration Guidelines .....................................................................96 
5.3.7.3 
Optional Home Health Visits .........................................................97 
5.3.8 
Duration of Treatment ...........................................................................97 
5.3.9 
Treatment Beyond Progression .............................................................97 
5.4 
End of Treatment (EOT) ........................................................................................99 
5.4.1 
Patients in Cohort 3d or Cohort 3e ........................................................99 


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Nektar Therapeutics 
 
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5.5 
Long-Term Follow-up .........................................................................................100 
5.6 
End of Study ........................................................................................................100 
5.7 
Tumor and Radiographic Assessments ................................................................100 
5.8 
Pharmacokinetic Measurements ..........................................................................101 
5.9 
Immunogenicity Measurements ...........................................................................102 
5.10 
 (Blood and Tumor Collection) ..................................103 
 
 
5.10.2 
Tumor Tissue Biopsy Collection Times and Analysis ........................104 
5.10.3 
Stool Sample Analysis ........................................................................104 
5.11 
Determination of Dose-Limiting Toxicities (DLTs) ............................................105 
5.11.1 
DLTs Related to Study Drug(s) ..........................................................105 
5.11.2 
Grade 3 or 4 AEs that Should Not be Considered a DLT ...................105 
5.12 
Delayed Dose-Limiting Toxicities (DLTs) ..........................................................106 
5.13 
Dose Delay and Reduction Criteria .....................................................................106 
5.13.1 
Nivolumab Dose Delay Criteria ..........................................................106 
5.13.2 
Ipilimumab Dose Delay Criteria .........................................................107 
5.13.3 
NKTR-214 Dose Delay and Reduction Criteria .................................108 
5.13.4 
Monitoring and Management of Adrenal Insufficiency and 
Hypophysitis .......................................................................................109 
5.13.5 
Monitoring and Management of NKTR-214-induced Eosinophilia ...109 
5.13.6 
Monitoring and Management of Elevated Hepatic Transaminases ....109 
5.13.7 
Cohorts 3d.1 and 3d.2 (NSCLC) Dose Delay and Reduction 
Criteria for Platinum and Pemetrexed .................................................110 
5.13.8 
Cohort 3e (NSCLC) Dose Delay and Reduction Criteria for 
Platinum and Taxane ...........................................................................111 
5.13.9 
Nab-Paclitaxel Dose Delay and Reduction Criteria ............................113 
5.13.10 
Eribulin Dose Delay and Reduction Criteria ......................................113 
5.13.11 
Criteria to Resume NKTR-214, Nivolumab, or Anti-Cancer Study 
Drugs ...................................................................................................114 
5.13.12 
Permanent Treatment Discontinuation Criteria ..................................115 
5.14 
Management Algorithms for Immune-mediated AEs Associated with 
Immuno-Oncology Agents...................................................................................118 
5.15 
Treatment of NKTR-214, Nivolumab, or Ipilimumab-Related Infusion 
Reactions ..............................................................................................................118 
5.16 
Prior and Concomitant Medications ....................................................................120 
5.17 
Permitted Concomitant Medications/Treatment ..................................................120 
5.18 
Prohibited and/or Restricted Concomitant Medications ......................................121 


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Nektar Therapeutics 
 
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5.18.1 
Prohibited Medications .......................................................................121 
5.18.2 
Blood Pressure Medications ................................................................122 
5.18.3 
Effect of NKTR-214 on the PK of Concomitant Medications ............122 
5.19 
Adverse Events ....................................................................................................123 
5.20 
Assigning Patient Numbers ..................................................................................123 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ............................................124 
6.1 
NKTR-214 Drug Description and Formulation ...................................................124 
6.2 
NKTR-214 Drug Packaging and Labeling ..........................................................124 
6.3 
NKTR-214 Drug Reconstitution and Handling ...................................................124 
6.4 
NKTR-214 Drug Storage .....................................................................................125 
6.5 
NKTR-214 Drug Shipment ..................................................................................125 
6.6 
Nivolumab, Ipilimumab, and Other Anti-Cancer Study Drugs Formulation, 
Reconstitution, Storage, and Packaging...............................................................125 
6.7 
Study Drug Accountability and Reconciliation ...................................................125 
7.0 
ASSESSMENT OF SAFETY OR AES AND SERIOUS AES ...................................127 
7.1 
AE Definition and Assessment ............................................................................127 
7.2 
Monitoring AEs ...................................................................................................127 
7.3 
Grading of AEs ....................................................................................................128 
7.4 
Causality Relationship of AEs .............................................................................128 
7.5 
AE Reporting and Follow-up ...............................................................................129 
7.6 
Serious AE Definition ..........................................................................................129 
7.7 
Serious AE Reporting ..........................................................................................130 
7.8 
Serious AE Follow-up..........................................................................................131 
7.9 
Disease Progression and Death due to Disease Progression – Not Reportable 
as an AE/SAE ......................................................................................................132 
7.10 
Immune-mediated Adverse Events ......................................................................132 
7.11 
Adverse Events of Special Interest ......................................................................132 
7.12 
Potential Drug-Induced Liver Injury ...................................................................132 
7.13 
Pregnancy .............................................................................................................133 
7.14 
Clinical Laboratory Tests .....................................................................................133 
7.15 
Physical Examinations .........................................................................................134 
7.16 
Vital Signs ............................................................................................................134 
7.17 
Electrocardiograms ..............................................................................................134 
7.18 
Echocardiograms..................................................................................................135 
7.19 
Pregnancy Tests ...................................................................................................135 
8.0 
ASSESSMENT OF EFFICACY EVALUATIONS.....................................................136 
8.1 
Definitions............................................................................................................136 


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Nektar Therapeutics 
 
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8.1.1 
Measurable Disease .............................................................................136 
8.1.2 
Non-measurable Disease .....................................................................136 
8.2 
Specifications by Methods of Measurements ......................................................136 
8.2.1 
Tumor Response Evaluation ...............................................................137 
8.2.1.1 
Assessment of Overall Tumor Burden at Baseline and 
Measurable Disease .....................................................................137 
8.2.1.2 
Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions ..137 
8.2.1.3 
Special Notes on the Assessment of Target Lesions ...................138 
8.2.2 
Response Criteria using RECIST 1.1 ..................................................138 
8.2.2.1 
Evaluation of Target Lesions .......................................................138 
8.2.2.2 
Evaluation of Non-Target Lesions ...............................................139 
8.2.2.3 
Confirmatory Measurement/Duration of Response .....................139 
8.2.2.3.1 
Confirmation ................................................................................139 
8.2.2.4 
Evaluation of Overall Response Using RECIST 1.1 ...................139 
9.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE ....................................................................141 
9.1 
General Considerations ........................................................................................141 
9.1.1 
Efficacy ...............................................................................................141 
9.2 
Determination of Sample Size .............................................................................141 
9.3 
Safety Monitoring ................................................................................................146 
9.4 
Replacement of Patients .......................................................................................146 
9.5 
Analysis Sets ........................................................................................................146 
9.6 
Planned Analyses .................................................................................................147 
9.6.1 
Demographics and Baseline Characteristics .......................................147 
9.6.2 
Safety ..................................................................................................147 
9.6.3 
Efficacy ...............................................................................................148 
9.6.4 
Immunogenicity ..................................................................................149 
 
 
9.6.6 
Pharmacokinetics ................................................................................149 
9.7 
Concomitant Medications ....................................................................................150 
9.8 
Missing Data ........................................................................................................150 
10.0 
STUDY OR STUDY SITE TERMINATION ..............................................................151 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...........................................152 
11.1 
Changes to the Protocol .......................................................................................152 
11.2 
Monitoring ...........................................................................................................152 
11.3 
Direct Access to Source Data/Documents for Audits and Inspections ................153 
12.0 
ETHICS ..........................................................................................................................154 


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Nektar Therapeutics 
 
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12.1 
IRB/IEC Approval ...............................................................................................154 
12.2 
Written Informed Consent ...................................................................................154 
13.0 
DATA HANDLING AND RECORD KEEPING ........................................................155 
13.1 
Data Collection Instruments and Source Documents ..........................................155 
13.1.1 
Study Records .....................................................................................155 
13.1.2 
Data Collection Instruments ................................................................155 
13.2 
Retention of Essential Documents .......................................................................155 
13.3 
Confidentiality .....................................................................................................156 
13.4 
Security Measures ................................................................................................156 
14.0 
PUBLICATION POLICY .............................................................................................157 
15.0 
REFERENCES ...............................................................................................................158 
 
LIST OF TABLES 
Table 1: 
Schedule of Events for Part 1.....................................................................39 
Table 2: 
Schedule of Events for Part 2.....................................................................42 
Table 3: 
Schedule of Events for Parts 3 and 4 .........................................................45 
Table 4. 
CVA Adverse Events in Study 16-214-02 .................................................51 
Table 5: 
Part 1:  Dose Escalation Scheme ...............................................................84 
Table 6: 
Part 1:  Dose Escalation Guide ..................................................................84 
Table 7: 
Part 1:  Treatment Cycle Duration and DLT Window ...............................85 
Table 8: 
Patient Exposure Supporting the RP2D .....................................................86 
Table 9: 
16-214-02: Overall Investigator-Assessed Tumor Response for 
Patients Treated at the NKTR-214 Recommended Phase 2 Dose and 
Nivolumab 360 mg q3w in the Dose Escalation Study Phase ...................89 
Table 10: 
Part 2 Treatment Cohorts (All Patients Receive NKTR-214 plus 
Nivolumaba) ...............................................................................................90 
Table 11: 
Example of Concurrent and Staggered Schedule Scenarios for Triplet 
(Dosing Schedule 1) ...................................................................................93 
Table 12: 
Part 3, Cohort A:  Concurrent Dosing Schedules ......................................94 
Table 13: 
Part 4 Indications and Dosing Schedules ...................................................95 
Table 14: 
Dose Levels for Platinum and Pemetrexed ..............................................110 
Table 15: 
Recommended Dose Modifications for Hematologic Toxicity for 
Platinum and Pemetrexed ........................................................................110 
Table 16: 
Recommended Dose Modifications for Non-Hematologic Toxicity for 
Platinum and Pemetrexed ........................................................................111 
Table 17: 
Dose Levels Platinum and Taxane ...........................................................111 


Protocol No. 16-214-02 Amendment 7.0 
 
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Nektar Therapeutics 
 
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Table 18: 
Recommended Dose Modifications for Hematologic Toxicity Platinum 
and Taxane ...............................................................................................112 
Table 19: 
Recommended Dose Modifications for Non-Hematologic Toxicity 
Platinum and Taxane ................................................................................112 
Table 20: 
Dose Recommendations for Eribulin .......................................................114 
Table 21: 
Criteria to Determine Objective Tumor Response for Target Lesions 
per RECIST 1.1 ........................................................................................138 
Table 22: 
Criteria to Determine Tumor Response for Non-Target Lesions per 
RECIST 1.1 ..............................................................................................139 
Table 23: 
Best Overall Response When Confirmation of CR and PR Required .....140 
Table 24: 
True (Target) and Historic Objective Response Rate for Each 
Indication in Part 2 ...................................................................................143 
Table 25: 
True (Target) and Historic Objective Response Rate for Each 
Indication in Parts 3 and 4 .......................................................................146 
Table 26: 
Cerebrovascular Accident Adverse Event Management Algorithm ........178 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic for Parts 1 and 2 .............................................................37 
Figure 2: 
Study Schematic for Parts 3 and 4 .............................................................38 
 
LIST OF APPENDICES 
Appendix 1: 
Clinical Laboratory Tests .........................................................................162 
Appendix 2: 
Schedule of Electrocardiogram, Vital Signs, Pharmacokinetics, 
 
, and Immunogenicity Sample Assessments ...........................165 
Appendix 3: 
Cerebrovascular Accident Adverse Event Management Algorithm ........178 
 


Protocol No. 16-214-02 Amendment 7.0 
 
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Nektar Therapeutics 
 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
1L 
first line 
2L 
second line 
3L 
third line 
5-FU 
fluorouracil 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
AEC 
absolute eosinophil count  
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALK 
anaplastic lymphoma kinase 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
area under the curve 
BOR 
best overall response  
BRAF 
proto-oncogene B-Raf 
BUN 
blood urea nitrogen 
C1D1, C2D1, C3D1, etc. 
Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, etc 
Cavgss 
steady-state average concentration 
Cmaxss 
steady-state peak concentration 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
cis 
cisplatin 
CL 
clearance 
Cmax 
maximum concentration 
CR 
complete response  
CRC 
colorectal carcinoma 
CrCl 
creatinine clearance 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
CVA 
cerebrovascular accident 
D5W 
dextrose 5% in water for injection  
DCI 
data collection instrument 


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Nektar Therapeutics 
 
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Abbreviation or Term 
Definition 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
dMMR 
mismatch repair deficient 
DOR 
duration of response 
DWI 
diffusion-weighted imaging 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCOA 
electronic clinical outcomes assessments 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FNR 
false-negative rate 
FOLFIRI 
5-fluorouracil, leucovorin, and irinotecan 
FOLFOX 
fluorouracil, leucovorin, and oxaliplatin 
FPR 
false-positive rate 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
hr 
hour(s) 
HR 
hormone receptor 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
IL2R 
IL-2 receptor alpha subunit  
IL2R 
IL-2 receptor beta subunit  
imAE 
immune-mediated adverse event 
IND 
Investigational New Drug application 


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Abbreviation or Term 
Definition 
I-O 
immuno-oncology 
IRB 
institutional review board 
irRECIST 
immune-related RECIST 
IV 
intravenous 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MAD 
maximally administered dose 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated protein kinase 
MEL 
melanoma 
min 
minute(s) 
mg 
milligram 
mL 
milliliter 
mm Hg 
millimeters of mercury 
mo 
month 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multigated acquisition  
N1 
sample size at stage 1 
N2 
sample size at stage 2 
NCI 
National Cancer Institute 
NKTR-214 
bempegaldesleukin (International Nonproprietary Name) 
NKTR-214/nivolumab/ipilimumab triplet containing NKTR-214 and nivolumab and ipilimumab 
NE 
non-evaluable 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate  
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 


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Abbreviation or Term 
Definition 
PD-L1 
programmed cell death ligand 1 
PEG 
polyethylene glycol 
PFS 
progression-free survival 
PK 
pharmacokinetic 
pMMR 
mismatch repair proficient 
PPK 
population pharmacokinetics 
PR 
partial response  
PSA 
prostate-specific antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
q1h × 2 
every hour for 2 hours 
q1h × 3 
every hour for 3 hours 
q1h × 4 
every hour for 4 hours 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
q4w 
every 4 weeks 
q6w 
every 6 weeks 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cells 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin 2 
RP2D 
recommended Phase 2 dose 
S1 
futility boundary at stage 1 
S2 
futility boundary at stage 2 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SD 
stable disease 
SLD 
sum of the longest diameters 
SCLC 
small-cell lung cancer 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
T1 
efficacy boundary at stage 1 
T2 
efficacy boundary at stage 2 
T1/2 
terminal elimination phase half-life 
T3 
triiodothyronine 
T4 
free thyroxine 
TEAE 
treatment-emergent adverse event 


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Abbreviation or Term 
Definition 
TIL 
tumor infiltrating lymphocyte 
TIA 
transient ischemic attack 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum concentration 
TNBC 
triple-negative breast cancer 
TP 
total protein 
Treg 
regulatory T cell 
TSH 
thyroid-stimulating hormone 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States of America 
Vd 
volume of distribution 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
WCBP 
women of childbearing potential 
WFI 
Water for Injection 
 


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Nektar Therapeutics 
 
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1.0 
STUDY SYNOPSIS 
Name of Sponsor: 
Nektar Therapeutics 
Name of Finished 
Products: 
Bempegaldesleukin (NKTR-214 drug product) 
Opdivo® 
Yervoy® 
Abraxane® 
Paraplatin® 
Platinol® 
Alimta®   
Halaven®  
Taxol® 
Name of Active 
Ingredients: 
NKTR-214 drug substance 
Nivolumab (anti-PD-1) 
Ipilimumab (anti-CTLA-4) 
Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) 
Carboplatin 
Cisplatin 
Pemetrexed (folate antimetabolite) 
Eribulin mesylate (nontaxane, microtubule dynamics inhibitor) 
Paclitaxel 
Title of Study: 
A Phase 1/2, Open-label, Multicenter Study of the Combination of NKTR-214 and 
Nivolumab or the Combination of NKTR-214, Nivolumab, and  Other Anti-Cancer 
Therapies in Patients with Select Locally Advanced or Metastatic Solid Tumor 
Malignancies 
Duration of Treatment: 
Patients will be treated until disease progression, death, unacceptable toxicity, 
symptomatic deterioration, achievement of maximal response, the Investigator’s 
decision to discontinue treatment, patient decision to discontinue treatment or 
withdraw consent, lost to follow up, or Nektar Therapeutics decides to terminate the 
trial.  Treatment may continue beyond progression if there is clinical benefit as 
determined by the Investigator. 
Phase of Development: 
Phase 1/2 
Objectives: 
The primary objectives are: 
• 
To evaluate the safety and tolerability, and define the maximum tolerated dose 
(MTD) and/or recommended Phase 2 dose (RP2D) of NKTR-214 in combination 
with nivolumab or in combination with nivolumab and other anti-cancer therapies 
• 
To evaluate the efficacy of NKTR-214 in combination with nivolumab or in 
combination with nivolumab and other anti-cancer therapies by assessing the 
objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1) at the RP2D 
The secondary objective is: 
• 
To evaluate the efficacy of NKTR-214 in combination with nivolumab or in 
combination with nivolumab and other anti-cancer therapies by assessing overall 
survival (OS), progression-free survival (PFS), clinical benefit rate (CBR), and 
duration of response (DOR) 




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Study Design: 
Part 1:  Dose Escalation (NKTR-214 plus nivolumab) 
NKTR-214, in escalating doses, will be combined with nivolumab.  The first 
NKTR-214 dose and schedule to be studied (i.e., 0.006 mg/kg once every 3 weeks 
[q3w]) was determined based on an ongoing monotherapy trial with NKTR-214.  The 
dose escalation scheme is provided below. 
Part 1:  Dose Escalation Scheme 
Cohort 
NKTR-214 
Nivolumab q2w 
Nivolumab q3w 
1 
0.006 mg/kg q3w 
240 mg 
 
2 
0.006 mg/kg q3w 
  
360 mg 
3 
0.006 mg/kg q2w 
240 mg 
 
4 
0.009 mg/kg q3w 
  
360 mg 
For dose escalation cohorts the Safety Review Committee will jointly decide the 
following: 
• 
Dose escalation to the next cohort and/or dose schedule 
• 
RP2D 
• 
Dose levels of NKTR-214 for a given cohort may be reduced depending on the 
severity, duration, and frequency of toxicities observed at the previous dose level 
tested. 
• 
Decision to evaluate NKTR-214 and nivolumab in additional patients at lower 
NKTR-214 doses and different dose schedules to assess the benefit/risk profile 
within the anticipated total number of patients. 
DLT evaluation will be based on the study dose schedule as detailed in Section 5.11. 
The Sponsor may choose to concurrently enroll patients and dose NKTR-214 at lower 
dose levels and/or different dose schedules to assess the benefit/risk profile within the 
anticipated 50 patients.  The Sponsor may also evaluate other doses and dose schedules 
based on the safety findings from ongoing clinical trials. 
 
Determination of the Recommended Phase 2 Dose: 
As of October 05, 2017, the safety of NKTR-214 in combination with nivolumab has 
been established in 38 patients across 5 dose cohorts.  In the highest dose tested, 
NKTR-214, 0.009 mg/kg + 360 mg nivolumab, two patients experienced a DLT.  One 
patient had Grade 3 hypotension and a second patient experienced Grade 4 metabolic 
acidosis, each of which resolved within 5 days and the patients continued on treatment 
at a lower dose of NKTR-214.  There were no Grade 3 TRAEs in the 25 patients 
treated at 0.006 mg/kg NKTR-214 with nivolumab 360 mg flat dose q3w.  At the data 
cut of October 05, 2017, there were 34 patients with at least 1 post-treatment tumor 
scan, including 10 with metastatic melanoma, 19 with renal cell carcinoma (RCC), and 
5 with non-small cell lung cancer (NSCLC).  Of these 34 response-evaluable patients, 
21 were treated at 0.006 mg/kg NKTR-214 with nivolumab 360 mg flat dose q3w; 17 
patients had partial or complete responses and 13 had stable disease.  The dose 
escalation portion for NKTR-214 and nivolumab (Part 1) is complete, with the RP2D 
established at 0.006 mg/kg NKTR-214 with nivolumab 360 mg flat dose q3w. 
 
Part 2:  Dose Expansion (NKTR-214 plus nivolumab ± other anti-cancer 
therapies) 
Approximately 936 patients will be enrolled in the cohorts specified in the table below. 
Part 2 is closed to patient screening and enrollment under Amendment 7. 


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Nektar Therapeutics 
 
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Part 2 Cohorts:  All Patients Receive NKTR-214 plus Nivolumaba 
Indication 
Cohort 
Description 
Melanoma 
1ab 
1L 
1bb 
2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
1cc 
2L, BRAF wild type anti-PD-1 or anti-PD-L1 relapse/refractory 
1dc 
1L, following prior adjuvant therapy 
1e 
Patients enrolled under an earlier protocol version who are no longer 
eligible for Cohorts 1a to 1d 
RCC   
2ab 
1L 
2bc 
2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
2c 
Patients enrolled under an earlier protocol version who are no longer 
eligible for Cohorts 2a or 2b 
NSCLC 
3a.1f 
1L, PD-L1< 1%  
3a.2f 
1L, PD-L1 ≥ 1% - < 50%  
3a.3f 
1L, PD-L1 ≥ 50% 
3a.4f 
1L, PD-L1 status unknown 
3bd 
2L, I-O therapy-naive following platinum-based therapy 
3cc 
2L-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
3d.1f 
1L, nonsquamous in combination with platinum/pemetrexed 
(+ maintenance pemetrexed) 
3d.2f 
1L, nonsquamous in combination with platinum/pemetrexed 
(no maintenance pemetrexed) 
3ef 
1L squamous in combination with platinum/taxane 
3fe 
3L+, ALK-translocation/ROS1 rearrangement positive 
3ge 
3L+, EGFR mutation/deletion 
3hf 
2L, following platinum-based doublet cytotoxic chemotherapy 
combined with anti-PD-1 
3i 
Patients enrolled under an earlier protocol version who are no longer 
eligible for Cohorts 3a.1 to 3h 
Urothelial 
4ad 
1L, cisplatin ineligible 
4ad,g 
1L, refused standard of care 
4bc 
2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
4c 
Patients enrolled under an earlier protocol version who are no longer 
eligible for Cohorts 4a and 4b 
TNBC 
5ab 
1-2L, I-O therapy naive 
5bc 
1-2L, I-O therapy naive in combination with nab-paclitaxel 
5cc 
1-2L, I-O therapy naive in combination with eribulin 
5d 
Patients enrolled under an earlier protocol version who are no longer 
eligible for Cohorts 5a to 5c 
HR+ 
HER2- 
BC 
6ac 
I-O therapy naive following hormonal therapy 
6bc 
I-O therapy naive following hormonal and cytotoxic therapy 
Gastric 
7d 
2-3L, I-O therapy naïve 
CRC 
8ac 
2-3L, I-O therapy naive; MSI-high 
8bc 
3-4L, I-O therapy naive; MSI-non-high 
SCLC 
9e  
2L, I-O therapy naive 
Abbreviations: CRC = colorectal carcinoma; HR+ HER2- BC = hormone-receptor positive, HER2-negative 
breast cancer; I-O = immuno-oncology; MSI = microsatellite instability; NSCLC = non-small cell lung 
cancer; RCC = renal cell carcinoma; RP2D = recommended Phase 2 dose; SCLC = small cell lung 
cancer; TNBC = triple-negative breast cancer 
a.   All patients receive the RP2D:  NKTR-214 0.006 mg/kg q3w with nivolumab 360 mg q3w 
b.   Cohorts closed under Amendment 5.1.  
c.   Cohorts closed with an administrative letter dated 29 March 2019. 
d.   Cohorts closed under Amendment 6. 
e.   Cohorts never opened for screening. 
f.   Cohorts closed with an administrative letter dated 22 January 2020. 




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Nektar Therapeutics 
 
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Melanomad 
1 mg/kg 
× 4 doses 
3 mg/kg  
q3w × 4 doses 
NKTR-214 
0.006 mg/kg 
+ nivolumab  
360 mg  
3 
RCCd 
12 
0.006 mg/kg 
3 mg/kg 
× 4 doses 
1 mg/kg q3w × 4 doses 
Melanomad 
a  Enrollment will be up to 12 patients. 
b  NKTR-214 at 0.006 mg/kg and nivolumab at 360 mg will be dosed continuously q3w after the last dose of 
ipilimumab for dosing schedules 2 and 3 following the 4 doses of nivolumab and ipilimumab and 
NKTR-214. 
c  This cohort is a historical cohort and was closed to patient enrollment under Amendment 6. 
d  Cohorts closed with an administrative letter dated 22 January 2020. 
 
The Safety Review Committee will jointly decide the following: 
• 
Dose and schedule for the next cohort 
• 
RP2D 
• 
Dose levels of NKTR-214, for a given dosing schedule, may be reduced 
depending on the severity, duration, and frequency of toxicities observed at the 
previous dose level tested. 
• 
Decision for a recommended phase 2 dose schedule will be determined by both 
safety and pharmacological parameters. 
• 
Decision to evaluate the triplet in additional patients at lower doses and/or 
different dose schedules within the anticipated 36 patients to better assess the 
benefit/risk profile. 
The Sponsor may choose to concurrently enroll patients at lower dose levels and/or 
different dose schedules to assess the benefit/risk profile within the anticipated 
36 patients.  In Part 3, the RP2Ds will be established for each of the 3 dosing schedules 
(it may be necessary for a separate RP2D be established for patients with melanoma 
and urothelial cancers, if the tolerability is different between these 2 groups).  When an 
RP2D is established in Part 3, enrollment for that dosing schedule will begin in Part 4.  
The sponsor will decide which dosing schedules will be opened in Part 4. 
Part 4:  Dose Expansion of Triplet (NKTR-214 plus nivolumab plus ipilimumab) 
Enrollment into the dose expansion cohorts will commence once the RP2D for the 
triplet has been established in Part 3 for each respective tumor type.  The maximum of 
patients in each cohort is listed in Section 9.2 Table 25 (based on a Historical and 
Target ORR); the total will include any patients from each of the 6 cohorts in Part 3, 
thus approximately 106 additional patients may be enrolled into Part 4 (below).   
Patients will be enrolled simultaneously to each indication; for patients with 
melanoma, enrollment will occur simultaneously with dose schedule assigned 
alternately based on date of screening until one of the respective dosing schedule’s 
enrollment is fulfilled.   
Part 4 is closed to patient screening and enrollment under Amendment 7. 
Part 4 Indications and Dosing Schedules 
Indication 
Cohort 
Concurrent Dosing Schedulea 
RCC 
10a.1b 
1 
10a.3d 
3 
NSCLC 
11a.1d 
1 
Melanoma 
12a.2d 
2 
12a.3c 
3 
Urothelial 
13a.2d 
2 


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a  If staggered dosing is to be tested, matching cohorts will be named as follows:  the letter ‘a’ will be 
substituted with ‘b’ (e.g., for the urothelial indication, concurrent dosing Cohort 13a.2 will be named 
staggered dosing Cohort 13b.2). 
b  This cohort is a historical cohort for both concurrent and staggered dosing and was closed to enrollment 
under Amendment 6. 
c  This cohort was closed with an administrative letter dated 29 March 2019. 
d  Cohorts closed with an administrative letter dated 22 January 2020.  
 
If multiple cohorts in the same tumor type are open for enrollment, the sponsor will 
assign the appropriate cohort (whether this is a Part 2 NKTR-214/nivolumab doublet 
cohort [with or without other anti-cancer therapies] or one of the dosing schedules 
investigating the NKTR-214/nivolumab/ipilimumab triplet in Parts 3 and 4). 
Key Eligibility Criteria: 
Under Amendment 7, the study is closed to patient screening and enrollment. 
For the purposes of patient eligibility determination, note the following definitions: 
• 
For the purposes of eligibility, “neoadjuvant therapy” is defined as systemic 
chemotherapy administered prior to definitive local surgery in a patient without 
distant metastases; “adjuvant therapy” is defined as systemic therapy administered 
following definitive local therapy (surgery or radiation) in a patient without distant 
metastases (with no evidence of disease). 
• 
A “line of therapy” is defined as any regimen – single-agent or combination 
therapy, cytotoxic therapy, immuno-oncology therapy separately or in 
combination – that is given for patients with advanced disease, and that is stopped 
for any reason, including progression of disease, toxicity, physician decision, or 
patient withdrawal of consent. 
 
For Parts 1-4 
Under Amendment 7, the study is closed to patient screening and enrollment. 
• 
Provide written, informed consent to participate in the study and follow the study 
procedures 
• 
Male or female patients, age 18 years or older at the time of signing the informed 
consent form (ICF) 
• 
Life expectancy > 12 weeks 
• 
Patients must not have received prior interleukin-2 (IL-2) therapy. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
• 
Measurable disease per RECIST 1.1 
• 
Fresh biopsy or recently obtained biopsy within the past 6 months without 
intervening treatment, and archival tumor tissue available 
 
For Parts 1 and 2 (NKTR-214 plus nivolumab ± other anti-cancer therapies) 
Under Amendment 7, the study is closed to patient screening and enrollment. 
For Disease-Specific Tumor Types 
Melanoma 
• 
Histologically confirmed stage III (unresectable) or stage IV melanoma, as per 
American Joint Committee on Cancer (AJCC) staging system. 
• 
Patients must consent to BRAF testing or have documented BRAF status as per 
regionally acceptable V600 mutational status testing. 
• 
Uveal melanoma will be excluded. 
• 
“Isolated limb perfusion” is not considered systemic chemotherapy. 


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Nektar Therapeutics 
 
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Cohort 1a − Melanoma (1L)  
• 
Have not received prior anti-cancer therapy for advanced or metastatic melanoma. 
For Part 2:   
• 
Prior to disease metastasis, patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens, including, but not limited 
to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other 
antibody or drug specifically targeting T cell co-stimulation or checkpoint 
pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, 
adoptive cell therapies, or other cytokine therapies. 
• 
Patients must not have received any prior therapy for melanoma (including 
therapy for neoadjuvant, adjuvant, locally advanced or metastatic disease, 
including all systemic therapy including tyrosine kinase inhibitors [BRAF, MEK, 
mTOR], bevacizumab, I-O therapy, cytotoxic chemotherapy, and/or isolated limb 
perfusion). 
Cohort 1b − Melanoma (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
• 
Patients must have received only 1 prior line of therapy with an anti-PD-1 or 
anti-PD-L1 containing regimen (doublet-based therapy), which must be their most 
recent anti-cancer treatment.  Patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens.   
• 
Patients must have confirmed radiographic or biopsy-proven disease progression 
at least 4 weeks after initial disease progression, or unequivocal radiographic 
progression as per the Investigator based on a single imaging assessment; this 
assessment must be within 90 days from last dose of anti-PD-1 or anti-PD-L1 
containing regimen.  Patients must consent to providing pre-study scans (if 
available) to confirm radiographic progression. 
• 
Patients may have received only 1 prior line of therapy with molecular-targeted 
therapy. 
• 
Patients who have received only 1 prior regimen of cytotoxic chemotherapy, but 
have not received prior molecular targeted therapy, are eligible.  
• 
Patients may not have primary refractory disease to prior anti-PD-1 therapy 
(radiographic or clinical progression within 120 days of initiation of immuno-
oncology therapy). 
Cohort 1c – Melanoma BRAF wild type (2L, anti-PD-1 or anti-PD-L1 
relapse/refractory) 
• 
Patients must be BRAF wild type. 
• 
Patients must have received only 1 prior line of therapy with single-agent 
anti-PD-1 or anti-PD-L1 therapy, which must be their most recent anti-cancer 
treatment.  Patients must not have received anti-CTLA-4 alone or in combination 
with anti-PD-1 or anti-PD-L1.  Patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens. 
• 
Patients are not eligible who received adjuvant or first-line therapy for 
advanced/metastatic disease consisting of molecular target therapies including, but 
not limited to, BRAF, MEK, or C-KIT targeted therapies (single agent or in any 
combination), or intralesional therapy. 
• 
Patients are not eligible who received doublet immuno-oncology therapy, 
including checkpoint inhibitors combined with either systemic or intralesional 
therapy.  Patients are not eligible who received cytotoxic chemotherapy such as 
dacarbazine, paclitaxel or others. 


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Nektar Therapeutics 
 
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• 
Patients must have confirmed radiographic or biopsy-proven disease progression 
at least 4 weeks after initial disease progression, or unequivocal radiographic 
progression as per the Investigator based on a single imaging assessment; this 
assessment must be within 90 days from last dose of anti-PD-1 or anti-PD-L1 
therapy.   
• 
Patients must consent to providing pre-study scans (if available) to confirm 
radiographic progression. 
Cohort 1d – Melanoma (1L following prior adjuvant therapy) 
• 
Have not received prior anti-cancer therapy for advanced or metastatic melanoma 
• 
Patient must have received prior adjuvant therapy for melanoma; adjuvant therapy 
may consist of any immuno-oncology regimens (single-agent or combination 
therapy) or molecularly targeted therapy(such as tyrosine kinase inhibitors). The 
disease-free interval from last dose of adjuvant therapy to a diagnosis of advanced 
or metastatic melanoma must be less than 180 days.  
Cohort 1e − Melanoma 
• 
Patients who were enrolled under an earlier version of the protocol who are no 
longer eligible for Cohorts 1a through 1d. 
 
Renal Cell Carcinoma (RCC) 
• 
Advanced (not amenable to curative surgery or radiation therapy) or metastatic 
(AJCC stage IV) RCC. 
• 
Histologically confirmed RCC with a clear-cell component. 
Cohort 2a − RCC (1L) 
• 
Have not received prior anti-cancer therapy for advanced or metastatic RCC. 
• 
Prior to disease metastasis, patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens, including, but not limited 
to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other 
antibody or drug specifically targeting T cell co-stimulation or checkpoint 
pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, 
adoptive cell therapies, or other cytokine therapies. 
Cohort 2b  − RCC (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
• 
Patients must have received only 1 prior line of therapy with an anti-PD-1 or 
anti-PD-L1 containing regimen, which must be their most recent anti-cancer 
treatment.  Patients must not have received neoadjuvant or adjuvant therapy with 
any immuno-oncology regimens. 
• 
Patients must have confirmed radiographic disease progression at least 4 weeks 
after initial disease progression, or unequivocal radiographic progression as per 
the Investigator based on a single imaging assessment; this assessment must be 
within 90 days from last dose of anti-PD-1 or anti-PD-L1 containing regimen.  
Patients must consent to providing pre-study scans (if available) to confirm 
radiographic progression. 
Cohort 2c – Renal Cell Carcinoma 
• 
Patients who were enrolled under an earlier version of the protocol who are no 
longer eligible for Cohorts 2a or 2b. 
 
Non-Small Cell Lung Cancer (NSCLC) 
• 
Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC 
(unless otherwise noted) 


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• 
Patients with nonsquamous NSCLC must lack both epidermal growth factor 
receptor (EGFR)-sensitizing mutation/deletion and anaplastic lymphoma kinase 
(ALK) translocation by local testing (assessment of ROS1 mutation status is not 
required, unless otherwise noted).  For ALK or EGFR testing, an FDA-approved 
test or validated assay should be used as applicable for selection of patients.  For 
patients with squamous NSCLC, testing for EGFR, ALK, or ROS1 is not required. 
Cohorts 3a.1, 3a.2, 3a.3, and 3a.4 − NSCLC (1L) 
• 
Patients must have known PD-L1 status as per validated immunohistochemistry 
testing.  Up to 20 efficacy-evaluable patients will be enrolled in each subgroup of 
PD-L1 negative (PD-L1 < 1%; Cohort 3a.1), PD-L1 highly positive 
(PD-L1 ≥ 50%; Cohort 3a.3), or PD-L1 low/intermediate (PD-L1 ≥ 1% - < 50%; 
Cohort 3a.2).  For patients who do not have known PD-L1 status, testing must be 
done using an FDA-approved PD-L1 test.  An abbreviated consent may be 
presented to the patient prior to the Screening period to permit early assessment of 
the PD-L1 status of the tissue sample.  Patients enrolled in Cohort 3a who do not 
have a PD-L1 status assessed by central testing will be assigned to Cohort 3a.4. 
• 
Patients must not have received prior anti-cancer therapy for advanced or 
metastatic NSCLC; patients must not have received prior immuno-oncology in 
any setting (including neoadjuvant, adjuvant, locally advanced or metastatic 
disease). 
Cohort 3b − NSCLC (2L, I-O therapy naive) following platinum-based therapy 
• 
Patients must have experienced disease recurrence or progression during or after 
one prior platinum doublet-based chemotherapy regimen for advanced or 
metastatic disease.  Patients are not eligible who refused prior platinum-based 
therapy.  
• 
Patients who received platinum-containing adjuvant, neoadjuvant, or definitive 
chemoradiation therapy given for locally advanced disease and developed 
recurrent (local or metastatic) disease within 6 months of completing therapy are 
eligible. 
• 
Patients must not have received any prior immuno-oncology in any setting 
regimens, including, but not limited to, checkpoint inhibitors such as anti-PD-1, 
anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte antigen 4 
(anti-CTLA-4)  antibody, or any other antibody or drug specifically targeting 
T cell co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase 
pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine 
therapies. 
Cohort 3c − NSCLC (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
• 
Patients must have received only 1 prior line of therapy with anti-PD-1 or 
anti-PD-L1 therapy. Patients are eligible if they received sequential therapy (e.g., 
cytotoxic chemotherapy followed by anti PD-1 or anti PD-L1 therapy, or vice 
versa). Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens.  
• 
Patients must not have received anti-CTLA-4 alone or in combination with 
anti-PD-1 or anti-PD-L1, unless the anti-CTLA-4 therapy stopped > 1 year prior 
to Cycle 1 Day 1. 
• 
Prior to the anti-PD-1 or anti-PD-L1 therapy regimen, patients must have received 
zero or 1 prior line of cytotoxic chemotherapy for metastatic disease. 
• 
Patients must have confirmed radiographic disease progression at least 4 weeks 
after initial disease progression, or unequivocal radiographic progression as per 
the Investigator based on a single imaging assessment; this assessment must be 
within 90 days from last dose of anti-PD-1 or anti-PD-L1 containing regimen. 


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Patients must consent to providing pre study scans (if available) to confirm 
radiographic progression. 
• 
Patients may not have primary immuno-oncology refractory disease (radiographic 
or clinical progression within 120 days of initiation of immuno-oncology therapy). 
Cohorts 3d.1 and 3d.2 − NSCLC (1L nonsquamous) (in combination with 
platinum/pemetrexed and maintenance pemetrexed [Cohort 3d.1] or without 
maintenance pemetrexed [Cohort 3d.2]) 
• 
Patients must have nonsquamous NSCLC.  The patient will be excluded if the 
histology is considered predominantly squamous cell NSCLC.  Mixed tumors will 
be categorized by the predominant cell type; if small cell elements are present, the 
patient is ineligible. 
• 
Patients must not have received prior anti-cancer therapy for advanced or 
metastatic NSCLC; patients who received adjuvant or neoadjuvant therapy are 
eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months 
prior to the development of metastatic disease.  Patients must not have received 
prior immuno-oncology therapy in any setting (including neoadjuvant, adjuvant, 
locally advanced or metastatic disease). 
• 
Patients must be candidates for platinum/pemetrexed chemotherapy and willing to 
take folic acid and vitamin B12 supplementation. 
• 
Patients must not have received radiation therapy to the lung that is > 30 Gy 
within 6 months of the first dose of study medication. 
Cohort 3e − NSCLC (1L squamous) (in combination with platinum/taxane) 
• 
Patients must have squamous NSCLC. 
• 
Patients must not have received prior anti-cancer therapy for advanced or 
metastatic NSCLC; patients who received adjuvant or neoadjuvant chemotherapy 
(after surgery and/or radiation therapy) and developed recurrent or metastatic 
disease within 6 months of completing therapy are eligible. Patients must not have 
received prior immuno-oncology therapy in any setting (including neoadjuvant, 
adjuvant, locally advanced or metastatic disease). 
• 
Patients must be candidates for platinum/taxane chemotherapy. 
• 
Patients must not have received radiation therapy to the lung that is > 30 Gy 
within 6 months of the first dose of study medication. 
• 
Known hypersensitivity to the selected cytotoxic chemotherapy study drugs.  
Cohort 3f − NSCLC (3L+, ALK-translocation/ROS1 rearrangement positive) 
• 
Patients must have ALK-translocation positive or ROS1 rearrangement NSCLC 
by local pathology report (assessment of ROS1 mutation status is not required).  
For ALK testing, an FDA-approved test or validated assay must be used. 
• 
Patients must have received at least two prior anti-cancer therapies for advanced 
or metastatic NSCLC (these may have included chemotherapy and must have 
included at least one ALK-directed and/or ROS-1-directed therapy), be ineligible 
to receive these therapies due to toxicity, or no longer be considered a candidate 
for additional tyrosine kinase inhibitor therapy; patients must not have received 
prior immuno-oncology therapy in any setting (including neoadjuvant, adjuvant, 
locally advanced or metastatic disease). 
• 
Patients may not have received more than one prior cytotoxic-based regimen (e.g., 
carboplatin with paclitaxel). 
Cohort 3g − NSCLC (3L+, EGFR mutation/deletion) 
• 
Patients must have EGFR mutation or relevant deletion NSCLC by local 
pathology report.  For EGFR testing, an FDA-approved test or validated assay 
should be used. 


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• 
Patients must have received at least two prior anti-cancer therapies for advanced 
or metastatic NSCLC (these may have included chemotherapy and must have 
included at least one EGFR-directed small molecule therapy), be ineligible to 
receive these therapies due to toxicity or no longer be considered a candidate for 
additional tyrosine kinase inhibitor therapy; patients must not have received prior 
I-O therapy in any setting (including neoadjuvant, adjuvant, locally advanced or 
metastatic disease). 
• 
Patients may not have received more than one prior cytotoxic-based regimen (e.g., 
carboplatin with paclitaxel). 
Cohort 3h − NSCLC (2L, anti PD 1 or anti PD L1 relapse/refractory) 
• 
Patients must have received only 1 prior line of therapy with anti PD-1 or anti 
PD-L1 therapy in combination with doublet platinum-containing cytotoxic 
chemotherapy, which must be their most recent anti-cancer treatment. Patients are 
not eligible if they received sequential therapy (e.g., cytotoxic chemotherapy 
doublet therapy followed by anti PD-1 or anti PD-L1 therapy or vice versa). 
Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens. 
• 
Patients must not have received more than 1 prior line of cytotoxic chemotherapy 
for metastatic disease. 
• 
Patients must have confirmed radiographic disease progression at least 4 weeks 
after initial disease progression, or unequivocal radiographic progression as per 
the Investigator based on a single imaging assessment; this assessment must be 
within 90 days from last dose of anti-PD-1 or anti-PD-L1 containing regimen.  
Patients must consent to providing pre study scans (if available) to confirm 
radiographic progression. 
• 
Patients may not have primary immuno-oncology refractory disease (radiographic 
or clinical progression within 120 days of initiation of immuno-oncology therapy). 
Cohort 3i – NSCLC 
• 
Patients who were enrolled under an earlier version of the protocol who are no 
longer eligible for Cohorts 3a.1 to 3h. 
 
Urothelial Carcinoma 
• 
Histologically or cytologically documented locally advanced or transitional cell 
carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or 
urethra.  Patients with mixed histologies are required to have a dominant 
transitional cell pattern. 
Cohort 4a – Urothelial Carcinoma (1L) 
• 
Enrollment of urothelial carcinoma 1L patients will target accrual of up to 
20 patients who are cisplatin-ineligible and up to 20 patients, who, after 
consultation with the Investigator, choose to forego front-line chemotherapy. 
• 
Treatment naive patients who refuse chemotherapy standard of care or treatment 
naive, cisplatin-ineligible patients who meet at least one of the following criteria: 
• 
Creatinine clearance (calculated or measured) < 60 mL/min. Cisplatin-ineligible 
patients must have a creatinine clearance < 60 mL/min and GFR ≥ 30 mL/min.  
• 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≥ 2 
audiometric hearing loss 
• 
CTCAE v4.03 Grade ≥ 2 peripheral neuropathy 
• 
No prior chemotherapy for inoperable locally advanced or metastatic urothelial 
carcinoma.  Prior local intravesical chemotherapy is allowed if completed at least 
4 weeks prior to the initiation of study treatment. 


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• 
For patients who received prior adjuvant/neoadjuvant chemotherapy or 
chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 
12 months between the last treatment administration and the date of recurrence is 
required to be considered treatment naive in the metastatic setting.  Patients must 
not have received neoadjuvant or adjuvant therapy with any immuno-oncology 
regimens. 
Cohort 4b – Urothelial Carcinoma (2-3L, anti-PD-1 or anti-PD-L1 
relapse/refractory) 
• 
Patients must have progressed on only one prior line of therapy that contains 
platinum-based chemotherapy in the metastatic setting or post platinum-based 
chemotherapy in an adjuvant setting with progression < 6 months.   
• 
Patients must have received only one prior line of therapy with single-agent 
anti-PD-1 or anti-PD-L1 therapy, which must be their most recent anti-cancer 
treatment.  Patients must not have received anti-CTLA-4 alone or in combination 
with anti-PD-1 or anti-PD-L1. Patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens. 
• 
Patients must have confirmed radiographic disease progression at least 4 weeks 
after initial disease progression, or unequivocal radiographic progression as per 
the Investigator based on a single imaging assessment; this assessment must be 
within 90 days from last dose of anti-PD-1 or anti-PD-L1 therapy.  Patients must 
consent to providing pre-study scans (if available) to confirm radiographic 
progression. 
Patients may not have primary immuno-oncology refractory disease (radiographic 
or clinical progression within 120 days of initiation of immuno-oncology therapy). 
Cohort 4c − Urothelial 
• 
Patients who were enrolled under an earlier version of the protocol who are no 
longer eligible for Cohorts 4a or 4b. 
 
Cohort 5 − Triple-Negative Breast Cancer (1-2L, I-O therapy naive) 
• 
Patients must have diagnosis of advanced triple-negative breast cancer (TNBC) 
(“advanced” is defined either locally advanced breast cancer not amenable to 
curative surgery or radiotherapy or distant metastases). 
• 
Less than 1% of tumor cell nuclei test positive for estrogen and progesterone 
receptors determined by using standard immunohistochemistry (IHC). 
• 
Human epidermal growth factor receptor 2 (HER2) negative as determined by 
local pathologist, using IHC or in situ hybridization. 
• 
Patients must have had triple negative phenotype of breast cancer in all available 
biopsies that have been examined during the course of the disease.  
• 
Patients must have received 0 or 1 prior line of therapy with systemic cytotoxic 
chemotherapy for advanced TNBC or patient refuses standard of 
care.  Substitution within a class of anti-cancer therapy (e.g., nab-paclitaxel for 
paclitaxel; carboplatin for cisplatin) is permitted; otherwise patients who 
discontinued therapy for reasons other than progressive disease are still considered 
to have received 1 prior line of therapy. 
• 
Patients are excluded whose disease-free interval (for patients with prior 
neoadjuvant or adjuvant chemotherapy: the interval between the last dose of 
neoadjuvant or adjuvant chemotherapy to the diagnosis of advanced breast cancer; 
for patients originally diagnosed with Stage I/II/III breast cancer who did not 
receive prior neoadjuvant or adjuvant chemotherapy: the interval between date of 
original diagnosis of breast cancer and date of diagnosis of advanced breast 
cancer) is less than 6 months and no clinically significant tumor-related symptoms 


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in the judgment of the investigator.  Patients with a diagnosis of de novo Stage IV 
breast are eligible. 
• 
Patients are excluded if the screening LDH > 2 × ULN (based on the central 
laboratory). 
• 
Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or 
other cytokine therapies. 
Cohort 5a – Triple-Negative Breast Cancer (1-2L, I-O therapy naive) 
• 
Patients must be a candidate for NKTR-214 in combination with nivolumab. 
Cohort 5b – Triple-Negative Breast Cancer (1-2L, I-O therapy naive) in 
combination with nab-paclitaxel 
• 
Patients must be a candidate for single-agent nab-paclitaxel; patients may not have 
received paclitaxel or docetaxel for metastatic carcinoma and may not have 
relapsed with metastatic disease within 1 year of adjuvant paclitaxel or docetaxel 
treatment. 
• 
Patients may not have received prior nab-paclitaxel in any setting. 
Cohort 5c – Triple-Negative Breast Cancer (1-2L, I-O therapy naive) in 
combination with eribulin 
• 
Patients must be a candidate for single-agent eribulin; patients may not have 
relapsed with metastatic disease within 1 year of adjuvant taxane-based treatment. 
• 
Patients may not have received prior eribulin in any setting. 
 
Cohort 6 − Hormone-Receptor Positive, HER2 Negative Breast Cancer 
• 
Patients must have diagnosis of advanced hormone-receptor positive breast 
carcinoma (“advanced” is defined either locally advanced breast cancer not 
amenable to curative surgery or radiotherapy or metastatic disease). 
• 
≥ 1% of tumor cell nuclei test positive for estrogen or progesterone receptors 
determined by using standard IHC  
• 
HER2 negative as determined by local pathologist, using IHC or in situ 
hybridization 
• 
For patients whose primary tumor was HER2-positive or hormone-receptor 
positive, eligibility will be based on the first biopsy for advanced disease.  
• 
Patients must have either archival or fresh tumor biopsy that demonstrates 
≥ 1% positive PD-L1 staining by the central pathology laboratory.  An abbreviated 
consent may be presented to the patient prior to the Screening period to permit 
early assessment of the PD-L1 status of the tissue sample. 
• 
Patients must have received prior aromatase and fulvestrant therapy for advanced 
breast cancer.  (Progression after prior adjuvant therapy with an aromatase 
inhibitor within 12 months will count as a line of therapy).  Hormonal therapy 
may have been administered as single-agent or in combination with CDK4-6 
inhibitors (such as palbociclib and others), mTOR inhibitors (everolimus and 
others), PI3K inhibitors (buparlisib and others), or other agents used in 
combination with hormonal agents (AKT inhibitors, WNT inhibitors, or others). 
• 
Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 


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2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or 
other cytokine therapies. 
Cohort 6a – Hormone-Receptor Positive, HER2-Negative Breast Cancer 
(I-O therapy naive following hormonal therapy) 
• 
Patients must not have received prior cytotoxic chemotherapy (such as tubulin-
targeting agents (paclitaxel, docetaxel, nab-paclitaxel, eribulin, vinca alkaloids, 
epothilones, and others), anti-metabolites (5-fluorouracil, capecitabine, 
gemcitabine, and others), platinum agents (carboplatin, cisplatin, and others), 
alkylating agents (cyclophosphamide and others), topoisomerase 1 or 2 inhibitors 
(irinotecan, doxorubicin, epirubicin, etoposide, and others) or VEGF-targeted 
monoclonal antibodies (bevacizumab and others).  Prior systemic therapy must be 
reviewed by the Medical Monitor prior to registration for the trial. 
Cohort 6b – Hormone-Receptor Positive, HER2-Negative Breast Cancer 
(I-O therapy naive following hormonal and cytotoxic therapy) 
• 
Patients must have received at least one and up to 2 prior lines of cytotoxic 
chemotherapy (such as tubulin-targeting agents (paclitaxel, docetaxel, nab-
paclitaxel, eribulin, vinca alkaloids, epothilones, and others), anti-metabolites 
(5-fluorouracil, capecitabine, gemcitabine, and others), platinum agents 
(carboplatin, cisplatin, and others), alkylating agents (cyclophosphamide and 
others), topoisomerase 1 or 2 inhibitors (irinotecan, doxorubicin, epirubicin, 
etoposide, and others).  Substitution within a class of anti-cancer therapy (e.g., 
carboplatin for cisplatin) is permitted; otherwise patients who discontinued 
therapy for reasons other than progressive disease are still considered to have 
received a prior line of therapy.  Prior systemic therapy must be reviewed by the 
Medical Monitor prior to registration for the trial. 
Cohort 7 − Gastric Carcinoma (2-3L, I-O therapy naive) 
• 
Patients must have diagnosis of advanced gastric adenocarcinoma or 
gastroesophageal carcinoma (GC) (“advanced” is defined either locally recurrent 
surgically unresectable advanced cancer or metastatic disease). 
• 
Patients must have either archival or fresh tumor biopsy that demonstrates PD-L1 
staining (Combined Positive Score ≥ 1 as determined by an FDA-approved test or 
validated assay).  An abbreviated consent may be presented to the patient prior to 
the Screening period to permit early assessment of the PD-L1 status of the tissue 
sample. 
• 
Patients must have received no more than two prior lines of therapy including 
fluoropyrimidine- and platinum-containing chemotherapy, and (if appropriate) 
HER2-targeted systemic therapy for gastric cancer. These drugs may have been 
administered in the neoadjuvant, adjuvant, locally advanced or metastatic setting. 
Patients may have progressed or been intolerant to these therapies. (“Systemic 
therapy” includes all agents, including cytotoxic, molecularly targeted or 
other).  Substitution within a class of anti-cancer therapy (e.g., capecitabine for 
fluorouracil [5-FU]; carboplatin for cisplatin) is permitted; otherwise patients who 
discontinued therapy for reasons other than progressive disease are still considered 
to have received a prior line of therapy. 
• 
Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or 
other cytokine therapies.  
 


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Cohort 8a − Colorectal Carcinoma (2-3L, I-O therapy naive); 
microsatellite instability (MSI)-high  
• 
Patients must have diagnosis of advanced colorectal carcinoma (CRC) 
(“advanced” is defined either locally advanced unresectable cancer or metastatic 
disease).   
• 
Patients must have either archival or fresh tumor biopsy that demonstrates 
microsatellite instability high or mismatch repair deficient disease.  An 
abbreviated consent may be presented to the patient prior to the Screening period 
to permit early assessment of the CD8+ TIL status of the tissue sample. 
• 
Patients who had disease progression during, after, or were intolerant to, prior 
treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy 
(patients must have received either fluoropyrimidine and oxaliplatin-containing 
chemotherapy OR fluoropyrimidine and irinotecan-containing chemotherapy for 
colorectal carcinoma (“FOLFOX” [fluorouracil, leucovorin, and oxaliplatin] or 
“FOLFIRI” [5-fluorouracil, leucovorin, and irinotecan]); and (if appropriate) 
EGFR-targeted and/or VEGF-targeted systemic therapy. These drugs may have 
been administered in the neoadjuvant, adjuvant, locally advanced or metastatic 
setting.  (“Systemic therapy” includes all agents, including cytotoxic, molecularly 
targeted or other).  Substitution within a class of anti-cancer therapy (e.g., 
capecitabine for 5-FU) is permitted; otherwise patients who discontinued therapy 
for reasons other than progressive disease are still considered to have received 
a prior line of therapy. 
• 
Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or 
other cytokine therapies. 
Cohort 8b − Colorectal Carcinoma (3-4L, I-O therapy naive); MSI-non-high 
• 
Patients must have diagnosis of advanced colorectal carcinoma (CRC) 
(“advanced” is defined either locally advanced unresectable cancer or metastatic 
disease). 
• 
Patients must have either archival or fresh tumor biopsy that demonstrates MSI 
not high (MSI-stable or MSI-low) or mismatch repair proficient (pMMR) disease.  
In addition, tumor tissue must demonstrate CD8+ tumor infiltrating lymphocytes 
(≥ 10% by IHC) by central laboratory.  An abbreviated consent may be presented 
to the patient prior to the Screening period to permit early assessment of the CD8+ 
TIL status of the tissue sample. 
• 
Patients must have received at least two but no more than 3 prior lines of therapy 
including fluoropyrimidine-, oxaliplatin and irinotecan-containing chemotherapy 
colorectal cancer; and (if appropriate) EGFR-targeted and/or VEGF-targeted 
systemic therapy. These drugs may have been administered in the neoadjuvant, 
adjuvant, locally advanced or metastatic setting.  (“Systemic therapy” includes all 
agents, including cytotoxic, molecularly targeted or other).  Substitution within a 
class of anti-cancer therapy (e.g., capecitabine for 5-FU) is permitted; otherwise 
patients who discontinued therapy for reasons other than progressive disease are 
still considered to have received a prior line of therapy. 
• 
Must not have received any prior immuno-oncology regimens, including, but not 
limited to checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 


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2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or 
other cytokine therapies. 
Cohort 9 − Small Cell Lung Cancer (2L, I-O therapy naive) 
• 
Patients must have diagnosis of limited-stage or extensive-stage SCLC.   
• 
Patients must have received no more than 1 prior line of platinum-based therapy.  
Substitution within a class of anti-cancer therapy (e.g., carboplatin for cisplatin) is 
permitted; otherwise patients who discontinued therapy for reasons other than 
progressive disease are still considered to have received a prior line of therapy.   
• 
Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or 
other cytokine therapies. 
 
For Parts 3 and 4 (NKTR-214/nivolumab/ipilimumab) 
Parts 3 and 4 are closed to patient screening and enrollment under Amendment 7. 
For Disease-Specific Tumor Types 
Cohorts 10a.1 and 10a.3 − Renal Cell Carcinoma (1L), as follows: 
Cohort 10a.1 concurrent dosing schedule 1 (this cohort was closed to 
enrollment under Amendment 6.0) 
Cohort 10a.3 concurrent dosing schedule 3 
• 
Advanced (not amenable to curative surgery or radiation therapy) or metastatic 
(AJCC stage IV) RCC. 
• 
Histologically confirmed RCC with a clear-cell component. 
• 
Patients must not have received prior anti-cancer therapy for advanced or 
metastatic RCC. 
• 
Prior to disease metastasis, patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens, including, but not limited 
to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other 
antibody or drug specifically targeting T cell co-stimulation or checkpoint 
pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, 
adoptive cell therapies, or other cytokine therapies. 
Cohort 11a.1 − Non-Small Cell Lung Cancer (1L) 
• 
Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC 
• 
Patients with nonsquamous NSCLC must lack both EGFR-sensitizing 
mutation/deletion and anaplastic lymphoma kinase (ALK) translocation by local 
testing (assessment of ROS1 mutation status is not required).  For ALK or EGFR 
testing, an FDA-approved test or validated assay should be used as applicable for 
selection of patients.  For patients with squamous NSCLC, testing for EGFR and 
ALK is not required. 
• 
Patients must not have received prior anti-cancer therapy for advanced or 
metastatic NSCLC. 
• 
Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens.  


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Cohorts 12a.2 and 12a.3 − Melanoma (1L), as follows: 
• 
Cohort 12a.2:  concurrent dosing schedule 2 
• 
Cohort 12a.3:  concurrent dosing schedule 3 
• 
Histologically confirmed stage III (unresectable) or stage IV melanoma, as per 
American Joint Committee on Cancer (AJCC) staging system. 
• 
Patients must consent to BRAF testing or have documented BRAF status as per 
regionally acceptable V600 mutational status testing. 
• 
Uveal melanoma will be excluded. 
• 
Have not received prior anti-cancer therapy for advanced or metastatic melanoma. 
• 
Prior to disease metastasis, patients must not have received neoadjuvant or 
adjuvant therapy with any immuno-oncology regimens, including, but not limited 
to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other 
antibody or drug specifically targeting T cell co-stimulation or checkpoint 
pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer vaccines, 
adoptive cell therapies, or other cytokine therapies. 
• 
Prior to disease metastasis, patients must not have received neoadjuvant or 
adjuvant tyrosine kinase (BRAF, MEK, mTOR), bevacizumab or intralesional 
therapy.   
 
Cohort 13a.2 – Urothelial Carcinoma (1L) 
• 
Histologically or cytologically documented locally advanced or transitional cell 
carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or 
urethra.  Patients with mixed histologies are required to have a dominant 
transitional cell pattern. 
• 
Treatment naive patients who refuse chemotherapy standard of care or treatment 
naive, cisplatin-ineligible patients who meet at least one of the following criteria: 
• 
Creatinine clearance (calculated or measured) < 60 mL/min. 
Cisplatin-ineligible patients must have a creatinine clearance < 60 mL/min 
and GFR ≥ 30 mL/min.  
• 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
Grade ≥ 2 audiometric hearing loss 
• 
CTCAE v4.03 Grade ≥ 2 peripheral neuropathy 
• 
No prior chemotherapy for inoperable locally advanced or metastatic urothelial 
carcinoma.  Prior local intravesical chemotherapy is allowed if completed at least 
4 weeks prior to the initiation of study treatment. 
• 
For patients who received prior adjuvant/neoadjuvant chemotherapy or 
chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 
12 months between the last treatment administration and the date of recurrence is 
required to be considered treatment naive in the metastatic setting.  Patients must 
not have received neoadjuvant or adjuvant therapy with any immuno-oncology 
regimens.   
Test Product, Dose and 
Mode of Administration:  
NKTR-214 administered IV over 30 (± 5) minutes at a starting dose of 0.006 mg/kg 
q3w (Parts 2, 3, and 4) 
Nivolumab (anti-PD-1) administered IV over 30 (± 5) minutes at either a 360 mg flat 
dose q3w (Parts 2, 3, and 4), 1 mg/kg q3w × 4 doses or  3 mg/kg q3w × 4 doses 
(Parts 3 and 4) 


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Ipilimumab administered IV over 30 (± 5)  minutes at 1 mg/kg q6w, 3 mg/kg q3w 
× 4 doses or 1 mg/kg q3w × 4 doses (Parts 3 and 4) 
 
Part 2 
Institutional guidelines for administration of other anti-cancer therapies should be 
followed in Part 2.  
• 
Cohort 3d.1 NSCLC (1L nonsquamous): NKTR-214 followed by nivolumab 
(q3w) followed by investigator’s choice of cisplatin 75 mg/m2 administered IV or 
carboplatin AUC 5 followed by pemetrexed 500 mg/m2 q3w by IV administration 
for 4 cycles followed by maintenance NKTR-214, nivolumab, and pemetrexed 
q3w 
• 
Cohort 3d.2 NSCLC (1L nonsquamous): NKTR-214 followed by nivolumab 
(q3w) followed by investigator’s choice of cisplatin 75 mg/m2 administered IV or 
carboplatin AUC 5 followed by pemetrexed 500 mg/m2 q3w by IV administration 
for 4 cycles followed by maintenance NKTR-214 and nivolumab q3w 
• 
Cohort 3e NSCLC (1L squamous): NKTR-214 followed by nivolumab (q3w) 
followed by either Cremophor-based paclitaxel 200 mg/m2 on Day 1 of each 
21-day cycle or nab-paclitaxel 100 mg/m2 by IV administration on Days 1, 8, and 
15 of each 21-day cycle with investigator’s choice of either carboplatin AUC 6 by 
IV administration on cycle Day 1 q3w for 4 cycles or cisplatin 75 mg/m2 q3w by 
IV administration for 4 cycles followed by maintenance NKTR-214 and 
nivolumab q3w. 
• 
Cohort 5b TNBC (1-2L): NKTR-214 followed by nivolumab (q3w) followed by 
nab-paclitaxel 260 mg/m2 by IV administration q3w. 
• 
Cohort 5c TNBC (1-2L): NKTR-214 followed by nivolumab (q3w) followed by 
eribulin mesylate 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2) by IV 
administration on Days 1 and 8 q3w. 
Safety: 
Assessment of safety will be determined by an ongoing review of the following: 
• 
incidence of adverse events (AEs), including serious AEs (SAEs) 
• 
clinical laboratory tests (blood and urine sampling) 
• 
vital signs 
• 
electrocardiograms (ECG) and echocardiograms (ECHO) 
• 
physical examination 
Pharmacokinetics: 
Blood samples for PK analyses will be collected from all patients.  Serial PK samples 
will be collected at multiple scheduled sampling times.  Plasma concentrations of 
NKTR-214 and its metabolites will be measured for each PK sample using validated 
method(s).  Serum concentrations of nivolumab and ipilimumab will be measured 
using validated methods.  Pharmacokinetic parameters such as maximum 
concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), clearance (CL), 
volume of distribution (Vd), and half-life (t1/2) will be estimated from plasma or serum 
concentration-time data where possible. 
Pharmacodynamics: 
Systemic and tumor tissue-based pharmacodynamic effects of NKTR-214 in 
combination with nivolumab and in combination with nivolumab and other anti-cancer 
therapies will be examined. 
Blood samples for systemic pharmacodynamic analyses will be collected pre- and 
post-combination treatment from all patients enrolled to assess the effects of the 
combination treatment on markers of immune system activation, and immune cell 
populations. 




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Nektar Therapeutics 
 
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1.1 
Study Schematics 
Figure 1: 
Study Schematic for Parts 1 and 2 
Abbreviations:  HR+ = hormone-receptor positive; I-O = immuno-oncology; L = line; MSI = microsatellite instability; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; 
RCC = renal cell carcinoma; RP2D = recommended Phase 2 dose; SOC = standard of care; TNBC = triple-negative breast cancer 
a. 
Up to 20 efficacy-evaluable NSCLC patients will be enrolled in each cohort of PD-L1 negative, PD-L1 low/intermediate, or PD-L1 positive.  Patients enrolled in Cohort 3a who do not have a 
PD-L1 status assessed by central testing will be assigned to Cohort 3a.4. 
b. 
Up to 20 urothelial carcinoma 1L patients who are cisplatin-ineligible and (for countries other than Italy) up to 20 patients who choose to forego standard of care. 




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1.2 
Schedule of Events 
Table 1: 
Schedule of Events for Part 1  
Assessment Period 
Screening 
Cycle 1 Only 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 8 
Day 11 
Day 1 
Day 8 
End of 
Treatmentu 
Follow 
up 
3 mot 
Physical examinationb 
X 
X 
X 
X 
 
 
X 
 
X  
 
X 
 
Vital signsc 
X  
Xc 
Xc 
Xc 
 
 
X 
X 
Xc 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
X 
 
 
 
ECGd 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
 
ECHO/MUGA 
Xe 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Hematologyg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Coagulationh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
Additional labsi 
X 
 
 
 
 
 
 
X 
Xi 
 
X 
 
Urinalysis (dipstick)j 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Serologyh 
X 
 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissuek 
X 
 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyl 
X 
Refer to Section 5.10.2 
 


Protocol No. 16-214-02 Amendment 7.0 
 
 Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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Table 1: 
Schedule of Events for Part 1 (Contd) 
Assessment Period 
Screening 
Cycle 1 Only 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 8 
Day 11 
Day 1 
Day 8 
End of 
Treatmentu
Follow 
up 
3 mot 
Immunogenicity serum 
samplem 
 
X 
 
 
 
 
 
 
Xm 
 
X 
Xm 
Tumor assessmentn 
X 
 
 
 
 
 
 
 
Every 8 weeks (± 7d)  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
NKTR-214 PK blood 
sampleq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Nivolumab PK blood sampleq 
 
X 
 
 
 
 
 
 
Xq 
 
 
 
Administer IV fluidsr 
 
X 
 
 
 
 
 
 
X 
 
 
 
Drug administrations 
 
X 
 
 
 
 
 
 
X 
 
 
 
Long-term follow-upt 
 
 
 
 
 
 
 
 
 
 
 
X 
Footnotes: 
Abbreviations: d = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; IV = intravenous; MUGA = multigated acquisition; 
PK = pharmacokinetic. 
a. 
The acceptable visit window is ± 3 days for Day 1.  Cycle intervals less than 21 days (e.g., 21 days minus-3 days) should only occur if the investigator believes there are no 
safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle.  Additional visit windows are:  ± 2 days for Day 8 in Cycle 2 and beyond; ± 7 days for the 
follow-up visits post-treatment and + 10 days for End of Treatment (EOT) visit at 30 days.  Visits may be skipped or postponed if prospectively identified by the Investigator 
(e.g., national holidays, patient holidays).  If Day 4 visit is missed, then Day 4 assessments must be done at the next in-clinic visit.  All procedures and examinations should be 
performed before the administration of study drug(s), except as indicated. 
b. See Section 7.15. 
c. 
Some clinic visits will have more frequent vital sign measurements.  See Sections 5.3.7.1 and 7.16. 
d. In Cycle 1 only, ECGs are performed prior to each NKTR-214 PK sampling time.  The frequency of ECGs may be increased if clinically indicated. 
e. 
A standard echocardiogram or MUGA will be performed for all patients within 60 days prior to dosing Cycle 1 Day 1.  See Section 7.18. 
f. 
See Section 7.19. 
g. Hematology assessments scheduled for the day of study drug(s) dosing must be available and assessed before dosing.  The sampling for hematology assessments can be drawn 
within 72 hours prior to dosing.  See Appendix 1. 
h. The sampling for laboratory tests can be drawn within 72 hours prior to dosing.  See Appendix 1. 




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Nektar Therapeutics 
 
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Table 2: 
Schedule of Events for Part 2 
Assessment Period 
Screening 
Cycle 1 Only 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 1 
Day 3 
Day 8 
End of 
Treatmentw 
Follow up 
3 mov 
Physical examinationb 
X 
X 
 
 
X 
X 
 
 
X 
 
Vital signsc 
X 
Xc 
Xc 
Xc 
X 
Xc 
 
Xc 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
 
 
 
 
ECGd 
X 
X 
 
X 
X 
 
 
 
 
 
ECHO/MUGAe 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy testf 
X 
X 
 
 
 
X 
 
 
X 
 
Hematologyg 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Serum chemistryh 
X 
X 
 
 
X 
X 
 
X 
X 
 
Coagulationh 
X 
X 
 
 
X 
X 
 
X 
X 
 
Additional labs h 
X 
 
 
 
 
Xh  
 
 
X 
 
Local labs prior to dosing i 
 
Xi 
 
 
 
Xi  
 
 
 
 
Urinalysis (dipstick)j 
X 
X 
 
 
 
X 
 
 
X 
 
Serologyh 
X 
 
 
 
 
 
 
 
 
 
Archival tumor tissuek 
X 
 
 
 
 
 
 
 
 
 
Tumor biopsyl 
X 
Refer to Section 5.10.2 
 


Protocol No. 16-214-02 Amendment 7.0 
 
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Nektar Therapeutics 
 
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Table 2: 
 
Schedule of Events for Part 2 (Cont’d) 
Assessment Period 
Screening 
Cycle 1 Only 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 1 
Day 3 
Day 8 
End of 
Treatmentw 
Follow up 
3 mov 
Immunogenicity serum 
samplem 
 
X 
 
 
 
X 
 
 
X 
X 
Tumor assessmentn 
X 
 
 
 
 
Every 8 weeks (± 7d) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Stool sample collectionp 
X 
 
 
 
 
Xp 
 
 
 
 
NKTR-214 PK blood 
sampleq 
 
X 
 
X 
X 
X 
 
 
 
 
Nivolumab PK blood sampleq 
 
X 
 
 
 
X 
 
 
 
 
BRAF mutation testingr 
X 
 
 
 
 
 
 
 
 
 
Administer IV fluidss 
 
X 
 
 
 
X 
 
 
 
 
Drug administrationt 
 
X 
 
 
 
X 
 
 
 
 
Oral hydration follow-upu 
 
 
 
Xv 
 
 
Xv 
 
 
 
Long-term follow-upv 
 
 
 
 
 
 
 
 
 
X 
Footnotes: 
Abbreviations: d = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; IV = intravenous; MUGA = multigated acquisition; 
PK = pharmacokinetic. 
a. 
The acceptable visit window is ± 3 days for Day 1.  Cycle intervals less than 21 days (e.g., 21 days minus-3 days) should only occur if the investigator believes there are no 
safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle.  Additional visit windows are:  ± 2 days for Day 8 in Cycle 2 and beyond; ± 7 days for the 
follow-up visits post-treatment and + 10 days for End of Treatment (EOT) visit at 30 days.  Study assessments, including imaging, may be delayed or moved ahead of the 
window to accommodate holidays, vacations, and unforeseen delays after permission from the medical monitor.  If Day 4 visit is missed, then Day 4 assessments must be done 
at the next in-clinic visit.  All procedures and examinations should be performed before the administration of study drug(s), except as indicated. 
b. See Section 7.15. 
c. 
Some clinic visits will have more frequent vital sign measurements.  See Appendix 2 Schedule of Assessments and Sections 5.3.7.1 and 7.16.  Beginning on Day 8 of Cycle 3 
and beyond, vital signs should be collected according to the Investigator’s discretion based on the clinical status of the patient. 




Protocol No. 16-214-02 Amendment 7.0 
 
 Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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Table 3: 
Schedule of Events for Parts 3 and 4 
Assessment Period 
Screening 
Cycle 1 Only 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 11 
Day 1 
Day 3 
Day 8 
End of 
Treatmentw 
Follow up 
3 mov 
Physical examinationb 
X 
X 
X 
X 
X 
 
X  
 
 
X 
 
Vital signsc 
X  
Xc 
Xc 
Xc 
X 
X 
Xc 
 
Xc 
X 
 
ECOG performance status 
X 
 
 
 
 
 
X 
 
 
 
 
ECGd 
X 
X 
 
X 
X 
 
 
 
 
 
 
ECHO/MUGAe 
X 
 
 
 
 
 
 
 
 
X 
 
Pregnancy testf 
X 
X 
 
 
 
 
X 
 
 
X 
 
Hematologyg 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Serum chemistryh 
X 
X 
 
 
X 
X 
X 
 
X 
X 
 
Coagulationh 
X 
X 
 
 
X 
X 
X 
 
X 
X 
 
Additional labs h 
X 
 
 
 
 
X 
Xh 
 
 
X 
 
Local labs prior to dosing i 
 
Xi 
 
 
 
 
Xi 
 
 
 
 
Urinalysis (dipstick)j 
X 
X 
 
 
 
 
X 
 
 
X 
 
Serologyh 
X 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissuek 
X 
 
 
 
 
 
 
 
 
 
 
Tumor biopsyl 
X 
Refer to Section 5.10.2 
Immunogenicity serum samplem 
 
X 
 
 
 
 
X 
 
 
X 
X 
Tumor assessmentn 
X 
 
 
 
 
 
Every 8 weeks (± 7d)  
 
X 
 


Protocol No. 16-214-02 Amendment 7.0 
 
 Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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11 February 2020 
Table 3: 
Schedule of Events for Parts 3 and 4 (Cont’d) 
Assessment Period 
Screening 
Cycle 1 Only 
Cycle 2 and Beyond 
Post-treatment 
Study Daysa 
Day 
-28 to -1 
Day 1 
Day 2 
Day 3 
Day 8 
Day 11 
Day 1 
Day 3 
Day 8 
End of 
Treatmentw 
Follow up 
3 mov 
 
 
 
 
 
 
 
 
 
  
 
 
Stool sample collectionp 
X 
 
 
 
 
 
X 
 
 
 
 
NKTR-214 PK blood sampleq 
 
X 
 
X 
X 
 
X 
 
 
 
 
Nivolumab or ipilimumab PK 
blood sampleq 
 
X 
 
 
 
 
X 
 
 
 
 
BRAF mutation testingr 
Part 3 only 
 
 
 
 
 
 
 
 
 
 
Administer IV fluidss 
 
X 
 
 
 
 
X 
 
 
 
 
Drug administrationt 
 
X 
 
 
 
 
X 
 
 
 
 
Oral hydration follow-upu 
 
 
 
Xv 
 
 
 
Xv 
 
 
X 
Long-term follow-upv 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: d = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; IV = intravenous; MUGA = multigated acquisition; 
PK = pharmacokinetic. 
a. 
The acceptable visit window is ± 3 days for Day 1.  Cycle intervals less than 21 days (e.g., 21 days minus-3 days) should only occur if the investigator believes there are no 
safety concerns with dosing the patient 1 to 3 days prior to a 21-day cycle.  Additional visit windows are:  ± 2 days for Day 8 in Cycle 2 and beyond; ± 7 days for the 
follow-up visits post-treatment and + 10 days for End of Treatment (EOT) visit at 30 days.  Study assessments, including imaging, may be delayed or moved ahead of the 
window to accommodate holidays, vacations, and unforeseen delays after permission from the medical monitor.  If Day 4 visit is missed, then Day 4 assessments must be done 
at the next in-clinic visit.  All procedures and examinations should be performed before the administration of study drug(s), except as indicated. Samples for hematology, 
chemistry, coagulation, and pregnancy are drawn at the same time points in Parts 3 and 4. Local laboratories will be used for Parts 1 and 3; a central laboratory will be used for 
Part 2 and Part 4. 
b. See Section 7.15. 
c. 
Some clinic visits will have more frequent vital sign measurements.  See Appendix 2 Schedule of Assessments and Sections 5.3.7.1 and 7.16.  Beginning on Day 8 of Cycle 3 
and beyond, vital signs should be collected according to the Investigator’s discretion based on the clinical status of the patient. 
d. See Section 7.17.  In Cycle 1 only, ECGs are performed prior to each NKTR-214 PK sampling time (see Appendix 2 Schedule of Assessments for PK and ECG sampling 
times).  The frequency of ECGs may be increased if clinically indicated.  
e. 
A standard echocardiogram or MUGA will be performed for all patients within 60 days prior to dosing Cycle 1 Day 1.  See Section 7.18. 
f. 
See Section 7.19. 




Protocol No. 16-214-02 Amendment 7.0 
 
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Nektar Therapeutics 
 
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2.0 
INTRODUCTION 
2.1 
Background 
2.1.1 
NKTR-214 Mechanism of Action 
Aldesleukin (recombinant human interleukin-2 [rhIL-2]) directly stimulates the immune system 
and has been shown to lead to durable responses in ~10% of people with metastatic melanoma 
and renal cancer (Payne, 2014).  However, in addition to aldesleukin acting as a stimulator of the 
immune system by activating tumor killing CD8+ T cells, it also suppresses the immune system 
by activating regulatory T (Treg) cells (Boyman, 2012).  Despite favorable clinical outcomes 
associated with aldesleukin, it has several therapeutic limitations including the need for inpatient 
hospital administration, 5 consecutive days of dosing, and the potential for serious toxicities, 
comprising capillary leak syndrome, hypotension, and pulmonary edema requiring medical 
management in the intensive care unit.  In contrast to aldesleukin, NKTR-214 was designed as an 
outpatient therapy.  In addition, NKTR-214 was designed to mitigate the serious toxicities 
associated with rapid systemic immune activation seen with administration of high-dose 
interleukin-2 (i.e., rhIL-2 also referred to as IL-2). 
Bempegaldesleukin (NKTR-214), a novel cytokine with enhanced immune system activation and 
the targeted profile of NKTR-214 (i.e., a superior safety profile allowing for outpatient 
administration and a longer duration of action requiring less frequent dosing) has the potential to 
be an important advancement for the treatment of patients with cancer.  NKTR-214 consists of 
IL-2, which has the same amino acid sequence as aldesleukin, conjugated at a defined region 
within the protein to releasable polyethylene glycol (PEG) chains.  The PEG chains render the 
molecule inactive.  After administration in vivo, the PEG chains are slowly hydrolyzed to 
generate active cytokine conjugates.  The most active IL-2 conjugates are 2-PEG-IL2 and 
1-PEG-IL2.  The location of the PEG chains on the active conjugated-IL-2 reduces its affinity to 
the IL-2 receptor alpha subunit (IL2R), responsible for activating undesirable Treg cells to a 
greater extent than affinity to the IL-2-receptor beta subunit (IL2R).  In the tumor, NKTR-214 
preferentially activates CD8+ T cells and natural killer (NK) cells over Treg cells and provides 
sustained exposure to active 1-PEG and 2-PEG-IL2. 
2.1.2 
Rationale for the Combination of NKTR-214 and Immune Checkpoint 
Inhibitors 
Accumulating evidence suggests that patients with low baseline CD8+ T cells within the tumor 
microenvironment (tumor infiltrating lymphocytes [TILs]) predict poor response to checkpoint 
inhibitor immunotherapies (Daud, 2016a; Daud, 2016b); thus, agents designed to specifically 
activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs.  
NKTR-214 targets the IL-2 pathway and is designed to provide biased sustained signaling 
through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand 
NK and effector CD8+ T cells over Treg cells.  Preliminary analyses of patients’ blood and 
tumor by flow cytometry and immunohistochemistry (IHC) demonstrate that NKTR-214, as a 
single agent, increases activated CD4+ and CD8+ T cells in peripheral blood, with an increase in 


Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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T cell infiltrates within the tumor tissue after 1 dose of NKTR-214.  In addition, there is an 
increase in programmed cell death receptor-1 (PD-1) expression on T cells in the blood and 
tumor after treatment with NKTR-214.  The ability to alter the immune environment and 
increase PD-1 expression on effector T cells may improve the effectiveness of anti-PD-1 
blockade. 
2.1.3 
Clinical Experience with IL-2 and Checkpoint Inhibitors 
Simultaneous administration of IL-2 with immune checkpoint inhibitors directed against PD-1 
(nivolumab and pembrolizumab) or its ligand has not been reported as of the date of this 
protocol, although several studies are ongoing in which IL-2 and an anti-PD-1 antibody are 
co-administered following an infusion of either adoptive CD8+ T cells or tumor-infiltrating 
lymphocytes (NCT02757391, NCT02500576). 
Published data on the sequential administration of IL-2 with an anti-PD-1 inhibitor have been 
reported recently.  A case report noted a near-complete response (near-CR) with extended 
duration of response when a patient with renal cell carcinoma (RCC; non-responsive to 
nivolumab) was treated with high-dose IL-2 (Brayer, 2014).  A larger experience from an 
observational clinical trial reported that patients with metastatic melanoma who received 
high-dose IL-2 and received either ipilimumab or an anti-PD-1 inhibitor experienced a 
differential increase in median overall survival (OS), 15.8 vs 28.7 months, respectively.  The 
12-month survival rate was 64% for patients receiving ipilimumab post high-dose IL-2 compared 
with 97% for patients receiving an anti-PD-1 inhibitor, suggesting that these two checkpoint 
inhibitors do not have overlapping mechanisms of action and that IL-2 may enhance the curative 
potential of the anti-PD-1 inhibitor (Wong, 2015).  In support of the hypothesis that IL-2 may 
have enhanced the curative potential of nivolumab/pembrolizumab, a recent report demonstrated 
that IL-12, which has been shown to induce tumor infiltrating lymphocytes and anti-tumor 
immunity similar to IL-2, appeared to prime response to anti-PD-1/PD-L1 inhibitors and 
demonstrated a clinical benefit rate of 75% (50% CR and 25% partial response [PR])  
(Algazi, 2016). 
2.1.4 
Clinical Experience with NKTR-214 
Study 15-214-01 (NCT02869295) is a Phase 1/2 open-label, multicenter, dose escalation and 
dose expansion monotherapy study of NKTR-214 in patients with locally advanced or metastatic 
solid tumors.  The objectives of the study are to evaluate the safety and tolerability of NKTR-214 
to determine the maximum tolerated dose (MTD) as well as to assess the objective response rate 
(ORR) at or below the MTD, or to identify the recommended Phase 2 dose (RP2D). 
In Study 15-214-01, hypotension has been identified as a principal toxicity.  Hypotension is a 
known adverse event (AE) associated with both IL-2 and engineered cytokines.  Instances of 
hypotension most commonly appeared 2-3 days following the first infusion, coinciding with the 
peak plasma concentration of the active metabolites formed after administration of NKTR-214.  
Patients for whom intravenous (IV) fluid administration was clinically indicated responded 


Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
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rapidly (in less than 24 hours) to IV hydration.  To mitigate the risk of hypotension, management 
guidelines were implemented and included the following recommendations: 
• Withholding antihypertensive therapy and drugs with hypotensive properties, prior to 
administration of NKTR-214. 
• Maintaining adequate oral fluid intake, particularly during the first 5 days post-dose. 
• Avoiding activities that could lead to dehydration (e.g., physically strenuous activity) or 
vasodilation (e.g., hot showers, sauna). 
• Providing additional corticosteroid support for patients with adrenal insufficiency on 
corticosteroid replacement therapy. 
Since the implementation of these mitigation measures, the frequency of hypotension, 
particularly Grade 3 hypotension, has been reduced. 
In contrast to aldesleukin, none of the 28 patients treated to date with NKTR-214 monotherapy 
have experienced capillary leak syndrome.  In addition, the severity and duration of any 
temporally associated hypotension is markedly reduced.  The most common Grade 1-2 
treatment-related AEs were fatigue, pruritus, chills, and decreased appetite.  Grade 3 
treatment-related AEs included hypotension, abdominal pain, and infusion-related reaction.  For 
the every 3 weeks (q3w) dosing frequency, NKTR-214 monotherapy doses up to 0.009 mg/kg 
were well tolerated.  At 0.012 mg/kg NKTR-214 monotherapy dose, one patient experienced 
DLTs of Grade 3 hypotension and syncope, which was rapidly reversed with fluids; this patient 
received another 2 doses at a lower dose of 0.006 mg/kg and tolerated treatment well.  Dosing at 
0.006 mg/kg q2w and q3w, as well as dosing at 0.003 and 0.009 mg/kg at q3w of NKTR-214 
monotherapy have been deemed safe per the Safety Review Committee.  No Grade 4 
treatment-related AEs were reported.  One patient dosed at 0.009 mg/kg discontinued the study 
due to a treatment-related AE of infusion-related reaction.  The pattern of AEs attributable to 
NKTR-214 observed in Study 15-214-01 is dissimilar from the immune-mediated AEs (imAEs) 
that commonly develop with the use of checkpoint inhibitors.  Neither clinical nor nonclinical 
data predict “immune-mediated inflammatory events,” such as endocrinopathies, colitis, 
nephritis, pneumonitis, dermatitis, or hepatitis to occur with NKTR-214.  The non-overlapping 
toxicities observed with NKTR-214 and nivolumab may therefore result in a reasonably well-
tolerated immuno-oncology combination. 
2.1.4.1 
Observed Events of Cerebrovascular Accident in Study 16-214-02 
Following the occurrence of three SAEs (one of which was fatal) of cerebrovascular accident 
(CVA) in the first 43 patients treated with NKTR-214, nivolumab, and ipilimumab (“triplet 
immunotherapy” cohort) in Study 16-214-02, a comprehensive review of CVA-related safety 
information for the entire clinical program for NKTR-214 (N=721) was performed.  The 
assessment included a broad search to identify any potential CVA cases among all NKTR-214 
studies; case reviews by independent neurology, cardiology, and coagulation expert consultants; 


Protocol No. 16-214-02 Amendment 7.0 
 
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Nektar Therapeutics 
 
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and an analysis of patient demographics, medical histories, drug exposure, laboratory values, 
vital signs, and PK/pharmacodynamic parameters. 
Table 4 summarizes the results of the comprehensive search, which utilized a data cut-off date of 
21 June 2019.  A total of 3 of 43 patients (7.0%) who received triplet immunotherapy and 8 of 
478 patients (1.7%) who received NKTR-214 and nivolumab (“doublet immunotherapy”) in 
Study 16-214-02 were determined to have CVA events that were confirmed by the neurology 
consultants.  No confirmed CVA events occurred in any patients in any other studies of 
NKTR-214 and nivolumab (n=115), in studies of NKTR-214 monotherapy (n=28), or in studies 
of NKTR-214 in combination with any other second agent (including pembrolizumab [n=12], 
atezolizumab [n=23], or NKTR-262 [n=22]).  The incidence of CVA, combining all clinical 
trials in which the doublet of NKTR-214 plus nivolumab was administered was 8 out of 
593 patients (1.3%). 
Sections 2.1.4.1.1 and 2.1.4.1.2 summarize the CVA events observed in Study 16-214-02 for 
patients who received triplet immunotherapy and doublet immunotherapy, respectively, and 
Section 2.1.4.2 summarizes the protocol sections with additional safety measures that were 
implemented to mitigate the risk of CVA events and to expedite reporting of CVA events. 
Table 4. 
CVA Adverse Events in Study 16-214-02 
Regimen 
Study 
Patients Treated with 
NKTR-214 
(N) 
Patients with  
CVAa 
(n [%]) 
Triplet 
NKTR-214 + nivolumab + ipilimumab 16-214-02 (PIVOT-02) 
43 
3 (7.0) 
Doublet  
NKTR-214 + nivolumab 
16-214-02 (PIVOT-02) 
478 
8 (1.7) 
a. 
Neurologist-confirmed CVA based on review of local magnetic resonance imaging (MRI) readings and images 
and other patient-related data (utilizing a data cut-off date of 21 June 2019). 
 
2.1.4.1.1 
Observed Events of Cerebrovascular Accident Following Triplet 
Immunotherapy 
A total of 3 patients treated with triplet immunotherapy (NKTR-214 in combination with 
nivolumab and ipilimumab) in Study 16-214-02 were confirmed to have had a CVA by 
independent neurologist review. 
All 3 patients (2 male, 1 female) experienced events with the preferred term of cerebrovascular 
accident and had the underlying malignancy of RCC.  These patients had various risk factors for 
stroke, such as hypertension, diabetes, hyperlipidemia, and venous thrombosis.  At the time of 
the CVA event, these patients were aged 64 years or older.   


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Two of the events were Grade 2 in severity and one was Grade 5.  The time to onset of the events 
from the initial dose ranged from 33 to 222 days.  All events were assessed by the investigator as 
related to NKTR-214, nivolumab, and ipilimumab.  Two patients recovered from the CVA 
events; neither patient received additional NKTR-214, nivolumab, or ipilimumab on study.  One 
patient experienced a fatal outcome.   
There were 2 types of stroke patterns described in imaging of these 3 patients.  The magnetic 
resonance imaging (MRI) of two patients included infarcts involving multiple vascular territories 
with border-zone appearance.  The MRI of the third patient revealed a subacute infarct involving 
a single vascular territory in the right midbrain lateral crus cerebri. 
2.1.4.1.2 
Observed Events of Cerebrovascular Accident Following Doublet 
Immunotherapy 
A total of 8 patients treated with doublet immunotherapy (NKTR-214 in combination with 
nivolumab) in Study 16-214-02 were confirmed to have had a CVA by independent neurologist 
review. 
Of the 8 events that occurred in the 478 patients (1.7%) treated with the doublet immunotherapy, 
4 patients experienced events with the preferred term of cerebrovascular accident, 2 with embolic 
stroke, one with subacute infarct, and one with encephalopathy. 
The underlying malignancy was melanoma (2 patients), NSCLC (2 patients), RCC (1 patient), 
urothelial carcinoma (2 patients) and TNBC (1 patient).  These patients had various risk factors 
for stroke, such as hypertension, peripheral vascular disease, hyperlipidemia, and venous 
thrombosis.  The patients (5 male, 3 female) ranged in age from 55 to 82 years old. 
All events were SAEs; none were fatal.  Two were Grade 4 in severity, 4 were Grade 3, and 
2 were Grade 2.  The time to onset of the events from the initial dose ranged from 13 to 
578 days.  Four events were deemed unrelated to study drug (NKTR-214 and nivolumab) by the 
investigator and 4 were deemed related to study drug by the investigator (3 related to the doublet 
immunotherapy and 1 related to nivolumab only).  These events led to discontinuation in 3 cases 
and dose delay in 1 case.  The study treatment was continued in 1 case; 2 cases had previously 
discontinued both drugs.  Five patients have recovered or are recovering from the CVA events, 
2 of whom have recovered with sequelae (left sided paralysis in one patient and not reported in 
the other patient); one patient had a recurrence of the same event following rechallenge with only 
nivolumab and the second event was not resolved; one patient died due to progressive disease on 
the same day the toxicity resolved; and in 1 patient, the event was reported as “not recovered” at 
the time of study drug discontinuation. 
Of these 8 patients: 
• 6 were considered to have had an infarct involving multiple vascular territories with 
border-zone appearance on diffusion-weighted MRI 
• 2 were considered to have had an infarct involving a single vascular territory 


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2.1.4.2 
Mitigation Measures 
Following the comprehensive review of the entire NKTR-214 clinical program, additional safety 
measures and analyses were implemented to mitigate the risk of CVA events and to expedite 
reporting of CVA events by identifying CVA as an AE of special interest (AESI).  These safety 
measures and analyses are reflected in changes to the following protocol sections: hydration 
guidelines (Sections 1.2 and 5.3.7.2), CVA AE management algorithm (Appendix 3), criteria to 
delay, resume, or permanently discontinue study drug (Sections 5.13.1 to 5.13.3, 5.13.11, and 
5.13.12, respectively), AESI (Section 7.11), and reporting AESI (Section 7.7). 
Additional details on the clinical experience with NKTR-214 are provided in the NKTR-214 
Investigator’s Brochure. 
2.1.5 
Flat Dose Regimens with Nivolumab (360 mg q3w and 480 mg q4w) 
Currently nivolumab is being studied at a flat 360 mg q3w and/or 480 mg q4w dose schedule in a 
number of clinical trials:  
Phase 3: NSCLC, NCT02864251, NCT02713867 
Phase 2: NSCLC, NCT02967133, NCT03041181, NCT02434081 
Phase 2: RCC, NCT02959554 
Population pharmacokinetic (PPK) analyses have shown that the PK of nivolumab is linear with 
proportional exposure over a dose range of 0.1 to 10 mg/kg, and no differences in PK across 
ethnicities and tumor types were observed.  As the PK of nivolumab is linear, the corresponding 
flat dose for a every 3 weeks (q3w) dosing regimen is nivolumab 360 mg.  Using the PPK model 
developed, the exposures following administration of several dosing regimens of nivolumab 
administered as a flat dose were simulated, including 360 mg administered q3w.  The simulated 
steady-state average concentration (Cavgss) following administration of nivolumab 360 mg q3w 
are expected to be similar to those following administration of nivolumab 3 mg/kg every 2 weeks 
(q2w) to patients weighing 80 kg, the approximate median weight of  patients used in the PPK 
analyses.  The predicted steady state peak (Cmaxss) concentrations following nivolumab 360 mg 
q3w are predicted to be less than those following the administration of nivolumab 10 mg/kg q2w 
providing sufficient safety margins. 
Nivolumab 480 mg administered every 4 weeks (q4w) is also currently under investigation.  The 
less frequent dosing schedule is designed to be more convenient for patients.  The 480 mg dose 
was chosen based on clinical data as well as modeling and simulation approaches using PPK and 
exposure-response analyses of data from studies in multiple tumor types (melanoma, non-small 
cell lung cancer [NSCLC], and RCC) to provide an approximately equivalent dose as 3 mg/kg 
q2w.  Exposures with the 480 mg q4w regimen are predicted to be within the exposure ranges 
observed at doses up to 10 mg/kg q2w assessed in the nivolumab clinical program and, therefore, 
are not considered to cause an increased risk to patients. 


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Based on these supportive data, nivolumab 360 mg q3w will be examined in the current study 
with NKTR-214. 
Additional details are provided in the nivolumab Investigator’s Brochure. 
2.1.6 
Nivolumab Shorter Infusion Duration 
Establishing that nivolumab can be safely administered using a shorter infusion time 
(30 minutes) is under investigation.  Previous clinical studies of nivolumab monotherapy have 
used a 60-minute infusion duration, and nivolumab has been safely administered up to 10 mg/kg 
over long treatment periods.  Infusion reactions including high-grade hypersensitivity reactions 
have been uncommon across the nivolumab clinical program.  In study CA209010, a dose 
association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 
0.3 mg/kg, 3.7% at 2 mg/kg, and 18.5% at 10 mg/kg).  All of the events were Grade 1-2 and 
were manageable.  An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the 
10 mg/kg dose) is not expected to present any safety concerns based on the prior experience of 
10 mg/kg infused over 60 minutes.  The safety of 3 mg/kg nivolumab administered as a 
30-minute infusion was assessed in CA209153 in patients (n = 322) with previously treated 
advanced NSCLC.  Overall, there were no clinically meaningful differences in the frequency of 
hypersensitivity/infusion-related reactions (of any cause or treatment related) between patients 
infused over 30 minutes versus the frequency reported for 60-minute infusions.  Thus, nivolumab 
is considered safe to infuse over 30 minutes. 
Additional details are provided in the nivolumab Investigator’s Brochure. 
2.1.7 
Nivolumab Safety Summary 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 patients treated to date. 
For monotherapy, the safety profile is similar across tumor types.  In Phase 3 controlled studies, 
the safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 
efficacy, and is manageable using established safety guidelines.  Clinically relevant AEs typical 
of stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and by timely immunosuppressive therapy or other supportive care. 
In several ongoing clinical studies, the safety of nivolumab in combination with other 
therapeutics is being explored.  Most studies are ongoing and, as such, the safety profile of 
nivolumab combinations continues to evolve.  The most advanced combination under 
development is nivolumab + ipilimumab, which is approved in patients with unresectable or 
metastatic melanoma, and is being investigated in multiple other tumor types.  Results to date 
suggest that the safety profile of nivolumab + ipilimumab combination therapy is consistent with 
the mechanisms of action of each drug.  The nature of the AEs is similar to that observed with 


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either agent as a monotherapy; however, the frequency and severity of most AEs are increased 
with combination therapy. 
Additional details on the safety profile of nivolumab are provided in the nivolumab 
Investigator’s Brochure. 
2.1.8 
Ipilimumab Shorter Infusion Duration 
Establishing that ipilimumab can be safely administered using a shorter infusion time 
(30 minutes) is under investigation.  Previous clinical studies of ipilimumab when administered 
at 3 or 10 mg/kg have used a 90-minute infusion duration; ipilimumab has been safely 
administered at a dose of 1 mg/kg over 30 minutes for extended treatment periods.  In 
120 patients treated prospectively with ipilimumab 3 mg/kg infused over 30 minutes, 7 patients 
(5.8%) had an infusion-related reaction; all infusion-related reactions occurred with the second 
dose; six were Grade 2, and one was Grade 3 (Momtaz, 2015).  All 7 patients received 
subsequent doses of ipilimumab safely, the majority with premedication.  For comparison, the 
3-mg/kg dose over 90 minutes in this series (n = 457) resulted in an incidence of infusion-related 
reactions at 2.2%.  In a second published series in which 46 melanoma patients received 
100 shortened cycles of combined 3 mg/kg ipilimumab and 1 mg/kg nivolumab (each over 
30 minutes), one patient (2.2%; 1 of 46 patients) had a questionable reaction after administration 
of 1 mg/kg nivolumab over 30 minutes (Gassenmaier, 2018).  The authors concluded that the 
shortened infusion times for combined ipilimumab and nivolumab treatment could be safely 
administered.  The shorter duration ipilimumab infusion is being currently investigated in larger 
clinical trials.  Given available information comparing the 30- and 90-minute ipilimumab 
infusion times, ipilimumab is considered safe to infuse over 30 minutes. 
2.1.9 
Ipilimumab Safety Summary 
The safety profile of ipilimumab was evaluated in two clinical studies in which 982 melanoma 
patients received ipilimumab either as monotherapy or in combination with other therapeutics. 
The safety profile of ipilimumab is acceptable in the context of the observed clinical efficacy, 
and is manageable using established safety guidelines.  The most common clinically relevant 
AEs typical of stimulation of the immune system were enterocolitis and hepatitis, which were 
manageable by delaying or stopping ipilimumab treatment and by timely immunosuppressive 
therapy or other supportive care. 
Additional details on the safety profile of ipilimumab are provided in the ipilimumab 
Investigator’s Brochure. 
2.1.10 
Safety Summary of Study Regimen in Patients with 1L Nonsquamous NSCLC 
Patients with 1L metastatic nonsquamous NSCLC were evaluated in the global, randomized, 
double-blind, placebo-controlled, KEYNOTE-189 study (NCT02578680), a Phase 3 study of 


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pemetrexed and a platinum-based drug with or without pembrolizumab, followed by 
pembrolizumab or placebo plus pemetrexed maintenance therapy (Gandhi, 2018).   
The most common adverse event observed for the chemotherapy drugs alone (any severity 
regardless of causality at incidence at least 25%) included nausea, anemia, fatigue, constipation, 
decreased appetite, cough, and dyspnea.  The most common adverse event observed for the 
chemotherapy drugs alone (of Grade 3 or higher severity regardless of causality at incidence at 
least 5%) included anemia, neutropenia, thrombocytopenia, and dyspnea.  Additional details on 
the safety profiles of carboplatin, cisplatin, and pemetrexed are provided in the respective 
Package Insert or Summary of Product Characteristics. 
2.1.11 
Safety Summary of Paclitaxel Formulations in Patients with 1L NSCLC 
A large, international, randomized Phase 3 trial compared the efficacy and safety of 100 mg/m2 
of weekly nab-paclitaxel with 200 mg/m2 Cremophor-based paclitaxel (both combined with 
carboplatin targeting an area under the curve [AUC] of 6 every 3 weeks [q3w]) in 1052 patients 
with advanced NSCLC (Socinski, 2012).   
The most common nonhematologic Grade ≥ 3 treatment-related AEs with nab-paclitaxel and 
Cremophor-based paclitaxel were fatigue.  The most common nonhematologic grade ≥3 TRAEs 
with nab-paclitaxel and Cremophor-based paclitaxel were fatigue (5% and 6%, respectively), 
sensory neuropathy (3% and 12%), anorexia (2% and < 1%), nausea (< 1% and < 1%), myalgia 
(< 1% and 2%), and arthralgia (0% and 2%).  The most common hematologic Grade ≥ 3 
treatment-related AEs were neutropenia (47% and 58%), leukopenia (24% and 23%), 
thrombocytopenia (18% and 9%), and anemia (27%).  Additional details on the safety profiles of 
carboplatin, paclitaxel, and nab-paclitaxel are provided in the respective Package Insert or 
Summary of Product Characteristics. 
2.1.12 
Safety Summary of Nab-Paclitaxel in Patients with TNBC 
Patients treated in the first or second line setting for metastatic TNBC will receive 
nab-paclitaxel.  Clinical data on nab-paclitaxel in combination with nivolumab are based on 
small numbers of patients (Wainberg, 2017).  Data on single-agent nab-paclitaxel are therefore 
provided here.  
In the 229 patients with metastatic breast cancer treated with single-agent nab-paclitaxel in the 
randomized controlled trial in patients with metastatic breast cancer, common Grade 3 to 4 
hematological toxicities included neutropenia (Grade 4, 9%) with febrile neutropenia in 2%; 
severe anemia and thrombocytopenia were rare.  Common severe non-hematological toxicities 
included sensory neuropathy (10%), myalgias/arthralgias (8%) and asthenia (8%).  
Cardiovascular toxicities included asymptomatic hypotension during the 30-minute infusion, in 
5% of patients in the randomized metastatic breast cancer trial.  Severe cardiovascular events 
possibly related to single-agent nab-paclitaxel occurred in approximately 3% of patients in the 
randomized trial.  These events included chest pain, cardiac arrest, supraventricular tachycardia, 


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edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension.  
Electrocardiogram (ECG) abnormalities were reported in 60% of patients, including non-specific 
repolarization abnormalities, sinus bradycardia, and sinus tachycardia.  Most required no 
intervention. Alopecia was nearly universal, occurring in 90% of patients (Summary basis of 
approval; Gradishar, 2005).  
Additional details on the safety profile of nab-paclitaxel are provided in the Package Insert or 
Summary of Product Characteristics. 
2.1.13 
Safety Summary of Eribulin in Patients with TNBC 
Patients treated in the first or second line setting for metastatic TNBC will receive eribulin.  
Clinical data on eribulin in combination with nivolumab are in progress.  Data on single-agent 
eribulin are therefore provided here. 
Based on a large international, randomized clinical trial comparing eribulin to treatment of 
physician’s choice conducted in 762 patients, the most common nonhematologic Grade ≥ 3 AEs 
included fatigue (8%), peripheral neuropathy (8%), and dyspnea (4%).  The most common 
hematologic grade ≥ 3 AEs were neutropenia (21%) and anemia (2%).  Alopecia occurred in 
45% of patients (Cortes, 2011).   
Additional details on the safety profile of eribulin are provided in the Package Insert or Summary 
of Product Characteristics. 
2.2 
Overall Benefit/Risk 
NKTR-214 was designed to mitigate the serious toxicities associated with rapid systemic 
immune activation seen with administration of aldesleukin.  The goal of engineering a 
PEGylated form of IL-2 that reduces the treatment-limiting toxicities of aldesleukin, i.e., those 
necessitating in-hospital administration, appears to have been realized with NKTR-214 at the 
doses tested.  The safety profiles of nivolumab and ipilimumab are well characterized and 
manageable when administered alone or in combination, including regimens where they are 
administered in combination with additional immuno-oncology products.  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 combination therapy appears to outweigh the known risks of these 
agents and warrants clinical investigation. 
2.3 
Data Monitoring Committee 
The detailed and frequent safety monitoring that will be undertaken in this open-label study 
precludes the necessity for an independent Data Monitoring Committee.  A separate Safety 
Review Committee will meet to review safety data (see Section 9.3). 


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives of this study are: 
• To evaluate the safety and tolerability, and define the MTD and/or RP2D of NKTR-214 in 
combination with nivolumab or in combination with nivolumab and other anti-cancer 
therapies 
• To evaluate the efficacy of NKTR-214 in combination with nivolumab or in combination 
with nivolumab and other anti-cancer therapies by assessing the objective response rate 
(ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) at the 
RP2D 
3.2 
Secondary Objectives 
The secondary objective of this study is: 
• To evaluate the efficacy of NKTR-214 in combination with nivolumab or in combination 
with nivolumab and other anti-cancer therapies by assessing OS, progression-free survival 
(PFS), clinical benefit rate (CBR), and duration of response (DOR) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.0 
SELECTION OF STUDY POPULATION 
Under Amendment 7, the study is closed to patient screening and enrollment. 
For the purposes of patient eligibility determination, note the following definitions: 
• For the purposes of eligibility, “neoadjuvant therapy” is defined as systemic chemotherapy 
administered prior to definitive local surgery in a patient without distant metastases; 
“adjuvant therapy” is defined as systemic therapy administered following definitive local 
therapy (surgery or radiation) in a patient without distant metastases (with no evidence of 
disease). 
• A “line of therapy” is defined as any regimen – single-agent or combination therapy, 
cytotoxic therapy, immuno-oncology therapy separately or in combination – that is given for 
patients with advanced disease, and that is stopped for any reason, including progression of 
disease, toxicity, physician decision, or patient withdrawal of consent. 
4.1 
Inclusion Criteria 
Under Amendment 7, the study is closed to patient screening and enrollment. 
Each patient will be entered into this study only if he/she meets all of the following criteria: 
For Dose Escalation (Part 1), Dose Expansion (Part 2), and Parts 3 and 4 (For Triplet 
Combination):  
 Provide written, informed consent to participate in the study and follow the study procedures 
 Male or female patients, age 18 years or older at the time of signing the informed consent 
form (ICF) 
 Life expectancy >12 weeks 
 Patients must not have received prior interleukin-2 (IL-2) therapy. 
 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
 Measurable disease per RECIST 1.1 
 Demonstrated adequate organ function, as defined below, within 28 days of treatment 
initiation 
a. White blood cell (WBC) count ≥ 2000/μL (after at least 7 days without growth factor 
support) 
b. Absolute neutrophil count (ANC) ≥ 1500/μL (after at least 7 days without growth 
factor support) 


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c. Platelet count ≥ 100 × 103/μL (no transfusions allowed within 7 days of Cycle 1 Day 1 
to meet entry criteria) 
d. Hemoglobin ≥ 9.0 g/dL (no transfusions allowed within 7 days of Cycle 1 Day 1 to 
meet entry criteria) 
e. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 mL/min); patients with 
urothelial carcinoma who are cisplatin ineligible (creatinine clearance < 60 mL/min) 
may be enrolled if the glomerular filtration rate is ≥ 30 mL/min. 
f. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3× upper limit of 
normal (ULN) 
g. Total bilirubin within normal limits (total bilirubin ≤ 2× ULN if associated with 
hepatobiliary metastases or Gilbert’s syndrome) 
h. Lipase and amylase ≤ 1.5× ULN.  Patients with pancreatic metastases and lipase 
and/or amylase < 3× ULN may enroll.  Patients may not enroll if there are clinical or 
radiographic signs of pancreatitis. 
 A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram or multigated acquisition (MUGA) scan test within 60 days prior to Cycle 1 
Day 1. 
 Oxygen saturation ≥ 92% on room air 
 Clinically significant toxic effect(s) of the most recent prior anti-cancer therapy must be 
Grade 1 or resolved (except alopecia and sensory neuropathy); patients with Grade 2 adrenal 
insufficiency related to prior anti-cancer therapy (defined as requiring medical intervention, 
such as concomitant steroids) or Grade 2 hypothyroidism (defined as requiring hormone 
replacement therapy) may be enrolled provided that clinical symptoms are adequately 
controlled and the daily dose is 10 mg or less of prednisone or equivalent.  If the patient 
received major surgery or radiation therapy of > 30 Gy, they must have recovered from the 
toxicity and/or complications from the intervention. 
 Women of childbearing potential (WCBP) must agree and commit to the use of highly 
effective methods of birth control throughout the duration of the study until 6 months 
following the last dose of study drug.  Acceptable methods are defined as those that result, 
alone or in combination, in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal 
contraception in combination with a barrier method.  It is currently unknown whether 
NKTR-214 may reduce the effectiveness of systemically acting hormonal contraceptives, and 
therefore women using systemically acting hormonal contraceptives should add a barrier 
method.  In certain countries (if permitted by law), WCBP may agree to abide by 
heterosexual sexual abstinence during the time of participation in this study. 


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 Male patients and their female partners of childbearing potential must agree and commit to 
use a double-barrier contraception (e.g., condom with spermicidal 
foam/gel/film/cream/suppository) throughout the duration of the study until 6 months 
following the last dose of study drug; in addition to their female partner using either an 
intrauterine device or hormonal contraception and continuing until 6 months following the 
last dose of study drug.  This criterion is not applicable for male patients who have had a 
vasectomy > 6 months before signing the informed consent form (ICF). 
 Patients must not have active brain metastases:   
a. Participants with brain metastases are eligible if these have been treated and there is no 
MRI evidence of progression for at least 8 weeks after treatment is complete and 
within 28 days prior to first dose of study treatment administration.  There must also 
be no requirement for immunosuppressive doses of systemic corticosteroids  
(>10 mg/day prednisone equivalents) for at least 2 weeks prior to study treatment 
administration. Stable dose of anticonvulsants is allowed.  Treatment for CNS 
metastases may include stereotactic radiosurgery (e.g. GammaKnife, CyberKnife, or 
equivalent) or neurosurgical resection.  Patient who received whole brain radiation 
therapy are not eligible. 
b. No new or progressing brain metastasis of any size 
c. No stereotactic radiation or craniotomy within 4 weeks of Cycle 1 Day 1 
d. No new central nervous system lesions on repeat radiographic imaging 4 weeks or more 
from last treatment 
e. No clinically significant symptoms secondary to brain metastases 
f. Head imaging must occur on study in accordance with Section 5.7. 


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 Sample of fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy 
specimen taken during screening) is required, except if inaccessible and with Medical 
Monitor approval (e.g., a biopsy specimen from a sample taken since completion of the most 
recent prior systemic treatment and no longer than 6 months prior to study start may be 
acceptable in lieu of a fresh biopsy with Medical Monitor approval).  Patients must also 
consent to allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) material 
(archival tumor tissue), either a block or unstained slides for performance of correlative 
studies. 
For Parts 1 and 2   
Under Amendment 7, the study is closed to patient screening and enrollment. 
For Disease-Specific Tumor Types 
 Melanoma 
a. Histologically confirmed stage III (unresectable) or stage IV melanoma, as per 
American Joint Committee on Cancer (AJCC) staging system. 
b. Patients must consent to BRAF testing or have documented BRAF status as per 
regionally acceptable V600 mutational status testing. 
c. Uveal melanoma will be excluded. 
d. “Isolated limb perfusion” is not considered systemic chemotherapy. 
Cohort 1a − Melanoma (1L) 
a. Have not received prior anti-cancer therapy for advanced or metastatic melanoma 
For Part 2:   
b. Prior to disease metastasis, patients must not have received neoadjuvant or adjuvant 
therapy with any immuno-oncology regimens, including, but not limited to, checkpoint 
inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic 
T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other 
cytokine therapies. 
c. Patients must not have received any prior therapy for melanoma (including therapy for 
neoadjuvant, adjuvant, locally advanced or metastatic disease, including all systemic 
therapy including tyrosine kinase inhibitors [BRAF, MEK, mTOR], bevacizumab, I-O 
therapy, cytotoxic chemotherapy, and/or isolated limb perfusion). 


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Cohort 1b − Melanoma (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
a. Patients must have received only 1 prior line of therapy with an anti-PD-1 or anti-PD-L1 
containing regimen (doublet-based therapy), which must be their most recent anti-cancer 
treatment.  Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens.   
b. Patients must have confirmed radiographic or biopsy-proven disease progression at least 
4 weeks after initial disease progression, or unequivocal radiographic progression as per 
the Investigator based on a single imaging assessment; this assessment must be within 
90 days from last dose of anti-PD-1 or anti-PD-L1 containing regimen.  Patients must 
consent to providing pre-study scans (if available) to confirm radiographic progression. 
c. Patients may have received only 1 prior line of therapy with molecular-targeted therapy. 
d. Patients who have received only 1 prior regimen of cytotoxic chemotherapy but have not 
received prior molecular targeted therapy, are eligible. 
e. Patients may not have primary refractory disease to prior anti-PD-1 therapy 
(radiographic or clinical progression within 120 days of initiation of immuno-oncology 
therapy).  
Cohort 1c − Melanoma BRAF wild type (2L, anti-PD-1 or anti-PD-L1 
relapse/refractory) 
a. Patients must be BRAF wild type. 
b. Patients must have received only 1 prior line of therapy with single-agent anti-PD-1 or 
anti-PD-L1 therapy, which must be their most recent anti-cancer treatment.  Patients 
must not have received anti-CTLA-4 alone or in combination with anti-PD-1 or 
anti-PD-L1.  Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens. 
c. Patients are not eligible who received adjuvant or first-line therapy for 
advanced/metastatic disease consisting of molecular target therapies including, but not 
limited, to BRAF, MEK, or C-KIT targeted therapies (single agent or in any 
combination), or intralesional therapy. 
d. Patients are not eligible who received doublet immuno-oncology therapy, including 
checkpoint inhibitors combined with either systemic or intralesional therapy.  Patients 
are not eligible who received cytotoxic chemotherapy such as dacarbazine, paclitaxel 
or others. 


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e. Patients must have confirmed radiographic or biopsy-proven disease progression at 
least 4 weeks after initial disease progression, or unequivocal radiographic progression 
as per the Investigator based on a single imaging assessment; this assessment must be 
within 90 days from last dose of anti-PD-1 or anti-PD-L1 therapy.   
f. Patients must consent to providing pre-study scans (if available) to confirm 
radiographic progression. 
Cohort 1d – Melanoma (1L, following prior adjuvant therapy) 
a. Have not received prior anti-cancer therapy for advanced or metastatic melanoma 
b. Patient must have received prior adjuvant therapy for melanoma; adjuvant therapy 
may consist of any immuno-oncology regimens (single-agent or combination therapy) 
or molecularly targeted therapy (such as tyrosine kinase inhibitors).  The disease-free 
interval from last dose of adjuvant therapy to a diagnosis of advanced or metastatic 
melanoma must be less than 180 days.  
Cohort 1e − Melanoma 
a. Patients who were enrolled under an earlier version of the protocol who are no longer 
eligible for Cohorts 1a through 1d. 
 Renal Cell Carcinoma (RCC) 
a. Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC 
stage IV) RCC 
b. Histologically confirmed RCC with a clear-cell component 
Cohort 2a − RCC (1L) 
a. Have not received prior anti-cancer therapy for advanced or metastatic RCC. 
b. Prior to disease metastasis, patients must not have received neoadjuvant or adjuvant 
therapy with any immuno-oncology regimens, including, but not limited to, checkpoint 
inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic 
T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other 
cytokine therapies. 


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Cohort 2b − RCC (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
a. Patients must have received only 1 prior line of therapy with an anti-PD-1 or 
anti-PD-L1 containing regimen, which must be their most recent anti-cancer treatment.  
Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens. 
b. Patients must have confirmed radiographic disease progression at least 4 weeks after 
initial disease progression, or unequivocal radiographic progression as per the 
Investigator based on a single imaging assessment; this assessment must be within 
90 days from last dose of anti-PD-1 or anti-PD-L1 containing regimen. Patients must 
consent to providing pre-study scans (if available) to confirm radiographic 
progression. 
Cohort 2c – Renal Cell Carcinoma 
a. Patients who were enrolled under an earlier version of the protocol who are no longer 
eligible for Cohorts 2a or 2b. 
 Non-Small Cell Lung Cancer (NSCLC) 
a. Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC  
(unless otherwise noted) 
b. Patients with nonsquamous NSCLC must lack both epidermal growth factor receptor 
(EGFR)-sensitizing mutation/deletion and anaplastic lymphoma kinase (ALK) 
translocation by local testing (assessment of ROS1 mutation status is not required, 
unless otherwise noted).  For ALK or EGFR testing, an FDA-approved test or 
validated assay should be used as applicable for selection of patients.  For patients 
with squamous NSCLC, testing for EGFR, ALK, or ROS1 is not required. 
Cohorts 3a.1, 3a.2, 3a.3, and 3a.4 − NSCLC (1L) 
a. Patients must have known PD-L1 status as per validated immunohistochemistry 
testing.  Up to 20 efficacy-evaluable patients will be enrolled in each subgroup of PD-
L1 negative (PD-L1 < 1%; Cohort 3a.1), PD-L1 highly positive (PD-L1 ≥ 50%; 
Cohort 3a.3), or PD-L1 low/intermediate (PD-L1 ≥ 1% - < 50%; Cohort 3a.2).  For 
patients who do not have known PD-L1 status, testing must be done using an 
FDA-approved PD-L1 test.  An abbreviated consent may be presented to the patient 
prior to the Screening period to permit early assessment of the PD-L1 status of the 
tissue sample.  Patients enrolled in Cohort 3a who do not have a PD-L1 status assessed 
by central testing will be assigned to Cohort 3a.4. 


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b. Patients must not have received prior anti-cancer therapy for advanced or metastatic 
NSCLC; patients must not have received prior immuno-oncology in any setting 
(including neoadjuvant, adjuvant, locally advanced or metastatic disease). 
Cohort 3b − NSCLC (2L, I-O therapy naive) following platinum-based therapy 
a. Patients must have experienced disease recurrence or progression during or after one 
prior platinum doublet-based chemotherapy regimen for advanced or metastatic 
disease.  Patients are not eligible who refused prior platinum-based therapy.  
b. Patients who received platinum-containing adjuvant, neoadjuvant, or definitive 
chemoradiation therapy given for locally advanced disease and developed recurrent 
(local or metastatic) disease within 6 months of completing therapy are eligible. 
c. Patients must not have received any prior immuno-oncology in any setting regimens, 
including, but not limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4)  
antibody, or any other antibody or drug specifically targeting T cell co-stimulation or 
checkpoint pathways, indoleamine 2,3-dioxygenase pathway inhibitors, cancer 
vaccines, adoptive cell therapies, or other cytokine therapies. 
Cohort 3c − NSCLC (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
a. Patients must have received only 1 prior line of therapy with anti-PD-1 or anti-PD-L1 
therapy.  Patients are eligible if they received sequential therapy (e.g., cytotoxic 
chemotherapy followed by anti PD-1 or anti PD-L1 therapy, or vice versa). Patients 
must not have received neoadjuvant or adjuvant therapy with any immuno-oncology 
regimens. 
b. Patients must not have received anti-CTLA-4 alone or in combination with anti-PD-1 
or anti-PD-L1, unless the anti-CTLA-4 therapy stopped > 1 year prior to Cycle 1 
Day 1. 
c. Prior to the anti-PD-1 or anti-PD-L1 therapy regimen, patients must have received 
zero or 1 prior line of cytotoxic chemotherapy for metastatic disease. 
d. Patients must have confirmed radiographic disease progression at least 4 weeks after 
initial disease progression, or unequivocal radiographic progression as per the 
Investigator based on a single imaging assessment; this assessment must be within 
90 days from last dose of anti-PD-1 or anti-PD-L1 containing regimen.  Patients must 
consent to providing pre-study scans (if available) to confirm radiographic 
progression. 
e. Patients may not have primary immuno-oncology refractory disease (radiographic or 
clinical progression within 120 days of initiation of immuno-oncology therapy). 


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Cohorts 3d.1 and 3d.2 − NSCLC (1L nonsquamous) (in combination with 
platinum/pemetrexed and maintenance pemetrexed [Cohort 3d.1] or without 
maintenance pemetrexed [Cohort 3d.2]) 
a. Patients must have nonsquamous NSCLC.  The patient will be excluded if the 
histology is considered predominantly squamous cell NSCLC.  Mixed tumors will be 
categorized by the predominant cell type; if small cell elements are present, the patient 
is ineligible. 
b. Patients must not have received prior anti-cancer therapy for advanced or metastatic 
NSCLC; patients who received adjuvant or neoadjuvant therapy are eligible if the 
adjuvant/neoadjuvant therapy was completed at least 12 months prior to the 
development of metastatic disease.  Patients must not have received prior 
immuno-oncology therapy in any setting (including neoadjuvant, adjuvant, locally 
advanced or metastatic disease). 
c. Patients must be candidates for platinum/pemetrexed chemotherapy and willing to take 
folic acid and vitamin B12 supplementation. 
d. Patients must not have received radiation therapy to the lung that is > 30 Gy within 
6 months of the first dose of study medication. 
Cohort 3e − NSCLC (1L squamous) (in combination with platinum/taxane) 
a. Patients must have squamous NSCLC. 
b. Patients must not have received prior anti-cancer therapy for advanced or metastatic 
NSCLC; patients who received adjuvant or neoadjuvant chemotherapy (after surgery 
and/or radiation therapy) and developed recurrent or metastatic disease within 
6 months of completing therapy are eligible.  Patients must not have received prior 
immuno-oncology therapy in any setting (including neoadjuvant, adjuvant, locally 
advanced or metastatic disease). 
c. Patients must be candidates for platinum/taxane chemotherapy. 
d. Patients must not have received radiation therapy to the lung that is > 30 Gy within 
6 months of the first dose of study medication. 
e. Known hypersensitivity to the selected cytotoxic chemotherapy study drugs.  
Cohort 3f − NSCLC (3L+, ALK-translocation/ROS1 rearrangement positive) 
a. Patients must have ALK-translocation positive or ROS1 rearrangement NSCLC by 
local pathology report (assessment of ROS1 mutation status is not required).  For ALK 
testing, an FDA-approved test or validated assay must be used. 


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b. Patients must have received at least two prior anti-cancer therapies for advanced or 
metastatic NSCLC (these may have included chemotherapy and must have included at 
least one ALK-directed and/or ROS-1-directed therapy), be ineligible to receive these 
therapies due to toxicity, or no longer be considered a candidate for additional tyrosine 
kinase inhibitor therapy; patients must not have received prior immuno-oncology 
therapy in any setting (including neoadjuvant, adjuvant, locally advanced or metastatic 
disease). 
c. Patients may not have received more than one prior cytotoxic-based regimen (e.g., 
carboplatin with paclitaxel). 
Cohort 3g − NSCLC (3L+, EGFR mutation/deletion) 
a. Patients must have EGFR mutation or relevant deletion NSCLC by local pathology 
report.  For EGFR testing, an FDA-approved test or validated assay should be used. 
b. Patients must have received at least two prior anti-cancer therapies for advanced or 
metastatic NSCLC (these may have included chemotherapy and must have included at 
least one EGFR-directed small molecule therapy), be ineligible to receive these 
therapies due to toxicity, or no longer be considered a candidate for additional tyrosine 
kinase inhibitor therapy; patients must not have received prior I-O therapy in any 
setting (including neoadjuvant, adjuvant, locally advanced or metastatic disease). 
c. Patients may not have received more than one prior cytotoxic-based regimen (e.g., 
carboplatin with paclitaxel). 
Cohort 3h − NSCLC (2L, anti PD 1 or anti PD L1 relapse/refractory) 
a. Patients must have received only 1 prior line of therapy with anti-PD-1 or anti-PD-L1 
therapy in combination with doublet platinum-containing cytotoxic chemotherapy, 
which must be their most recent anti-cancer treatment.  Patients are not eligible if they 
received sequential therapy (e.g., cytotoxic chemotherapy doublet therapy followed by 
anti PD-1 or anti PD-L1 therapy or vice versa).  Patients must not have received 
neoadjuvant or adjuvant therapy with any immuno-oncology regimens. 
b. Patients must not have received more than 1 prior line of cytotoxic chemotherapy for 
metastatic disease. 
c. Patients must have confirmed radiographic disease progression at least 4 weeks after 
initial disease progression, or unequivocal radiographic progression as per the 
Investigator based on a single imaging assessment; this assessment must be within 90 
days from last dose of anti-PD-1 or anti-PD-L1 containing regimen.  Patients must 
consent to providing pre study scans (if available) to confirm radiographic 
progression. 


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d. Patients may not have primary immuno-oncology refractory disease (radiographic or 
clinical progression within 120 days of initiation of immuno-oncology therapy). 
Cohort 3i – NSCLC 
a. Patients who were enrolled under an earlier version of the protocol who are no longer 
eligible for Cohorts 3a.1 to 3h. 
 Urothelial Carcinoma 
a. Histologically or cytologically documented locally advanced or transitional cell 
carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or urethra.  
Patients with mixed histologies are required to have a dominant transitional cell 
pattern. 
Cohort 4a − Urothelial Carcinoma (1L) 
a. Enrollment of urothelial carcinoma 1L patients will target accrual of up to 20 patients 
who are cisplatin-ineligible and up to 20 patients, who, after consultation with the 
Investigator, choose to forego front-line chemotherapy. 
b. Treatment naive patients who refuse chemotherapy standard of care or treatment naive, 
cisplatin-ineligible patients who meet at least one of the following criteria: 
• Creatinine clearance (calculated or measured) < 60 mL/min. Cisplatin-ineligible 
patients must have a creatinine clearance < 60 mL/min and GFR ≥ 30 mL/min. 
• Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≥ 2 
audiometric hearing loss 
• CTCAE v4.03 Grade ≥ 2 peripheral neuropathy 
c. No prior chemotherapy for inoperable locally advanced or metastatic urothelial 
carcinoma.  Prior local intravesical chemotherapy is allowed if completed at least 
4 weeks prior to the initiation of study treatment. 
d. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-
radiation for urothelial carcinoma, a treatment-free interval of more than 12 months 
between the last treatment administration and the date of recurrence is required to be 
considered treatment naive in the metastatic setting.  Patients must not have received 
neoadjuvant or adjuvant therapy with any immuno-oncology regimens. 
Cohort 4b – Urothelial Carcinoma (2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory) 
a. Patients must have progressed on only one prior line of therapy that contains 
platinum-based chemotherapy in the metastatic setting or post platinum-based 
chemotherapy in an adjuvant setting with progression < 6 months.   


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b. Patients must have received only one prior line of therapy with single-agent anti-PD-1 
or anti-PD-L1 therapy, which must be their most recent anti-cancer treatment.  Patients 
must not have received anti-CTLA-4 alone or in combination with anti-PD-1 or 
anti-PD-L1.  Patients must not have received neoadjuvant or adjuvant therapy with any 
immuno-oncology regimens. 
c. Patients must have confirmed radiographic disease progression at least 4 weeks after 
initial disease progression, or unequivocal radiographic progression as per the 
Investigator based on a single imaging assessment; this assessment must be within 90 
days from last dose of anti-PD-1 or anti-PD-L1 therapy.  Patients must consent to 
providing pre-study scans (if available) to confirm radiographic progression. 
d. Patients may not have primary immuno-oncology refractory disease (radiographic or 
clinical progression within 120 days of initiation of immuno-oncology therapy). 
Cohort 4c − Urothelial 
a. Patients who were enrolled under an earlier version of the protocol who are no longer 
eligible for Cohorts 4a or 4b. 
 Cohort 5 − Triple-Negative Breast Cancer (1-2L, I-O therapy naive) 
a. Patients must have diagnosis of advanced triple-negative breast cancer (TNBC) 
(“advanced” is defined either locally advanced breast cancer not amenable to curative 
surgery or radiotherapy or distant metastases).  
• Less than 1% of tumor cell nuclei test positive for estrogen and progesterone 
receptors determined by using standard IHC 
• Human epidermal growth factor receptor 2 (HER2) negative as determined by local 
pathologist, using IHC or in situ hybridization 
• Patients must have had triple negative phenotype of breast cancer in all available 
biopsies that have been examined during the course of the disease. 
b. Patients must have received 0 or 1 prior line of therapy with systemic cytotoxic 
chemotherapy for advanced TNBC or patient refuses standard of care.  Substitution 
within a class of anti-cancer therapy (e.g., nab-paclitaxel for paclitaxel; carboplatin for 
cisplatin) is permitted; otherwise patients who discontinued therapy for reasons other 
than progressive disease are still considered to have received 1 prior line of therapy. 


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c. Patients are excluded whose disease-free interval (for patients with prior neoadjuvant 
or adjuvant chemotherapy: the interval between the last dose of neoadjuvant or 
adjuvant chemotherapy to the diagnosis of advanced breast cancer; for patients 
originally diagnosed with Stage I/II/III breast cancer who did not receive prior 
neoadjuvant or adjuvant chemotherapy: the interval between date of original diagnosis 
of breast cancer and date of diagnosis of advanced breast cancer) is less than 6 months 
and no clinically significant tumor-related symptoms in the judgment of the 
investigator.  Patients with a diagnosis of de novo Stage IV breast are eligible. 
d. Patients are excluded if the screening LDH > 2 × ULN (based on the central 
laboratory). 
e. Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase 
pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine 
therapies. 
Cohort 5a − Triple-Negative Breast Cancer (1-2L, I-O therapy naive) 
a. Patients must be candidates for NKTR-214 in combination with nivolumab. 
Cohort 5b − Triple-Negative Breast Cancer (1-2L, I-O therapy naive) in combination 
with nab-paclitaxel  
a. Patients must be candidates for single-agent nab-paclitaxel; patients may not have 
received paclitaxel or docetaxel for metastatic carcinoma and may not have relapsed 
with metastatic disease within 1 year of adjuvant paclitaxel or docetaxel treatment. 
b. Patients may not have received prior nab-paclitaxel in any setting. 
Cohort 5c − Triple-Negative Breast Cancer (1-2L, I-O therapy naive) in combination 
with eribulin  
a. Patients must be a candidate for single-agent eribulin; patients may not have relapsed 
with metastatic disease within 1 year of adjuvant taxane-based treatment. 
b. Patients may not have received prior eribulin in any setting. 
Cohort 5d – TNBC 
a. Patients who were enrolled under an earlier version of the protocol who are no longer 
eligible for Cohorts 5a to 5c. 


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 Cohort 6 − Hormone-Receptor Positive, HER2 Negative Breast Cancer  
a. Patients must have diagnosis of advanced hormone-receptor positive breast carcinoma 
(“advanced” is defined either locally advanced breast cancer not amenable to curative 
surgery or radiotherapy or metastatic disease). 
• ≥ 1% of tumor cell nuclei test positive for estrogen or progesterone receptors 
determined by using standard IHC  
• HER2 negative as determined by local pathologist, using IHC or in situ hybridization 
• For patients whose primary tumor was HER2-positive or hormone-receptor positive, 
eligibility will be based on the first biopsy for advanced disease.  
b. Patients must have either archival or fresh tumor biopsy that demonstrates 
≥ 1% positive PD-L1 staining by the central pathology laboratory.  An abbreviated 
consent may be presented to the patient prior to the Screening period to permit early 
assessment of the PD-L1 status of the tissue sample. 
c. Patients must have received prior aromatase inhibitor and fulvestrant therapy for 
advanced breast cancer.  (Progression after prior adjuvant therapy with an aromatase 
inhibitor within 12 months will count as a line of therapy).  Hormonal therapy may 
have been administered as single-agent or in combination with CDK4-6 inhibitors 
(such as palbociclib and others), mTOR inhibitors (everolimus and others), PI3K 
inhibitors (buparlisib and others), or other agents used in combination with hormonal 
agents (AKT inhibitors, WNT inhibitors, or others). 
d. Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase 
pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine 
therapies. 


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Cohort 6a − Hormone-Receptor Positive, HER2-Negative Breast Cancer (I-O therapy 
naive following hormonal therapy) 
a. Patients must not have received prior cytotoxic chemotherapy (such as tubulin-
targeting agents (paclitaxel, docetaxel, nab-paclitaxel, eribulin, vinca alkaloids, 
epothilones, and others), anti-metabolites (5-fluorouracil, capecitabine, gemcitabine, 
and others), platinum agents (carboplatin, cisplatin, and others), alkylating agents 
(cyclophosphamide and others), topoisomerase 1 or 2 inhibitors (irinotecan, 
doxorubicin, epirubicin, etoposide, and others) or VEGF-targeted monoclonal 
antibodies (bevacizumab and others).  Prior systemic therapy must be reviewed by the 
Medical Monitor prior to registration for the trial. 
Cohort 6b − Hormone-Receptor Positive, HER2-Negative Breast Cancer (I-O therapy 
naive following hormonal and cytotoxic therapy) 
a. Patients must have received at least one and up to 2 prior lines of cytotoxic 
chemotherapy (such as tubulin-targeting agents (paclitaxel, docetaxel, nab-paclitaxel, 
eribulin, vinca alkaloids, epothilones, and others), anti-metabolites (5-fluorouracil, 
capecitabine, gemcitabine, and others), platinum agents (carboplatin, cisplatin, and 
others), alkylating agents (cyclophosphamide and others), topoisomerase 1 or 2 
inhibitors (irinotecan, doxorubicin, epirubicin, etoposide, and others).  Substitution 
within a class of anti-cancer therapy (e.g., carboplatin for cisplatin) is permitted; 
otherwise patients who discontinued therapy for reasons other than progressive disease 
are still considered to have received a prior line of therapy.  Prior systemic therapy 
must be reviewed by the Medical Monitor prior to registration for the trial. 
 Cohort 7 − Gastric Carcinoma (2-3L, I-O therapy naive) 
a. Patients must have diagnosis of advanced gastric adenocarcinoma or gastroesophageal 
carcinoma (GC) (“advanced” is defined either locally recurrent surgically unresectable 
advanced cancer or metastatic disease). 
b. Patients must have either archival or fresh tumor biopsy that demonstrates PD-L1 
staining (Combined Positive Score ≥ 1 as determined by an FDA-approved test or 
validated assay).  An abbreviated consent may be presented to the patient prior to the 
Screening period to permit early assessment of the PD-L1 status of the tissue sample. 
c. Patients must have received no more than two prior lines of therapy including 
fluoropyrimidine- and platinum-containing chemotherapy, and (if appropriate) 
HER2-targeted systemic therapy for gastric cancer.  These drugs may have been 
administered in the neoadjuvant, adjuvant, locally advanced or metastatic setting. 
Patients may have progressed or been intolerant to these therapies. (“Systemic 
therapy” includes all agents, including cytotoxic, molecularly targeted or other).  
Substitution within a class of anti-cancer therapy (e.g., capecitabine for fluorouracil 


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[5-FU]; carboplatin for cisplatin) is permitted; otherwise patients who discontinued 
therapy for reasons other than progressive disease are still considered to have received 
a prior line of therapy. 
d. Must not have received any prior immuno-oncology regimens, including, but not limited 
to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell 
co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase pathway 
inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies. 
 Cohort 8a – Colorectal Carcinoma (2-3L, I-O therapy naive); microsatellite instability 
(MSI)-high 
a. Patients must have diagnosis of advanced colorectal carcinoma (CRC) (“advanced” is 
defined either locally advanced unresectable cancer or metastatic disease).   
b. Patients must have either archival or fresh tumor biopsy that demonstrates 
microsatellite instability (MSI) high or mismatch repair deficient (dMMR) disease.  
An abbreviated consent may be presented to the patient prior to the Screening period 
to permit early assessment of the CD8+ TIL status of the tissue sample. 
c. Patients who had disease progression during, after, or were intolerant to, prior 
treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy 
(patients must have received either fluoropyrimidine and oxaliplatin-containing 
chemotherapy OR fluoropyrimidine and irinotecan-containing chemotherapy for 
colorectal carcinoma cancer (“FOLFOX” [fluorouracil, leucovorin, and oxaliplatin] or 
“FOLFIRI” [5-fluorouracil, leucovorin, and irinotecan]); and (if appropriate) EGFR-
targeted and/or VEGF-targeted systemic therapy.  These drugs may have been 
administered in the neoadjuvant, adjuvant, locally advanced or metastatic setting.  
(“Systemic therapy” includes all agents, including cytotoxic, molecularly targeted or 
other).  Substitution within a class of anti-cancer therapy (e.g., capecitabine for 5-FU) 
is permitted; otherwise patients who discontinued therapy for reasons other than 
progressive disease are still considered to have received a prior line of therapy. 
d. Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase 
pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine 
therapies. 


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Cohort 8b – Colorectal Carcinoma (3-4L, I-O therapy naive); MSI-non-high 
a. Patients must have diagnosis of advanced colorectal carcinoma (CRC) (“advanced” is 
defined either locally advanced unresectable cancer or metastatic disease).   
b. Patients must have either archival or fresh tumor biopsy that demonstrates MSI not 
high (MSI-stable or MSI-low) or mismatch repair proficient (pMMR) disease.  In 
addition, tumor tissue must demonstrate CD8+ tumor infiltrating lymphocytes (≥ 10% 
by IHC) by central laboratory.  An abbreviated consent may be presented to the patient 
prior to the Screening period to permit early assessment of the CD8+ TIL status of the 
tissue sample. 
c. Patients must have received at least two but no more than 3 prior lines of therapy 
including fluoropyrimidine-, oxaliplatin and irinotecan-containing chemotherapy 
colorectal cancer; and (if appropriate) EGFR-targeted and/or VEGF-targeted systemic 
therapy.  These drugs may have been administered in the neoadjuvant, adjuvant, 
locally advanced or metastatic setting.  (“Systemic therapy” includes all agents, 
including cytotoxic, molecularly targeted or other).  Substitution within a class of 
anti-cancer therapy (e.g., capecitabine for 5-FU) is permitted; otherwise patients who 
discontinued therapy for reasons other than progressive disease are still considered to 
have received a prior line of therapy. 
d. Must not have received any prior immuno-oncology regimens, including, but not 
limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T cell co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase 
pathway inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine 
therapies. 
 Cohort 9 –Small Cell Lung Cancer (2L, I-O therapy naive) 
a. Patients must have diagnosis of limited-stage or extensive-stage SCLC.   
b. Patients must have received no more than 1 prior line of platinum-based therapy.  
Substitution within a class of anti-cancer therapy (e.g., carboplatin for cisplatin) is 
permitted; otherwise patients who discontinued therapy for reasons other than 
progressive disease are still considered to have received a prior line of therapy.   
c. Must not have received any prior immuno-oncology regimens, including, but not limited 
to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell 
co-stimulation or checkpoint pathways, indoleamine 2,3-dioxygenase pathway 
inhibitors, cancer vaccines, adoptive cell therapies, or other cytokine therapies. 


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For Parts 3 and 4 (NKTR-214/nivolumab/ipilimumab) 
Under Amendment 7, the study is closed to patient screening and enrollment. 
For Disease-Specific Tumor Types 
 Cohorts 10a.1 and 10a.3 − Renal Cell Carcinoma (1L), as follows: 
• Cohort 10a.1: concurrent dosing schedule 1 (this cohort was closed to enrollment 
under Amendment 6.0) 
• Cohort 10a.3: concurrent dosing schedule 3 
a. Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC 
stage IV) RCC. 
b. Histologically confirmed RCC with a clear-cell component. 
c. Patients must not have received prior anti-cancer therapy for advanced or metastatic 
RCC. 
d. Prior to disease metastasis, patients must not have received neoadjuvant or adjuvant 
therapy with any immuno-oncology regimens, including, but not limited to, checkpoint 
inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic 
T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other 
cytokine therapies. 
 Cohort 11a.1 − Non-Small Cell Lung Cancer (1L) 
a. Histologically confirmed or cytologically confirmed diagnosis of stage IV NSCLC  
b. Patients with nonsquamous NSCLC must lack both epidermal growth factor receptor 
(EGFR)-sensitizing mutation/deletion and anaplastic lymphoma kinase (ALK) 
translocation by local testing (assessment of ROS1 mutation status is not required).  
For ALK or EGFR testing, an FDA-approved test or validated assay should be used as 
applicable for selection of patients.  For patients with squamous NSCLC, testing for 
EGFR and ALK is not required. 
c. Patients must not have received prior anti-cancer therapy for advanced or metastatic 
NSCLC.   
d. Patients must not have received neoadjuvant or adjuvant therapy with any immuno-
oncology regimens. 


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 Cohorts 12a.2 and 12a.3 − Melanoma (1L), as follows: 
• Cohort 12a.2:  concurrent dosing schedule 2 
• Cohort 12a.3:  concurrent dosing schedule 3 
a. Histologically confirmed stage III (unresectable) or stage IV melanoma, as per 
American Joint Committee on Cancer (AJCC) staging system. 
b. Patients must consent to BRAF testing or have documented BRAF status as per 
regionally acceptable V600 mutational status testing. 
c. Uveal melanoma will be excluded. 
d. Have not received prior anti-cancer therapy for advanced or metastatic melanoma. 
e. Prior to disease metastasis, patients must not have received neoadjuvant or adjuvant 
therapy with any immuno-oncology regimens, including, but not limited to, checkpoint 
inhibitors such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic 
T-lymphocyte antigen 4 (anti-CTLA-4) antibody, or any other antibody or drug 
specifically targeting T cell co-stimulation or checkpoint pathways, indoleamine 
2,3-dioxygenase pathway inhibitors, cancer vaccines, adoptive cell therapies, or other 
cytokine therapies. 
f. Prior to disease metastasis, patients must not have received neoadjuvant or adjuvant 
tyrosine kinase (BRAF, MEK, mTOR), bevacizumab or intralesional therapy.   
 Cohort 13a.2 – Urothelial Carcinoma (1L) 
a. Histologically or cytologically documented locally advanced or transitional cell 
carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or urethra.  
Patients with mixed histologies are required to have a dominant transitional cell 
pattern. 
b. Treatment naive patients who refuse chemotherapy standard of care or treatment naive, 
cisplatin-ineligible patients who meet at least one of the following criteria: 
• Creatinine clearance (calculated or measured) < 60 mL/min. Cisplatin-ineligible 
patients must have a creatinine clearance < 60 mL/min and GFR ≥ 30 mL/min.  
• Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade ≥ 2 
audiometric hearing loss 
• CTCAE v4.03 Grade ≥ 2 peripheral neuropathy 
c. No prior chemotherapy for inoperable locally advanced or metastatic urothelial 
carcinoma.  Prior local intravesical chemotherapy is allowed if completed at least 
4 weeks prior to the initiation of study treatment. 


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d. For patients who received prior adjuvant/neoadjuvant chemotherapy or 
chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 
12 months between the last treatment administration and the date of recurrence is 
required to be considered treatment naive in the metastatic setting.  Patients must not 
have received neoadjuvant or adjuvant therapy with any immuno-oncology regimens.   
4.2 
Exclusion Criteria 
Under Amendment 7, the study is closed to patient screening and enrollment. 
A patient will be excluded from this study if he/she meets any of the following criteria: 
 Use of an investigational agent or an investigational device within 28 days before 
administration of first dose of study drug 
 Females who are pregnant or breastfeeding 
 Patients who have an active, known or suspected autoimmune disease.  Patients requiring 
systemic treatment within the past 3 months or a documented history of clinically severe 
autoimmune disease that requires systemic steroids or immunosuppressive agents.  
(Exceptions include any patient on 10 mg or less of prednisone or equivalent, patients with 
vitiligo, hypothyroidism stable on hormone replacement, Type I diabetes, Graves’ disease, 
Hashimoto's disease, alopecia areata, eczema, or with Medical Monitor approval.) 
 History of allergy or hypersensitivity to study drug components 
 Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that 
has undergone potentially curative therapy, or in situ cervical cancer.  An incidental finding 
of prostate cancer (identified upon resection of the prostate) is acceptable, provided that the 
following criteria are met: Stage T2N0M0 or lower; Gleason score ≤ 6, and prostate-specific 
antigen (PSA) below lower limit of normal by local laboratory. 
 History of organ or tissue transplant that requires systemic use of immune suppressive agents 
 Evidence of clinically significant interstitial lung disease or active, noninfectious 
pneumonitis 
 Prior surgery or radiotherapy within 14 days of therapy.  Patients must have recovered from 
all radiation-related toxicities, and not require corticosteroids.  


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 Patients who have had < 28 days since the last chemotherapy, biological therapy, or 
< 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, 
vemurafenib, dabrafenib, cobimetinib, erlotinib, gefitinib, afatinib, osimertinib), < 14 days 
from last dose of hormonal therapy (for patients with breast cancer) or systemic or inhaled 
steroid therapy at doses greater than 10 mg of prednisone or equivalent before administration 
of the first dose of study drug. 
 Parts 1 and 2: Patients in whom prior anti PD-1 / anti-PD-L1 therapy was intolerable and 
required discontinuation of treatment; Parts 3 and 4: Patients in whom prior anti PD-1 / 
anti-PD-L1 therapy and/or prior CTLA-4 therapy was intolerable and required 
discontinuation of treatment; patients who have discontinued prior checkpoint inhibitor 
therapy due to adrenal insufficiency that is now managed by replacement steroid therapy may 
be eligible for the trial upon Medical Monitor approval. 
 NSCLC patients who require supplemental oxygen 
 Uveal melanoma is excluded. 
 Active infection requiring systemic therapy 
 Has known hepatitis B virus (HBV) infection (e.g., hepatitis B surface antigen [HBsAg] 
reactive) or hepatitis C virus (HCV) infection (e.g., HCV ribonucleic acid [RNA] qualitative 
is detected) 
 Has known immunodeficiency or active human immunodeficiency virus (HIV-1/2 
antibodies) 
 Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for 
women at Screening 
 History of unstable or deteriorating cardiac disease or cerebrovascular disease within the 
previous 2 years 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 
d. Prior cerebrovascular accident or transient ischemic attack. 
 Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics) 
 Known current drug or alcohol abuse 


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 Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of 
the Investigator, would preclude the patient from adhering to the protocol or would increase 
the risk associated with study participation or study drug administration or interfere with the 
interpretation of safety results (e.g., a condition associated with diarrhea or acute 
diverticulitis). 
For sites located in France only 
 Vulnerable populations described in Article L. 1121-6 of the French Public Health Code 
 Legally protected majors or majors who are unable to express their consent as described in 
Article L. 1121-8 of the French Public Health Code 
For sites located in Italy only 
 Patients may not be enrolled if they have first-line urothelial cancer with cisplatin-eligible 
disease (Cohort 4a and Cohort 13a.2). 


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5.0 
TREATMENT PLAN 
5.1 
Overview 
This is a Phase 1/2, open-label, multicenter study of NKTR-214 in combination with nivolumab 
or in combination with nivolumab and other anti-cancer therapies in patients with locally 
advanced or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, triple-negative breast 
cancer (TNBC), hormone-receptor-positive breast cancer, gastric, colorectal, or SCLC.  The 
study is divided into a Screening period, Treatment period, End of Treatment period, and 
Long-Term Follow-up period. 
The NKTR-214 treatment period of the study is divided into a 21-day (q3w) cycle with 
associated evaluations and procedures.  Treatment cycle is defined by the frequency of 
NKTR-214 administration (see Table 7). 
Results of the assessments must be reviewed and documented before administering the first dose 
of the next cycle.  Every effort should be made to schedule visits within the protocol-specified 
windows.  NKTR-214 treatment period may be evaluated at different frequencies based on safety 
and biomarker data collected in an ongoing NKTR-214 monotherapy clinical trial 
(NCT02869295). 
The study will be conducted in 4 parts:  Part 1, Dose Escalation, Part 2, Dose Expansion  
(Figure 1), Part 3 (Schedule Finding for Triplet), and Part 4 (Dose Expansion of Triplet)  
(Figure 2).  The sponsor will notify sites when individual cohorts are open for screening and 
when screening is closed.  Certain cohorts may only open at select participating sites. 
If multiple cohorts in the same tumor type are open for enrollment, the sponsor will assign the 
appropriate cohort (whether this is a Part 2 NKTR-214/nivolumab doublet cohort [with or 
without other anti-cancer therapies] or one of the dosing schedules investigating the 
NKTR-214/nivolumab/ipilimumab triplet in Parts 3 and 4). 
All procedures are outlined in the Schedule of Events (Section 1.2). 
5.2 
Screening Period 
Patients will provide written informed consent to participate in the study before completing any 
protocol-specified procedures or evaluations not considered to be part of the patient’s standard 
care.  For those cohorts that require assessment of PD-L1 or tumor infiltrating lymphocytes 
(TILs) by immunohistochemistry as part of screening procedures, an abbreviated informed 
consent that only permits assessment of PD-L1 status by the central laboratory may be used.  If 
eligible, a patient must sign the full study informed consent before any other screening 
procedures may proceed.  After signing the ICF, patients will be evaluated for entry criteria 
during the Screening period within 28 days before administration of study drug(s).  Rescreening 
after screen failure will be allowed. 


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For melanoma patients whose BRAF mutation status is unknown, the patient must have 
submitted sample(s) for BRAF status testing prior to the first administration of study drugs. 
5.3 
Treatment Period 
Patients will be treated until disease progression, death, unacceptable toxicity, symptomatic 
deterioration, achievement of maximal response, the Investigator’s decision to discontinue 
treatment, the patient decides to discontinue treatment or withdraw consent, lost to follow up, or 
Nektar Therapeutics decides to terminate the trial. 
Patients with progressive disease (PD) per RECIST 1.1 but with otherwise stable or improved 
performance and clinical status may continue to be treated in the event of a perceived benefit per 
Investigator; see Section 5.3.9 for treatment beyond progression.  Patients with a PR or stable 
disease (SD) will continue to receive NKTR-214 combination until achievement of a confirmed 
CR, disease progression, or intolerability to therapy.  It is at the discretion of the Investigator to 
continue treating patients with a confirmed CR, for a maximum treatment of 2 years. 
5.3.1 
Administration of Study Drug 
Each patient’s NKTR-214 dose will be determined by the NKTR-214 dose escalation scheme 
and the patient’s weight in kilograms.  The patient’s weight in kilograms will be determined 
before the start of each 3-week cycle.  If the patient’s weight is within 10% of the Cycle 1 Day 1 
weight, the study drug doses do not need to be recalculated depending on institutional 
guidelines/preference.  If the patient’s weight has changed more than 10% from the Cycle 1 
Day 1 weight, the dose of NKTR-214 must be recalculated and subsequent weight measurements 
should be compared with this new baseline weight to determine if further NKTR-214 dose 
recalculations are necessary.   
When administered on the same day, NKTR-214 will be administered first before nivolumab, 
ipilimumab, or other anti-cancer therapy. NKTR-214 will be administered IV over 
30 (± 5) minutes at a starting dose of 0.006 mg/kg every 3 weeks (± 3 days).  Patients should be 
carefully monitored for infusion reactions during NKTR-214 administration.  If an acute infusion 
reaction is noted, patients should be managed according to Section 5.15.  
Nivolumab administration should start at least 30 minutes from the end of NKTR-214 
administration.  It is highly recommended that ipilimumab administration should start within 
30 minutes after completion of nivolumab administration.   
The ipilimumab infusion is set at 30 minutes for both the 1 mg/kg and 3 mg/kg doses.  The safety 
of this shortened infusion time was investigated and demonstrated to show an acceptable 
tolerability profile (Momtaz, 2015 and Gassenmaier, 2018; also see Section 2.1.8).   
Institutional guidelines for administration of other anti-cancer therapies should be followed in 
Part 2. 


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• NKTR-214 administered IV over 30 (± 5) minutes at a starting dose of 0.006 mg/kg q3w 
• Nivolumab (anti-PD-1) administered IV over 30 (± 5) minutes at either a 360 mg flat dose 
q3w (Parts 2, 3, and 4); 1 mg/kg q3w × 4 doses or 3 mg/kg q3w × 4 doses (Parts 3 and 4) 
• Parts 3 and 4:  Ipilimumab (anti-CTLA-4) administered IV over 30 (± 5) minutes at 1 mg/kg 
q6w, 1 mg/kg q3w × 4 doses or 3 mg/kg q3w × 4 doses (Parts 3 and 4) 
• Part 2: Cohort 3d.1 (NSCLC): NKTR-214 followed by nivolumab (q3w) followed by 
investigator’s choice of cisplatin 75 mg/m2 administered IV or carboplatin AUC 5 with 
pemetrexed 500 mg/m2 q3w by IV administration for 4 cycles followed by maintenance 
NKTR-214, nivolumab, and pemetrexed 
• Part 2: Cohort 3d.2 (NSCLC): NKTR-214 followed by nivolumab (q3w) followed by 
investigator’s choice of cisplatin 75 mg/m2 administered IV or carboplatin AUC 5 with 
pemetrexed 500 mg/m2 q3w by IV administration for 4 cycles followed by maintenance 
NKTR-214 and nivolumab (see Section 5.13.12 for treatment discontinuation criteria of 
maintenance NKTR-214 and nivolumab). 
• Part 2: Cohort 3e (NSCLC):  NKTR-214 followed by nivolumab (q3w) followed by either 
Cremophor-based paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle or nab-paclitaxel 
100 mg/m2 by IV infusion on Days 1, 8, and 15 of each 21-day cycle for 4 cycles with either 
carboplatin AUC 6 administered IV on cycle Day 1 q3w for 4 cycles or cisplatin 75 mg/m2 
q3w for 4 cycles followed by maintenance NKTR-214 and nivolumab (see Section 5.13.12 
for treatment discontinuation criteria of maintenance NKTR-214 and nivolumab). 
• Part 2: Cohort 5b (TNBC): NKTR-214 followed by nivolumab (q3w) followed by 
nab-paclitaxel 260 mg/m2 q3w by IV administration 
• Part 2: Cohort 5c (TNBC): NKTR-214 followed by nivolumab (q3w) followed by eribulin 
mesylate 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2) by IV administration on Days 1 
and 8 q3w; dose modification based on liver function tests should be made as outlined in the 
Package Insert or Summary of Product Characteristics.  
5.3.2 
Part 1:  Dose Escalation 
Dose escalation is described in Table 5 and will be carried out as listed in Table 6. 
The first NKTR-214 dose to be studied was determined based on a monotherapy trial with 
NKTR-214 (i.e., 0.006 mg/kg q3w).  Once a dose escalation cohort has been evaluated for safety 
by a Safety Review Committee, which includes the Sponsor Medical Monitor and 1 site 
Investigator, the Sponsor may choose to concurrently enroll patients and dose NKTR-214 at 
lower dose levels and different dose schedules to assess the benefit/risk profile within the 
anticipated 50 patients.  The sponsor may also evaluate other doses and dose schedules based on 
the safety findings from ongoing clinical trials. 


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For dose escalation cohorts, the Sponsor and at least one Investigator will jointly decide the 
following: 
• Dose escalation to the next cohort and/or dose schedule 
• RP2D 
• Dose levels of NKTR-214 for a given cohort may be reduced depending on the severity, 
duration, and frequency of toxicities observed at the previous dose level tested 
• Decision to evaluate NKTR-214 in combination with nivolumab in additional patients at 
lower doses and different dose schedules to assess the benefit/risk profile within the 
anticipated total number of 50 patients 
Table 5: 
Part 1:  Dose Escalation Scheme 
Cohort 
NKTR-214 
Nivolumab q2w 
Nivolumab q3w 
1 
0.006 mg/kg q3w 
240 mg 
 
2 
0.006 mg/kg q3w 
 
360 mg 
3 
0.006 mg/kg q2w 
240 mg 
 
4 
0.009 mg/kg q3w 
 
360 mg 
 
Table 6: 
Part 1:  Dose Escalation Guide 
Number of Patients with DLT at a 
Given Dose Level  
Dose Escalation Decision Guide 
0 out of 3 
Enter 3 patients at the next higher dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level.  If 0 of these additional 
3 patients experience a DLT, will proceed to the next dose level.  If 1 or 
more of this group suffers a DLT, then the dose escalation is stopped, and 
this dose is declared the maximally administered dose (MAD).  Three 
additional patients will be entered at a lower dose level if only 3 patients 
were treated previously at that dose. 
≥ 2 
Dose escalation will be stopped.  This dose level will be declared the MAD 
(highest dose administered).  Three additional patients will be entered at a 
lower dose level if only 3 patients were treated previously at that dose. 
≤ 1 out of 6 at highest dose level 
below the MAD 
This is the MTD.  Depending on toxicity, PK and/or pharmacodynamic 
markers, this may also be the RP2D.  At least 6 patients must be entered at 
the recommended dose for Phase 2. 
Abbreviations:  DLT = dose-limiting toxicity; MAD = maximally administered dose; MTD = maximum tolerated 
dose; PK = pharmacokinetics; RP2D = recommended Phase 2 dose 
 
The dose-limiting toxicity (DLT) evaluation period for the combinations will be a minimum of 
3 weeks (21 days).  For example, for q2w dosing the DLT window is 2 cycles (28 days), for q3w 


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dosing the DLT window is 1 cycle (21 days), and for q4w dosing the DLT window is 1 cycle 
(28 days) (Table 7).  Any DLT past the DLT window is a delayed DLT. 
Table 7: 
Part 1:  Treatment Cycle Duration and DLT Window 
Dosing Schedule 
of NKTR-214 
Cycle Definition 
DLT Window 
q2w 
14 days 
28 days 
q3w 
21 days 
21 days 
q4w 
28 days 
28 days 
Abbreviations:  DLT = dose-limiting toxicity; q2w = every 2 weeks; q3w = every 3 weeks; q4w = every 4 weeks 
 
Patients will be enrolled in groups of at least 3 patients in each cohort for the dose escalation 
cohorts unless unacceptable toxicity is observed.  The first patient of each escalating dose cohort 
will be monitored for safety and tolerability on Cycle 1, Days 1 through 5 before additional 
patients are dosed within the same cohort.  Enrollment into a new cohort with an escalating dose 
of NKTR-214 cannot begin until the DLT window has elapsed since the last patient’s first dose 
in the previous cohort. 
The definition of a DLT is provided in Section 5.11.  If no DLTs occur in a cohort of at least 
3 patients, a new cohort of 3 patients may be treated at the next higher dose level (Table 6).  If 
only 1 of 3 patients in a cohort experiences a DLT, that cohort will be expanded to 6 patients.  If 
3 patients have already been enrolled into a cohort and additional patients have signed the ICF 
and are undergoing the screening process, they may be enrolled to the cohort with Sponsor 
approval; however, these patients are not required to be included in the dose escalation decision 
for that cohort.  If only 1 of the 6 patients experiences a DLT, then the next cohort of 3 patients 
may be treated at the next higher dose level.  If 2 or more patients within a cohort experience 
DLTs, then that dose level will be above the MTD (the highest dose tested where no more than 
1 of 6 patients has experienced a DLT), and new patients will be enrolled at the previous lower 
(tolerated) dose level until that cohort has 6 patients.  Moreover, the cohort Safety Review 
Committee or Sponsor may determine that inadequate information has been obtained in a cohort 
of 3 patients and to further understand the benefit/risk profile at a given dose level, additional 
patients may be enrolled. 
All drug-related AEs after the DLT window will continue to be collected and evaluated by the 
Investigators and the Sponsor on an ongoing basis and may be taken into consideration in 
determining the MTD and/or RP2D.  During dose escalation, patients who are withdrawn from 
the study during the DLT window for reasons other than occurrence of a DLT will be replaced. 
Additional cohorts of up to 12 patients may be enrolled at doses deemed to be safe to more fully 
explore the safety, tolerability, pharmacokinetics, biomarker assessments, and preliminary 
efficacy of the NKTR-214 dose in combination with nivolumab.  It is estimated that 


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approximately 50 patients will be enrolled into the dose escalation phase of the study.  If 
additional cohorts are enrolled, the sample size will increase accordingly. 
At least 1 study Investigator and the Sponsor Medical Monitor will meet and decide the RP2D 
regimen to be studied in Part 2 before the initiation of Part 2.  The RP2D may be determined 
based on the MTD dose or a dose lower than MTD.  The RP2D may also be determined based on 
a biological effect of the study drugs as determined by anti-tumor activity and immune 
activation.  The Sponsor will amend the protocol to include the RP2D and will also communicate 
the RP2D via an administrative dosing letter to allow enrollment to begin, where permitted, 
before the protocol amendment is finalized. 
5.3.3 
Rationale for Recommended Phase 2 Dose for Part 2 
Two data analyses of patients receiving NKTR-214 and nivolumab in Study 16-214-02 are 
provided in this section; the rationale for the recommended Phase 2 dose for Part 2 based on a 
data cut of October 05, 2017 is provided below and Section 5.3.3.1 provides updated safety and 
efficacy data as of February 8, 2018. 
The safety of NKTR-214 as a single agent has been assessed in 5 monotherapy cohorts 
administered NKTR-214 q3w (22 patients) at doses ranging from 0.003 mg/kg to 0.012 mg/kg; a 
dosing frequency of q2w (6 patients) was further explored at 0.006 mg/kg (Table 8 and see 
Clinical Experience with NKTR-214 in Section 2.1.4).  The safety of NKTR-214 in combination 
with nivolumab at doses shown in Table 8 has been assessed in 38 patients. 
Table 8: 
Patient Exposure Supporting the RP2D 
 
NKTR-214 
Dosing 
Frequency 
Nivolumab  
(Flat Dosea) 
Dosing 
Frequency 
NKTR-214 
Dose (mg/kg) 
No. Patients 
Examined for 
Safety 
Positive Biomarker Data 
and/or Evidence of 
Clinical Activity? 
NKTR-214 
Monotherapy 
q3w 
n/a 
0.003, 0.006, 
0.009, 0.012 
22 
Yes 
q2w 
n/a 
0.006 
6 
Yes 
NKTR-214+ 
Nivolumab 
q3w 
q2w 
0.006 
4 
Yes 
q2w 
0.006 
3 
Yes 
q3w 
0.006 
25 
Yes 
q2w 
0.003 
3 
Yes 
q3w 
0.009 
3 
Yes 
Abbreviations:  q2w = every 2 weeks; q3w = every 3 weeks; n/a = not applicable. 
a. 
Nivolumab q2w = 240 mg, q3w = 360 mg. 
 


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The Safety Review Committee reviewed the totality of data and concluded the following for all 
5 combination dose cohorts with a data cut of October 05, 2017: 
• Two patients at the NKTR-214 0.009 mg/kg q3w + nivolumab 360 mg q3w dose level 
experienced dose limiting toxicities: Grade 3 hypotension and Grade 4 metabolic acidosis, 
each of which resolved within 5 days and the patients continued on treatment at a lower dose 
of NKTR-214. 
• There were no Grade ≥ 3 treatment-related adverse events (TRAEs) at NKTR-214 
0.006 mg/kg q3w + nivolumab 360 mg q3w: the recommended Phase 2 dose. 
• TRAEs that occurred in ≥ 50% of the patients included fatigue, flu-like symptoms (combined 
MedDRA preferred terms of influenza-like illness, pyrexia, and chills), rash (combined 
MedDRA preferred terms of rash, rash erythematous, rash macular, rash maculopapular, and 
rash pruritic), and pruritus. 
• TRAEs were consistent across all five dose cohorts. 
• Management guidelines implemented in the combination program for hypotension were 
effective to mitigate the risk for Grade ≥ 3 hypotension. 
• No Grade ≥ 3 immune-mediated AEs were observed. 
• Cytokine-related AEs such as fever, chills, pruritus, fatigue, and rash are predictable based 
on the mechanism of action and were generally of mild severity and short duration. 
• The addition of NKTR-214 did not exacerbate nivolumab-related AEs that are commonly 
classified as immune-mediated AEs. 
• NKTR-214 alone or in combination with nivolumab did not produce capillary leak 
syndrome, which is commonly observed in patients treated with high-dose IL-2. 
Tumor response data were available as of October 05, 2017 for 34 patients, including 10 with 
metastatic melanoma, 19 with renal cell carcinoma (RCC), and 5 with non-small cell lung cancer 
(NSCLC).  Of these 34 response-evaluable patients, 21 were treated at 0.006 mg/kg NKTR-214 
with nivolumab 360 mg flat dose q3w; 17 patients had partial or complete responses and 13 had 
stable disease.  Given the totality of data, including safety/tolerability, reproducible PK, dose-
independent PD profile, immune cell activation, and promising efficacy data (see Clinical 
Experience with NKTR-214 in Section 2.1.4), the Safety Review Committee approved 
NKTR-214 0.006 mg/kg q3w plus nivolumab 360 mg q3w as the recommended dose to be 
administered in the expansion cohorts included in Part 2 of the study. 
Additional dosing schedules may be explored during the expansion phase.  Any change to the 
recommended dose or frequency (either of NKTR-214 or nivolumab) will require endorsement 
by the Safety Review Committee, prior written approval by ethics committees, and notification 
to/approval by regulatory authorities in accordance with regulatory requirements.  Where 
permitted this notification may be in the form of an administrative letter followed by a formal 
protocol amendment (see Section 11.1 on Changes to the Protocol). 


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5.3.3.1 
Update of Safety and Efficacy Data for Protocol Amendment 6 (dated 
18 June 2018) 
As of February 8, 2018, a total of 130 patients have received NKTR-214 in combination with 
nivolumab for various tumor types in this study.  Of the 130 patients, 38 were in the dose 
escalation part of the study and 92 in the dose expansion part.  A total of 117 patients have 
received the RP2D (NKTR-214 0.006 mg/kg q3w with nivolumab 360 mg q3w) in the dose 
escalation phase (25 patients) and the dose expansion phase (92 patients). 
The majority of treatment-emergent AEs (TEAEs) were mild in severity, and the most common 
treatment-related AEs were Grade 1 or 2 flu-like symptoms (in 70.8% of patients), Grade 1 
or 2 fatigue (47.7%), and Grade 1 or 2 rash (42.3%).  Overall, 14 patients (10.8%) experienced 
treatment-related AEs of Grade 3 or 4 severity, the most common being syncope in 3 patients 
(2.5%).  No patient discontinued study treatment due to treatment-related AEs and there were no 
treatment-related deaths. 
Two patients at the NKTR-214 0.009 mg/kg q3w + nivolumab 360 mg q3w dose level 
experienced dose limiting toxicities: Grade 3 hypotension and Grade 4 metabolic acidosis, each 
of which resolved within 5 days and the patients continued on treatment at a lower dose of 
NKTR-214. 
Five patients in the dose escalation phase had a total of 7 SAEs that were considered possibly 
related or related to NKTR-214 or nivolumab, or both, and 9 patients in the dose expansion 
phase had a total of 12 SAEs that were considered possibly related or related to NKTR-214 or 
nivolumab, or both.  The individual SAEs were as follows: 
• related to NKTR-214 only:  Grade 1 face edema, Grade 2 headache, Grade 2 and Grade 3 
pyrexia (2 patients), Grade 3 lung infection (empyema), and Grade 3 rash erythematous 
• related to nivolumab only:  Grade 1 autoimmune hepatitis, Grade 2 hypophysitis, and 
Grade 2 hypothyroidism 
• related to NKTR-214 and nivolumab:  Grade 1 pyrexia, Grade 2 autoimmune 
hypothyroidism, Grade 3 hypotension, Grade 3 hyperthyroidism, Grade 3 syncope, Grade 3 
rash, Grade 3 dehydration, Grade 3 pain, Grade 3 hyponatremia, and Grade 4 acidosis. 
Tumor response data were available for the 24 patients who received the RP2D in the dose 
escalation phase, including 7 with metastatic melanoma, 14 with renal cell carcinoma (RCC), 
and 3 with NSCLC (Table 9).  Of these 24 response-evaluable patients, 15 patients (62.5%) had 
partial or complete responses and 5 (20.8%) had stable disease. 


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Table 9: 
16-214-02: Overall Investigator-Assessed Tumor Response for 
Patients Treated at the NKTR-214 Recommended Phase 2 Dose and 
Nivolumab 360 mg q3w in the Dose Escalation Study Phase 
 
1L RCC - Esc 
(N=11) 
2L RCC - Esc 
(N=4) 
Melanoma - Esc 
(N=7) 
NSCLC - Esc 
(N=3) 
All 
(N=25) 
Efficacy Evaluable 
Populationa - RECIST 
1.1, n (%) 
11 
3 
7 
3 
24 
  ORR (CR+PR) 
7 (63.6%) 
0 
6 (85.7%) 
2 (66.7%) 
15 (62.5%) 
    95% CI of ORR 
30.8%, 89.1% 
0%, 60.2% 
42.1%, 99.6% 
9.4%, 99.2% 
40.6%, 81.2% 
    CR 
0 
0 
1 (14.3%) 
1 (33.3%) 
2 (8.3%) 
  PR 
7 (63.6%) 
0 
5 (71.4%) 
1 (33.3%) 
13 (54.2%) 
  SD 
1 (9.1%) 
3 (100.0%) 
1 (14.3%) 
0 
5 (20.8%) 
  DCR (CR+PR+SD) 
8 (72.7%) 
3 (100.0%) 
7 (100.0%) 
2 (66.7%) 
20 (83.3%) 
  PD 
3 (27.3%) 
0 
0 
1 (33.3%) 
4 (16.7%) 
CR = complete response; DCR = disease control rate; Esc =patient as part of dose escalation study phase; ND = not 
done. PD = progressive disease; PR = partial response; SD = stable disease; RCC = renal cell carcinoma; 
RECIST = Response Evaluation Criteria in Solid Tumors 
a. 
Number of patients with baseline and at least one post-baseline tumor assessment. 
Source: Tables 14.2.1.2 and 14.2.2.2; Database: 07Feb2018; Created: 12Mar2018 
 
5.3.4 
Part 2:  Dose Expansion 
All procedures are outlined in the Schedule of Events (Section 1.2).  Enrollment into a dose 
expansion cohort will commence once the RP2D is established and communicated to sites. 
Approximately 936 patients will be enrolled (Table 10).  During dose expansion, patients who 
drop out prior to completion of Cycle 1 will not be replaced.  Sponsor may choose not to open or 
complete all expansion cohorts.  
Part 2 is closed to patient screening and enrollment under Amendment 7.0. 


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Table 10: 
Part 2 Treatment Cohorts (All Patients Receive NKTR-214 plus 
Nivolumaba) 
Part 2 Cohorts:  All Patients Receive NKTR-214 plus Nivolumaba 
Indication 
Cohort Description 
Melanoma 
1ab 
1L 
1bb 
2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
1cc 
2L, BRAF wild type anti-PD-1 or anti-PD-L1 relapse/refractory 
1dc 
1L, following prior adjuvant therapy 
1e 
Patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 1a 
to 1d 
RCC   
2ab 
1L 
2bc 
2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
2c 
Patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 2a 
or 2b 
NSCLC 
3a.1f 
1L, PD-L1< 1%  
3a.2f 
1L, PD-L1 ≥ 1% - < 50%  
3a.3f 
1L, PD-L1 ≥ 50% 
3a.4f 
1L, PD-L1 status unknown 
3bd 
2L, I-O therapy naïve following platinum-based therapy 
3cc 
2L-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
3d.1f 
1L, nonsquamous in combination with platinum/pemetrexed (+ maintenance pemetrexed) 
3d.2f 
1L, nonsquamous in combination with platinum/pemetrexed (no maintenance pemetrexed) 
3ef 
1L squamous in combination with platinum/taxane 
3fe 
3L+, ALK-translocation/ROS1 rearrangement positive 
3ge 
3L+, EGFR mutation/deletion 
3hf 
2L, following platinum-based doublet cytotoxic chemotherapy combined with anti-PD-1 
3i 
Patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 
3a.1 to 3h 
Urothelial 
4ad 
1L, cisplatin ineligible 
4ad,g 
1L, refused standard of care 
4bc 
2-3L, anti-PD-1 or anti-PD-L1 relapse/refractory 
4c 
Patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 4a 
and 4b 
TNBC 
5ab 
1-2L, I-O therapy naive 
5bc 
1-2L, I-O therapy naive in combination with nab-paclitaxel 
5cc 
1-2L, I-O therapy naive in combination with eribulin 
5d 
Patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 5a 
to 5c 
 


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Table 10: 
Part 2 Treatment Cohorts (All Patients Receive NKTR-214 plus 
Nivolumaba) (Cont’d) 
Part 2 Cohorts:  All Patients Receive NKTR-214 plus Nivolumaba 
Indication 
Cohort Description 
HR+ HER2- 
BC 
6ac 
I-O therapy naive following hormonal therapy 
6bc 
I-O therapy naive following hormonal and cytotoxic therapy 
Gastric 
7d 
2-3L, I-O therapy naive 
CRC 
8ac 
2-3L, I-O therapy naive; MSI-high 
8bc 
3-4L, I-O therapy naive; MSI-non-high 
SCLC 
9e  
2L, I-O therapy naive 
Abbreviations: CRC = colorectal carcinoma; HR+ HER2- BC = hormone-receptor positive, HER2-negative breast 
cancer; I-O = immuno-oncology; MSI = microsatellite instability; NSCLC = non-small cell lung cancer; 
RCC = renal cell carcinoma; RP2D = recommended Phase 2 dose; SCLC = small cell lung cancer; 
TNBC = triple-negative breast cancer 
a. 
All patients receive the RP2D:  NKTR-214 0.006 mg/kg q3w with nivolumab 360 mg q3w 
b. Cohorts closed under Amendment 5.1.  
c. 
Cohorts closed with an administrative letter dated 29 March 2019. 
d. Cohorts closed under Amendment 6. 
e. 
Cohorts never opened for screening. 
f. 
Cohorts closed with an administrative letter dated 22 January 2020. 
g. For sites located in Italy only:  patients may not be enrolled if they have 1L urothelial cancer with 
cisplatin-eligible disease. 
 
5.3.4.1 
Other Anti-Cancer Study Drugs Administered in Part 2 
In Part 2, patients in the 4 cohorts described below have additional anti-cancer study drugs 
administered with the RP2D (NKTR-214 0.006 mg/kg q3w with nivolumab 360 mg q3w).  The 
details of the dosing regimens for these cohorts are described below.  For each of these 4 cohorts, 
an initial group of 6 patients should be enrolled and observed for at least 1 cycle before 
additional patients are enrolled into the cohort.  The Safety Review Committee will review these 
patients before full enrollment will occur (see Section 9.3).  Institutional guidelines for 
administration of other anti-cancer therapies should be followed. 
5.3.4.1.1 
Cohorts 3d.1 and 3d.2:  NSCLC (1L nonsquamous) 
Patients receive NKTR-214 followed by nivolumab (q3w) followed by investigator’s choice of 
cisplatin 75 mg/m2 administered IV or carboplatin AUC 5 with pemetrexed 500 mg/m2 q3w by 
IV administration for 4 cycles.  Following the fourth cycle, Cohort 3d.1 will continue to receive 
NKTR-214, nivolumab, and pemetrexed at a dose of 500 mg/m2 q3w as maintenance therapy and 
Cohort 3d.2 will receive NKTR-214 and nivolumab maintenance, but not pemetrexed.  Patients 
receive premedication with folic acid, vitamin B12, and glucocorticoids administered according 
to local guidelines for pemetrexed use.  Unless otherwise stipulated at the medical center, the 
following supportive care should be used: 


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• Dexamethasone should be administered at a dose of 4 mg by mouth twice daily the day 
before, the day of, and the day after pemetrexed administration.   
• At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first 
dose of pemetrexed; and dosing should continue during the full course of therapy and for 
21 days after the last dose of pemetrexed.   
• Patients must receive one intramuscular injection of vitamin B12 (1000 μg) during the week 
preceding the first dose of pemetrexed and every 3 cycles thereafter.  Subsequent vitamin B12 
injections may be given the same day as pemetrexed.  
5.3.4.1.2 
Cohort 3e:  NSCLC (1L squamous) 
Patients in this cohort will be treated for a total of 4 cycles of NKTR-214 followed by nivolumab 
(q3w) followed by either Cremophor-based paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle 
or nab-paclitaxel 100 mg/m2 IV on Days 1, 8, and 15 of each 21-day cycle with investigator’s 
choice of either carboplatin AUC 6 IV on cycle Day 1 q3w for 4 cycles or cisplatin 75 mg/m2 
q3w for 4 cycles.  Following the fourth cycle, Cohort 3e will continue to receive NKTR-214 and 
nivolumab maintenance. Standard supportive care for infusion-related reactions may be 
administered.  
5.3.4.1.3 
Cohort 5b:  TNBC in Combination with Nab-Paclitaxel 
Patients receive NKTR-214 followed by nivolumab (q3w) followed by nab-paclitaxel 260 mg/m2 
by IV administration q3w.  Standard supportive care for infusion-related reactions may be 
administered.   
5.3.4.1.4 
Cohort 5c:  TNBC in Combination with Eribulin 
Patients receive NKTR-214 followed by nivolumab (q3w) followed by eribulin mesylate 
1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2) by IV administration on Days 1 and 8 q3w.  Dose 
modification for patients with baseline liver function test abnormalities should follow the 
Package Insert or Summary of Product Characteristics.  Standard supportive care for 
infusion-related reactions may be administered.   
5.3.5 
Part 3: Schedule Finding for Triplet (NKTR-214, Nivolumab, and Ipilimumab) 
The safety and tolerability of NKTR-214 in combination with nivolumab and ipilimumab will be 
evaluated in approximately 36 1L patients with metastatic or advanced RCC, NSCLC, 
melanoma, or urothelial carcinoma. 
Dose schedules and scenarios for triplet therapy are summarized in Table 11.  The dose-limiting 
toxicity (DLT) evaluation period for the triplet therapy (NKTR-214/nivolumab/ipilimumab) will 
begin with the first dose of ipilimumab and the evaluation period will be a minimum of 3 weeks 
(21 days). 




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Table 12: 
Part 3, Cohort A:  Concurrent Dosing Schedules 
Dosing 
Schedules Indication 
Na 
NKTR-214 q3w 
Nivolumab 
q3w 
Ipilimumab 
q3w or q6w 
Maintenance 
Doseb 
q3w 
1 
RCCc  
12 
0.006 mg/kg 
360 mg flat dose 
1 mg/kg q6w 
n/a 
NSCLCd 
2 
Urotheliald  
12 
0.006 mg/kg 
1 mg/kg × 4 doses 
3 mg/kg q3w × 4 doses 
NKTR-214 
0.006 mg/kg + 
nivolumab  
360 mg  
Melanomad 
3 
RCCd 
12 
0.006 mg/kg 
3 mg/kg × 4 doses 
1 mg/kg q3w × 4 doses 
Melanomad 
a. 
Enrollment will be up to 12 patients. 
b. NKTR-214 at 0.006 mg/kg and nivolumab at 360 mg will be dosed continuously q3w after the last dose of 
ipilimumab for dosing schedules 2 and 3 following the 4 doses of nivolumab and ipilimumab. 
c. 
This cohort is a historical cohort for both concurrent and staggered dosing and was closed to patient enrollment 
under Amendment 6. 
d. Cohorts closed with an administrative letter dated 22 January 2020. 
 
The Safety Review Committee will jointly decide the following: 
• Dose and schedule for the next cohort 
• RP2D 
• Dose levels of NKTR-214, for a given dosing schedule, may be reduced depending on the 
severity, duration, and frequency of toxicities observed at the previous dose level tested. 
• Decision for a recommended phase 2 dose schedule will be determined by both safety and 
pharmacological parameters. 
• Decision to evaluate the triplet in additional patients at lower doses and/or different dose 
schedules within the anticipated 36 patients to better assess the benefit/risk profile 
The Sponsor may choose to concurrently enroll patients at lower dose levels and/or different 
dose schedules to assess the benefit/risk profile within the anticipated 36 patients.  In Part 3, the 
RP2Ds will be established for each of the 3 dosing schedules (it may be necessary for a separate 
RP2D be established for patients with melanoma and urothelial cancers, if the tolerability is 
different between these 2 groups).  When an RP2D is established in Part 3, enrollment for that 
dosing schedule will begin in Part 4.  The sponsor will decide which dosing schedules will be 
opened in Part 4. 


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5.3.6 
Part 4:  Dose Expansion of Triplet (NKTR-214 plus Nivolumab plus 
Ipilimumab) 
Enrollment into the dose expansion cohorts will commence once the RP2D for the triplet has 
been established in Part 3 for each respective tumor type.  The maximum of patients in each 
cohort is listed in Table 25 (based on a Historical and Target ORR); the total will include any 
patients from each of the 6 cohorts in Part 3, thus approximately 106 additional patients may be 
enrolled into Part 4 (Table 13).  Patients will be enrolled simultaneously to each indication; for 
patients with melanoma, enrollment will occur simultaneously with dose schedule assigned 
alternately based on date of screening until one of the respective dosing schedule’s enrollment is 
fulfilled.   
Part 4 is closed to patient screening and enrollment under Amendment 7.0. 
Table 13: 
Part 4 Indications and Dosing Schedules 
Indication 
Cohort 
Concurrent Dosing Schedulea 
RCC 
 10a.1b 
1 
10a.3d 
3 
NSCLC 
11a.1d 
1 
Melanoma 
12a.2d 
2 
12a.3c 
3 
Urothelial 
13a.2d 
2 
a. 
If staggered dosing is to be tested, matching cohorts will be named as follows:  the letter ‘a’ will be substituted 
with ‘b’ (e.g., for the urothelial indication, concurrent dosing Cohort 13a.2 will be named staggered dosing 
Cohort 13b.2). 
b. This cohort is a historical cohort for both concurrent and staggered dosing and was closed to patient enrollment 
under Amendment 6. 
c. 
This cohort was closed with an administrative letter on 29 March 2019. 
d. Cohorts closed with an administrative letter dated 22 January 2020. 
 
If multiple cohorts in the same tumor type are open for enrollment, the sponsor will assign the 
appropriate cohort (whether this is a Part 2 NKTR-214/nivolumab doublet cohort [with or 
without other anti-cancer therapies] or one of the dosing schedules investigating the 
NKTR-214/nivolumab/ipilimumab triplet in Parts 3 and 4). 
5.3.7 
Monitoring, Vital Signs, and Hydration Guidelines 
The study site must be equipped for medical emergencies. 


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5.3.7.1 
Frequent Vital Signs 
Refer to Section 7.16 for vital sign measurements. 
For Part 1 Cycle 1 only, monitoring windows will be as follows: 
• Cycle 1 Day 1 (dosing day) monitor predose, and every hour for 3 hours (q1h × 3) 
• Cycle 1 Day 2 monitor every hour for 4 hours (q1h × 4) 
• Cycle 1 Day 3 monitor every hour for 2 hours (q1h × 2) 
For Parts 2, 3, and 4, vital signs should be monitored according to the Appendix 2 Schedule of 
Assessments.   
If the patient experienced a Grade ≥ 2 infusion-related reaction or hypotension on the dosing day, 
the patient may be monitored overnight at the discretion of the Investigator.  Longer periods of 
monitoring may be implemented at the discretion of the Investigator. 
5.3.7.2 
Hydration Guidelines 
Important safety information and hydration instructions are to be provided to patients. 
Adequate hydration mitigates the development of hypotension associated with NKTR-214 
administration.  Hydration and renal function must be assessed within 24 hours, or as soon as 
locally feasible, prior to each study drug administration (see Appendix 1B for the list of analytes 
that require collection and evaluation prior to study drug administration).  For patients who must 
delay study treatment due to creatinine increase, see additional information regarding criteria to 
delay (Sections 5.13.1 to 5.13.3), resume (Section 5.13.11), or permanently discontinue study 
treatment (Section 5.13.12).  Underlying reasons for decreased oral intake (e.g., nausea) should 
be addressed and treatment (e.g., IV hydration) should be provided.  The Investigator may 
modify these recommendations based on the needs of the individual patient.  Patients will also be 
provided a handout with hydration guidance. 
Patients should be administered 1 liter of IV fluids on the day of each dosing of NKTR-214.  For 
the next 3 days (Days 2–4) after NKTR-214 administration, instruct patients to drink at least 
2 liters per day of self-administered oral hydration.  Advise patients to restrain from activity that 
may contribute to dehydration (including, but not limited to, strenuous activity, long hot 
showers, and saunas) for Days 1 to 4 of every cycle of NKTR-214 treatment.  Per clinical 
judgment, IV fluids may be administered in any cycle.  The Investigator may decide to forego 
administering IV fluids to a patient or adjust the recommendation for self-administered oral 
hydration to a particular patient if this is deemed in the best interest of the patient (e.g., evidence 
of fluid overload).  Advise participants with orthostatic symptoms to call their treating oncologist 
and consider increasing oral hydration. 


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Patients with pre-existing adrenal impairment requiring corticosteroid supplementation may be at 
increased risk for hypotensive episodes during treatment with NKTR-214 (Section 5.13.4). 
Between Days 3 and 5, inclusive, following administration of the first two doses of NKTR-214 
in Cycles 1 and 2, site personnel must contact the patient (by telephone or clinic visit) to remind 
the patient of the oral hydration guidelines, to assess for any symptomatology and compliance 
with the guidelines, and document the results of the discussion (Section 1.2).  In subsequent 
NKTR-214 administrations in Cycle 3 and beyond, the oral hydration follow-up should be 
conducted as clinically indicated for patients receiving the NKTR-214/nivolumab doublet (with 
or without other anti-cancer therapies) in Part 2; the oral hydration follow-up is mandatory for 
patients receiving the NKTR-214/nivolumab/ipilimumab triplet in Parts 3 or 4 following study 
drug administration in any cycle. 
5.3.7.3 
Optional Home Health Visits 
In addition to planned study site visits, vital signs (temperature, pulse, respiration, systolic and 
diastolic blood pressure, and oxygen saturation), concomitant medications, and potential AEs 
may be assessed at a Home Health visit as needed.  The results of these measurements will be 
provided to the Investigator or designee.  The Investigator will be responsible for assessing any 
AEs and for following up with the patient. 
5.3.8 
Duration of Treatment 
Patients will be treated until: 
• Disease progression 
• Death 
• Unacceptable toxicity 
• Symptomatic deterioration 
• Achievement of maximal response or up to 2 years of therapy 
• Investigator’s decision to discontinue treatment 
• Patient decision to discontinue treatment  
• Patient withdraws consent 
• Lost to follow up 
• Nektar Therapeutics decides to terminate the study 
5.3.9 
Treatment Beyond Progression 
Accumulating evidence indicates that a minority of patients with solid tumors treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD. Patients will be 


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permitted to continue on treatment beyond initial RECIST 1.1-defined PD, including following 
radiotherapy or surgery on a target lesion, as long as they meet the following criteria: 
• Investigator-assessed clinical benefit and without rapid disease progression. 
• Continue to meet all other study protocol eligibility criteria. 
• Patient tolerates study drug(s). 
• Patient has stable ECOG performance status of 0 or 1. 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., central nervous system metastases). 
The assessment of clinical benefit should take into account whether the patient is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.  All decisions to 
continue treatment beyond initial progression or radiotherapy/surgery on a target lesion must be 
discussed with the Medical Monitor, and an assessment of the risk/benefit of continuing with 
study drug(s) must be documented in the study records.  The ICF contains language explaining 
treatment beyond progression; should the Investigator recommend continuing treatment 
following disease progression, the patient must be re-consented prior to continuing study 
treatment. 
For patients who stay on treatment beyond RECIST 1.1-defined PD, all study procedures 
(Section 1.2) should be performed continuously, including radiographic assessment by computed 
tomography (CT) (preferred) or magnetic resonance imaging (MRI) every 8 weeks as described 
in Section 8.2.  Patients will be discontinued from the treatment upon further evidence of disease 
progression, defined as an additional 20% or greater increase in the total tumor burden from the 
time of initial disease progression, unless otherwise approved by the Medical Monitor.  The total 
tumor burden is calculated as the sum of the longest diameter (SLD) of all target tumors and 
SLD of all new measurable lesions.  A new lesion is measurable if the longest diameter is at least 
10 mm except for pathological lymph nodes, which must have a short axis of at least 15 mm.  
Any new lesions that are non-measurable at the time of initial appearance and become 
measurable later will be included in the calculation of total tumor burden. 


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5.4 
End of Treatment (EOT) 
Patients may choose to discontinue the trial at any time, for any reason, and without prejudice to 
further treatment.  Patients may discontinue treatment of all or one of the study drugs based on 
AEs (see Section 5.13 pertaining to Study Drug Discontinuation).  The EOT visit should occur 
30 (+10) days after the last study therapy used in the study is permanently discontinued or before 
a new antineoplastic regimen starts, whichever occurs earlier. 
Reasons for EOT are listed below: 
• Disease progression in the absence of clinical benefit as determined by the Investigator. 
• Occurrence of a clinically significant AE found to be unacceptable or non-resolution of a 
clinically significant AE for > 6 weeks. 
• Symptomatic deterioration in the absence of tumor progression per RECIST 1.1. 
• Achievement of maximal response after at least 6 months of dosing with study drug(s); 
patients may receive a maximum of 2 years therapy under this protocol. 
• Noncompliance of the patient with protocol-mandated procedures based on the judgment and 
agreement of both the Investigator and Sponsor. 
• At the discretion of the Investigator (continued participation is no longer in the patient’s best 
interest in the opinion of the Investigator). 
• If a female patient becomes pregnant, administration of the study drugs must be discontinued 
immediately. 
• Patient’s decision to discontinue treatment. 
• Patient withdraws consent for the study. 
• Lost to follow-up (defined as after three attempts at contact by phone followed by one 
attempt by sending a certified letter). 
• The study is terminated by the Sponsor. 
In the event of a patient’s withdrawal, the Investigator will promptly notify the Sponsor and 
make every effort to complete the End of Treatment procedures specified in the Schedule of 
Events (Section 1.2). 
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or Institutional Review Boards (IRBs)/ Independent Ethics Committees (IECs). 
5.4.1 
Patients in Cohort 3d or Cohort 3e 
Patients enrolled in Cohorts 3d or 3e who discontinue NKTR-214 and/or nivolumab may remain 
on study and continue to receive the other protocol-defined anticancer therapies. 


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5.5 
Long-Term Follow-up 
Long-term follow-up should continue until withdrawal of consent, death, lost to follow-up, or 
study termination by the Sponsor.  At the long-term follow-up visits, data will be collected 
regarding toxicity, as well as information related to start of new anticancer therapy and survival.  
See also Section 7.5 and Section 7.8.  Timing for long-term follow-up will be as follows: 
• Long-term follow-up visits should occur every 30 (+ 10) days for 3 visits after the last dose 
of any of the study treatment medications (whichever is the last to be administered), then 
every 90 (± 10) days, or as needed for data deliverables for survival status, which may be 
captured by telephone contact.  However, if the date of decision to discontinue all study 
drugs is greater than 40 days from the last dose of any study treatment medication, long-term 
follow-up visits should begin from the date of EOT decision.  In addition, a safety follow-up 
visit should take place 100 days after the last administration of nivolumab/ipilimumab; this 
visit may be combined with the 90-day visit with the window of ± 10 days.  Per clinical 
judgment, the patient may come in earlier.  The long-term follow-up visit and EOT visit may 
occur on the same date. When these two visits occur on the same date, all the requirements of 
the EOT visit and the long-term follow-up visits should be fulfilled. 
• All patients will be contacted for survival and information about initiation of new anticancer 
therapy every 3 months. Survival follow up should continue until patient withdrawal of 
consent for survival follow up, death, loss to follow-up, or study termination by the Sponsor. 
• For patients who do not discontinue study drug treatment for progression of disease by 
RECIST v 1.1 or withdrawal of consent, radiographic tumor assessments will occur every 
90 (± 10) days and continue to be collected until disease progression, patient withdraws 
consent, death, initiation of a new systemic antineoplastic regimen, or study termination by 
the Sponsor. 
• A sample for immunogenicity testing for NKTR-214 will be collected at the first 30-day 
follow up visit.  
For AE and SAE reporting periods, please refer to Sections 7.5 and 7.7. 
5.6 
End of Study 
End of study is defined as no more than 3 years after the last patient received their first dose of 
NKTR-214, or Sponsor decision to terminate the study, whichever comes first.  . 
5.7 
Tumor and Radiographic Assessments 
Tumor assessments for all patients will be performed at Screening and every 8 weeks (± 7 days).  
If a patient has an unconfirmed PR or CR, a scan is recommended no sooner than 4 weeks later 
(e.g., if the initial observation of PR was seen at Week 8, a Week 12 scan should occur); 
subsequent tumor assessments must remain on the original 8-week assessment schedule (i.e., at 
Week 16, Week 24, then at Week 32, Week 40, etc.)  For patients with unconfirmed progressive 
disease, subsequent tumor assessments must remain on the original 8-week assessment schedule 


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(i.e., at Week 16, Week 24, then at Week 32, etc.), unless an early scan is clinically indicated.  
 
Radiographic assessments (chest/abdomen/pelvis) are required for all patients for tumor 
measurements.  Imaging of the brain on-study at 8-week intervals must occur for patients with 
known brain metastases at baseline.   
Documented tumor measurements are required using CT scans, MRI, physical examination, 
and/or digital photography, as appropriate.  Any imaging used to assess disease at any time point 
will be submitted for an independent radiology review. 
The same method of assessment (CT or MRI and/or digital photography) and the same technique 
for acquisition of images must be used for all study assessments (contrast must be used unless 
medically contraindicated).  Baseline imaging should be done at the same institution/facility that 
will be used to measure response during the patient’s participation in the study.  Radiographic 
assessments and efficacy analyses will be conducted by the Investigator site as well as the 
independent radiology review. 
5.8 
Pharmacokinetic Measurements 
Blood samples for pharmacokinetic (PK) analyses of NKTR-214 and its metabolites will be 
collected in all cycles. 
Part 1:  For Cycle 1 only, blood samples will be collected on Days 1 to 5, 8, and 11.  PK 
sample times are predose and at the following times after initiation of NKTR-214 dosing:  
30 min ± 2 min (end of NKTR-214 infusion), 1.5 hr ± 10 min, 3 hr ± 10 min, and 6 hr 
+ 2 hrs.  PK assessments for Cycles ≥ 2 will be on Day 1 (predose and 30 min ± 2 min 
[end of NKTR-214 infusion]) and Day 8. 
For all other Parts of the study except Part 1, blood samples will be collected according to 
the Appendix 2 Schedule of Assessments.   
Blood samples for PK analyses of nivolumab and ipilimumab will be collected as follows: 
Part 1 (nivolumab only): predose Cycle 1 Day 1, end of infusion Cycle 1 Day 1, and 
predose Cycle 3 Day 1, Cycle 8 Day 1, Cycle 16 Day 1, Cycle 24 Day 1, Cycle 36 Day 1 
or a maximum of 2 years 
For all other Parts of the study except Part 1, blood samples will be collected according to 
the Appendix 2 Schedule of Assessments. 
In the event of a possible study drug(s)-related serious adverse event (SAE) throughout the 
study, it is advised that additional PK blood samples are drawn as close to the event as possible 
to help characterize any possible relationships between drug exposure and the clinical event. 


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Blood samples for PK analysis will be collected and processed as outlined in a Laboratory 
Manual that will be provided to the site.  All on-treatment time points are intended to align with 
days on which study drug is administered; if dosing occurs on a different day, the PK sampling 
should be adjusted accordingly.  If it is known that a dose is going to be delayed, then the 
predose sample should be collected just prior to the delayed dose.  However, if a predose sample 
is collected but the dose is subsequently delayed, an additional predose sample should not be 
collected. 
For all PK blood samples, the date and actual time collected must be recorded. 
5.9 
Immunogenicity Measurements 
Immunogenicity samples for NKTR-214 will be drawn as follows: 
Part 1: predose Cycle 1 Day 1, predose on Cycle 2 Day 1 and predose on Day 1 of all 
odd-numbered cycles thereafter (Cycles 3, 5, 7, etc.), EOT, and the first 30-day follow-up 
visit. 
For all other Parts of the study except Part 1, immunogenicity samples will be collected 
according to the Appendix 2 Schedule of Assessments.   
Immunogenicity samples for nivolumab/ipilimumab will be drawn as follows: 
Immunogenicity samples for nivolumab in Part 1 will be collected as follows:  predose Cycle 1 
Day 1, and predose Cycle 3 Day 1, Cycle 8 Day 1, Cycle 16 Day 1, Cycle 24 Day 1, Cycle 36 
Day 1, or a maximum of 2 years.  If dosing occurs on a different day, the immunogenicity 
sampling should be adjusted accordingly. 
Immunogenicity samples for nivolumab in Part 2 and immunogenicity samples for nivolumab 
and ipilimumab in Parts 3 and 4 will be collected according to the Appendix 2 Schedule of 
Assessments.  If dosing occurs on a different day, the immunogenicity sampling should be 
adjusted accordingly. 
If it is known that a dose is going to be delayed, then the predose sample should be collected just 
prior to the delayed dose.  
However, if a predose sample is collected but the dose is subsequently delayed, an additional 
predose sample should not be collected. 
Serum samples for immunogenicity assessments will be collected and processed as outlined in 
the Laboratory Manual that will be provided to the site.   


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5.10 
Biomarker Measurements (Blood and Tumor Collection) 
Refer to the Laboratory Manual for specific instructions on sample processing, storage, and 
shipping. 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 


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5.10.2 
Tumor Tissue Biopsy Collection Times and Analysis 
A fresh tumor biopsy obtained from core biopsy, punch biopsy, excisional biopsy, or surgical 
specimen (fine-needle aspiration, cytology specimens, and bone lesions are not acceptable) will 
be required during Screening.  Sufficient, recent tumor tissue obtained within 6 months prior to 
enrollment from a metastatic tumor lesion or from an unresectable primary tumor lesion which 
has not been previously irradiated (formalin-fixed paraffin-embedded block or minimum of 
20 slides, obtained from core biopsy, punch biopsy, excisional biopsy, or surgical specimen) may 
be submitted in lieu of a fresh tumor biopsy during the Screening period. Exceptions may be 
made with the Sponsor’s Medical Monitor approval in cases where fresh tumor tissue and/or 
archival tumor samples are inaccessible. 
Target lesions should not be biopsied unless there are no other lesions suitable for biopsy.  If a 
target lesion is used for biopsy, the lesion must be ≥ 2 cm in the longest diameter. 
One optional tumor biopsy may be collected during Days 15-21 (Week 3) in Cycle 1; 1 optional 
on-treatment tumor tissue biopsy may be collected at least 30 days after Cycle 1 Day 1 but prior 
to the Week 8 scan. An additional tumor tissue biopsy may be collected at the time of suspected 
or known disease progression.   
Pretreatment and on-treatment biopsies should be taken from the same lesion, if feasible.  
Biopsies should only be performed on lesions that have not been exposed to prior radiation. 
Tumor tissue biopsies will be used for characterization of infiltrating immune cell populations 
using a panel of markers, using IHC, flow cytometry, mass spectroscopy, or other similar 
techniques.  Biopsy samples may also be used to investigate molecular signatures.  DNA and/or 
RNA may be extracted from these samples for somatic mutation analysis and gene expression 
analysis.  Genes to be assayed may include, but not be limited to, those with known driver 
mutations in solid tumors.  These samples will be analyzed by the Sponsor or designee. 
5.10.3 
Stool Sample Analysis 
A stool sample from a single bowel movement will be collected by patients participating in 
Parts 2-4 of the study prior to administration of the first dose and at Cycle 3 Day 1 ± 10 days.  
Patients will be provided with a materials kit and instructions for collecting the stool sample.  
Stool samples will be processed to extract and sequence microbial DNA and RNA as outlined in 
a Laboratory Manual. 


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5.11 
Determination of Dose-Limiting Toxicities (DLTs) 
Based on the nonclinical toxicology, safety data from the dose escalation study (Study 
15-214-01; NCT02869295) and the half-lives of NKTR-214 and metabolites (approximately 
20 hours), drug-related toxicity is most likely to occur 1 to 5 days following treatment.  In Part 1 
of the study, DLTs will be assessed during the DLT window shown in Table 7.  If DLTs are not 
observed, dose escalation will be permitted and enrollment of the next dosing cohort may begin.  
Intra-patient dose escalation is not permitted.  In Part 3, the DLT evaluation period will begin 
with the first dose of ipilimumab and the evaluation period will be a minimum of 3 weeks 
(21 days).  If DLTs are not observed, patients will continue to enroll until 12 patients have been 
evaluable for safety.  Grading of AEs is described in Section 7.3. 
5.11.1 
DLTs Related to Study Drug(s) 
Examples of AEs related to study drug(s) that will be defined as a DLT include the following: 
• Any Grade ≥ 3 drug-related non-hematological AE that does not resolve to Grade 1 or 
baseline within 7 days except those listed in Section 5.11.2. 
• Any drug-related Grade ≥ 2 myocarditis, Grade ≥ 2 uveitis, Grade ≥ 3 pneumonitis, or 
Grade ≥ 3 neurotoxicity 
• Any Grade 4 drug-related hematological AE that is clinically significant. 
• Any Grade 4 nausea or vomiting. 
• Any Grade ≥3 drug-related hypotension lasting > 48 hours post-dose, cytokine-release 
syndrome, capillary leak syndrome, pulmonary edema, symptomatic hypereosinophilic 
syndrome, or qualifying drug-induced liver injury (DILI) 
All AEs that meet DLT criteria must be recorded in the electronic data capture system within 
approximately 24 hours of awareness. 
5.11.2 
Grade 3 or 4 AEs that Should Not be Considered a DLT 
The following Grade 3 or 4 AEs should not be considered a DLT: 
• Endocrinopathy AEs, such as adrenal insufficiency, adrenocorticotropic hormone (ACTH) 
deficiency, hyper- or hypothyroidism, that resolve or are adequately controlled with 
physiologic hormone replacement (corticosteroids, thyroid hormones) or glucose intolerance 
managed with glucose-controlling agents. 
• Asymptomatic amylase or lipase elevations. 
• Lymphopenia < 14 days in duration or not associated with clinical manifestations. 
• Electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are 
corrected with supplementation/appropriate management within 72 hours of their onset. 


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• Tumor flare defined as local pain, irritation, or rash localized at sites of known or suspected 
tumor. 
• Grade 3 nausea or vomiting that can be medically managed to ≤ Grade 2 within 72 hours. 
• Grade 3 hypotension during Cycles 1 or 2 that lasts ≤ 48 hours post-dose. 
• Fatigue that improves to ≤ Grade 2 within 7 days. 
5.12 
Delayed Dose-Limiting Toxicities (DLTs) 
Delayed DLTs are AEs as defined in Section 5.11.1 that occur after the DLT window listed in 
Table 7.  Delayed DLTs will not be used to determine the MTD for dose escalation.  Delayed 
DLTs will be collected and evaluated by the Investigators and the Medical Monitor on an 
ongoing basis. 
All AEs that meet DLT criteria must be recorded in the electronic data capture (EDC) system 
within 24 hours of awareness. 
5.13 
Dose Delay and Reduction Criteria 
Dose delays of more than 1 drug are allowed for management of treatment-related toxicities 
during a give treatment cycle.  For dose delay and reduction criteria, see grading of AEs 
described in Section 7.3.  Tumor assessments for all patients should continue as per protocol 
even if dosing is delayed. 
5.13.1 
Nivolumab Dose Delay Criteria 
Dose reductions for nivolumab are not permitted in this study.  Nivolumab may be delayed based 
on observed drug-related toxicities.  If nivolumab is delayed, NKTR-214 administration can 
continue in the absence of NKTR-214-related toxicity that would warrant a dose delay and once 
the criteria to resume are met (Section 5.13.11).  If the Investigator cannot determine which 
study drug is causing the toxicity, then all study drugs should be delayed. 
Nivolumab administration should be delayed for the following: 
• Grade 2 non-skin, drug-related AE, except for fatigue  
• Grade 2 drug-related creatinine, AST, ALT and/or total bilirubin abnormalities 
• Grade 3 skin, drug-related AE 
• Grade 3 drug-related laboratory abnormality, with the following exceptions:  
o Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay  
o Grade  3 AST, ALT, total bilirubin will require dose discontinuation.  


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• Patient has acute infection (e.g., fever, upper or lower respiratory tract infection) requiring 
systemic antibiotic therapy. Patient may resume study treatment once free of signs or 
symptoms for 72 hours after completion of antibiotic therapy (See Section 5.13.11). 
• Any AE, laboratory abnormality, or inter-current illness that, in the judgment of the 
Investigator, warrants delaying the dose of study medication. 
Patients who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.  Dose 
delays of up to 6 weeks are permitted. 
5.13.2 
Ipilimumab Dose Delay Criteria 
Dose reductions for ipilimumab are not permitted in this study.  Dose delays are permitted for 
ipilimumab. Per recommendation of the Investigator and approval of the Sponsor’s Medical 
Monitor, ipilimumab may be delayed based on observed drug-related toxicities.  If ipilimumab is 
delayed, NKTR-214 or nivolumab administration can continue in the absence of NKTR-214- or 
nivolumab-related toxicity that would warrant a dose delay and once the criteria to resume are 
met (Section 5.13.11).  If the Investigator cannot determine which study drug is causing the 
toxicity, then all study drugs should be delayed. 
Ipilimumab must be delayed for the following reasons.   
• Any Grade ≥ 2 pneumonitis (in the case of Grade 1 pneumonitis, delay should be considered 
but is not required). 
• Any Grade ≥ 2 non-skin, drug-related AE, except for fatigue and asymptomatic laboratory 
abnormalities that are corrected with supplementation/appropriate management within 
72 hours of onset, or Grade 3/4 endocrinopathies that can be successfully treated with 
administration of replacement therapy. 
• Any Grade ≥ 3 skin drug-related AE, except when occurring during the first 48 hours of 
NKTR-214 administration. 
• Any Grade 3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia, creatinine, AST, ALT, or total bilirubin or asymptomatic amylase or lipase: 
– Grade 3 lymphopenia does not require a dose delay. 
– If a patient has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade ≥ 2 toxicity. 
– If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade ≥ 3 toxicity. 
– Grade 2 serum creatinine requires a dose delay, if not resolved to a Grade 1 or baseline 
prior to the next dose. 


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– Any Grade 3 or Grade 4 drug-related amylase and/or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis does not require dose 
delay.   
• Any AE, laboratory abnormality, or inter-current illness that, in the judgment of the 
Investigator, warrants delaying the dose of study medication. 
5.13.3 
NKTR-214 Dose Delay and Reduction Criteria 
Dose delays and reductions are permitted for NKTR-214.  Per recommendation of the 
Investigator, NKTR-214 may be delayed or reduced (to 0.003 mg/kg) based on observed 
drug-related toxicities.  Medical Monitor consultation is required for dose reduction.  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.  If NKTR-214 is delayed, nivolumab or ipilimumab administration can 
continue in the absence of nivolumab- or ipilimumab-related toxicity that would warrant a dose 
delay and once the criteria to resume are met (Section 5.13.11). 
NKTR-214 may be delayed or reduced for the following reasons: 
• For persistent Grade 2 drug-related toxicity, at the discretion of the Investigator, with the 
exception of: 
o Grade ≥ 2 creatinine increase: 
− For patients who must delay study treatment due to Grade ≥ 2 creatinine increase due 
to a non-inflammatory cause, delay retreatment with study drug for approximately 
3 to 5 days.  After the dosing delay, the patient may resume study drug when serum 
creatinine has returned to Grade ≤ 1, as assessed within 24 hours prior to redosing.  
For further guidance, refer to the Renal AE Management Algorithm in current 
Nivolumab Investigator’s Brochure. 
• Patient has acute infection (e.g., fever, upper or lower respiratory tract infection) requiring 
systemic antibiotic therapy. Patient may resume study treatment once free of signs or 
symptoms for 72 hours after completion of antibiotic therapy (See Section 5.13.11) 
• Grade ≥ 3 toxicity at least possibly related to NKTR-214: NKTR-214 dosing must be 
delayed until resolution to Grade 1 or baseline (unless otherwise requiring permanent 
discontinuation, per Section 5.13.12), with the following exceptions: 
o Grade ≥ 3 lymphopenia 
o Grade ≥ 3 asymptomatic amylase or lipase elevation 
NKTR-214 dosing may resume at the same dose or at a lower dose 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 patient (see Section 5.13.12 for permanent discontinuation criteria).  


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5.13.4 
Monitoring and Management of Adrenal Insufficiency and Hypophysitis 
Adrenal insufficiency and hypophysitis have been observed in patients receiving nivolumab and 
ipilimumab.  Consider prompt evaluation when patients have signs or symptoms of hypophysitis 
or adrenal insufficiency which includes levels of early-morning ACTH, cortisol, 
thyroid-stimulating hormone (TSH), and free thyroxine (T4).  Co-management with an 
endocrinologist is recommended for patients with pre-existing adrenal insufficiency. 
5.13.5 
Monitoring and Management of NKTR-214-induced Eosinophilia 
Frequent and significant eosinophilia has been observed in patients receiving NKTR-214, 
primarily starting at Cycle 2 or later, consistent with the known effect of IL-2 therapy.  Clinical 
data analysis demonstrated that frequency of selected AEs (primarily Grade 1 or 2 in severity) 
such as rash, pruritus, edema, nausea, vomiting, diarrhea, and dizziness increased with level of 
eosinophilia.  Isolated cases of hypereosinophilic syndrome and other eosinophilic disorders 
have been reported.   
Absolute eosinophil count (AEC) should be closely monitored per protocol.  If a study patient is 
suspected to have eosinophilic disorder (symptoms may involve skin, lungs, digestive tract, 
heart, blood, and nervous systems) with AEC at or above 5000/µL (5 × 109/L) level, NKTR-214 
treatment may need to be withheld, and the patient should be treated as clinically indicated.  
5.13.6 
Monitoring and Management of Elevated Hepatic Transaminases 
Elevated hepatic transaminases are an overlapping toxicity that can occur for both NKTR-214 
and nivolumab.  The elevations in hepatic transaminases associated with NKTR-214 typically 
occur at the time of peak active cytokine concentration in the blood (Days 2-4), and are often 
accompanied by other cytokine-related toxicities such as flu-like symptoms, rash or pruritus.  
The transient elevations in hepatic transaminases are usually mild or moderate in severity, not 
associated with increased total bilirubin, resolve spontaneously without treatment, and 
predominantly occur in Cycle 1 and Cycle 2.  Grade 3 abnormalities with these characteristics 
have been observed in PIVOT-02 study during Cycle 1, and patients were able to continue study 
treatment uninterrupted with close laboratory monitoring.   
Hepatic events, including elevated liver function tests, have also been observed for nivolumab. 
Most cases were of low or moderate severity.  Higher grade abnormalities are concerning for 
immune mediated hepatitis, and typically occur with a later onset (median time to onset of 
3.3 months) (nivolumab package insert).  Immune-mediated hepatitis generally results in a quick 
rise in liver function tests, and responds to corticosteroids or immune-modulating agents.  For 
transaminase elevations occurring in Cycle 2 onwards potentially involving an immune-
mediated mechanism, follow the immune-mediated hepatic adverse event management 
guidelines in the current nivolumab Investigator’s Brochure or package insert for 
appropriate management. 


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5.13.7 
Cohorts 3d.1 and 3d.2 (NSCLC) Dose Delay and Reduction Criteria for 
Platinum and Pemetrexed 
Dose delays and reductions are required for hematological and non-hematological toxicity.  
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 14, 
Table 15, and Table 16.  These serve as a guide and do not replace investigator judgment and 
applicable local label recommendations. 
Table 14: 
Dose Levels for Platinum and Pemetrexed 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Cisplatin 
75 mg/m2 
56 mg/m2 
38 mg/m2 
Discontinue 
Carboplatin 
AUC 5, maximum dose 
750 mg 
AUC 3.75, maximum 
dose 562.5 mg 
AUC 2.5, maximum 
dose 375 mg 
Discontinue 
Pemetrexed 
500 mg/m2 
375 mg/m2 
250 mg/m2 
Discontinue 
 
Table 15: 
Recommended Dose Modifications for Hematologic Toxicity for 
Platinum and Pemetrexed 
 
 
Pemetrexed 
Platinum 
Platelets 
ANC 
DOSE LEVEL 
≥ 50 × 103/μL AND 
≥ 0.5 × 103/μL 
Dose Level 0 
Dose Level 0 
≥ 50 × 103/μL AND 
< 0.5 × 103/μL 
Dose Level -1 
Dose Level -1 
< 50 × 103/μL without bleeding AND 
ANY 
Dose Level -1 
Dose Level -1 
< 50 × 103/μL with ≥ Grade 2 bleeding 
AND 
ANY 
Dose Level -2 
Dose Level -2 
ANY AND 
< 1.0 + fever ≥ 38.5°C  
(101°F) 
Dose Level -1 
Dose Level -1 
 


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Table 16: 
Recommended Dose Modifications for Non-Hematologic Toxicity for 
Platinum and Pemetrexed 
Event 
 
Pemetrexed 
Cisplatin 
Carboplatin 
CTC Grade 
DOSE LEVEL 
 
Nausea or vomiting 
3 or 4 
Dose Level 0 
Dose Level 0 
Dose Level 0 
Diarrhea 
3 or 4 
Dose Level -1 
Dose Level -1 
Dose Level 0 
Mucositis 
3 or 4 
Dose Level -2 
Dose Level 0 
Dose Level 0 
Neurotoxicity 
2 
Dose Level 0 
Dose Level -2 
Dose Level 0 
Neurotoxicity 
3 or 4 
Discontinue 
Discontinue 
Dose Level -1 
Transaminase Elevation 
3 
Dose Level -1 
Dose Level -1 
Dose Level -1 
Transaminase Elevation 
4 
Discontinue 
Discontinue 
Discontinue 
Other non-hematological toxicity 
3 or 4 
Dose Level -1 
Dose Level -1 
Dose Level -1 
Abbreviations:  CTC = common terminology criteria 
 
Creatinine clearance (CrCl) will be based on the original weight-based Cockcroft and Gault 
formula.  CrCl must be ≥ 45 mL/min prior to the administration of chemotherapy.  Pemetrexed 
and/or cisplatin may be delayed for up to 42 days to allow the patient time to recover from the 
toxicity.  If a  patient’s CrCl value has not returned to ≥ 45 mL/min within 42 days after the 
previous dose, cisplatin and/or pemetrexed must be discontinued. 
5.13.8 
Cohort 3e (NSCLC) Dose Delay and Reduction Criteria for Platinum and 
Taxane 
Dose delays and reductions are required for hematological and non-hematological toxicity.  
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 17, 
Table 18, and Table 19.  These serve as a guide and do not replace investigator judgment and 
applicable local label recommendations. 
Table 17: 
Dose Levels Platinum and Taxane 
Drug 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Cisplatin 
75 mg/m2 
56 mg/m2 
38 mg/m2 
Discontinue 
Carboplatin 
AUC 6 
AUC 4.5 or 5  
AUC 3 or 4 
Discontinue 
Nab-Paclitaxel 
100 mg/m2 
75 mg/m2 
50 mg/m2 
Discontinue 
Paclitaxel 
200 mg/m2 
175 mg/m2 
150 mg/m2 
Discontinue 
 


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Table 18: 
Recommended Dose Modifications for Hematologic Toxicity Platinum 
and Taxane 
Platelets 
ANC 
Nab-Paclitaxel 
Platinum 
DOSE LEVEL 
≥ 50 × 103/μL AND 
≥ 0.5 × 103/μL 
Dose Level 0 
Dose Level 0 
≥ 50 × 103/μL AND 
< 0.5 × 103/μL 
Dose Level -1 
Dose Level -1 
ANY AND 
Delay of initiation of 
next cycle by > 7 days 
due to < 1.5 × 103/μL 
Dose Level -1 
No change  
< 50 × 103/μL without bleeding AND 
ANY 
Dose Level -1 
Dose Level -1 
< 50 × 103/μL with ≥ Grade 2 
bleeding AND 
ANY 
Dose Level -2 
Dose Level -2 
ANY AND 
< 1.0 + fever ≥ 38.5°C 
(101°F) 
Dose Level -1 
Dose Level -2  
(2nd episode) 
Discontinue  
(3rd episode) 
Dose Level -1 
 
Table 19: 
Recommended Dose Modifications for Non-Hematologic Toxicity 
Platinum and Taxane 
Event 
CTC Grade 
Nab-Paclitaxel or 
Paclitaxel 
Cisplatin 
Carboplatin 
DOSE LEVEL 
Nausea or vomiting 
3 or 4 
Dose Level 0 
Dose Level 0 
Dose Level 0 
Diarrhea 
3 or 4 
Dose Level -1 
Dose Level -1 
Dose Level 0 
Neurotoxicity 
2 
Dose Level -1 
Dose Level -2 
Dose Level 0 
Neurotoxicity 
3 or 4 
Dose Level -1 or -2 
Dose Level -2  
(2nd episode) 
Discontinue 
Dose Level -1 or -2 
Dose Level -2  
(2nd episode) 
Transaminase Elevation 
3 
Dose Level -1 
Dose Level -1 
Dose Level -1 
Transaminase Elevation 
4 
Discontinue 
Discontinue 
Discontinue 
Other non-hematological toxicity 
3 or 4 
Dose Level -1 
Dose Level -1 
Dose Level -1 
 
CrCl will be based on the original weight-based Cockcroft and Gault formula.  CrCl must be 
≥ 45 mL/min prior to the administration of cisplatin.  Nab-paclitaxel, paclitaxel, and/or platinum 
may be delayed for up to 42 days to allow the patient time to recover from the toxicity.  If a 


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patient’s CrCl value has not returned to ≥ 45 mL/min within 42 days after the previous dose, 
cisplatin must be discontinued. 
5.13.9 
Nab-Paclitaxel Dose Delay and Reduction Criteria 
Dose delays and reductions are for hematological and non-hematological toxicity.  For these, 
please refer to country specific approved product label for dose modifications (Abraxane 
package insert).  
5.13.10 
Eribulin Dose Delay and Reduction Criteria 
Dose delays and reductions are required for hematological and non-hematological toxicity.   
The administration of eribulin should be delayed on Day 1 or Day 8 for any of the following:  
• Absolute neutrophil count (ANC) < 1 × 103/μL  
• Platelets < 75 × 103/μL  
• Grade 3 or 4 non-hematological toxicities 
These recommendations in Table 20 serve as a guide and do not replace investigator judgment 
and applicable local label recommendations. 


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Table 20: 
Dose Recommendations for Eribulin 
Adverse Reaction After Previous Administration  
Recommended Dose 
Hematological: 
1.1 mg/m2 (eribulin mesylate) 
0.97 mg/m2 (eribulin) 
ANC < 0.5 × 103/μL lasting more than 7 days  
ANC < 1 × 103/μL neutropenia complicated by fever or infection  
Platelets < 25 × 103/μL l thrombocytopenia  
Platelets < 50 × 103/μL thrombocytopenia complicated by hemorrhage or 
requiring blood or platelet transfusion  
Non-hematological:  
Any Grade 3 or 4 in the previous cycle OR omission or delay of Day 8 dose in 
previous cycle for toxicity 
Reoccurrence of any hematological or non-hematological adverse reactions as 
specified above: 
  
Despite reduction to 1.1 mg/m2 (eribulin mesylate); 0.97 mg/m2 (eribulin) 
0.7 mg/m2 (eribulin mesylate) 
0.62 mg/m2 (eribulin) 
Despite reduction to 0.7 mg/m2 (eribulin mesylate); 0.62 mg/m2 (eribulin) 
Consider discontinuation 
 
5.13.11 
Criteria to Resume NKTR-214, Nivolumab, or Anti-Cancer Study Drugs 
Patients 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 
patients who meet criteria for permanent discontinuation as specified in Section 5.13.12.  
Patients who meet criteria for permanent discontinuation must not receive further study therapy. 
If the decision is made to resume study drug(s) dosing, the patient should restart treatment on the 
next regularly scheduled study drug(s) dosing visit.  Skipped doses are not to be replaced. 
Patients may resume treatment when the drug-related AE(s) resolve(s) to Grade  1 or baseline, 
with the following exceptions: 
• Patients who delayed dosing for acute infection requiring systemic antibiotic therapy must be 
free of signs or symptoms of infection for 72 hours after completion of antibiotic therapy 
prior to resuming study treatment. 
• Patients may resume treatment in the presence of Grade 2 fatigue. 
• Patients who have not experienced a Grade 3 drug-related skin AE may resume study 
treatment in the presence of Grade 2 skin toxicity. 
• Patients 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. 


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• Patients with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (see Section 5.13.12) should have treatment permanently discontinued. 
• Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed.  Patients 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.  Grade ≥ 3 
adrenal insufficiency or Grade ≥ 4 hypophysitis require discontinuation regardless of control 
with hormone replacement (see Section 5.13.12 for permanent treatment discontinuation 
criteria).  Hospitalization for diagnostic workup of adrenal insufficiency without severe 
symptoms should not require discontinuation. 
• Patients who delay study treatment due to any Grade  3 amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis may resume 
nivolumab when the amylase or lipase abnormality has resolved to Grade < 3. 
• For patients who must delay study treatment due to Grade ≥ 2 creatinine increase due to a 
non-inflammatory cause (see Sections 5.13.1, 5.13.2, and 5.13.3), delay retreatment with 
study drug for approximately 3 to 5 days.  After the dosing delay, the patient may resume 
study drug when serum creatinine has returned to Grade ≤ 1, as assessed within 24 hours, or 
as soon as locally feasible, prior to redosing with study drug, except where permanent 
discontinuation of study drug is required (see Section 5.13.12). 
• Dose delay of NKTR-214 that results in treatment delay of > 6 weeks requires treatment 
discontinuation, with exceptions as noted in Section 5.13.12.  However, if the toxicity 
resolves to ≤ Grade 1 or baseline > 6 weeks after the last dose, but the patient does not 
otherwise meet the criteria for permanent discontinuation (see Section 5.13.12), and the 
Investigator believes that the patient is deriving clinical benefit, then the patient may be 
eligible to resume the study drug(s) following the approval of the Medical Monitor. 
For patients in Parts 3 and 4 (NKTR-214 plus nivolumab plus ipilimumab), treatment with 
NKTR-214 plus nivolumab may continue if patients experience toxicities or are unable to 
tolerate ipilimumab. 
5.13.12 
Permanent Treatment Discontinuation Criteria 
Patients meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s).  However, per the investigator’s assessment, treatment with NKTR-214 
or with nivolumab alone may continue if the toxicities listed below are considered not related to 
the respective drug, or are considered related to ipilimumab and/or other anti-cancer study drugs 
only once the criteria to resume are met (Section 5.13.11).  For CVA events and suspected TIA 


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events, follow the criteria described below (additional details are provided in the CVA 
management algorithm in Appendix 3).  
• Disease progression in the absence of clinical benefit (see details regarding continuing 
treatment beyond initial assessment of progression per RECIST 1.1 in Section 5.3.9). 
• 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 the nivolumab Investigator’s Brochure). 
• Grade 3 or 4 infusion reaction of any duration that occurs during the: 
− NKTR-214 infusion or prior to the nivolumab infusion requires discontinuation of 
NKTR-214. 
− Nivolumab infusion or later requires discontinuation of both NKTR-214 and nivolumab. 
• Any Grade 3 non-skin, drug-related AE lasting > 7 days, with the following exceptions for 
uveitis, pneumonitis, myocarditis, bronchospasm, diarrhea, colitis (ipilimumab and 
nivolumab must be discontinued for ≥ Grade 3 colitis related to ipilimumab), neurologic 
toxicity, hypersensitivity reactions, endocrinopathies, and laboratory abnormalities: 
– Grade 3 drug-related uveitis, pneumonitis, myocarditis, bronchospasm, diarrhea, colitis, 
neurologic toxicity, or hypersensitivity reaction of any duration requires 
discontinuation. 
– Grade 3 drug-related endocrinopathies (excluding adrenal insufficiency) adequately 
controlled with only physiologic hormone replacement do not require discontinuation. 
o Note:  For Grade ≥ 3 adrenal insufficiency, treatment needs to be discontinued 
regardless of control with hormone replacement (hospitalization for diagnostic 
workup of adrenal insufficiency without severe symptoms should not require 
discontinuation). 
– Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
▪ 
Grade 3 drug-related thrombocytopenia > 7 days or associated with clinically 
significant bleeding requires discontinuation. 


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▪ 
Any drug-related liver function test abnormality that meets the following criteria 
require discontinuation (also see Hepatic Adverse Event Management Algorithm in 
the nivolumab Investigator’s Brochure): 
o AST or ALT > 5 × to 10 × ULN for > 2 weeks 
o AST or ALT > 10 × ULN 
o Total bilirubin > 5 × ULN 
o 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: 
– Grade 4 neutropenia  7 days 
– Grade 4 lymphopenia or leukopenia ≤ 14 days in duration 
– Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis.  
– Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
– Grade 4 drug-related endocrinopathy AEs (except adrenal insufficiency or hypophysitis) 
such as, 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 per investigator discretion.  
o Note:  For Grade ≥ 3 adrenal insufficiency or Grade ≥ 4 hypophysitis, treatment 
needs to be discontinued regardless of control with hormone replacement 
(hospitalization for diagnostic workup of adrenal insufficiency without severe 
symptoms should not require discontinuation). 
• Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued treatment. 
• Any dosing delay lasting > 6 weeks after the last dose, with the following exceptions: 
– Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed.  Prior to re-initiating treatment in a patient with a dosing delay lasting > 6 weeks 
after the last dose and with no more than 3 missed doses, the Medical Monitor must be 
consulted.  Tumor assessments should continue as per protocol even if dosing is delayed. 


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– 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 
patient with a dosing delay lasting > 6 weeks after the last dose and with no more than 
3 missed doses, the Medical Monitor must be consulted.  Tumor assessments should 
continue as per protocol even if dosing is delayed, and patients must otherwise meet the 
criteria for continued treatment at the time re-initiation of study therapy is considered. 
• Any new CVA event confirmed by imaging (diffusion-weighted imaging [DWI] MRI is 
preferred, unless contraindicated), regardless of neurological symptoms (see Appendix 3): 
o For patients in Parts 3 or 4 receiving triplet immunotherapy: discontinue study treatment.  
o For patients in Part 2 receiving doublet immunotherapy:  study treatment may be 
continued only after careful risk-benefit assessment by the Investigator.  
5.14 
Management Algorithms for Immune-mediated AEs Associated with 
Immuno-Oncology Agents  
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes.  Nivolumab and ipilimumab are considered 
immuno-oncology agents in this protocol.  Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity.  Management Algorithms including 
the use of systemic corticosteroids (see the nivolumab and ipilimumab Investigator’s Brochures) 
have been developed to assist Investigators in assessing and managing AEs related to the 
following organs/systems (including, but may not be limited to): 
• Gastrointestinal 
• Renal 
• Pulmonary 
• Hepatic 
• Endocrinopathy 
• Skin 
• Myocarditis 
and  
• Neurological 
5.15 
Treatment of NKTR-214, Nivolumab, or Ipilimumab-Related Infusion Reactions 
Infusion reactions have been reported during infusions with NKTR-214, nivolumab, or 
ipilimumab.  If such a reaction were to occur with either the NKTR-214, nivolumab, or 
ipilimumab infusion, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions.  Infusion 


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reactions should be graded as outlined below (consistent with CTCAE v4.03 grading of 
infusion-related reactions; please also refer to Section 7.3). 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
• Remain at the bedside and monitor the patient until recovery from symptoms.  The following 
prophylactic premedications are recommended for future infusions:  diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
subsequent infusions. 
For Grade 2 symptoms (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
 24 hours): 
• Stop the NKTR-214, nivolumab, or ipilimumab infusion, begin an IV infusion of normal 
saline, and treat the patient with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at the bedside and monitor the patient 
until resolution of symptoms.  Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate.  If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate.  If symptoms 
recur after restarting the nivolumab or ipilimumab infusion, then no further nivolumab or 
ipilimumab will be administered at that visit.  Administer diphenhydramine 50 mg IV, 
remain at the bedside, and monitor the patient until resolution of symptoms. 
• For future infusions, the following prophylactic premedications are recommended:  
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before the infusion.  If necessary, corticosteroids 
(up to 25 mg of Solu-Cortef or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms (severe reaction, Grade 3:  prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 


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[e.g., renal impairment, pulmonary infiltrates].  Grade 4:  life-threatening; pressor or ventilatory 
support indicated): 
• Immediately discontinue infusion of NKTR-214, nivolumab, or ipilimumab.  Begin an IV 
infusion of normal saline and treat the patient as follows:  recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 
0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or 
diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed.  
Nivolumab, ipilimumab, or NKTR-214 will be permanently discontinued (see 
Section 5.13.12).  The patient should be monitored until the Investigator is comfortable that 
the symptoms will not recur.  Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis.  Remain at the bedside and monitor the patient until recovery of the 
symptoms. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine or corticosteroids).  
5.16 
Prior and Concomitant Medications 
Complications, including fatal events, have occurred in patients who received allogeneic 
hematopoietic stem cell transplantation (HSCT) before or after nivolumab. 
Premedications should not be administered prior to the initial administration of NKTR-214, 
nivolumab, or ipilimumab, but if a patient reports symptoms (such as nausea and/or vomiting), 
prophylactic use of anti-emetics may be used. 
Recording of prior medications should include prior cancer treatments:  previous 
immunotherapy, chemotherapy, targeted therapy, radiation, over-the-counter (OTC) medications, 
herbs, and dietary supplements. 
All medications (prescription and OTC), vitamin and mineral supplements, and/or herbs taken by 
the patient from Screening through the EOT visit will be documented and recorded, including 
start and stop date, dose and route of administration, frequency, and indication.  Medications 
taken for a procedure (e.g., biopsy) should also be included.  Additionally, document 
medications or other therapeutic measures administered for SAEs occurring within 100 days of 
last dose of nivolumab or ipilimumab (see Section 7.7). 
5.17 
Permitted Concomitant Medications/Treatment 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption).  Patients with pre-existing adrenal 
impairment requiring corticosteroid supplementation may be at increased risk for hypotensive 
episodes during treatment with NKTR-214 and may require co-management with an 
endocrinologist (see Section 5.13.4).  A brief course of corticosteroids for prophylaxis (e.g., 


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contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted.  Use of corticosteroids for 
the management of autoimmune conditions (as outlined in the Investigator’s Brochures for 
nivolumab and ipilimumab) is permitted.  Short-term use of systemic corticosteroids or 
immunosuppressive medication is permitted if administered for AE treatment. 
Prophylaxis for flu-like symptoms with either acetaminophen or ibuprofen is permitted on study 
per the Investigator’s discretion (as appropriate, additional treatment measures may be provided 
based on local treatment standards and guidelines, see Section 5.15).  Prophylaxis for flu-like 
symptoms can be initiated on either Day 1 or Day 2 of the dosing cycle and may continue 
through Day 5 or longer as needed. 
Prophylaxis for rash and/or pruritus with anti-histamines is permitted on study per the 
Investigator’s discretion (as appropriate, additional treatment measures may be provided based 
on local treatment standards and guidelines, see Section 5.15).  Prophylaxis for rash and/or 
pruritus can be initiated on either Day 1 or Day 2 of the dosing cycle and may continue through 
Day 5 or longer as needed. 
Concomitant palliative and supportive care for disease related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed.  Prior palliative radiotherapy must have 
been completed > 14 days before administration of first dose of study drug.  On-study palliative 
radiotherapy may occur only on non-target lesions and only after discussion with the Medical 
Monitor. On-study radiotherapy to target lesions is not permitted.   
If a patient receives radiotherapy or surgery on a target lesion, the patient may be allowed to 
continue in the study (if written request is received from the study investigator) and may remain 
on study treatment for as long as there is clinical benefit as assessed by the investigator and in 
consultation with the medical monitor. 
5.18 
Prohibited and/or Restricted Concomitant Medications  
5.18.1 
Prohibited Medications 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.17), 
defined as a daily dose of greater than 10 mg prednisone or equivalent.  
• Any antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, 
investigational agent, or radiation therapy [except as described in Section 5.17]) is prohibited 
during the study.   


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• Any live / attenuated vaccines (e.g., varicella zoster, yellow fever, rotavirus, oral polio, and 
measles, mumps, rubella [MMR], or Flumist® Quadrivalent) are not allowed during study 
treatment and until 100 days after the last dose of study drug.  Vaccination with inactivated 
viruses is permitted consistent with the institutional guidelines.  Allow appropriate time 
interval between the most recent study treatment administration and the next date of study 
treatment.  If the patient experiences side effects post flu vaccine or other inactivated 
vaccine, please manage study treatment administration per protocol guideline. 
In addition, prohibited medications listed in the current nivolumab or ipilimumab prescribing 
information are not allowed.  For cohorts that administer NKTR-214 and nivolumab in 
combination with cytotoxic chemotherapy, sites should follow prescribing guidelines listed in the 
current Package Insert or Summary of Product Characteristics.   
5.18.2 
Blood Pressure Medications 
Consideration should be given to withholding antihypertensive medications including diuretics, 
as well as other drugs with hypotensive properties (e.g., 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 withholding antihypertensive 
medications, withhold no less than 12 hours and no more than 48 hours prior to each dose of 
NKTR-214.   
Patients who are on medications with antihypertensive effects for the treatment of coronary 
artery disease (e.g., beta-blockers, calcium channel blockers, nitrates, etc.) should be able to 
withhold these drugs.   
Antihypertensive medications may be reinitiated in between doses of NKTR-214 at any time as 
clinically indicated (i.e., based on blood pressure monitoring results).  
For patients receiving beta-blockers, consider a step-wise tapering of doses before initiation of 
NKTR-214 to avoid reflex tachycardia. If Grade ≥ 2 hypertension is observed in any cycle, 
patients should be monitored more frequently (at least weekly) until a new stable 
antihypertensive regimen is identified.  Patients may be monitored more frequently at the 
discretion of the investigator as clinically warranted. 
5.18.3 
Effect of NKTR-214 on the PK of Concomitant Medications 
NKTR-214 may have the potential to affect the PK of co-administered drugs based on its 
intended pharmacology as a modulator of immune function.  NKTR-214 causes increases in 
circulating cytokines typical of those associated with an acute inflammatory response to infection 
or tissue injury.  The increases in inflammatory cytokines induced by NKTR-214 are generally 
moderate, persist for about one week after NKTR-214 dosing, and return to baseline levels prior 
to the next dose.  Several of these cytokines (IFN-γ, IL-6, IL-10, etc.) have the potential to 
decrease the activity of multiple enzymes and drug transporters, and the suppressive effects can 
be additive (Haas, 2005; Zidek, 2009).  Similar to changes that occur during a typical 


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inflammatory response, NKTR-214 may lead to down regulation of drug metabolizing enzymes, 
such as CYP enzymes, hepatic flavin monooxygenases, UDP-glucuronosyltransferases, 
sulfotransferases, and glutathione S-transferases.  Consequently, treatment with NKTR-214 may 
lead to temporary decrease in clearance of drugs that are substrates of these Phase I and Phase II 
drug metabolizing enzymes, or drug transporters.  Clinicians should carefully monitor patients 
who receive drugs with narrow therapeutic indices or drugs that are sensitive substrates of drug 
metabolizing enzymes or drug transporters for occurrence of adverse effects, and adjust the dose 
if needed. 
5.19 
Adverse Events 
All AEs, either reported by the patient or observed by study staff, will be reported from the time 
of first study drug(s) administration until 100 days after the last dose of all study drug(s).  This 
trial will use the Medical Dictionary for Regulatory Activities (MedDRA) for coding all AEs.  
AEs will be summarized by preferred term, system organ class, grade of severity, and 
relationship to each study drug (NKTR-214 and/or nivolumab and/or ipilimumab). For SAEs, 
additional reporting requirements also apply (see Section 7.7). 
5.20 
Assigning Patient Numbers 
Each patient will be assigned a unique patient number after signing the ICF.  Patient numbers 
will be used on all patients’ study information.  Patient numbers will not be reassigned. 


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6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS 
6.1 
NKTR-214 Drug Description and Formulation 
 
 
  
 
 
  
 
 
 
 
 
6.2 
NKTR-214 Drug Packaging and Labeling 
NKTR-214 will be packaged and labeled according to current good manufacturing practices.  
Each vial will be labeled with the study drug number/name, strength, name of the Sponsor, 
storage condition, lot number, and the required cautionary statement. 
6.3 
NKTR-214 Drug Reconstitution and Handling 
 
 
 
 
 
 
 




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The Site Drug Accountability Log will be reviewed by the monitor during site visits and at the 
completion of the study. 


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7.0 
ASSESSMENT OF SAFETY OR AEs AND SERIOUS AEs 
7.1 
AE Definition and Assessment 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, at any dose, not necessarily related to the treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.  An AE can also arise from any use of the drug and from any route of 
administration, formulation, dose, or overdose.  This definition includes intercurrent illnesses or 
injuries, and exacerbation of preexisting conditions.  Clinical laboratory, vital sign, or physical 
examination abnormalities will only be reported as AEs if they are deemed clinically significant 
by the Investigator (e.g., associated with signs and symptoms, require treatment, or require 
follow-up). 
An AE does not include: 
• A medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion); 
an AE is the underlying condition that leads to the procedure. 
• Pre-existing diseases or conditions present or detected before start of study drug(s) 
administration that do not worsen or increase in severity or frequency after the administration 
of study drug(s). 
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery for a condition that has not worsened on study, social and/or convenience 
admissions to grant families a respite in caring for a patient). 
• Overdose of either study drug(s) or concomitant medication without any signs or symptoms. 
7.2 
Monitoring AEs 
All AEs will be assessed by the Investigator and recorded, including, but not limited to, the 
following:  the event term, the date of onset and resolution, seriousness, severity, relationship to 
study drug(s), outcome, treatment of the event, and action taken with the study drug(s).  AEs will 
be reported from the time of first study drug(s) administration until 100 days after the last dose 
of all study drug(s).  For SAEs, additional reporting requirements also apply (see Section 7.7). 
An event occurring after the patient has provided informed consent, but before the first dose of 
study treatment, will be collected as medical history unless the event is either new and attributed 
to protocol-mandated procedures by the Investigator or there is a significant change in the rate of 
occurrence or an increase in the severity of the pre-existing condition which is judged to be 
clinically important and attributed to the protocol-mandated procedures by the Investigator.  
Under the latter 2 circumstances, the event will be considered an AE and will be captured as 
such. 


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Example 1: 
Thrombophlebitis associated with a blood draw for assessments required prior to dosing per 
protocol is an event that is related to protocol-mandated procedures.  In this scenario, the 
event of “thrombophlebitis” will be captured as an AE, and it will be documented as being 
“unrelated” to study drug(s), as applicable. 
Example 2: 
An ankle sprain following an unexpected fall from a flight of stairs while at home, after the 
patient has provided informed consent, but before the first dose of study drug(s), is clearly 
unrelated to any protocol-mandated procedures and would therefore be captured as medical 
history. 
7.3 
Grading of AEs 
The severity of an event and the seriousness are not to be considered synonymous.  The severity 
is grading the intensity of an event.  The seriousness of event is based on the patient/event 
outcome or action criteria.  All AEs will be assessed for severity using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 
guidelines.  If a particular AE is not listed in the NCI-CTCAE, the following criteria will be 
used: 
• Grade 1 = Mild (event results in mild or transient discomfort, not requiring or needing only 
minimal intervention or treatment; does not limit or interfere with daily activities 
[e.g., insomnia, mild headache]). 
• Grade 2 = Moderate (event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment [e.g., fever requiring antipyretic medication]). 
• Grade 3 = Severe (event results in significant symptoms that prevent normal daily activities; 
may require hospitalization or invasive intervention). 
• Grade 4 = Life threatening or disabling. 
• Grade 5 = Death. 
AEs will be reported with an individual start and stop date for each level of severity. 
7.4 
Causality Relationship of AEs 
The relationship of each AE to each study drug (NKTR-214 and/or nivolumab and/or 
ipilimumab and/or other cytotoxic chemotherapy) as applicable will be evaluated by the 
Investigator using the following definitions: 


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• Not related:  The AE is clearly not related to the study drug(s).  The AE can be explained to 
be likely related to other factors such as concomitant medications or the patient’s clinical 
state. 
• Possibly related:  The AE may be related to the investigational agent(s).  A plausible 
temporal sequence exists between the time of administration of the investigational product 
and the development of the AE, and it follows a known response pattern to the 
investigational product.  The reaction may have been produced by the patient’s clinical state 
or other concomitant therapies or interventions. 
• Related:  The AE is clearly related to the investigational agent(s).  A plausible temporal 
sequence exists between the time of administration of the investigational product and the 
development of the AE, and it follows a known response pattern to the investigational 
product.  The occurrence of this AE can be confirmed with a positive re-challenge test or 
supporting laboratory data. 
The causality criteria of related and possibly related will be considered “related” to the study 
drug(s) for regulatory reporting requirements. 
7.5 
AE Reporting and Follow-up 
After initiation of study drug treatment, all AEs will be reported from the time of first study 
drug(s) administration until 100 days after the last dose of all study drug(s).  For patients 
initiating a new antineoplastic regimen, the decision date of study drug discontinuation and the 
EOT visit date must be prior to the start date of the new antineoplastic regimen.  
All ongoing AEs will be followed until resolution, the patient is lost to follow-up, patient death, 
or until the EOT visit, whichever is earlier.  In case the AE has not completely resolved by the 
EOT visit, the final outcome of these ongoing AEs will be captured as “Not Recovered/Not 
Resolved” or “Recovering/Resolving”, whichever is applicable.  Any new AEs occurring after 
the EOT visit will not be captured unless related to a study drug.  
After informed consent has been obtained but prior to initiation of study treatment, only SAEs 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported.  After initiation of study treatment, all SAEs 
will be reported as described above.  After the end of the reporting period for SAEs, the 
investigator must report any SAE that is believed to be related to prior exposure to study 
treatment or protocol-specified procedure.   
For specific instructions on identifying and reporting SAEs, see Sections 7.6 and 7.7. 
7.6 
Serious AE Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 


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• Is life threatening, i.e., in the opinion of the Investigator, the AE places the patient at 
immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a patient’s participation in a clinical study, except for those due to the 
following: 
– A surgery or procedure that was planned before the patient entered the study and which is 
part of the planned study procedure. 
– Nonmedical reasons, in the absence of an AE. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that, based upon appropriate medical judgment, may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed above. 
Death is an outcome of an AE and not an AE in itself.  All events leading to death, regardless of 
relationship to study drugs, that occur during the protocol-specified reporting period, must be 
reported with the exception of deaths attributed to disease progression (refer to Section 7.9).  An 
efficacy failure is not considered an SAE.  “Life-threatening” means that the patient was at 
immediate risk of death from the event as it occurred.  This does not include an event that might 
have led to death if it had occurred with greater severity.  “Inpatient hospitalization” means the 
patient has been admitted to a hospital for medical reasons for any length of time.  The 
Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the AE 
and/or SAE and not the individual signs/symptoms. 
7.7 
Serious AE Reporting 
Serious AEs occurring after the patient has provided informed consent, but before the first dose 
of study treatment, will be collected as medical history unless the event is either new and 
attributed to protocol-mandated procedures by the Investigator or there is a significant change in 
the rate of occurrence or an increase in the severity of the pre-existing condition which is judged 
to be clinically important and attributed to the protocol-mandated procedures by the Investigator.  
Any new or clinically significant changes in the patient’s medical and/or cancer history that 
occur immediately after the first dose of drug will be recorded as SAEs.  All SAEs, regardless of 
causality attribution, will be reported to Nektar Therapeutics Drug Safety within 24 hours of 
when the site becomes aware of the event.  The duration of the reporting period is described in 
Section 7.5, AE Reporting and Follow-up. 


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For SAEs that occur within 100 days of last dose of nivolumab or ipilimumab, medications and 
other therapeutic measures used to treat the SAE will be recorded on the eCRF. 
In addition, all SAEs that occur beyond 100 days after the last dose of all study drug(s) that are 
assessed by the Investigator as related to study drug(s) will also be reported to Nektar 
Therapeutics Drug Safety within 24 hours of when the site becomes aware of the event. 
SAEs must be reported to Nektar Therapeutics Drug Safety via email or Fax as listed at the 
beginning of this protocol. 
The Investigator must complete the SAE Report Form, assess the causality relationship to the 
study treatment as applicable, and send the completed SAE form via email or fax to Nektar 
Therapeutics Drug Safety.  A follow-up report and any additional records (such as hospital 
records, consultant reports, and autopsy findings) will be emailed or faxed to Nektar 
Therapeutics Drug Safety within 24 hours of receipt.  Any medication or other therapeutic 
measures used to treat the event will be recorded on the SAE Report Form. 
All SAEs will be followed as described in Section 7.8. 
Reporting of SAEs to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
will be done in accordance with the standard operating procedures (SOPs) and policies of the 
IRB/IEC.  Adequate documentation must be provided to Nektar Therapeutics, showing that the 
IRB/IEC was properly notified.  Serious AEs will be reported by Nektar Therapeutics or 
designee to the Regulatory Authorities, per local regulations. 
7.8 
Serious AE Follow-up 
All study treatment-related SAEs that have not resolved by the EOT visit (Section 5.4) will be 
followed until any of the following occur (whichever comes first): 
• The event resolves. 
• The event has stabilized. 
• The event returns to baseline, if a baseline value is available. 
• It is unlikely that any additional information can be obtained (e.g., patient or health care 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
• The patient dies or is lost to follow-up. 
All ongoing SAEs assessed as “unrelated” to study drug(s) will be followed until resolution or 
until the EOT visit (Section 5.4), whichever is earlier.  In the case where an unrelated SAE has 
not completely resolved by the EOT visit, the final outcome of these ongoing SAEs will be 
captured as “Not Recovered/Not Resolved” or “Recovering/Resolving”, whichever is applicable. 


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7.9 
Disease Progression and Death due to Disease Progression – Not Reportable as an 
AE/SAE 
It is anticipated that during this study a proportion of patients will experience disease progression 
prior to study discontinuation.  Progressive disease (PD) in some patients may result in 
hospitalization or death.  Such events leading to hospitalization or death of a study patient are 
typically considered “serious,” requiring submission of an SAE report.  However, because PD is 
an endpoint for this study, reporting the term “disease progression” as either an AE or SAE is not 
necessary. 
However, if there are separate identifiable clinical manifestations of the PD, (e.g., pleural 
effusion or weight loss), the primary manifestations may be reported as non-fatal AEs or SAEs.  
For all SAEs associated with fatal PD, the following criteria will apply: 
• Seriousness Criteria = Cannot equal Death 
• Severity = Cannot equal Grade 5 
• Outcome = Ongoing at time of Death 
7.10 
Immune-mediated Adverse Events  
Nektar will evaluate imAEs associated with either NKTR-214, nivolumab, and/or ipilimumab.  
Investigators should use clinical judgment when characterizing an AE as immune mediated, 
including the requirement for steroid treatment, and are encouraged to rule out neoplastic, 
infectious, metabolic, toxic, or other etiologies to the extent possible, before characterizing an 
event as immune mediated.   
See Section 5.14 for additional information on management algorithms for immune mediated 
AEs. 
7.11 
Adverse Events of Special Interest 
Cerebrovascular accident (CVA, any grade) is considered an “adverse event of special interest” 
(AESI) and should be assessed for seriousness using the standard seriousness definition.  
However, all CVAs are required to follow the timeline for SAE reporting (within 24 hours as 
described in Section 7.7) from the sites to Nektar Drug Safety: pharmacovigilance@nektar.com.  
CVA Management Guidelines are provided in Appendix 3. 
7.12 
Potential Drug-Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 7.7 for reporting details). 
A potential DILI is defined as: 
• Treatment-emergent ALT or AST > 3 times ULN, 


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AND 
• Total bilirubin > 2 times ULN or clinical jaundice, without initial findings of cholestasis 
(elevated serum alkaline phosphatase),  
AND 
• No other immediately apparent possible causes of elevated liver enzymes and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
7.13 
Pregnancy 
The Sponsor must be notified within 24 hours of the initial report and any follow-up reports of a 
male patient’s female partner or a female patient becoming pregnant during the course of the 
study and for up to 5 months for female patients or 7 months for female partners of male patients 
after the last dose of the study drug(s) via the Pregnancy Form.  Pregnancy, although reportable, 
is not considered an AE/SAE unless a female patient or male patient’s female partner 
experiences signs or symptoms of pregnancy complications; however, the contact information 
for pregnancy reporting is the same as for SAE reporting and listed in Section 7.7.  In order for 
the Sponsor or designee to collect any pregnancy surveillance information, the pregnant patient 
or partner must sign an informed consent form for disclosure information.  Information on this 
pregnancy will be collected on the Pregnancy Form.  Female patient(s) or female partner(s) of 
male patient(s) who become pregnant will be followed until the outcome of the pregnancy is 
known.  Pregnancy follow-up should describe the outcome of the pregnancy, including any 
voluntary or spontaneous termination, details of the birth, and the presence or absence of any 
congenital abnormalities or birth defects in the offspring. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. 
If, for whatever reason, the pregnancy has ended, confirmed by negative serum pregnancy test, 
treatment may be resumed at the discretion of the investigator (at least 3 weeks and not greater 
than 6 weeks after the pregnancy has ended) following approvals of the patient/IRB/IEC, as 
applicable. 
7.14 
Clinical Laboratory Tests 
Clinical laboratory tests will be conducted according to the Schedule of Events (Section 1.2).  
Clinical laboratory tests will be performed by the local laboratory for Part 1 and Part 3 and 
central laboratory for Parts 2 and 4 (except as designated in Appendix 1).  (For Parts 2 and 4, if 
the central laboratory tests are cancelled, lost, or considered inadequate for analysis, the site may 
forward an identical set of local laboratory samples for eligibility review.  Central laboratory 
testing must be repeated prior to the first dose of study drug.  If local laboratory results are 
determined to be acceptable by the Medical Monitor [or designee] during eligibility review, 
enrollment may proceed.)  Clinical laboratory test data will be reviewed by the Investigator or 


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qualified Sub-Investigator.  Additional clinical laboratory tests may be ordered at the 
Investigator’s or qualified Sub-Investigator’s discretion.  Additional testing for PK and 
biomarkers will be performed by the designated central laboratory. 
The Investigator or qualified Sub-Investigator will review all laboratory results for clinical 
significance.  Any laboratory result deemed clinically significant (i.e., is associated with signs 
and symptoms, requires treatment, or requires follow up) will be recorded as an AE as described 
in Section 7.1. 
7.15 
Physical Examinations 
Physical examinations should be conducted according to the Schedule of Events (Section 1.2).  
Full physical examinations should be conducted at screening, Day 1 of each cycle, Cycle 1 Day 2 
(C1D2), C1D3, C1D8, and EOT (evaluate all major organ systems, including the following 
categories:  general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, 
joints, extremities, integumentary, neurologic, and psychiatric).  Other examinations may be 
focused, at the discretion of the Investigator, to identify changes from baseline or evaluate 
changes based on the patient’s clinical symptoms.   
7.16 
Vital Signs 
Vital sign measurements will be recorded according to the Schedule of Assessments 
 (Appendix 2).  Vital signs include pulse rate, respiratory rate, systolic and diastolic blood 
pressure, oxygen saturation (oxygen saturation on dosing days only), and temperature.  It is 
preferred that the same arm be used for all blood pressure readings, if possible.  Instructions for 
more frequent vital sign monitoring after completion of study drug administration are provided 
in Section 5.3.7.1.  Weight is to be reported at each vital sign visit, height at screening visit only. 
7.17 
Electrocardiograms 
Prior to each NKTR-214 PK sampling time in Cycle 1 of treatment, 5 minutes of ECG data will 
be recorded (for details see Appendix 2 Schedule of Assessments).   
Patients must be resting quietly in the supine position for at least 5 minutes before the ECG 
collection.  Five-minute ECG will be performed on a calibrated 12-lead machine and the 
5-minute recording will be converted into a summary ECG (simulated 10-second ECG).  The 
summary ECG will be submitted to a designated ECG laboratory for interpretation of ECG and 
interval duration measurements.  Interpretation of ECGs and interval duration measurements will 
be provided to the site. 
The Investigator or qualified Sub-Investigator will review all ECG interpretations and interval 
duration measurements for clinical significance.  Any ECG interpretation deemed to be clinically 
significant will be reported as an AE as described in Section 7.1.   


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7.18 
Echocardiograms 
Standard echocardiogram will be performed to assess cardiac function and LVEF according to 
the Schedule of Events (Section 1.2).  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 patient throughout the study. After a number of 
patients have been enrolled in the dose escalation, the Safety Review Committee may determine 
that an ECHO is not needed, in this case the ECHO assessment may be removed from study. 
7.19 
Pregnancy Tests 
Serum or urine pregnancy tests will be performed on women of childbearing potential during 
screening.  Urine or serum pregnancy tests will be performed on women on Day 1 of each cycle 
prior to dosing and at EOT.  A negative pregnancy test result must be obtained before the 
administration of the study drug(s). 
A pregnancy test does not need to be performed on women who are postmenopausal for at least 
1 year or surgically sterile for at least 5 months before signing the ICF, or for female patients 
who reach 1 year of postmenopausal status after study entry (or reach 5 month post-surgical 
sterilization after entering the study). 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately.  Requirements for reporting a pregnancy are provided in Section 7.13. 


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


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


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sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. 
8.2.1.3 
Special Notes on the Assessment of Target Lesions 
Lymph nodes:  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  For PR, SD, and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’:  While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm).  However, if the lesion is believed to 
be present and is faintly seen but is too small to measure with any accuracy, a default value of 
5 mm should be assigned. 
8.2.2 
Response Criteria using RECIST 1.1 
8.2.2.1 
Evaluation of Target Lesions 
Table 21 provides the definitions of the criteria used to determine objective tumor response for 
target lesions. 
Table 21: 
Criteria to Determine Objective Tumor Response for Target Lesions 
per RECIST 1.1 
Complete Response (CR) Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, 
taking as reference the baseline SLD 
Progressive Disease (PD) At least a 20% increase in the SLD of target lesions, taking as reference the smallest 
SLD on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm relative to nadir.  (Note:  the appearance of one or more new 
lesions is considered progression.) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study 
 


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8.2.2.2 
Evaluation of Non-Target Lesions 
Table 22 provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  Although some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points of 
radiographic assessments. 
Table 22: 
Criteria to Determine Tumor Response for Non-Target Lesions per 
RECIST 1.1 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions.  (Note:  the appearance of 
one or more new lesions is also considered progression).a 
NOTE:  If tumor markers are assessed for a given patient and are initially above the ULN, they must normalize for 
a patient to be considered in complete CR. 
a. 
In this setting, when a patient has measurable disease, to achieve “unequivocal progression” on the basis of the 
non-target disease, there must be an overall level of substantial worsening in the non-target disease such that, 
even in the presence of SD or PR in the target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.  A modest increase in size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare 
(from Section 4.3.4 of RECIST 1.1). 
 
8.2.2.3 
Confirmatory Measurement/Duration of Response 
8.2.2.3.1 
Confirmation 
Confirmation of response (either PR or CR) is required.  Changes in tumor measurements must 
be confirmed by repeat assessments that should be performed ≥ 4 weeks after the criteria for 
response are first met. 
8.2.2.4 
Evaluation of Overall Response Using RECIST 1.1 


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Table 23: 
Best Overall Response When Confirmation of CR and PR Required 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise.  PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise.  PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise.  NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise.  PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise.  NE 
NE 
NE 
NE 
Abbreviations:  CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; 
SD = stable disease 
a. 
If a CR is truly met at the first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared 
after CR).  Best response would depend on whether minimum duration (7 weeks) for SD was met.  However, 
sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in 
fact the patient had PR, not CR at the first time point.  Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
Source:  Eisenhauer, 2009 
 


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9.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
9.1 
General Considerations 
In general, continuous data will be summarized by descriptive statistics, including number of 
patients, mean, standard deviation, median, minimum, and maximum.  Categorical data will be 
summarized by the number and percentage of patients.  Unless otherwise specified, data 
collected during the dose escalation/schedule finding phase (Parts 1 and 3) will be summarized 
by dose cohort, and data collected during the dose expansion phase (Parts 2 and 4) will be 
summarized by tumor type. 
9.1.1 
Efficacy 
All efficacy endpoints except OS and PFS will be analyzed using the response evaluable 
population and the ITT population.  OS and PFS will be reported for the ITT population.  All 
safety endpoints will be summarized using the safety population. 
A description of analysis methods and detailed definitions for efficacy and safety endpoints will 
be provided in the statistical analysis plan (SAP). 
9.2 
Determination of Sample Size 
During Part 1, cohorts of at least 3 patients will be treated at each dose level.  Additional patients 
will be added to each dose cohort based on the scheme and rules outlined in Section 5.3.2 or 
Sponsor determination of the need for additional data to further evaluate the benefit/risk profile.  
It is estimated that approximately 50 patients will be enrolled into the Part 1 dose escalation 
phase. 
During Part 3, cohorts of at least 6 patients will be enrolled to each of the 3 dosing schedules in 
Cohort A (concurrent dosing).  Additional patients will be added to each dose schedule based on 
the scheme and rules outlined in Section 5.3.5 or Sponsor determination of the need for 
additional data to further evaluate the benefit/risk profile.  If a DLT is observed in 2 or more 
patients of 6 in Cohort A, patients may enroll into Cohort B (staggered dosing), where 
ipilimumab will be staggered to be administered at a later cycle (e.g., Cycle 3 Day 1).  It is 
estimated that approximately 36 patients will be enrolled into the Part 3 dose escalation phase. 
During Parts 2 and 4, patients will be enrolled as described in Sections 5.3.4 and 5.3.6.  The 
sample size is strictly based on efficacy, specifically based on the target ORR relative to historic 
response rate.  The Fleming 2-stage design (Fleming, 1982) framework will be used as a guide 
for the tumor cohorts.  The total sample size for each expansion cohort (including patients treated 
at the RP2D during the dose escalation period) will be calculated using a normal approximation 
to provide a reasonable false-positive rate (FPR < 10%) and false-negative rate (FNR < 10%) 
based on assumptions of true (target) and historic ORR for each indication (Table 24 and 
Table 25).  The historic and target response rate assumptions may change over time and may 


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need to be adjusted at the time of response data from this study are available.  The 2-stage design 
provides an option to stop early for futility as well as allowing an early start for Phase 3 
preparation if a strong antitumor activity signal is observed.  However, the final decision will be 
based on the totality of overall treatment effect for multiple study endpoints and their 
associations with the tumor response rate.  Enrollment may continue into Part 2 while the 
planned number of patients for Part 1 are followed for efficacy-evaluable tumor assessments.  
There will be no stopping of enrollment to a tumor cohort for efficacy, although early planning 
for the next stage of clinical development may be initiated. 


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Table 24: 
True (Target) and Historic Objective Response Rate for Each 
Indication in Part 2 
Cohorta 
Indication 
Objective 
Response Rate (%) Sample Sizeb 
Futility 
Efficacy 
Reference for 
Historical ORR 
Assumption 
Historical 
Target N1 N2 Total S1 
S2 
T1 
T2 
1a 
MEL 1L 
40 
65 
13 15 
28 
≤ 5 ≤ 14 ≥ 10 ≥ 15 
Robert, 2015 
1b 
MEL 2-3L, I-O 
relapse/ refractory 
10 
30 
15 11 
26 
≤ 1 
≤ 5 
≥ 4 
≥ 6 
Unmet medical 
need 
1c 
MEL 2L BRAF wild 
type I-O relapse/ 
refractory 
10 
30 
15 11 
26 
≤ 1 
≤ 5 
≥ 4 
≥ 6 
Unmet medical 
need 
1d 
MEL 1L following 
prior adjuvant therapy 
10  
30 
16 12 
28 
≤ 1 
≤ 5 
≥ 4 
≥ 6 
Nomura, 2017;  
Weber, 2013 
2a 
RCC 1L  
25 
50 
11 15 
26 
≤ 2 
≤ 9 
≥ 6 ≥ 10 
Topalian, 2012 
2b 
RCC 2-3L, I-O 
relapse/ refractory 
5 
25 
15 11 
26 
≤ 0 
≤ 3 
≥ 3 
≥ 4 
Unmet medical 
need 
3a 
NSCLC regardless of 
PD-L1 expression 
23 
45 
16 18 
34 
≤3 
≤11 
≥7 
≥12 
Garon 2015; 
Gettinger 2016; 
Carbone, 2017 
3a.1 
NSCLC 1L PD-L1 
< 1% 
8 
30 
12 
8 
20 
≤ 0 
≤ 3 
≥ 3 
≥ 4 
Garon, 2015; 
Carbone, 2017 
3a.2 
NSCLC 1L PD-L1 
≥ 1%-< 50% 
14 
40 
8 
10 
18 
≤ 0 
≤ 4 
≥ 4 
≥ 5 
3a.3 
NSCLC 1L PD-L1 
≥ 50% 
25 
55 
11 
9 
20 
≤ 3 
≤ 7 
≥ 6 
≥ 8 
3b 
NSCLC 2L, I-O 
therapy naive 
following 
platinum-based 
therapy 
20 
40 
20 16 
36 
≤ 4 ≤ 10 ≥ 8 ≥ 11 
Brahmer, 2015 
3c 
NSCLC 2L, I-O 
relapse/refractory 
5 
20 
12 25 
37 
≤0 
≤3 
≥3 
≥4 
Unmet medical 
need 
3d.1 
NSCLC, 1L 
nonsquamous 
(+ maintenance 
pemetrexed) 
45 
66 
20 19 
39 
≤ 9 ≤ 21 ≥ 14 ≥ 22 
Gandhi, 2018 
3d.2 
NSCLC, 1L 
nonsquamous 
(no maintenance 
pemetrexed) 
45 
66 
20 19 
39 
≤ 9 ≤ 21 ≥ 14 ≥ 22 
Gandhi, 2018 
3e 
NSCLC 1L squamous 
in combination with 
platinum/taxane 
20 
40 
20 16 
36 
≤ 4 ≤ 10 ≥ 8 ≥ 11 
Rizvi, 2016 


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Table 24: 
True (Target) and Historic Objective Response Rate for Each 
Indication in Part 2 (Contd) 
Cohorta 
Indication 
Objective 
Response Rate (%) Sample Sizeb 
Futility 
Efficacy 
Reference for 
Historical ORR 
Assumption  
Historical 
Target N1 N2 Total S1 
S2 
T1 
T2 
3f 
3L+ NSCLC 
ALK-translocation/ 
ROS1 rearrangement 
positive 
5 
20 
12 25 
37 
≤0 
≤3 
≥3 
≥4 
Unmet medical 
need 
3g 
3L+ NSCLC, EGFR 
mutation/deletion 
5 
20 
12 25 
37 
≤0 
≤3 
≥3 
≥4 
Unmet medical 
need 
4a 
Urothelial 1L 
Cis-ineligible 
16 
45 
10 
8 
18 
≤1 
≤5 
≥4 
≥6 
Balar, 2017 
Urothelial 1L 
(refused standard of 
care) 
16 
45 
10 
8 
18 
≤1 
≤5 
≥4 
≥6 
4b 
Urothelial 2-3L, I-O 
relapse/ refractory 
5 
25 
13 
7 
20 
0 
≤2 
≥3 
≥3 
Patel, 2018 
5a 
TNBC 1-2L, I-O 
therapy naïve 
10 
26 
21 17 
38 
≤ 1 
≤ 6 
≥ 5 
≥ 7 
Schmid, 2017 
5b 
TNBC 1-2L, I-O 
therapy 
naive + nab-paclitaxel 
24 
45 
20 18 
38 
≤ 5 ≤ 12 ≥ 9 ≥ 13 
Forero-Torres, 
2015; 
Gradishar, 2005 
5c 
TNBC 1-2L, I-O 
therapy 
naive + eribulin 
20 
40 
20 16 
36 
≤ 4 ≤ 10 ≥ 8 ≥ 11 Kaufman, 2015; 
McIntyre, 2014 
6a 
HR+ breast cancer, 
I-O therapy naive 
following hormonal 
therapy 
25 
(cytotoxic 
chemo-
therapy) 
 
5% (for 
single 
agent CPI) 
45 
 
 
 
20 
18 
 
 
 
12 
21 
 
 
 
25 
39 
 
 
 
37 
≤ 5 
 
 
 
0 
≤ 14 
 
 
 
≤ 3 
≥ 9 
 
 
 
≤ 3 
≥ 15 
 
 
 
≥ 4 
Harris, 2006; 
Twelves, 2014 
 
 
Rugo 2016;  
Dirix 2018 
6b 
HR+ breast cancer, 
I-O therapy naive 
following hormonal 
and cytotoxic therapy 
20 
(cytotoxic 
chemo-
therapy) 
 
5% (for 
single 
agent CPI) 
40 
 
 
 
20 
20 
 
 
 
12 
16 
 
 
 
25 
36 
 
 
 
37 
≤ 4 
 
 
 
0 
≤ 10 
 
 
 
≤ 3 
≥ 8 
 
 
 
≤ 3 
≥ 11 
 
 
 
≥ 4 
 
Harris, 2006; 
Twelves, 2014 
 
Rugo 2016;  
Dirix 
 
 


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Table 24: 
True (Target) and Historic Objective Response Rate for Each 
Indication in Part 2 (Contd) 
Cohorta 
Indication 
Objective 
Response Rate (%) Sample Sizeb 
Futility 
Efficacy 
Reference for 
Historical ORR 
Assumption  
Historical 
Target N1 N2 Total S1 
S2 
T1 
T2 
7 
Gastric carcinoma 
2-3L, I-O therapy 
naïve 
13 
30 
22 15 
37 
≤ 2 
≤ 7 
≥ 7 
≥ 8 
Kang, 2017 
8a 
CRC 2-3L, MSI-high, 
I-O therapy naïve 
30 
50 
26 13 
39 
≤ 7 ≤ 15 ≥ 13 ≥ 16 
Overman, 2017 
8b 
CRC 3-4L, 
MSI-non-high, I-O 
therapy naïve 
5 
20 
12 25 
37 
≤ 0 
≤ 3 
≥ 3 
≥ 4 
Le, 2015 
(mismatch repair 
proficient) 
Abbreviations:  cis = cisplatin; CPI = checkpoint inhibitor; CRC = colorectal carcinoma; EGFR = epidermal growth 
factor receptor; HR = hormone-receptor positive; I-O = immuno-oncology; L = line; MEL = melanoma; 
MSI = microsatellite instability; NA = not available; ORR = objective response rate; NSCLC = non-small cell lung 
cancer; RCC = renal cell carcinoma; TNBC = triple-negative breast cancer 
a. 
Cohort 3h is not included in this table but is discussed separately in the following paragraph. 
b. Total sample size for each expansion cohort is calculated using a normal approximation to provide a reasonable 
false-positive rate (FPR < 10%) and false-negative rate (FNR < 10%). 
 
For efficacy assessment of Cohort 3h (patients with immuno-oncology relapsed-refractory 
NSCLC whose disease has progressed on combination therapy of anti-PD-1/anti-PD-L1 with 
cytotoxic chemotherapy), the following statistical assumptions have been incorporated into the 
protocol.  For this cohort, the Historical Comparator is single-agent docetaxel which showed 
9% overall response rate in a second-line NSCLC population (Herbst, 2016).  With this historical 
control rate as null hypothesis, using a two-sided alpha of 0.05, 100 patients will provide over 
90% power to demonstrate statistical significance if the response rate of NKTR-214/nivolumab 
is 20% or more.  If the observed response rate in this cohort (ITT population) is 18% or better, 
the lower bound of the 95% confidence interval will rule out 10% response rate. 
Two interim analyses will be conducted in Cohort 3h to gate the trial progression based on the 
ITT Population (see Section 9.5).  The first interim evaluation will be conducted when 20 
evaluable patients have been followed for 4 months or terminated from the study.  If 3 or more 
responses are observed, the trial may continue to the next stage.  The second interim analysis will 
be performed when 40 evaluable patients have been followed for 4 months or terminated from 
the study.  If there are 6 or more responders, the trial may continue to enroll approximately 
100 patients.  Enrollment will continue without pause during the conduct of the interim analyses.  
Approximately 936 patients will be enrolled into Part 2.  Additional patients may be added to 
selected expansion cohorts to further evaluate the benefit/risk profile or the Sponsor may choose 
not to open or complete all expansion cohorts. 


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Approximately 36 patients will be enrolled into Part 3. 
Approximately 106 additional patients will be enrolled into Part 4. 
Table 25: 
True (Target) and Historic Objective Response Rate for Each 
Indication in Parts 3 and 4 
Indication 
Objective Response Rate 
Sample Sizea 
Futility 
Efficacy 
Historical 
Target 
N1 
N2 
Total 
S1 
S2 
T1 
T2 
RCC 1L 
25 
50 
11 
15 
26 
≤ 2 
≤ 9 
≥ 6 
≥ 10 
NSCLC 1Lb 
25 
50 
11 
15 
26 
≤ 2 
≤ 9 
≥ 6 
≥ 10 
Melanoma 1L 
40 
65 
13 
15 
28 
≤ 5 
≤ 14 
≥ 10 
≥ 15 
Urothelial 1L 
25 
50 
11 
15 
26 
≤ 2 
≤ 9 
≥ 6 
≥ 10 
Abbreviations:  L = line; N1, N2 = sample size at stage 1, 2; NSCLC = non-small cell lung cancer; RCC = renal cell 
carcinoma; S1, S2 = futility boundary at stage 1, 2; T1, T2 = efficacy boundary at stage 1, 2 
a. 
Total sample size for each cohort is calculated using a normal approximation to provide a reasonable 
false-positive rate (FPR < 10%) and false-negative rate (FNR < 10%). 
b. Total sample size for 1L NSCLC is based on the assumption that a mixed population of PD-L1 positive and 
negative patients will be enrolled.  If unequal distribution of patients are enrolled, sample size may be modified 
accordingly. 
 
9.3 
Safety Monitoring 
A Safety Review Committee consisting of representatives from the Sponsor’s Clinical 
Development, Drug Safety, Biostatistics, other functional representatives, as needed, and at least 
one site Investigator will meet at least quarterly during the Dose Escalation phase of the trial to 
review safety data for potential safety risks or more frequently if needed.  The Safety Review 
Committee will be convened to make a recommendation on the continuation, modification, or 
discontinuation of the study.   
9.4 
Replacement of Patients 
Patients in Parts 1 and 3 who do not complete the DLT observation period for reasons other than 
a DLT will be replaced to provide sufficient number of patients included for the dose escalation 
decision.  During Parts 2 and 4, patients who were enrolled and did not meet the eligibility 
criteria will be replaced. 
9.5 
Analysis Sets 
ITT Population/Safety Population:  All patients who receive at least 1 dose (or partial dose) of 
study drug will be included in the analysis. 
DLT Population:  All patients who complete at least the DLT observation period or discontinue 
from the study treatment due to DLT will be included. 


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Pharmacokinetic Population:  All patients in the Safety Population who have evaluable analyte 
concentration-time profiles that allow for the computation of meaningful PK parameter values. 
Response Evaluable Population:  Patients who have measurable disease (per RECIST 1.1) at 
baseline and also have at least one post-baseline assessment of tumor response and (for Parts 2 
and 4) meet eligibility criteria are response evaluable.  
Any interim efficacy analysis based on the ITT population will exclude ongoing patients who do 
not have any post-baseline efficacy assessment due to insufficient follow-up. 
9.6 
Planned Analyses 
9.6.1 
Demographics and Baseline Characteristics 
Demographic data (age, sex, ethnicity, body weight) and baseline disease characteristics will be 
tabulated and summarized by dose cohort (for Parts 1 and 3) and by tumor type (for Parts 2 and 
4) and presented in data listings. 
9.6.2 
Safety 
The primary endpoints of the study are to determine the MTD of NKTR-214 in combination with 
nivolumab and in combination with nivolumab and ipilimumab.  Safety assessments will be 
summarized separately for Parts 1 through 4.  AEs and toxicity will be evaluated according to 
NCI CTCAE version 4.03.  Safety assessments will be performed by medical review of AEs and 
laboratory results. 
The incidence rate of DLTs will be evaluated by dose cohort for the DLT population. 
Treatment emergent AEs (TEAEs) will be summarized by preferred term, system organ class, 
NCI-CTCAE grade of severity, and relationship to the study treatment. 
A TEAE is defined as:  (regardless of intensity) 
• Any AE that happens after treatment initiation 
• AE that was present at time of treatment initiation but worsened after treatment initiation 
• AE that was present and resolved prior to treatment and reappeared after treatment initiation 
Vital signs (including change in weight) and clinical laboratory test results will be summarized 
descriptively by dose/schedule (for Parts 1 and 3) and by tumor type (for Parts 2 and 4).  Any 
significant physical examination findings will be listed.  ECG data will be evaluated by central 
review and abnormalities, if present, will be listed.  A separate listing and summary of all imAEs 
will be provided.  A listing and summary of patients who discontinued study drug(s) due to an 
AE will be provided. 
A data listing for deaths will be provided. 


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9.6.3 
Efficacy 
Efficacy analyses will be performed on data provided by the Investigator sites as well as from an 
independent radiology review for the following efficacy outcomes: 
• ORR using RECIST 1.1 
• Best overall response (BOR) using RECIST 1.1 
• Time to response (TTR) using RECIST 1.1 
• Duration of response (DOR) using RECIST 1.1 
• Clinical benefit rate (CBR) using RECIST 1.1 
• Overall Survival (OS) 
• PFS using RECIST 1.1 
The primary efficacy measurement is the ORR per RECIST 1.1 using the response evaluable 
population.  Except as stated otherwise in the SAP, the ORR based on the Investigator’s 
assessment will be the primary efficacy endpoint and will be summarized using the response 
evaluable population.  ORR will also be summarized for the ITT population based on an 
independent radiology review.  Any interim efficacy analysis based on the ITT population will 
exclude ongoing patients who do not have any post-baseline efficacy assessment due to 
insufficient follow-up.  The number and percentage of patients with CR or PR as their best 
overall response will be calculated.  The 95% confidence interval (CI) will be calculated using 
the exact binomial method.  In addition, the ORR analysis will be performed on the number of 
patients treated.  All tumor assessments and response data will be listed.  The BOR will be 
summarized similarly using the response evaluable population.   
The TTR will be defined for patients who had confirmed CR or confirmed PR as the time from 
the date of first dose to date of first documented CR or PR.  TTR will be summarized using 
descriptive statistics. 
DOR will be defined for patients who have confirmed CR or confirmed PR as the date from first 
documented CR or PR to the date of the first objectively documented disease progression per 
RECIST 1.1 or death due to any cause, whichever is earlier.  Patients who do not have disease 
progression per RECIST 1.1 will be censored on the date of last evaluable tumor assessment.  
Patients who started any subsequent antineoplastic regimen, including target-lesion 
tumor-directed radiotherapy and target-lesion tumor-directed surgery, without a prior reported 
progression will be censored at the last evaluable tumor assessment prior to initiation of the 
subsequent antineoplastic therapy as described.  The DOR will be estimated using the 
Kaplan-Meier method.  The 25%, median and 95% CI, and 75% quartiles will be summarized. 
CBR, defined as the number of patients with confirmed CR, confirmed PR, or SD, will be 
summarized similarly to ORR using the response evaluable population and the ITT population.  


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Additionally, CBR at 16 weeks (CBR16) and CBR at 24 weeks (CBR24), defined as confirmed 
CR, confirmed PR, or SD for ≥ 16 weeks or ≥ 24 weeks, respectively, will be summarized.  
PFS is defined as the time from the date of first dose to the date of the first objectively 
documented progressive disease per RECIST 1.1 or death, whichever is first.  For patients who 
do not have date of disease progression per RECIST 1.1 and date of death, patients will be 
censored on the date of last evaluable tumor assessment.  For patients who started a new 
antineoplastic regimen, or had surgery or radiotherapy to the target lesion prior to disease 
progression per RECIST 1.1, patients will be censored on the date of last evaluable tumor 
assessment prior to receiving new treatment.  For patients whose disease progression or death 
appears after missing two consecutive tumor assessments, patients will be censored on the date 
of last evaluable tumor assessment.  Patients who are lost to follow up will be censored on the 
date of their last evaluable tumor assessment.  Additional censoring rules will be discussed in the 
SAP. 
PFS will be estimated using the Kaplan-Meier method.  The 25%, median and 95% CI, and 75% 
quartiles will be summarized using the ITT population. 
OS will be defined as the date of first dose to the date of death.  Patients who do not have a date 
of death will be censored on the last date for which a patient was known to be alive.  OS will be 
analyzed similarly to PFS. 
9.6.4 
Immunogenicity 
Validated assays will be used for the determination of anti-drug antibodies to NKTR-214 and 
related components, nivolumab, and ipilimumab in human serum.  Only patients who receive at 
least 1 dose of NKTR-214, nivolumab, and/ or ipilimumab and who provide at least 
1 post-treatment sample will be evaluated.  Immunogenicity results will be analyzed 
descriptively by summarizing the number and percentage of patients who develop detectable 
anti-drug antibodies.  Samples confirmed positive may also be evaluated for neutralizing 
antibody activity. Anti-drug antibodies to NKTR-214, nivolumab, and ipilimumab will be 
analyzed according to a prespecified analysis plan. 
 
 
  
 
 
 
 
9.6.6 
Pharmacokinetics 
Plasma concentrations of NKTR-214 and its metabolites, and serum concentrations of nivolumab 
and ipilimumab, will be measured using validated method(s).  Before analysis of samples, assay 


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sensitivity, specificity, linearity, and reproducibility will be determined.  Pharmacokinetic 
parameters such as maximum concentration (Cmax), time to Cmax (Tmax), area under the curve 
(AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) will be estimated from 
concentration-time data where possible.  Pharmacokinetic data from this study may also be 
pooled with data from other clinical studies for the purpose of PK modeling.  Pharmacokinetic 
parameters will be tabulated and summarized with descriptive statistics.  Select pharmacokinetic 
parameter values will be correlated with select safety and response measurements for assessment 
of exposure-response relationships.  Data from patients prematurely ending participation in the 
study may be excluded from the PK data evaluation. 
9.7 
Concomitant Medications 
All reported concomitant medications will be mapped using the World Health Organization Drug 
Dictionary.  Concomitant medications will be tabulated in summary tables and data listings. 
9.8 
Missing Data 
Statistical considerations and methodology for handling missing data will be detailed in the 
Statistical Analysis Plan. 


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


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


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


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


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


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13.3 
Confidentiality 
Patient confidentiality will be maintained per local legal and regulatory requirements and 
applicable US federal regulations and ICH GCP guidelines.  To comply with GCP guidelines and 
requirements, patient records will be reviewed during monitoring visits and audits conducted by 
the Sponsor, Sponsor's representatives, or health authorities.  During these activities, every 
reasonable effort will be made to keep medical information, including patient identifying 
information, as confidential as possible as required by law.  
13.4 
Security Measures 
Sites will employ both technical and organizational measures (such as, but not limited to, 
controlling access to personal patient data to only those with a need to know such data, data 
encryption, data anonymization and pseudonymization, and so forth) to ensure patient and 
patient data privacy.  Sites will adhere to a “privacy by design” and “privacy by default” 
approach in collecting, storing, and processing personal patient data. 
In the event of a breach of the security measures used by the Site to ensure patient and patient 
data privacy, the Site will immediately notify the Sponsor. 


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14.0 
PUBLICATION POLICY 
All data are the property of the Sponsor.  Any formal presentation or publication of data from 
this study will be considered for joint publication by the Sponsor personnel and Investigator(s). 
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries. 


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15.0 
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Brayer J, Fishman M. Regression of metastatic clear cell kidney cancer with interleukin-2 
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Carbone DP, Reck M, Paz-Ares L, et al. First-Line Nivolumab in Stage IV or Recurrent 
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Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of 
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Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
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14. 
Fleming TR. One-sample multiple testing procedure for phase II clinical trials. 
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15;21(12):2722-9. 
16. 
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in 
Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018; doi: 
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17. 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell 
lung cancer. N Engl J Med. 2015;372:2018-28. 
18. 
Gassenmaier M, Lipp HP, Scheu A, et al. Safety of shortened infusion times for 
combined ipilimumab and nivolumab. Cancer Immunol Immunother. 2018;67:135-140. 
19. 
Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, Gerber DE, 
Shepherd FA, Antonia S, Goldman JW, Juergens RA. Nivolumab monotherapy for first-
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2016 Sep 1;34(25):2980. 
20. 
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21. 
Haas CE, Nelsen JL. Drug-cytokine interactions. In Piscitelli SC, Rodvold KA, eds. Drug 
Interactions in Infectious Diseases. Human Press Inc, Totowa NJ, USA. 2005 pp 431-61. 
22. 
Harris LN, Broadwater G, Lin NU, et al. Molecular subtypes of breast cancer in relation 
to paclitaxel response and outcomes in women with metastatic disease: results from 
CALGB 9342. Breast Cancer Research. 2006;8(6):R66. 
23. 
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a 
randomised controlled trial. Lancet. 2016;387:1540-50. 
24. 
Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-
oesophageal junction cancer refractory to, or intolerant of, at least two previous 
chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, 
placebo-controlled, phase 3 trial. Lancet. 2017;390:2461-71. 
25. 
Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of 
eribulin mesylate versus capecitabine in patients with locally advanced or metastatic 
breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 
2015;33:594-601. 


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26. 
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair 
deficiency. N Engl J Med. 2015;372:2509-20. 
27. 
McIntyre K, O'Shaughnessy J, Schwartzberg L, et al. Phase 2 study of eribulin mesylate 
as first-line therapy for locally recurrent or metastatic human epidermal growth factor 
receptor 2-negative breast cancer. Breast Cancer Res Treat. 2014;146:321-8. 
28. 
Momtaz P, Park V, Panageas KS, et al. Safety of Infusing Ipilimumab Over 30 Minutes. J 
Clin Oncol. 2015;33:3454-8. 
29. 
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing 
a common language for tumor response to immunotherapy: immune-related response 
criteria using unidimensional measurements. Clinical Cancer Res. 2013;19(14):3936-43. 
30. 
Nomura M, Otsuka A, Kondo T, et al. Efficacy and safety of retreatment with nivolumab 
in metastatic melanoma patients previously treated with nivolumab. Cancer Chemother 
Pharmacol. 2017;80:999-1004. 
31. 
Overman MJ, McDermott R,Leach JL, et al.  Nivolumab in patients with metastatic DNA 
mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 
142): an open-label, multicentre, phase 2 study. 2017;18:1182-91. 
32. 
Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after 
platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of 
an open-label, phase 1 trial. Lancet Oncol. 2018;19:51-64. 
33. 
Payne R, Glenn L, Hoen H, et al. Durable responses and reversible toxicity of high-dose 
interleukin-2 treatment of melanoma and renal cancer in a Community Hospital 
Biotherapy Program. J Immunother Cancer. 2014;2:13. 
34. 
Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in Combination With Platinum-
Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell 
Lung Cancer. J Clin Oncol. 2016;34:2969-79. 
35. 
Rizvi N, Antonia S, Callahan MK, et al.  Impact of tumor mutation burden on the 
efficacy of nivolumab or nivolumab + ipilimumab in small cell lung cancer: an 
exploratory analysis of CheckMate 032 (Abstract 11063).  Presented at the International 
Association for the Study of Lung Cancer 18th World Conference on Lung Cancer, 
15-18 October 2017, Yokohama, Japan. 
36. 
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma 
without BRAF mutation. N Engl J Med. 2015;372:320-30. 
37. 
Rugo HS, Delord JP, Im SA, et al. Safety and Antitumor Activity of Pembrolizumab in 
Patients with Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–
Negative Advanced Breast Cancer. Clinical Cancer Research. 2018;24(12):2804-11. 


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Nektar Therapeutics 
 
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38. 
Schmid P, Cruz C, Braiteh F, et al. Atezolizumab in metastatic TNBC (mTNBC): 
long-term clinical outcomes and biomarker analyses. Cancer Res. 2017;77(13 
Suppl):Abstract 2986 Presented at the 2017 annual meeting of the American Association 
for Cancer Research, 1-5 April 2017.  Washington, DC. 
39. 
Scott M, Ratcliffe MJ, Sharpe A, et al. Concordance of tumor and immune cell staining 
with Ventana SP142, Ventana SP263, Dako 28-8 and Dako 22C3 PD-L1 tests in NSCLC 
patient samples. DOI: 10.1200/JCO.2017.35.7_suppl.7 Journal of Clinical Oncology 35, 
no. 7_suppl (March 1 2017) 7-7. 
40. 
Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination 
with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in 
patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin 
Oncol. 2012;30:2055-62. 
41. 
Topalian S, Hodi F, Brahmer J, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med 2012;366:2443–2454. 
42. 
Tsao MS, Kerr KM, Kockx M, et al.  PD-L1 Immunohistochemistry Comparability Study 
in Real-Life Clinical Samples: Results of Blueprint Phase 2 Project.  J Thorac 
Oncol. 2018;13(9):1302-11. doi: 10.1016/j.jtho.2018.05.013. 
43. 
Twelves C, Cortes J, Vahdat L, et al. Efficacy of eribulin in women with metastatic 
breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 
2014;148(3):553-61. 
44. 
Wainberg ZA, Hochster HS, George B, et al. Phase I study of nivolumab (nivo) + 
nab-paclitaxel (nab-P) ± gemcitabine (Gem) in solid tumors: Interim results from the 
pancreatic cancer (PC) cohorts. J Clin Oncol. 2017;35: 412-412. 
45. 
Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab 
with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 
2013;31:4311-8. 
46. 
Wong MKK, Morse MA, McDermott DF, et al. Overall survival of metastatic melanoma 
patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 
or the PD-1 pathways:  analysis of data on the current use of HD IL-2. J Immunother 
Cancer. 2015;3(Suppl 2):P359. 
47. 
Zídek Z, Anzenbacher P, Kmoníčková E. Current status and challenges of cytokine 
pharmacology. Br J Pharmacol. 2009;157:342–61. 


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APPENDIX 1: 
CLINICAL LABORATORY TESTS 
Descriptions of the laboratory tests performed in this study are provided in the following 
appendices: 
• Appendix 1A: 
Laboratory Tests Performed in This Study 
• Appendix 1B: 
Local Clinical Laboratory Tests Obtained Prior to Study Drug 
                              Administration 
 
 


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Appendix 1A: 
Laboratory Tests Performed in This Study 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Serology 
• 
Hemoglobin (Hgb) 
• 
Hematocrit (HCT) 
• 
Red blood cell (RBC) count 
• 
Platelet count 
• 
White blood cell (WBC) count 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
• 
Mean corpuscular volume 
(MCV) 
• 
Mean corpuscular hemoglobin 
(MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
AST (SGOT) 
• 
ALT (SGPT) 
• 
Alkaline phosphatase (ALP) 
• 
Gamma-glutamyl transferase 
(GGT) 
• 
Albumin 
• 
Creatinine 
• 
Calculated creatinine clearance 
• 
Calcium 
• 
Glucose 
• 
Total protein (TP) 
• 
Total bilirubin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
CO2 content or bicarbonate 
• 
Blood urea nitrogen (BUN) 
• 
Lactate dehydrogenase (LDH) 
• 
Uric acid 
• 
Hepatitis B surface antigen 
(HBsAg) 
• 
Hepatitis C virus antibody 
(anti-HCV) 
• 
Human immunodeficiency virus 
(HIV) antibody 
Additional Labs 
• 
Creatine kinase 
• 
Thyroid stimulating hormone 
(TSH) 
• 
Free thyroxine (T4) 
• 
Free or total triiodothyronine 
(T3) 
• 
Lipase 
• 
Amylase 
• 
Serum or urine pregnancy 
(HCG) 
Coagulation 
• 
Partial thromboplastin time 
(PTT) 
• 
Prothrombin time (PT) 
Urinalysis 
• 
Specific gravity 
• 
pH 
• 
Glucose 
• 
Protein 
• 
Bilirubin 
• 
Ketones 
• 
Leukocyte esterase 
• 
Blood 
For positive protein, white blood cell or blood, a 
microscopic examination including: 
• 
Red blood cells 
• 
White blood cells 
• 
Epithelial cells 
• 
Bacteria 
• 
Crystals 
• 
Casts 
Local laboratory will be used for Part 1 and Part 3; central laboratory will be used for Part 2 and Part 4. 
 




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APPENDIX 2: 
SCHEDULE OF ELECTROCARDIOGRAM, VITAL SIGNS, 
PHARMACOKINETICS, 
, AND 
IMMUNOGENICITY SAMPLE ASSESSMENTS  
 




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Appendix 2 Table 1: Part 2 - Assessment Schedule for NKTR-214 + Nivolumab (Contd) 
Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Post-treatment 
Day -28 to -1 
Day 1b 
Day 2 
Day 3 
Day 8 
Day 1 b 
Day 8 
Day 1 b 
Day 8 
EOT & 
Follow-up 
T=00:30 - 
01:00  
Within 30 min 
of the end of 
214 infusion 
and before 
Nivolumab 
(Nivo) infusion 
 
ECGd + 
PK-214f 
 
 
 
PK-214 
 
PK-214 
 
 
T=01:00 - 
01:30g 
Nivo Infusiong 
 
Nivo 
Infusion 
 
 
 
Nivo 
Infusion 
 
Nivo 
Infusion 
 
 
T=01:30 - 2:00 End of Nivo 
Infusion 
 
PK-nivo 
 
 
 
 
 
 
 
 
T=03:00 (± 30 min) SOI 
 
ECGd + 
PK-214f 
 
 
 
 
 
 
 
 
T=03:00 SOI or 1 hour 
following the end of nivo 
infusion 
 
VS 
 
 
 
VS 
 
VS 
 
 
T=06:00 + 2 hrs SOI 
 
ECGd + 
PK-214f 
 
 
 
 
 
 
 
 
T=48:00 ± 4 hrs SOI 
 
 
 
ECGd + 
PK-214f 
 
 
 
 
 
 
T=168:00 ± 4 hrs SOI 
 
 
 
 
ECGd +  
PK-214f 
 
 
 
 
 
Abbreviations:  
; ECG = electrocardiogram; IG-214 = immunogenicity samples for NKTR-214; IG-nivo = immunogenicity 
samples for nivolumab; Nivo = Nivolumab; PK-214 = blood samples for pharmacokinetic (PK) analyses of NKTR-214 and its metabolites; PK-nivo = blood 
samples for PK analyses of nivolumab; SOI = Start of NKTR-214 infusion; VS = vital signs 
Footnotes: 
a. 
All assessments are done at any time during the Screening Period and all other Screening assessments are outlined in the Schedule of Events (Section 1.2). 




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Appendix 2 Table 2: Parts 3/4, Cohort A (Concurrent Dosing) 
• Schedule 1: Concurrent Dosing NKTR-214 0.006 mg/kg q3w + Nivo 360mg flat dose     + Ipi 1 mg/kg q6w 
• Schedule 2: Concurrent Dosing NKTR-214 0.006 mg/kg q3w + Nivo 1 mg/kg × 4 doses + ipi 3 mg/kg q3w × 4 doses (then NKTR-214 0.006 mg/kg q3w + Nivo 360 mg q3w maintenance) 
• Schedule 3: Concurrent Dosing NKTR-214 0.006 mg/kg q3w + Nivo 3 mg/kg × 4 doses + ipi 1 mg/kg q3w × 4 doses (then NKTR-214 0.006 mg/kg q3w + Nivo 360 mg q3w maintenance) 
Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Post 
Treatment 
Day -28  
to -1 
Day  
1b 
Day  
2 
Day  
3 
Day  
8 
Day 
11 
Day  
1b 
Day  
3 
Day  
8 
Day  
1b 
Day  
8 
EOT &  
Follow-up 
Predose 
VS 
VS 
VSc 
(q1h 
x4) for 
Part 3; 
VSc 
(once) 
for Part 
4 
VSc 
(q1h 
x2) for 
Part 3; 
VSc 
(once) 
for Part 
4 
VSc 
(once) 
VSc 
(once) 
for 
Part 3 
only 
VS 
  
VSc 
(once) 
VS 
VSc 
VSc (EOT 
only) 
 
ECG 
ECGd + 
PK-214 
  
  
  
  
PK-214 
  
  
PK-214 
  
 
 
 
PK-
nivo 
  
  
  
  
PK-nivo 
  
  
PK-nivo 
(Cycles 3, 
5, 7, 9, 
13, 
17,23,35) 
  
 
 
 
PK-ipi 
 
 
 
 
 
PK-ipi 
(Schedules 
2&3 only) 
 
 
PK-ipih 
Schedule 
1: Cycles 
3, 5, 7, 9, 
13, 17, 
23, 35 
Schedules 
2&3: 
Cycles 3, 
4, 5 and 7 
only 
 
 




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Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Post 
Treatment 
Day -28  
to -1 
Day  
1b 
Day  
2 
Day  
3 
Day  
8 
Day 
11 
Day  
1b 
Day  
3 
Day  
8 
Day  
1b 
Day  
8 
EOT &  
Follow-up 
T=0:00 hr  
Start of 30 
min NKTR-
214 
Infusion 
(SOI) 
 
214 
Infusio
n 
  
  
  
  
214 
Infusion 
  
  
214 
Infusion 
  
 
T=00:30 - 
01:00  
Within 30 
min of the 
end of 214 
infusion and 
before 
Nivolumab 
(Nivo) 
infusion 
 
ECGd 
+PK-
214f 
 
 
 
 
PK-214 
 
 
PK-214 
 
 
T=01:00 - 
01:30g 
Nivo 
Infusiong 
 
Nivo 
Infusio
n 
  
  
  
  
Nivo 
Infusion 
  
  
Nivo 
Infusion 
  
 
T=01:30 - 
02:00 
End of nivo 
infusion 
 
PK-
nivo 
  
  
  
  
 
  
  
 
  
 
T=02:00 - 
02:30i  
Ipilimumab 
(Ipi) 
infusioni  
 
Ipi 
infusio
n 
 
 
 
 
Ipi 
infusion 
(Schedules 
2&3 only) 
 
 
Ipi 
infusion 
Schedule 
1: only on 
cycles Ipi 
is given  
Schedules 
2&3: 
Cycles 3 
and 4 
only 
 
 
T=02:30 – 
03:00  
End of Ipi 
infusion 
 
PK-ipi  
 
 
 
 
 
 
 
 
 
 
T=03:00 (± 30 min) SOI 
 
ECGd 
+PK-
214f 
  
  
  
  
PK-214 
  
  
  
  
 


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Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Post 
Treatment 
Day -28  
to -1 
Day  
1b 
Day  
2 
Day  
3 
Day  
8 
Day 
11 
Day  
1b 
Day  
3 
Day  
8 
Day  
1b 
Day  
8 
EOT &  
Follow-up 
T=03:00-04:00 SOI or 1 hr 
following the end of the 
last study drug infusion 
(whether nivo or ipi) 
 
VS 
  
  
  
  
VS 
  
  
VS 
 
 
T=04:00-05:00 SOI or 2 
hrs following the end of the 
last study drug infusion 
(whether nivo or ipi) 
 
VS 
  
  
  
  
  
  
  
  
  
 
T=05:00-06:00 SOI or 3 
hrs following the end of the 
last study drug infusion 
(whether nivo or ipi) 
 
VS 
  
  
  
  
  
  
  
  
  
 
T=06:00 + 2 hrs SOI 
 
ECGd 
+PK-
214f 
  
  
  
  
PK-214 
  
  
  
  
 
T=48:00 ± 4 hrs SOI 
 
  
  
ECGd 
+ 
PK-
214f 
  
  
  
PK-
214 
  
  
  
 
T=168:00 ± 4 hrs SOI 
 
 
 
 
ECGd
+ 
PK-
214f 
 
 
 
PK-214 
 
 
 
Footnotes and abbreviations appear at the end of Appendix 2 
 


Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 173 of 178 
Confidential and Proprietary 
 
11 February 2020 
Appendix 2 Table 2: Parts 3/4, Cohort B (Staggered Dosing of Ipilimumab) 
• Schedule 1: Staggered Dosing NKTR-214 0.006 mg/kg q3w + Nivo 360mg flat dose     + Ipi 1 mg/kg q6w 
• Schedule 2: Staggered Dosing NKTR-214 0.006 mg/kg q3w + Nivo 1 mg/kg × 4 doses + ipi 3 mg/kg q3w × 4 doses (then NKTR-214 0.006 mg/kg q3w + Nivo 360 mg q3w maintenance) 
• Schedule 3: Staggered Dosing NKTR-214 0.006 mg/kg q3w + Nivo 3 mg/kg × 4 doses + ipi 1 mg/kg q3w × 4 doses (then NKTR-214 0.006 mg/kg q3w + Nivo 360 mg q3w maintenance) 
Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3j 
Cycle 4 and Beyondk 
Post 
Treatment 
Day -28  
to -1 
Day  
1b 
Day  
2 
Day  
3 
Day  
8 
Day 
11 
Day  
1b 
Day  
8 
Day  
1b 
Day 
3 
Day  
8 
Day  
1b 
Day  
8 
EOT & 
Follow-up 
Predose  
VS 
VS 
VS c (q1h 
x4) for 
Part 3; 
VS 
(once) for 
Part 4 
VS c (q1h 
x2) for 
Part 3; 
VS 
(once) for 
Part 4 
VS c 
(once) 
VS c 
(once) 
for 
Part 3 
only 
VS 
VS c 
(once) 
VS 
  
VS c 
VS 
VS c  
VSc  
(EOT 
only) 
 
ECG 
ECGd + 
PK-214 
  
  
  
  
PK-214 
  
PK-214 
  
  
PK-214 
  
 
 
 
PK-
nivo 
  
  
  
  
  
  
 PK-
nivo 
  
  
PK-nivo  
(Cycles 5, 
7, 9, 13, 
17, 23, 
35)  
  
 
 
 
 
 
 
 
 
 
 
PK-ipih 
 
 
PK-ipih  
Schedule 
1: Cycles 
5, 7, 9, 13, 
17, 23, 35  
Schedules 
2&3: 
Cycles 4, 
5, 6, 7, 9 
 
 




Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 175 of 178 
Confidential and Proprietary 
 
11 February 2020 
Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3j 
Cycle 4 and Beyondk 
Post 
Treatment 
Day -28  
to -1 
Day  
1b 
Day  
2 
Day  
3 
Day  
8 
Day 
11 
Day  
1b 
Day  
8 
Day  
1b 
Day 
3 
Day  
8 
Day  
1b 
Day  
8 
EOT & 
Follow-up 
T=00:30 
- 01:00 
Within 30 
min of the 
end of 214 
infusion 
and before 
Nivolumab 
(Nivo) 
infusion 
 
ECGd 
+PK-
214f 
  
  
  
  
PK-214 
  
PK-214 
  
  
PK-214 
  
 
T=01:00 
- 01:30g 
Nivo 
Infusiong 
 
Nivo 
Infusio
n 
  
  
  
  
Nivo 
Infusion 
  
Nivo 
Infusion 
  
  
Nivo 
Infusion 
  
 
T=01:30 
- 02:00 
End of 
nivo 
infusion 
 
PK-
nivo 
  
  
  
  
 
  
 
  
  
 
  
 
T=02:00 
- 02:30i  
Ipilimuma
b (Ipi) 
infusioni  
 
 
 
 
 
 
 
 
Ipi 
infusion 
 
 
Ipi 
infusion 
Schedule 
1: only on 
cycles Ipi 
is given  
Schedules 
2&3: 
Cycles 4, 
5, 6  
 
 
T=02:30 
– 03:00 
End of Ipi 
infusion 
 
 
 
 
 
 
 
 
PK-ipih 
 
 
 
 
 
T=03:00 (± 30 min) 
SOI 
 
ECGd 
+PK-
214f 
  
  
  
  
  
  
PK-214 
  
  
  
  
 


Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 176 of 178 
Confidential and Proprietary 
 
11 February 2020 
Event 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3j 
Cycle 4 and Beyondk 
Post 
Treatment 
Day -28  
to -1 
Day  
1b 
Day  
2 
Day  
3 
Day  
8 
Day 
11 
Day  
1b 
Day  
8 
Day  
1b 
Day 
3 
Day  
8 
Day  
1b 
Day  
8 
EOT & 
Follow-up 
T=03:00-04:00 SOI 
or 1 hr following the 
end of the last study 
drug infusion 
(whether nivo or ipi) 
 
VS 
  
  
  
  
VS 
  
VS 
  
  
VS 
 
 
T=04:00-05:00 SOI 
or 2 hrs hr following 
the end of the last 
study drug infusion 
(whether nivo or ipi) 
- (for Part 3 only) 
 
VS 
  
  
  
  
  
  
  
  
  
  
  
 
T=05:00-06:00 SOI 
or 3 hrs hr following 
the end of the last 
study drug infusion 
(whether nivo or ipi) 
- (for Part 3 only) 
 
VS 
  
  
  
  
  
  
  
  
  
  
  
 
T=06:00 + 2 hrs SOI  
ECGd + 
PK-
214f 
  
  
  
  
  
  
PK-214 
  
  
  
  
 
T=48:00 ± 4 hrs SOI  
  
  
ECGd + 
PK-214f 
  
  
  
  
  
PK-
214 
  
  
  
 
T=168:00 ± 4 hrs 
SOI 
 
 
 
 
ECGd 
+ 
PK-
214f 
 
 
 
 
 
PK-
214 
 
 
 
Abbreviations:  
; ECG = electrocardiogram; IG-214 = immunogenicity samples for NKTR-214; IG-nivo = immunogenicity 
samples for nivolumab; IG-ipi = immunogenicity samples for ipilimumab; Ipi = Ipilimumab; Nivo = Nivolumab; PK-214 = blood samples for pharmacokinetic 
(PK) analyses of NKTR-214 and its metabolites; PK-ipi = blood samples for PK analyses of ipilimumab; PK-nivo = blood samples for PK analyses of 
nivolumab; SOI = Start of NKTR-214 infusion; VS = vital signs; 




Protocol No. 16-214-02 Amendment 7.0 
 
Bempegaldesleukin (NKTR-214) 
Nektar Therapeutics 
 
Page 178 of 178 
Confidential and Proprietary 
 
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APPENDIX 3: 
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM 
Table 26 provides a management algorithm for possible signs of CVA and follow-up of CVA.  
This general guideline constitutes guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. 
Table 26: 
Cerebrovascular Accident Adverse Event Management Algorithm 
CEREBROVASCULAR ACCIDENT  
ADVERSE EVENT MANAGEMENT ALGORITHM 
This guideline pertains to all patients in the doublet or triplet immunotherapy cohorts. 
For unexplained neurological symptoms (such as hemiparesis, confusion, dysarthria, or visual disturbances) that 
may be associated with CVA: perform neurological imaging with MRI including diffusion-weighted imaging 
(DWI) as soon as feasible after initial presentation of symptoms, preferably within 24 hours (DWI MRI is 
preferred, but if contraindicated, alternative imaging modalities may be used). 
If imaging is consistent with a CVA, proceed to the following: 
1 
For any new CVA events confirmed by imaging (DWI MRI is preferred, unless contraindicated), 
regardless of neurological symptoms (e.g., cryptogenic CVA):  
• 
Discontinue study treatment for patients receiving doublet and triplet immunotherapy 
For suspected TIA without clear alternative etiology: 
• 
Discontinue study treatment for patients receiving triplet immunotherapy 
• 
Study treatment for patients receiving doublet immunotherapy may be continued only after careful 
risk-benefit assessment by the Investigator 
2 
Obtain a neurology consultation 
3 
Perform laboratory assessments (complete blood count [CBC] with differential, serum blood urea 
nitrogen [BUN], and creatinine) 
4 
Consider cardiac echocardiogram (trans-esophageal as appropriate) to evaluate for potential source of 
emboli 
Abbreviations: CVA = cerebrovascular accident; DWI = diffusion-weighted imaging; MRI = magnetic resonance 
imaging; TIA = transient ischemic attack. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Protocol16-214-02 
Nektar Therapeutics 
STATISTICAL ANALYSIS PLAN 
A PHASE 1/2, OPEN-LABEL, MULTICENTER STUDY OF THE COMBINATION OF 
NKTR-214 AND NIVOLUMAB OR THE COMBINATION OF NKTR-214, NIVOLUMAB, AND 
OTHER ANTI-CANCER THERAPIES IN PATmNTS WITH SELECT LOCALLY 
ADVANCED OR METASTATIC SOLID TUMOR MALIGNANCIES 
Nektar Therapeutics 
Confidential and Proprietary 
Protocol Number: 16-214-02 
Amendment 7.0 (11 February 2020) 
SAP Version: Version 1.0 
Date: 02 March 2021 
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Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


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4) 


Statistical Analysis Plan 
Protocol16-214-02 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................. 3 
LIST OF ABBREVIATIONS AN'D ACRONYMS ..................................................................... 7 
1.0 
INTRODUCTION ............................................................................................................ lO 
2.0 
STUDY O.B.JECTIVES .................................................................................................... lO 
2.1 
Primary Objectives ................................................................................................. I 0 
2.2 
Secondary Objective .............................................................................................. 10 
 
 
3.0 
STUDY DESIGN .AN'D PL.AN' ........................................................................................ 11 
3.1 
Study Design .......................................................................................................... 11 
3.2 
Study Population .................................................................................................... 11 
3.3 
Study Medications ................................................................................................. 11 
3.4 
Study Schematic ..................................................................................................... 13 
4.0 
STUDY ENDPOINTS ...................................................................................................... 15 
4.1 
Primary Endpoints ................................................................................................. 15 
4.2 
Secondary Endpoints ............................................................................................. 15 
 
 
5.0 
STATISTICAL CONSIDERA.TIONS ........................................................................... 15 
5.1 
General Analysis Considerations and Definitions ................................................. 15 
5.2 
Determination of Sample Size ............................................................................... 16 
5.3 
Cohort Assignment ................................................................................................ 21 
5.4 
Analysis Populations .............................................................................................. 22 
5.5 
Handling of Missing Data ...................................................................................... 23 
5.5 .1 
Prior and Concomitant Medication ....................................................... 23 
5.5.2 
Cancer History and Prior Systemic Cancer Therapy ............................ 24 
5.5.3 
New Anti-Cancer Therapy .................................................................... 24 
5.5.4 
Adverse Events ...................................................................................... 24 
5.5.5 
Death ..................................................................................................... 25 
5.5.6 
Other imputation ................................................................................... 26 
6.0 
MAL YTIC DEFIN"ITIONS ........................................................................................... 26 
6.1 
General Defmition ................................................................................................. 26 
6.2 
Baseline Characteristics ......................................................................................... 26 
6.3 
Exposure ................................................................................................................ 26 
7.0 
STATISTICAL .AN'AL YSES .......................................................................................... 28 
7.1 
Subject Disposition ................................................................................................ 28 
7.2 
Protocol Deviations ................................................................................................ 28 
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Bempegaldesleukin (NKTR-214)


Statistical Analysis Plan 
Protocol16-214-02 
7.3 
Demographic and Baseline Characteristics ........................................................... 29 
7.4 
Cancer llistory ....................................................................................................... 30 
7.5 
Prior Anti-Cancer Therapy .................................................................................... 30 
7.6 
Medicalllistory and Prior Cancer Related Surgery .............................................. 31 
7. 7 
Prior, Concomitant and Follow-up Radiotherapy ................................................. .31 
7.8 
Prior and Concomitant Medications and Procedures ............................................. 31 
7.9 
Immune Modulating Medication ........................................................................... 31 
7.10 
Subsequent Cancer Therapy .................................................................................. 32 
7.11 
Study Exposure and Follow-Up ............................................................................. 32 
7.12 
Efficacy Analysis ................................................................................................... 32 
7.12.1 
Best Overall Response, Objective Response Rate, and Clinical Benefit Rate 
7.12.2 
7.12.3 
7.12.4 
7.12.5 
7.12.6 
............................................................................................................... 32 
Time to Response .................................................................................. 33 
Duration ofResponse ............................................................................ 33 
Progression Free Survival ..................................................................... 34 
Overall Survival .................................................................................... 34 
Current Status ofPFS and OS Follow-Up ............................................ 34 
7.12.7 
SubgroupAnalysis ................................................................................ 35 
7.13 
Safety Analyses ...................................................................................................... 36 
7.13.1 
Dose Limiting Toxicities ....................................................................... 36 
7.13.2 
Adverse Events ...................................................................................... 36 
7.13.3 
Adverse Events of Special Interest for Checkpoint Inhibitors ............. .38 
7.13.4 
7.13.5 
7.13.6 
7.13.7 
7.13.8 
Adverse Events of Special Interest to Bempegaldesleukin .................. .41 
Deaths .................................................................................................... 48 
Clinical Laboratory Evaluation ............................................................ .48 
Vital Signs ............................................................................................. 49 
Electrocardiogram. ................................................................................. 49 
8.0 
IMM'UN OG ENI CITY ..................................................................................................... 58 
8.1 
General Analysis Considerations .......................................................................... .50 
8.2 
Immunogenicity Measurements and Endpoints ..................................................... 50 
8.3 
Safety Evaluation of ADA ..................................................................................... 51 
8.4 
Definitions .............................................................................................................. 51 
 
 
 
 
 
 
 
 
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16.1.9 Documentation of Statistical Methods 
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Bempegaldesleukin (NKTR-214)


Statistical Analysis Plan 
Protocol16-214-02 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
l 0.0 
PHARMACOKINETICS ..•.....•.....•......•.....•.....•......•.....•.....•.....••.....•.....•.....•......•.....•..... 60 
10.1 
Objectives of the Pharmacokinetic Analysis ......................................................... 60 
10.1.1 
Pharmacokinetic Analysis Set (PKAS) ................................................. 61 
10.2 
General Analysis Considerations and Definitions ................................................. 61 
10.2.1 
Pharmacokinetic Parameters ................................................................. 61 
10.3 
Pharmacokinetic Measurements and Endpoints .................................................... 62 
10.3.1 
Presentation of Individual and Mean Data ............................................ 62 
11.0 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ..•...•..•..•..•..•..•..•...•..•..•..•..•..• 63 
12.0 
REFERENCES ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 63 
13.0 
APPENDICES .•..•..•..•..•..•..••..•..•..•..•..•..•...•..•..•..•..•..•..•...•..•..•..•..•..•..••..•..•..•..•..•..•...•..•..•.. 66 
APPENDIX 1: EVALUATION OF OVERALL RESPONSE USING RECIST 1.1 ••••••••••• 66 
APPENDIX 2: COHORT GROUPS IN THE FINAL ANALYSIS •..••..•..•..•..•..•..•...•..•..•..•.. 67 
APPENDIX 3: TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-MEDIATED 
ADVERSE EVENTS AND EVENTS OF INTEREST ................................................. 71 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


Statistical Analysis Plan 
LIST OF TABLES 
Table 1: 
Table 2: 
Table 3: 
Table 4: 
Table 5: 
Table 6: 
Table 7: 
 
 
 
Table 11: 
Table 12: 
Table 13: 
LIST OF FIGURES 
Figure 1: 
Figure 2: 
Protocol16-214-02 
True (Target) and Historic Objective Response Rate for Each Indication in 
Part 2 .......................................................................................................... 18 
True (Target) and Historic Objective Response Rate for Each Indication in 
Parts 3 and 4 ............................................................................................... 21 
Calculation of Actual Dose Intensity and Relative Dose Intensity for Each 
Study Medication ....................................................................................... 27 
Censoring Rules for Progression Free Survival ......................................... 34 
Summary of AE Based Analyses for Other AESI .................................... .46 
ADA Status: Individual Samples ............................................................... 51 
ADA Response Categories: Patient Leve1 ............................................... .53 
 
 
 
Pharmacokinetic Parameter Definitions .................................................... 61 
Noncompartmental Analysis Requirements .............................................. 62 
Derivation of Clustered AE ....................................................................... 72 
Study Schematic for Part I Dose Escalation and Part 2 Dose Expansion .13 
Study Schematic for Triplet Part 3 Schedule Finding and Part 4 Dose 
Expansion ................................................................................................... 14 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


Statistical Analysis Plan 
Acronym/Abbreviation 
lL 
2L 
3L 
ADA 
AE 
AJCC 
ALK 
ALT(SGP1) 
AST(SGOT) 
ATC 
AUC 
BAS 
BL 
BLQ 
BMI 
BOR 
BRAF 
BSA 
ClDl, C2Dl, C3Dl, etc. 
CBR 
cis 
CL 
Cm.x 
CR 
CRC 
CTCAE 
CTLA-4 
cv 
CVA 
DLT 
DOR 
ECG 
ECLA 
ECOG 
eCRF 
EDC 
EGFR 
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Confidential and Proprietary 
Protocol16-214-02 
LIST OF ABBREVIATIONS AND ACRONYMS 
Defmition 
fli'St line 
second line 
tbirdline 
anti-drug antibody 
adverse event 
American Joint Committee on Cancer 
anaplastic lymphoma kinase 
alanine aminotransferase (senun glutamic pyruvic transaminase) 
aspartate aminotransferase (senun glutamic oxaloacetic transaminase) 
anatomical therapeutic chemical 
area under the curve 
biomarker analysis set 
Baseline 
below the limit of quantification 
body mass index 
best overall response 
proto-oncogene B-Raf 
body surface area 
Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, etc. 
clinical benefit rate 
Cisplatin 
Clearance 
maximum observed concentration/Maximum observed count 
complete response 
colorectal carcinoma 
Common Terminology Criteria for Adverse Events 
cytotoxic T lymphocyte-associated protein 4 
coefficient of variation 
cerebrovascular accident 
dose-limiting toxicity 
duration of response 
electrocardiogram 
electrochemiluminescence assays 
Eastern Cooperative Oncology Group 
electronic case report form 
electronic data capture 
epidermal growth factor receptor 
Page 7 of72 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Acronym/Abbreviation 
EOS 
EOT 
FDA 
FNR 
FPR 
GCP 
GGT 
HR 
ICH 
IL-2 
imAE 
I-0 
irRECIST 
IRT 
N 
KM 
LDH 
MCV 
MedORA 
MEL 
mg 
MSI 
MTD 
N1 
N2 
NCA 
NCI 
NK 
NKTR-214-AC 
NKTR-214-RC 
NSCLC 
ORR 
OS 
PD 
PD-1 
PD-L1 
PEG 
PFS 
Nektar Therapeutics 
Confidential and Proprietary 
Protocol16-214-02 
Defmition 
end of study 
end of treatment 
Food and Drug Administration 
false-negative rate 
false-positive rate 
Good Clinical Practice 
gamma-glutamyl transferase 
hormone receptor 
International Council for Harmonisation 
interleukin-2 
immune-mediated adverse event 
immuno-oncology 
immune-related Response Evaluation Criteria in Solid Tumors 
interactive response technology 
Intravenous 
Kaplan-Meier 
lactate dehydrogenase 
mean corpuscular volume 
Medical Dictionary for Regulatory Activities 
Melanoma 
Milligram 
microsatellite instability 
maximum tolerated dose 
sample size at stage 1 
sample size at stage 2 
noncompartmental analysis 
National Cancer Institute 
natural killer 
NKTR-214 active cytokine metabolites 
NKTR-214 related cytokines 
non-small cell lung cancer 
objective response rate 
overall survival 
progressive disease 
programmed cell death protein 1 
programmed cell death ligand 1 
polyethylene glycol 
progression-free survival 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Acronym/Abbreviation 
PK 
PKAS 
PR 
PT 
q2w 
q3w 
q4w 
q6w 
QTcF 
RCC 
RECIST 
RP2D 
Sl 
S2 
SAE 
SAP 
SD 
SCLC 
soc 
Tl 
T2 
T,/2 
T3 
T4 
TEAE 
TIL 
TIA 
Tmox 
TNBC 
TTR 
WHODDE 
Nektar Therapeutics 
Confidential and Proprietary 
Protocol16-214-02 
Defmition 
pharmacokinetic/s 
pharmacokinetic analysis set 
partial response 
preferred term 
every 2 weeks 
every 3 weeks 
every 4 weeks 
every 6 weeks 
Fridericia's corrected QT interval 
renal cell carcinoma 
Response Evaluation Criteria in Solid Tumors 
recommended Phase 2 dose 
futility boundary at stage I 
futility boundary at stage 2 
serious adverse event 
statistical analysis plan 
stable disease 
small-cell lung cancer 
system organ class 
efficacy boundary at stage I 
efficacy boundary at stage 2 
terminal elimination phase half-life 
Triiodothyronine 
free thyroxine 
treatment-emergent adverse event 
tumor-infiltrating lymphocyte 
transient ischemic attack 
time to maximum concentration/Time to reach maximum count 
triple-negative breast cancer 
time to response 
World Health Organization Drug Dictionary Enhanced 
Page 9of72 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Protocol16-214-02 
1.0 
INTRODUCTION 
Ibis statistical analysis plan (SAP) outlines the statistical methods to be implemented during the 
analyses of the data collected within the scope ofNektar Therapeutics Protocoll6-214-02 [A Phase 1/2, 
Open-label, Multicenter Study of the Combination ofNKTR-214 and Nivolumab or the Combination of 
NKTR-214, Nivolumab, and Other Anti-Cancer Therapies in Patients with Select Locally Advanced or 
Metastatic Solid Tumor Malignancies] Amendment 7.0 dated 11 February 2020. The purpose of this 
SAP is to provide details on the planned statistical analyses of the efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity data. Any deviations from the SAP will be documented in the 
clinical study report (CSR). 
Ibis Phase 1/2 study is conducted in accordance with the protocol, Good Clinical Practice (GCP), and 
all applicable regulatory requirements. Ibis SAP was written with consideration of the 
recommendations outlined in the International Council for Harmonization (ICH) E9 Guideline entitled 
"Statistical Principles for Clinical Trials". 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
• 
To evaluate the safety and tolerability, and define the maximum tolerated dose (MTD) and/or 
recommend Phase 2 dose (RP2D) ofNKTR-214 in combination with nivolumab or in combination 
with nivolumab and other anti-cancer therapies 
• 
To evaluate the efficacy ofNKTR-214 in combination with nivolumab or in combination with 
nivolumab and other anti-cancer therapies by assessing the objective response rate (ORR) by 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) at the RP2D 
2.2 
Secondary Objective 
• 
To evaluate the efficacy ofNKTR-214 in combination with nivolumab or in combination with 
nivolumab and other anti-cancer therapies by assessing overall survival (OS), progression-free 
survival (PFS), clinical benefit rate (CBR), and duration of response (DOR) 
 
 
 
 
 
 
 
 
 
 
 
 
 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


Statistical Analysis Plan 
Protocol16-214-02 
 
 
 
 
 
 
 
3.0 
STUDY DESIGN AND PLAN 
3.1 
Study Design 
This is a Phase 1/2, open-label, multicenter, dose escalation, and dose expansion study ofNKTR-214 in 
combination with nivolumab or in combination with nivolumab and other anti-cancer therapies in 
patients with locally advanced or metastatic solid tumor malignancies who have measurable disease 
including locally advanced or metastatic melanoma, renal cell carcinoma (RCC), non-small cell lung 
cancer (NSCLC), urothelial carcinoma, triple-negative breast cancer (TNBC), hormone-receptor positive 
breast cancer, gastric cancer, colorectal cancer (CRC), or small cell lung cancer (SCLC). The study 
design consists of four parts: dose escalation (Part 1) for the combination ofNKTR-214 and nivolumab, 
dose expansion (Part 2) for the combination ofNKTR-214 and nivolumab with/without other 
anti-cancer therapies, and dose escalation or schedule finding (Part 3) and dose expansion (Part 4) for 
NKTR-214 in combination with nivolumab and ipilimumab. 
The study is divided into a Screening period, Treatment period, End of Treatment period, and 
Long-Term Follow-up period. Patients will receive treatment depending on the study period and the 
cohort into which they are enrolled. Cohorts are classified by indication and further sub-classified by 
line of therapy and type of most recent anti-cancer treatment received (See Figure 1 and Figure 2 in 
Section 3.4 and Appendix 2). Treatment cycle is defined by the frequency ofNKTR-214 administration. 
3.2 
Study Population 
Adults aged 18 years and older with select locally advanced or metastatic solid tumor malignancies who 
have measurable disease with melanoma, RCC, NSCLC, urothelial carcinoma, TNBC, 
hormone-receptor positive breast cancer, gastric cancer, CRC, or SCLC. 
3.3 
Study Medications 
In the doublet dose escalation phase (i.e., Part 1 of the study), the 3 + 3 design was used to investigate 
NKTR-214 at a dose level 0.006 mglkg q2w or q3w and 0.009 mglkg q3w in combination with 
nivolumab at a dose level of240 mg q2w or 360 mg q3w in various solid tumor malignancies. Other 
dose levels and dosing frequencies ofNK.TR-214 may also have been evaluated. 
In the triplet dose escalation phase (i.e., Part 3 of the study), NKTR-214 0.006 mglkg q3w was evaluated 
in combination with nivolumab and ipilimumab at 3 different dosing schedules. Additional patients may 
have been enrolled into the dose escalation cohorts in Part 1 or Part 3. 
In the dose expansion phases, the doublet and triplet regimens (i.e., Part 2 and Part 4 of the study, 
respectively) were evaluated in various solid tumor malignancies to further evaluate the safety and 
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Statistical Analysis Plan 
Protocol16-214-02 
efficacy of the treatment combinations. In Part 2, NK.TR-214 0.006 mg/k.g q3w and nivolumab 360mg 
q3w was administered in combination with other anti-cancer therapies for selected solid tumor 
malignancies. In Part 4, NK.TR-214 0.006 mg/k.g q3w was evaluated in combination with nivolumab 
and ipilimumab at the 3 different dosing schedules from Part 3. 
Each patient's NKTR-214 dose was determined by the NK.TR-214 dose escalation scheme and the 
patient's weight in kilograms, which was determined before the start of each cycle. Depending on 
institutional guidelines/preferences, if the patient's weight was within 10% of the Cycle I Day 1 weight, 
the study drug doses may not have been recalculated. NKTR-214 was administered intravenously (IV). 
NK.TR-214 was administered before nivolumab, ipilimumab, or other anti-cancer therapy. 
In case ofNKTR-214 drug-related toxicities requiring dose delays, reductions or discontinuation, 
nivolumab or ipilimumab could continue in the absence of nivolumab-related or ipilimumab-related 
toxicities. If the NK.TR-214 dose was reduced to 0.003 mg/k.g, the dose remained at this level 
throughout the remainder of the study. Dose delays were also permitted for nivolumab and ipilimumab, 
but dose reductions were not permitted. 
Patients were treated until disease progression, death, unacceptable toxicity, symptomatic deterioration, 
achievement of maximal response or up to 2 years to therapy, the Investigator's decision to discontinue 
treatment, patient decision to discontinue treatment or withdraw consent, the patient was lost to follow-
up, or Nektar Therapeutics decision to terminate the trial. Patients with progressive disease (PD) per 
RECIST 1.1, but with otherwise stable or improved performance and clinical status, may have continued 
treatment in the event that the Investigator perceived benefit provided the patients met the protocol-
defmed criteria. 
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Statistical Analysis Plan 
Protocol16-214-02 
3.4 
Study Schematic 
Figure 1: 
Study Schematic for Part 1 Dose Escalation and Part 2 Dose Expansion 
Part l -Dose Escalation 
I 
Part 2 -Dose Expansion 
Melanoma 
Cohort Ia: IL 
,-----. Cohort lb: 2-3L, anti-PD-1 or anti-PD-Ll relapse/refractory 
Cohort lc: 2L, BRAF wild type, anti-PD-1 or anti-PD-Ll relapse/refractory 
Cohort l d: IL, following prior adjuvant therapy 
Cohort le: patients enrolled under an earlier protocol version who are no longer eligible for Cohorts Ia to Jd 
Renal Cell Cancer 
Cohort 2a: IL 
f-------+ Cohort 2b: 2L, anti-PD-1 or anti-PD-Ll relapse/refractory 
Cohort 2c: patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 2a or 2b 
Non-Small Cell Lung Cancer 
Cohorts 3a.l to 3a.4: IL, PD-Ll negative, PD-Ll low/intermediate, PD-Ll positive, or PD-Ll unknown, respectively' 
Melanoma, 
~I r 
Cohort 3b: 2L, I-0 therapy naive following platinum-based therapy 
RCC, 
MTDor 
Cohort 3c: 2-3L, anti-PD-1 or anti-PD-Ll relapse/refractory 
NSCLC, 
RP2D 
Cohort 3d. I : lL, nonsquamous in combination with platinum/pemetrexed) (+maintenance pemetrexed) 
Urothelial 
f-------. 
Cohort 3d.2: IL, nonsquarnous in combination with platinum/pemetrexed) (no maintenance pemetrexed) 
Carcinoma~ 
Cohort 3e: lL, squamous in combination with platinum/ta.xane 
orTNBC 
Cohort 3f: 3L +, ALK-translocation/ROSJ rearrangement positive 
Cohort 3g: 3L +, EGFR mutation/deletion 
Cohort 3h: 2L, following platinum-based doublet cytotoxic chemotherapy combined with anti-PD-1 
Cohort 3i: patients enrolled under an earlier protocol version who are no longer eligible for Cohorts 3a to 3h 
Urothelial Cancer 
Cohort 4a: JL, cisplatin-ineligible or refused standard of careb 
f-------. Cohort 4b: 2-3L, anti-PD-1 or anti-PD-Ll relapse/refractory 
Cohort 4c: patients enrolled under an earlier protocol version who are no longer eligible for Cohons 4a or 4b 
Triple-Negative Breast Cancer 
Gastric/GastroesophageaJ 
Cohort Sa: I-2L. 1-0 therapy naive 
Cohort 7: 2-3L, 1-0 therapy naive 
f-------. Cohort Sb: 1-2L, I-0 therapy naive in combination with nab-paclitaxel 
Cohort 5c: 1-2L, 1-0 therapy naive in combination with eribulin 
Colorectal Cancer 
Cohort Sa: 2-3L, I-0 therapy naive, MSI-rugh 
Hormone-Receptor Positive HER2- Breast Cancer 
Cohort Sb: 3-4L, I-0 therapy naive, MSI-non-high 
r-------+ Cohort 6a: I-0 therapy naive following hormonal therapy 
Small Cell Lung Cancer 
Cohort 6b: I-0 therapy naive follo\¥iug hormonal and cytotoxic therapy 
Cohort 9: 2L~ I-0 therapy naive 
HR + = hormone-receptor positive; 1-0 = immuno-oncology; L = line; MSI = microsatellite instability; MID = maximum tolerated dose; 
NSCLC = non-small cell lung cancer; RCC = renal cell carcinoma; RP2D = recommended Phase 2 dose; SOC = standard of care; TNBC = 
triple-negative breast cancer 
a. 
Up to 20 efficacy-evaluable NSCLC patients will be enrolled in each cohort ofPD-Ll negative, PD-Ll 
low/intermediate, or PD-Ll positive. Patients enrolled in Cohort 3a who do not have a PD-Ll status assessed by 
central testing will be assigned to Cohort 3a.4. 
b. 
Up to 20 urothelial carcinoma IL patients who are cisplatin-ineligible and (for countries other than Italy) up to 20 patients 
who choose to forego standard of care. 
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Statistical Analysis Plan 
Protocol Hi-214--02 
Figure 2: 
Study S~hemati~ for Triplet Part 3 S~hedule Finding and Part 4 Dose 
Expansion 
RCC, 
NSCLC, 
Melanoma, 
or Urothelial 
Part 3 -Schedule Finding for Triplet 
a. 
If administration of all3 study drugs on the SIUile day in Cohort A meets criteria listed in Section 5.3.5 of the study protocol. 
Cohort B may be initiated. where ipilimumab will be staggered to be administered at a later cycle (e.g., Cycle•3 Day• 1) 
b. In Part 3, the RP2Ds will be established for each of the 3 dosing schedules (it may be necessary for a separate RP2D to be 
established for patients with melanoma and urothelial cancers, if the tolerability is different between these 2 groups). 
c. 
Includes patients from both Part 3 and Part 4. 
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Statistical Analysis Plan 
Protocol16-214-02 
4.0 
STUDY ENDPOINTS 
4.1 
Primary Endpoints 
In Part 1 and Part 3, the primary endpoint is the incidence of dose limiting toxicity (DL n during the 
DL T evaluation window. 
For efficacy, the primary endpoint is ORR per RECIST 1.1 at RP2D. 
4.2 
Secondary Endpoints 
For safety, the secondary endpoints include: 
• 
Incidence of adverse events (AEs) 
• 
Incidence of serious adverse events (SAEs) 
• 
Incidence of Grade 3 or above adverse events (AEs) 
• 
Incidence of clinically significant laboratory abnormalities, vital signs, electrocardiography (ECG), 
and physical exams. 
For efficacy at RP2D, the secondary endpoints include: 
• 
Best overall response (BOR) using RECIST 1.1. 
• 
Time to response (TTR) using RECIST 1.1 
• 
DOR using RECIST 1.1 
• 
CBR using RECIST 1.1 
• 
PFS using RECIST 1.1 
• 
OS 
 
 
 
 
 
 
 
 
5.0 
STATISTICAL CONSIDERATIONS 
5.1 
General Analysis Considerations and Definitions 
The statistical analyses will be reported using summary tables, figures, and data listings. Data listings 
will be presented by treatment group and patient identification number. Unless otherwise specified, data 
collected during the Part 1 will be presented by dose and overall for Part I patients. Data collected from 
patients who are dosed at the RP2D level in Part 1 and Part 2 will be combined and presented by tumor 
indication and cohort (see Appendix 2 for more details). Data collected from Parts 3 and 4, dose finding 
and expansion phases for the triplet combination respectively, will be combined and presented by tumor 
indication and dosing schedule. 
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Statistical Analysis Plan 
Protocol16-214-02 
Because of the nature of basket trial design and the evolving landscape, some indications have been 
further classified and/or re-classified into sub-indications through protocol amendments. Therefore, 
patients to be reported in the same cohort may have different diagnoses/sub-diagnoses in the cancer 
history CRF form depending on the protocol version and study phase under which they are enrolled. For 
statistical analysis purposes, the final classification of cohorts is provided in the Appendix 2. 
Summary statistics for continuous variables will include the mean, standard deviation, median, 
minimum, and maximum. The mean will be presented to one decimal place beyond which the data were 
captured. The standard deviation will be presented to two decimal places beyond which the data were 
captured. The minimum and maximum will be presented to the precision with which the data were 
captured. 
Categorical variables will be presented by frequency counts and percentages. A row or column denoted 
'Missing' will be included in count tabulations where necessary to account for dropouts and missing 
values. Percentages will be rounded to one decimal place and the percent will be suppressed when the 
count is zero. The denominator will be the number of patients in that dose cohort/tumor type within the 
population of interest unless otherwise noted. 
Time-to-event variables will be analyzed using the Kaplan-Meier (KM) method. The number and 
percentage of patients with events or censored will be presented. The KM estimates for quartiles (i.e., 
25%, median, and 75%) and 95% confidence interval using log(-log(s(t))) transformation with 
Greenwood's formula for variance for the median will be presented. All time to event variables will be 
plotted using the KM method with censoring and risk set displayed. 
All data will be listed, including data collected from the electronic case report form ( eCRF) and derived 
for statistical analysis. Unless otherwise specified, incomplete data will not be imputed in the listing. 
No formal statistical hypothesis testing is planned. All statistical analyses will be carried out using SAS® 
version 9.4 or later (Statistical Analysis System software, SAS Institute, North Carolina, USA) unless 
otherwise noted. 
5.2 
Determination of Sample Size 
During Part 1, cohorts of at least 3 patients were treated at each dose level. Additional patients were 
added to each dose cohort based on the scheme and rules outlined in the protocol or Sponsor 
determination of the need for additional data to further evaluate the benefit/risk profile. Approximately 
50 patients were to be enrolled into the Part 1 dose escalation phase. 
During Part 3, cohorts of at least 6 patients were enrolled into each of the 3 concurrent dosing schedules 
as listed in the protocol. Additional patients were added to each dose schedule based on the scheme and 
rules outlined in the protocol or the Sponsor's determination of the need for additional data to further 
evaluate the benefit/risk profile. Based on emerging safety and biomarker data from the concurrent 
dosing schedules, patients may have enrolled into staggered dosing, where ipilimumab was staggered to 
be administered at a later cycle (e.g., Cycle 3 Day 1). Approximately 36 patients were to be enrolled into 
the Part 3 dose-escalation phase. 
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Statistical Analysis Plan 
Protocol16-214-02 
During Parts 2 and 4, the sample size was calculated based on the target ORR relative to historic 
response rate. The Fleming 2-stage design (Fleming, 1982) framework was used as a guide. The total 
sample size (including patients dosed at the RP2D from the dose escalation phase of Part 1) for each 
expansion cohort was calculated using a normal approximation to provide a reasonable false-positive 
rate (FPR < 10%) and false-negative rate (FNR < 10%) based on assumptions of true (target) and 
historic ORR for each indication Table 1 and Table 2). The historic and target response rate 
assumptions may have changed over time and may have been adjusted at the time the response data 
from this study were available. The 2-stage design provided an option to stop early for futility as well as 
allowing an early start for Phase 3 preparation if a strong antitumor activity signal was observed. 
However, the final decision was to be based on the totality of overall treatment effect for multiple study 
endpoints and their associations with the tumor response rate. Enrollment may have continued into Part 
2 while the planned number of patients for Part 1 were followed for tumor assessments. There was to be 
no stopping of enrollment to a tumor cohort for efficacy, although early planning for the next stage of 
clinical development may have been initiated. 
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Statistical Analysis Plan 
Protocoll6-214-02 
Table 1: 
True (Target) and Historic Objective Response Rate for Each Indication in Part 2 
Cohort• 
Indication 
1a 
MEL1L 
1b 
MEL 2-3L, 1-0 relapse/ refractory 
1c 
MEL 2L BRAF wild type 1-0 
relapse/ refractory 
1d 
MEL 1L following prior adjuvant 
therapy 
2a 
RCC1L 
2b 
RCC 2-3L, 1-0 relapse/ refractory 
3a 
NSCLC regardless ofPD-Ll 
expression 
3a.1 
NSCLC 1L PD-L1 < 1% 
3a.2 
NSCLC 1L PD-Ll ~ 1 %-< 50% 
3a.3 
NSCLC 1L PD-Ll ~ 50% 
3b 
NSCLC 2L, 1-0 therapy naive 
following platinum-based therapy 
3c 
NSCLC 2L, 1-0 relapse/refractory 
3d.1 
NSCLC, 1L nonsquamous in 
combination with 
platinum/pemetrexed 
( + maintenance pemetrexed) 
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Objective Response Rate(%) 
Historical 
Target 
40 
65 
10 
30 
10 
30 
10 
30 
25 
50 
5 
25 
23 
45 
8 
30 
14 
40 
25 
55 
20 
40 
5 
20 
45 
66 
Sample Sizeb 
Futility 
N1 
N2 
Total 
S1 
S2 
13 
15 
28 
~5 
~ 14 
15 
11 
26 
~1 
~5 
15 
11 
26 
~1 
~5 
16 
12 
28 
~1 
~5 
11 
15 
26 
~2 
~9 
15 
11 
26 
~0 
~3 
16 
18 
34 
$1 
~11 
12 
8 
20 
~0 
~3 
8 
10 
18 
~0 
~4 
11 
9 
20 
~3 
~7 
20 
16 
36 
~4 
~ 10 
12 
25 
37 
~0 
$1 
20 
19 
39 
~9 
~21 
Efficacy 
T1 
T2 
~ 10 
~ 15 
~4 
~6 
~4 
~6 
~4 
~6 
~6 
~ 10 
~3 
~4 
~7 
~12 
~3 
~4 
~4 
~5 
~6 
~8 
~8 
~11 
~3 
~4 
~ 14 
~22 
Reference for Historical 
ORR Assumption 
Robert, 2015 
Unmet medical need 
Unmet medical need 
Nomura, 2017; 
Weber, 2013 
Topalian, 2012 
Unmet medical need 
Garon 2015; Gettinger 2016; 
Carbone, 2017 
Garon, 2015; Carbone, 2017 
Brahmer, 2015 
Unmet medical need 
Gandhi, 2018 
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Statistical Analysis Plan 
Protocoll6-214-02 
Table 1: 
True (Target) and Historic Objective Response Rate for Each Indication in Part 2 (Contd) 
Cohort• 
Indication 
3d.2 
NSCLC, 1L nonsquamous 
(no maintenance pemetrexed) 
3e 
NSCLC 1L squamous in 
combination with platinumltaxane 
3f 
3L+ NSCLC ALK-translocation/ 
ROS 1 rearrangement positive 
3g 
3L+ NSCLC, EGFR 
mutation/deletion 
Urothelial1L Cis-ineligible 
4a 
Urothelial1L (refused standard of 
care) 
4b 
Urothelial2-3L, 1-0 relapse/ 
refractory 
Sa 
lNBC 1-2L, 1-0 therapy naive 
5b 
lNBC 1-2L, 1-0 therapy 
naive + nab-paclitaxel 
Sc 
lNBC 1-2L, 1-0 therapy 
naive + eribulin 
6a 
HR.+ breast cancer, 1-0 therapy 
naive following hormonal therapy 
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Objective Response Rate(%) 
Historical 
Target 
N1 
45 
66 
20 
20 
40 
20 
5 
20 
12 
5 
20 
12 
16 
45 
10 
16 
45 
10 
5 
25 
13 
10 
26 
21 
24 
45 
20 
20 
40 
20 
25 (cytotoxic 
45 
18 
chemo-therapy) 
5% (for single 
agentCPI) 
20 
12 
Sample Sizeb 
Futility 
Efficacy 
N2 
Total 
S1 
S2 
T1 
T2 
19 
39 
~9 
~21 
~ 14 
~22 
16 
36 
~4 
~ 10 
~8 
~11 
25 
37 
~0 
9 
~3 
~4 
25 
37 
~0 
9 
~3 
~4 
8 
18 
~1 
~5 
~4 
~6 
8 
18 
~1 
~ 
~4 
~6 
7 
20 
0 
~ 
~3 
~3 
17 
38 
~1 
~6 
~5 
~7 
18 
38 
~5 
~ 12 
~9 
~ 13 
16 
36 
~4 
~ 10 
~8 
~11 
21 
39 
~5 
~ 14 
~9 
~ 15 
25 
37 
0 
~3 
~3 
~4 
Reference for Historical 
ORR Assumption 
Gandhi, 2018 
Rizvi, 2016 
Unmet medical need 
Unmet medical need 
Balar, 2017 
Patel, 2018 
Schmid, 2017 
Forero-Torres, 2015; 
Gradishar, 2005 
Kaufman, 2015; 
Mcintyre, 2014 
Harris, 2006; 
Twelves, 2014 
Rugo 2016; 
Dirix 2018 
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Statistical Analysis Plan 
Protocoll6-214-02 
Table 1: 
True (Target) and Historic Objective Response Rate for Each Indication in Part 2 (Contd) 
Objective Response Rate(%) 
Sample Sizeb 
Futility 
Efficacy 
Reference for Historical 
Cohort• 
Indication 
Historical 
Target 
N1 
N2 
Total 
S1 
S2 
T1 
T2 
ORR Assumption 
6b 
HR.+ breast cancer, 1-0 therapy 
20 (cytotoxic 
40 
20 
16 
36 
~4 
~ 10 
~8 
~11 
naive following hormonal and 
chemo-therapy) 
Harris, 2006; 
cytotoxic therapy 
Twelves, 2014 
5% (for single 
agentCPI) 
20 
12 
25 
37 
0 
~3 
~3 
~4 
Rugo 2016; 
Dirix 2018 
7 
Gastric carcinoma 2-3L, 
13 
30 
22 
15 
37 
~2 
~7 
~7 
~8 
Kang, 2017 
1-0 therapy naYve 
Sa 
CRC 2-3L, MSI-high, I-0 therapy 
30 
50 
26 
13 
39 
~7 
~ 15 
~ 13 
~ 16 
Overman, 2017 
narve 
8b 
CRC 3-4L, MSI-non-high, 1-0 
5 
20 
12 
25 
37 
~0 
~3 
~3 
~4 
Le, 2015 (mismatch repair 
therapy nal"ve 
proficient) 
BRAF =proto-oncogene B-Raf; cis = cisplatin; CPI =checkpoint inhibitor; CRC = colorectal carcinoma; EGFR = epidermal growth factor receptor; HR.+= hormone-receptor 
positive; 1-0 = immuno-oncology; L =line; MEL= melanoma; MSI = microsatellite instability; N1, N2 =sample size at stage 1, 2; NA =not available; ORR= objective response 
rate; NSCLC =non-small cell lung cancer; RCC =renal cell carcinoma; S1, S2 =futility boundary at stage 1, 2; Tl, T2 =efficacy boundary at stage 1, 2; TNBC =triple-negative 
breast cancer 
a. 
Cohort 3h is not included in this table but is discussed separately in the following paragraph. 
b. 
Total sample size for each expansion cohort is calculated using a normal approximation to provide a reasonable false-positive rate (FPR < 10%) and false-negative rate 
(FNR< 10%). 
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Statistical Analysis Plan 
Protocol16-214-02 
For efficacy assessment of Cohort 3h (patients with immuno-oncology relapsed-refractory NSCLC 
whose disease has progressed on combination therapy of anti-PD-llanti-PD-L1 with cytotoxic 
chemotherapy), the historical comparator was single-agent docetaxel which showed 9% overall response 
rate in a second-line NSCLC population (Herbst, 2016). With this historical control rate as the null 
hypothesis, using a two-sided alpha of 0.05, 100 patients provided over 90% power to demonstrate 
statistical significance if the response rate ofNKTR-214/nivolumab was 20% or more. If the observed 
response rate in this cohort was 18% or better, the lower bound of the 95% confidence interval would 
rule out a 10% response rate. 
Two interim analyses were to be conducted in Cohort 3h to gate the trial progression based on the 
Response Evaluable Population. The first interim evaluation was to be conducted when 20 evaluable 
patients had been followed for 4 months or terminated from the study. If 3 or more responses are 
observed, the trial may have continued to the next stage. The second interim analysis was to be 
performed when 40 evaluable patients had been followed for 4 months or terminated from the study. If 
there were 6 or more responders, the trial may have continued to enroll approximately 100 patients. 
Enrollment was to continue without pause during the conduct of the interim analyses. 
Approximately 936 patients were to be enrolled into Part 2. Additional patients may have been added to 
selected expansion cohorts to further evaluate the benefit/risk profile. 
Approximately 36 patients were to be enrolled into Part 3. 
Up to an additional106 patients were to be enrolled into Part 4. 
Table2: 
True (Target) and Historic Objective Response Rate for Each Indication in 
Parts3 and4 
Objective Response Rate 
Sample Size• 
Futility 
Efficacy 
Indication 
Historical 
Target 
Nl 
N2 
Total 
Sl 
S2 
Tl 
T2 
RCC1L 
25 
50 
11 
15 
26 
:S2 
:S9 
~6 
~ 10 
NSCLC 1Lb 
25 
50 
11 
15 
26 
:S2 
:S9 
~6 
~ 10 
Melanoma 1L 
40 
65 
13 
15 
28 
:S5 
:s 14 
~ 10 
~ 15 
Urothelial1L 
25 
50 
11 
15 
26 
:S2 
:S9 
~6 
~ 10 
Abbreviations: L =line; N1, N2 =sample size at stage 1, 2; NSCLC =non-small cell lung cancer; RCC =renal cell 
carcinoma; S1, S2 =futility boundary at stage 1, 2; Tl, T2 =efficacy boundary at stage 1, 2 
a. 
Total sample size for each cohort is calculated using a normal approximation to provide a reasonable FPR < 10% and 
FNR< 10%. 
b. 
Total sample size for 1L NSCLC is based on the assumption that a mixed population ofPD-L1 positive and negative 
patients will be enrolled. If unequal distribution of patients are enrolled, sample size may be modified accordingly. 
5.3 
Cohort Assignment 
lbis is an open-label, non-randomized study. The patient, Investigator and Sponsor were not blinded to 
the patient's treatment. Patients were assigned via interactive response technology (IRT) to each cohort 
based on the Investigator's assessment during the Screening period, prior to enrollment. The Sponsor 
reviewed and identified any discrepancies with the Investigator's cohort assignment. Patients assigned to 
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Statistical Analysis Plan 
Protocol16-214-02 
the incorrect cohort were reclassified or remapped to the appropriate cohort by the Sponsor (Appendix 
2). 
Patients enrolled in Parts 1 and 3 who did not complete the DL T observation period for reasons other 
than a DL T were to be replaced to provide a sufficient number of patients to support the dose escalation 
decision. Patients enrolled in Parts 2 and 4 who did not meet all eligibility criteria were replaced. 
5.4 
Analysis Populations 
All Enrolled Population: All patients enrolled into the study and assigned a patient identification 
number. 
Safety Population: All patients who receive at least 1 dose (or partial dose) of study drug. 
DL T Population: 
Part 1: All Part 1 patients meeting either of the following two criteria: 
1) Took study treatment and followed up at least through the DL T evaluation period depending on the 
dosing schedule listed below: 
a) For q2w dosing: patients received at least 2 cycles of study medication and stayed in the study 
for at least 28 days. 
b) For q3w dosing: patients received at least 1 cycle of study medication and stayed in the study for 
at least 21 days. 
or 
2) Discontinued from the study treatment due to DLT. 
Part 3: All Part 3 patients meeting either of the following two criteria: 
1) Patients received at least 1 cycle of study medication and stayed in the study for at least 21 days after 
first dose of ipilimumab. 
or 
2) Discontinued from the study treatment due to DLT. 
Response Evaluable Population: Patients who have measurable disease (per RECIST 1.1) at baseline 
and also have at least 1 post-baseline assessment of tumor response prior to receiving new systemic anti-
cancer therapy, surgical procedures or radiotherapy on target lesions. 
Pharmacokinetic Population: All patients in the Safety Population who have sufficient concentration-
time data to support computation of at least one PK parameter value. 
Immunogenicitv Population: All patients in the Safety Population with at least baseline and 
1 post-baseline ADA assessment. 
 
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Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


Statistical Analysis Plan 
Protocol16-214-02 
5.5 
Handling of Missing Data 
In order to sununarize and perform the statistical analyses~ missing or incomplete data will be imputed. 
Missing data will be handled as follows as described in Sections 5.5.1 through 5.5.6. 
5.5.1 
Prior and Concomitant Medication 
For determination of prior medication~ any medication with a start date prior to Cycle 1 Day 1 (C1D1) 
will be classified as prior medication regardless of the stop date. Missing or partial dates will be 
handled as follows: 
• 
If missing day and/or month of the start date, the medication will be classified as prior unless the 
month and/or year of the start date is after C1D1 
For determination of concomitant medication, the following will be classified as concomitant 
medication: 
• 
Any medication with a start date prior to or on C 1 D 1 and continued after C 1 D 1 
• 
Any medication with a start date after C 1 D 1, and prior to or on the last study dose + 1 00 days or 
(date of initiation of new antineoplastic regimen-1 day), whichever is earlier 
Missing or partial dates for concomitant medication will be handled as follows: 
• 
If missing day and/or month of the start date~ the medication will not be considered as concomitant if 
the month and/or year of the start date is after the last dose date + 100 days or (date of initiation of 
new antineoplastic regimen - 1 day), whichever is earlier 
• 
If missing day and/or month of the stop date, the medication will not be considered as concomitant if 
the month and/or year of the stop date is prior to C1D1 
• 
A medication with completely missing start and stop dates will be classified as concomitant 
Any medication with a start date prior to C1D1 and continued after C1D1 will be considered as both 
prior and concomitant medication. 
In order to calculate the duration of immune modulating medication for management of drug-related 
select AEs or imAEs, missing or partial dates for these medications will be handled as follows: 
Missing or partial start date: 
• 
If the start date is complete missing, it will not be imputed. Only the number of days that the 
medication was taken on or after the AE start date will be counted toward the duration of IMM for 
management of certain AE. 
• 
If only year is provided, impute the start date to January 1st of the year, 
• 
If only day is missing, impute the start date to the first day of the month. 
Missing or partial stop date: 
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Statistical Analysis Plan 
Protocol16-214-02 
• 
If the stop date is complete missing, impute stop date to last known alive date. 
• 
If only year is provided, impute the stop date to December 31 '1 of the year. If the imputed date is 
after the last known alive date, then set the stop date to the last known alive date. 
• 
If only day is missing, impute the stop date to the last day of the month. If the imputed date is after 
the last known alive date, then set the stop date to the last known alive date. 
5.5.2 
Cancer History and Prior Systemic Cancer Therapy 
In order to determine the time from initial diagnosis of primary cancer to C 1D I and time from initial 
metastasis diagnosis or most recent local recurrence to C 1 D I, the incomplete date of diagnosis will be 
imputed as follows: 
• 
If the year is missing, then the date of diagnosis will not be imputed, 
• 
If the day is missing but the month and year are not missing, then the date of diagnosis will be 
imputed as the frrst day of the month, 
• 
If both day and month are missing and the year is prior to the year ofC1D1, then the date of 
diagnosis will be imputed as 01 July, otherwise if the year is the same as the year ofC1D1, then the 
date of diagnosis will be imputed as 01 January. 
5.5.3 
New Anti-Cancer Therapy 
For new anti-cancer therapy, the incomplete start date will be imputed as follows: 
• 
Completely missing start dates will remain missing, with no imputation applied; 
• 
If the day is missing but the month and year are not missing: 
o If the end date of new anti-cancer therapy is complete: 
Minimum of (the last day of the month, end date of new anti-cancer therapy) 
o If the end date of new anticancer therapy is not complete: 
the last day of the month. 
• 
If both month and day are missing but year is not missing, then the date will be imputed as 
o If the end date of new anti-cancer therapy is complete: 
Maximum of (Minimum of (01 July+ partial year, end date of new anti-cancer therapy), 
C1D1 +I) 
o If the end date of new anticancer therapy is not complete: 
Maximum of(Ol July+ partial year, C1D1 + 1). 
5.5.4 
Adverse Events 
In order to determine the duration of AEs, incomplete start date of any AE will be imputed as follows: 
• 
Missing day, month, and year should be queried. 
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Statistical Analysis Plan 
Protocol16-214-02 
• 
If the start date of AE is completely missing, then the missing date will be imputed as the C 1 D 1 
date. 
• 
Start day of AE is missing and the year is same as C1D1 
If the reported month of occurrence of AE is after the month of C1D1 then missing day will be 
imputed as the first day of the month of occurrence of AE. 
If the reported month of occurrence of AE is the month of C 1D1 then the missing day will be 
imputed as the same day as C1Dl. 
If the reported month of AE start date is before the month of C 1D 1 then the missing day will be 
imputed as day 15 of the month of AE start date. This event is not a TEAE. 
If the month of AE start date is missing, missing day will be imputed as the date of C 1D1. 
• 
Start day of AE is missing and the year is after the year of C1D1 
Missing day will be imputed as the fust day of the month of occurrence of AE. 
If the month of AE start date is missing, missing day will be imputed as 01 January of the year of 
AE start date. 
For duration of AEs, partially missing dates for stop of AE will be imputed as follows: 
• 
Missing day, month, and year are not allowed and should be queried. In case of non-resolution of 
missing year, no imputation will be performed. 
• 
If only the day is missing, the last day of that month, the last known alive date, or the date of death, 
whichever is earliest, will be used as the stop date 
• 
If month and day are missing, then 31 December, the last known alive date, or the date of death, 
whichever is earliest, will be used as the stop date. 
5.5.5 
Death 
For death dates, the following conventions will be used for imputing partial dates: 
-
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known alive date and the maximum will be 
considered as the death date. 
-
If only the month and the day are missing, January 1st will be used to replace the missing 
month/day. The imputed date will be compared to the last known alive date and the maximum will 
be considered as the death date. 
-
If the date is completely missing but the reason for death is present, the death date will be imputed 
as the last known date alive. 
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Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Protocol16-214-02 
5.5.6 
Other imputation 
Some laboratory analytes may be reported by range (e.g., gamma-glutamyl transferase [GGT] < 17 UIL) 
and will be imputed by the boundary (e.g., 17 UIL). 
Handling of missing data for the efficacy analyses ofPFS, OS, and DORis described in Section 7.12. 
No imputation of other missing data is planned. 
6.0 
ANALYTIC DEFINITIONS 
6.1 
General Definition 
Age: due to regulatory restrictions, collection of complete date of birth data is not permitted at some 
sites. The age at screening will be collected via IRT, and will be used for analysis. No derivation will be 
performed. 
Baseline: unless medically justified and documented, baseline is defmed as the results collected at the 
last assessment on or before C 1 D 1 date and time (last assessment on or before C 1 D 1 date if time is not 
available). 
Study day: there is no study day zero. Date of C 1 D 1 is study day 1. For any events prior to C 1 D 1, the 
study day is derived as date of event minus date ofC1Dl. For any events after ClDl, the study day is 
defmed as date of event minus the date C 1 D 1 plus 1. 
Visceral disease: given the study will enroll patients across various tumor malignancies, there is no 
general definition for visceral disease. Visceral disease will be determined based on medical review for 
each specific tumor malignancy. 
6.2 
Baseline Characteristics 
Body mass index (BMI) (kg/m2) is defined as weight (kg)/ height2 (m2) 
Body surface area (BSA) will be calculated using the Mosteller formula (Mosteller, 1987): 
BSA (m2) ={ [height (em) x weight (kg) ]/3600 }112 
6.3 
Exposure 
The following parameters will be calculated for all study drugs: 
• 
Duration of regimen: Minimum(Cutoffdate, max(last dose date+ 20 days ifq3w/13 days ifq2w/41 
days if q6w for each study treatment, including NKTR-214, nivolumab, ipilimumab ), date of death, 
date of end of study)- C1D1 + 1 
• 
Duration of follow-up: Maximum (Min( date of last visit including survival follow-up, date of death) 
- C1D1 + 1, Duration of regimen) 
• 
Duration of exposure to each study treatment (days): date of last dose - date of first dose + 1 
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Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Protocol16-214-02 
• 
Number of cycles or doses for each study treatment (infusions): total number of cycles or doses 
(infusions) for which patient received treatment at planned or reduced (non-zero) level across all 
cycles. 
• 
Calculated cumulative dose level for treatment administrated: Total actual dose (mg/kg and mg) the 
patient received across all cycles, defined as the sum of actual doses (mg/kg and mg) received across 
all cycles. 
See Table 3 for calculation of actual dose intensity, expected dose intensity, and relative dose intensity. 
Table3: 
Calculation of Actual Dose Intensity and Relative Dose Intensity for Each 
Study Medication 
Study Drug and Dosing 
Regimen 
NKTR.-214 
- 0.003 mg/kg Q2W 
(Part 1 only) 
- 0.006 mglkg Q3W 
-0.006 mglkg Q2W 
(Part 1 only) 
- 0.009 mglkg Q3W 
(Part 1 only) 
Nivolumab 
- 240 mg flat dose Q2W 
(Part 1 only) 
- 360 mg flat dose Q3W 
-1 mg/kgQ3W 
-3mglkgQ3W 
Ipilimumab (Part 3 and Part 4 
only) 
-1 mglkgQ6W 
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Actual Dose intensity (mg/kg/week)• 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 13 Days)] x 7 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 20 Days)] x 7 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 13 Days)] x 7 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 20 Days)] x 7 
{[(Total cumulative dose (mg)c I weight 
(kg) across all cycles)] 
I (Exposure duration in days+ 13 Days)] 
}x7 
{[(Total cumulative dose (mg)c I weight 
(kg) across all cycles)] 
I (Exposure duration in days+ 20 Days)] 
}x7 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 20 Days)] x 7 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 20 Days)] x 7 
[Cumulative dose (mglkg)b I (Exposure 
duration in days+ 41 Days)] x 7 
Expected Dose Intensity 
(mg/kg/week) 
(0.003 mglkg) I (2 weeks)= 
0.0015 mglkg/week 
(0.006 mglkg) I (3 weeks)= 
0.002 mglkg/week 
{0.006 mglkg) I (2 weeks)= 
0.003 mglkg/week 
(0.009 mglkg) I (3 weeks)= 
0.003 mglkg/week 
[(240 mg I weight (kg) across 
all cycles)] I (2 weeks) 
[(360 mg I weight (kg) across 
all cycles)] I (3 weeks) 
{1 mglkg) I {3 weeks)= 
0.3333 mglkg/week 
(3 mglkg) I (3 weeks)= 
1 mglkglweek 
(1 mglkg) I (6 weeks) 
= 0.16667 mglkglweek 
Relative Dose 
Intensity (o/o) 
(Actual Dose 
intensity I 
Expected dose 
intensity) x 100 
Actual Dose 
intensity I 
Expected dose 
intensity) x 100 
Actual Dose 
intensity I 
Expected dose 
intensity) x 100 
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Statistical Analysis Plan 
Protocol16-214-02 
Study Drug and Dosing 
Expected Dose Intensity 
Relative Dose 
Regimen 
Actual Dose intensity (mglkglweek)' 
(mglkglweek) 
Intensity (%) 
-I mglkgQ3W 
[Cumulative dose (mglkg)• I (Exposure 
(I mglkg) I (3 weeks) 
duration in days+ 20 Days)] x 7 
~ 0.3333 mglkg/week 
-3mglkgQ3W 
[Cumulative dose (mglkg)• I (Exposure 
(3 mglkg) I (3 weeks) 
duration in days+ 20 Days)] x 7 
~ I mglkg/week 
a. 
For patients WI1h dosmg frequency sWitched, 1he calculation of Actual Dose Intensity will be depended on 1he dosmg 
frequency of 1he last dose, e.g., 
• 
If1he last dose regimen is Q2W 1hen Actual Dose Intensity ~[Cumulative dose (mglkg)' I (Exposure duration in 
days + 13 Days)] x 7 
• 
If1he last dose regimen is Q3W 1hen Actual Dose Intensity ~[Cumulative dose (mglkg)a I (Exposure duration in 
days +20 Days)] x 7 
b. 
Cumulative dose (mglkg) ~Sum of"Total dose (mg) field from eCRF" across all treatment cycles I weight (kg) across 
all treatment cycles 
c. 
For nivolumab 360 mg flat dose Q3W: Total cumulative dose (mg) ~Sum of"Total dose (mg) field from eCRF" across 
all treatment cycles 
7.0 
STATISTICAL ANALYSES 
7.1 
Subject Disposition 
Patient disposition summary will include the number and percentage of patients who were enrolled and 
who comprised each analysis population (safety, pharmacokinetic, DLT [Part 1 and Part 3 only], 
biomarker, immunogenicity, and response evaluable) by cohort (see Appendix 2 for details). The 
number and percentage of patients who discontinue from treatment (EOT) (NK.TR-214, nivolumab, 
ipilimumab, and other anti-cancer therapy), discontinue from study (end of study [EOS]), both overall 
and by reason for EOT and EOS will be summarized. 
All disposition data will be provided in a listing. In addition, patients who did not meet all inclusion and 
exclusion criteria will be listed separately. 
7.2 
Protocol Deviations 
All protocol deviations are reported in Electronic Data Capture system and the management of protocol 
deviations are detailed in Protocol Deviation Management Plan. 
The following deviations will be considered as important protocol deviations (IPD) and will be 
summarized. 
• 
Patient not meeting certain key inclusion/exclusion criteria at study entry. 
o Patient received prior interleukin-2 (IL-2) therapy. 
o Patient does not have measurable disease per RECIST 1.1. 
o Patient has active brain metastases. 
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Statistical Analysis Plan 
Protocol16-214-02 
o Patient does not meet inclusion/exclusion criteria for lab values (e.g., LDH, WBC, ANC, 
platelet count, hemoglobin, serum creatinine, ALT, AST, etc). 
o Patient does not have ECOG status as 0 or I. 
o Patient needing more than 2 anti-hypertensive medications for managing hypertension. 
o Patient received prior palliative radiotherapy within 14 days before administration of first 
dose of study drug. 
• 
Relative dose intensity> 125% for NKTR-214 or nivolumab or ipilimumab (progranunatically 
derived). Only when the overdose is affiliated with adverse events will be considered as IPD. 
The Part I patients who switched to RP2D when RP2D was determined are not considered as 
IPD. The Part 3 and 4 patients who switched to RP2D doublets when Part 3 and 4 were 
terminated are not considered as IPD. 
• 
Patient receiving any antineoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, or investigational agent) while on study treatment.. 
• 
Critical consent issues: Patient didn't sign the informed consent for the study before first dose of 
the treatment (progranunatically derived). 
Prior to database lock, any other important deviations identified by Clinical will be reviewed and 
summarized together with the IPDs above. 
7.3 
Demographic and Baseline Characteristics 
The following baseline characteristics will be summarized by cohort. All baseline presentations will 
identify participants with missing measurements. 
• 
Age (descriptive statistics) 
• 
Age category I(< 65, ~ 65) 
• 
Age category II(< 65, ~ 65 and< 75, ~ 75) 
• 
Gender (Male, Female) 
• 
Race (White, Black or African American, Asian, Other) 
• 
Region (US/Canada, EU, Rest of World) 
• 
ECOG Performance Status (0, 1) (for adults 18 years or older) 
• 
M Stage at Study Entry- AJCCS (MO, M1a, Mlb, M1c, Mid) (source: CRF) 
• 
M Stage at Study Entry- AJCC7 (MO,Mla,M1 b,Mlc) (Source: Medical adjudication) 
• 
Stage at Most Recent Recurrence (III, IV) 
• 
Stage at Initial Diagnosis (1/IIIIIIIIV) 
• 
Disease Classification at Study Entry 
• 
Weight (descriptive statistics) 
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Statistical Analysis Plan 
Protocol16-214-02 
• 
Baseline PD-L I+ status based on a 1% cut off(~ I% vs. < I% or indeterminate when collected) 
• 
Baseline PD-Ll +status based on a 5% cut off(~ 5% vs. < 5% or indeterminate when collected) 
• 
Baseline PD-Ll+ status based on a 10% cut off(~ 10% vs. < 10% or indeterminate when collected) 
• 
BRAF mutation status (BRAF mutant, wildtype) where applicable 
• 
NRAS mutation status (NRAS mutant, wildtype) 
• 
Baseline LDH (!> ULN, > ULN) 
• 
Baseline LDH (!> 2•ULN, > 2*ULN) 
• 
Baseline LDH (!> 3*ULN, > 3*ULN) 
• 
History of Brain Metastases (Yes, No) 
• 
Time from Initial Disease Diagnosis to C1D1 (< 1 year, 1-< 2 years, 2-< 3 years, 3-< 4 years, 4-< 5 
years, ~ 5 years) 
• 
All lesions (BICR Assessments at Baseline): sites of disease, number of disease sites per participant. 
• 
Target lesions (Investigator and BICR Assessments at Baseline): Presence of target lesions, sum of 
reference diameters of target lesion. 
• 
TMB (<median Mut!Mb vs >=median Mut/Mb) 
• 
CDS(< median score vs >= median score) 
• 
IFNG Score(< median score vs >=median score). 
• 
Reproductive Status (female only) 
• 
Smoking History (current, former, never) 
All demographic and baseline characteristics data will be provided in a listing. 
7.4 
Cancer History 
The summary of cancer history for the safety population will include stage at initial diagnosis, time from 
initial diagnosis to C I D I, stage at most recent recurrence, time from initial metastatic or locally 
advanced diagnosis to C I D 1, history of brain metastases, and PD-L I results. Additionally, disease 
specific history will be summarized for each tumor type. 
All cancer history data will be provided in a listing. 
7.5 
Prior Anti-Cancer Therapy 
The number and percentage of patients who received a prior neoadjuvant, adjuvant, locally advanced, or 
metastatic regimen will be summarized by cohort and histology. 
All prior systemic therapies will be summarized by the World Health Organization Drug Dictionary 
Enhanced (WHODDE) using the Anatomical Therapeutic Chemical (ATC) Classification System level 
2 term (therapeutic main group) and preferred term (PT). Patients will be counted only once within each 
ATC level2 term and PT. 
All prior cancer therapies will be provided in a listing. 
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Clinical Study Report 16-214-02 (PIVOT-02)
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Statistical Analysis Plan 
Protocol16-214-02 
7.6 
Medical History and Prior Cancer Related Surgery 
All medical history and surgery procedures prior to study enrollment will be coded by the Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.0 and summarized by system organ class 
(SOC) and preferred term (P1). 
All medical history and prior cancer related surgery will be provided in a listing. 
7. 7 
Prior, Concomitant and Follow-up Radiotherapy 
Number and percentage of patients who have had prior, concomitant, or follow-up radiotherapy will be 
summarized by type of radiotherapy. Prior radiotherapy are radiotherapies with stop date prior to C 1 D 1. 
Follow-up radiotherapies are defmed as therapies with start date after the decision is made for the patient 
to discontinue from all study treatments. Otherwise, radiotherapies are considered as concomitant. For 
radiotherapy with incomplete start/stop date, comparison will be based on data available. If comparison 
is not feasible because of missing data, radiotherapy will be considered as prior, concomitant, and 
follow-up at the same time. 
All radiotherapy will be provided in a listing. 
7.8 
Prior and Concomitant Medications and Procedures 
All medications will be coded by the WHODrug Extended March 2016 B2 Version using ATC level2 
term and PT. Medications with start date prior to CIDI are defined as prior medications otherwise they 
are defmed as concomitant. Concomitant medications are defmed as medications taken on or after the 
date of first dose, including medications initiated prior to the date of first dose and continued during 
treatment, and medications initiated on or after the date of first dose, but before the last study dose + I 00 
days or date of initiation of new antineoplastic regimen - 1 day, whichever is earlier. Medications with 
incomplete stop date will be imputed according to the rules defined in Section 5.5.1. 
All procedures performed during the study will be coded by MedDRA version 19.0 using SOC and PT. 
All prior and concomitant medications and procedures will be listed. 
7.9 
Immune Modulating Medication 
The list of anatomic class, therapeutic class and generic name used for the selection of immune 
modulating medication (IMM) at the time of the database lock will be provided. 
The percentage of subjects who received immune modulating concomitant mediations for the following 
will be reported by medication class and generic term. 
• 
Management of drug-related select adverse event (any grade, grade 3-5) by select AE 
category/subcategory (see section 7.13.3 for select AEs) 
• 
Management ofimAEs (any grade, grade 3-5) by imAE category (see section 7.13.4 for imAEs) 
For each category/subcategory of drug-related select AEs (any grade, grade 3-5) and imAEs (any grade, 
grade 3-5) , the following will be reported: 
• 
Percentage of subjects who received IMM 
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Statistical Analysis Plan 
Protocol16-214-02 
• 
Total duration ofiMM use (excluding overlaps) 
7.10 
Subsequent Cancer Therapy 
The number and percentage of patients who have subsequent cancer therapy will be summarized by 
ATC level 2 term and PT. Patients will be counted only once under each ATC level2 term and preferred 
term. 
All subsequent cancer therapy will be listed. 
7.11 
Study Exposure and Follow-Up 
Duration of regimen, duration of follow-up, total number of cycles (based on NK.lR-214), and duration 
of exposure for each study treatment will be summarized by descriptive statistics. For NK.lR-214, 
nivolumab and ipilimumab, dose intensity, relative dose intensity, the number and percentage of patients 
who had cycles with dose delay dose reduction, dose infusion interruption, and corresponding reasons 
will be summarized. 
All treatment exposure data will be listed by patient. 
7.12 
Efficacy Analysis 
Given this is an open label non-comparative study, the efficacy analysis including ORR, CBR, and TTR 
will be summarized by descriptive statistics. The following parameters, DOR, PFS, and OS will be 
summarized by the Kaplan-Meier method. 
Tumor response will be evaluated by Investigator per RECIST 1.1 and by BICR per RECIST 1.1, and 
irRECIST. Patients who achieve CR or PR will require confirmation (after 4 weeks). For patients who 
have subsequent cancer therapies, surgery or radiotherapy on target lesions, all data after the date of fust 
subsequent cancer therapy or procedure will be excluded in any efficacy analysis. 
All efficacy endpoints will be summarized by cohort (see Appendix 2 for details) and PD-L1 status. 
Selected efficacy endpoints maybe summarized for group of patients who have homogenous baseline, 
disease characteristics, or biomarker of interest identified during study. 
The exact confidence interval for proportions will be based on the Clopper-Pearson method. The 
confidence interval for the quartiles of time to event variables will be based on the Brookmeyer and 
Crowley method. 
All efficacy endpoints will be listed. 
7.12.1 
Best Overall Response, Objective Response Rate, and Clinical Benefit Rate 
The primary endpoint for the efficacy analysis is the ORR per RECIS T 1.1 at the RP2D for the doublet 
combination from Part I and 2 and at the RP2D for the triplet combination from Part 3 and 4. 
All lesions including lymph nodes will be categorized as target or non-target lesions at baseline per 
RECIST 1.1 (Eisenhauer, 2009; also see Appendix 1) and evaluated at each post-baseline tumor 
assessment to determine the overall response as one of the following: complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD), and not-evaluable (NE). The BOR is 
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Statistical Analysis Plan 
Protocol16-214-02 
detennined based on the overall response from each post-baseline tumor assessment in the following 
order: CR, PR, SD, PD, and NE. For CR and PR, tumor response must be confirmed by a subsequent 
assessment at least 4 weeks after the fust CR or PR. For the confirmation of CR or PR, there could be 
multiple tumor assessments with overall response NE between the fust and the subsequent CR or PR. 
Additionally for the confumation of PR, there could be one SD between the first PR to the subsequent 
PR. For best response of SD, changes in tumor measurements must last for at least 7 weeks or longer 
from C1Dl. Tumor assessment after the frrst PD, new systemic anti-cancer therapy, surgical procedures 
or radiotherapy on target lesions will not contribute to the BOR assessment. 
The ORR is defined as the proportion of patients who have CR or PR as their BOR. The CBR is defined 
as the proportion of patients who have CR, PR, or SD (at least 7 weeks or longer from C1D1) as their 
BOR. 
The primary analysis of ORR will be evaluated by Investigator per RECIST 1.1 and by BICR per 
RECIST 1.1, using the response evaluable population. Additional analyses of ORR will include tumor 
assessment based on Investigator and BICR per RECIST 1.1 using safety population. ORR by BICR is 
based on the BOR assessments by BICR. 
Maximum percent change from baseline in the tumor size of target lesion per RECIST 1.1 by 
Investigator assessment and BICR will be summarized by waterfall plot. Tumor burden (tumor size 
based on the sum of reference diameters (longest for non-nodal lesions, short axis for nodal lesions) of 
all target lesions) overtime per RECIST 1.1 by Investigator and BICR will be summarized by spider 
plot. All waterfall and spider plots will be presented by PD-Ll categories of: negative(< 1 %), positive 
~ I%), and unknown. 
Swimmer plots will be provided for patients' disposition status and tumor assessment results over time. 
 
 
 
7.12.2 
Time to Response 
For patients who achieved CR or PR, the TTR is calculated as the time from the date offrrst dose to the 
date of frrst response (i.e. CR or PR). TTR will be summarized using descriptive statistics by 
Investigator assessment and BICR based on RECIST 1.1 using response evaluable population. 
7.12.3 
Duration of Response 
For patients who achieved CR or PR, the DORis calculated as the time between the fust response (i.e., 
CR or PR) to progressive disease or death, whichever is earlier. DOR are subject to censoring rules 
specified for PFS in Section 7.12.4. DOR will be summarized by Investigator assessment and BICR 
based on RECIST 1.1 using the response evaluable population. The number and percentage of patients 
who have events or censored (including reasons for censoring), the quartiles (25%, median, and 75%) 
and 95% confidence interval by the Kaplan-Meier method will be provided. 
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7.12.4 
Progression Free Survival 
PFS is defined as the time between the date of first dose to the date of radiographic progressive disease 
per RECIST 1.1 or death due to any cause, whichever is earlier. For patients without PD or death, PFS 
will be censored following the rules specified below. PFS will be summarized following RECIST 1.1 for 
the safety population based on Investigator assessment and BICR using the Kaplan-Meier method. The 
summary will include number and percentage of patients who have event or censored (including reasons 
for censoring), quartiles (25%, median and 95% confidence interval, and 75%), and progression free rate 
every 6 months until 24 months. 
The primary and secondary censoring rules for PFS are provided in Table 4. 
Table 4: 
Censoring Rules for Progression Free Survival 
Situation 
Date of Disease Progression or Censoring 
Outcome 
No baseline assessments for tumor response 
Date of :frrst dose 
Censored 
No post-baseline assessments for tumor response 
Date of first dose 
Censored 
and no death 
Not known to have progressed or died according 
Date of last evaluable tumor assessment 
Censored 
to data in the database as of data-cut-off 
showing no evidence of disease progression 
Documented progression per RECIST v 1.1 and no Date of the first documented progression per 
Progressed 
new anti-cancer started before 
RECISTvl.l 
Subsequent anti-cancer therapy I irradiation or 
Date of last evaluable tumor assessment prior 
resection started without death or progression per to or on the date of initiation of the 
Censored 
RECIST vl.l reported prior to or on the same day subsequent anti-cancer therapy 
observing PD or death 
Death without progression per RECIST vl.l and 
Date of death 
Progressed 
no new anti-cancer started before 
7.12.5 
Overall Survival 
The overall survival (OS) is defined as the time between the date of first dose to the date of death from 
any cause. Patients who do not have date of death will be censored on the last date shown to be alive. 
OS will be summarized for the safety population using the Kaplan-Meier method. The summary will 
include number and percentage of patients who have an event or are censored (including reasons for 
censoring), quartiles (25%, median and 95% confidence interval, and 75%), and survival rate every 6 
months up to 24 months. 
7.12.6 
Current Status of PFS and OS Follow-Up 
The extent of follow-up defined as the time between C1D1 and last known date 
alive (for participants who are alive) or death date (for participants who died) will be 
summarized descriptively (median, min, max) in months for safety population. 
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7.12.7 
Subgroup Analysis 
Selected efficacy endpoints may be summarized separately for group of patients who have homogenous 
baseline, disease characteristics, or biomarker of interest identified during study. The following 
subgroups will be considered for all cohorts: 
• 
Age(< 65 vs. ~ 65; < 75 vs. ~ 75) 
• 
Gender (male vs. female) 
• 
Race (white, black, Asian, other) 
• 
Time from initial cancer diagnosis to first dose date (<I year vs. ~ 1 year) 
• 
Patients with history ofliver metastases; visceral metastases (Yes vs. No) 
• 
Geographic region (US/Canada, EU, Rest of World) 
• 
ECOG Performance status (0, 1, > 1) 
• 
Patients with history of brain metastases (Yes vs. No) 
• 
PD-Ll status at baseline(>= 1% vs <1 %) based on 28-8 TPS test results 
• 
TMB (<median Mut!Mb vs >=median Mut!Mb) 
• 
CDS(< median score vs >= median score) 
• 
IFNG Score(< median score vs >=median score). 
Additionally, the following disease-specific subgroup will be considered: 
For lL Melanoma: 
• 
M stage by American Joint Committee on Cancer (AJCC) version 8 (Mia, Mlb, Mlc, Mid) 
• 
M stage by AJCC version 7 (Mia, Mlb, Mlc) 
• 
Baseline LDH level (normal, high) 
• 
Baseline BRAF status (mutant type, wild type) 
• 
Baseline liver metastasis status (with or without liver metastasis) 
For lLRCC: 
• 
International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score (favorable, 
intermediate, poor) 
For 1/2L TNBC: 
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Statistical Analysis Plan 
• 
Baseline PD-Ll by SP142 (IC <1 %, IC 2:1 %) 
For 1LmUC: 
Protocol16-214-02 
• 
Baseline PD-L1 combined proportional score (CPS) (CPS Score< 1, CPS Score 2: 1, CPS Score 
< 10, CPS Score 2: 1 0) 
If the number of patients in a subgroup has less than 10 per cohort, selected efficacy analysis will not be 
computed/displayed. 
7.13 
Safety Analyses 
All safety analyses will be based on the overall safety population. Safety data will be s11mmarized by the 
treatment received from study (See Section 3.3 for details): dose levels in Part 1 will be combined as one 
cohort (with the exception ofDLT summary), RP2D in Part 1 and Part 2, NK.lR-214 and nivolumab in 
combination with other anti-cancer therapies in Part 2, NK.lR-214 in combination with nivolumab and 
ipilimumab in Part 3 and Part 4 unless otherwise specified (exceptions include CV A analysis in Section 
7.13.5). Additionally, safety data will also be analyzed by tumor indications for patients who received 
RP2D. 
7.13.1 
Dose Limiting Toxicities 
In Part 1 and Part 3, DLTs will be evaluated within the DLT evaluation window as specified in the 
protocol. Delayed DL Ts are AEs that are defined in the protocol that occur after the DL T evaluation 
window. DLTs and delayed DLTs will be summarized separately by SOC and PT. All DLTs and 
delayed DL Ts will be listed by patient. 
7.13.2 
Adverse Events 
A treatment emergent adverse event (1EAE) is: 
• 
Any AE that happens on or after treatment initiation 
• 
AE that was present prior to treatment initiation but worsened after treatment initiation 
• 
AE that was present and resolved prior to treatment and reappeared after treatment initiation 
Incomplete start and end date for 1EAEs will be imputed. Any AE will be considered as a 1EAE if its 
status cannot be fully determined because of incomplete data. The treatment-emergent period will be 
defmed as the period of time on or after the date/time of the first dose of study drug administration (on 
or after the date of the first dose of study drug administration, if time is not available) until the earlier 
date of the two dates: 
• 
Date of initiation of new antineoplastic regimen- 1 day 
• 
30 days after the date of the last dose of all study drug. 
All AEs will be coded by MedDRA version 19.0. The severity of AE will be determined based on the 
National Cancer Institute Co=on Terminology Criteria for Adverse Events (NCI CTCAE) Grade 
(version 4.03). A TEAE is considered as related to treatment if it is related to either NKTR-214 or 
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nivolumab or other anti-cancer therapy (a causality of 'related' or 'possibly related' is considered related 
to treatment). A TEAE is considered as leading to treatment discontinuation if it is leading to 
discontinuation of either NKTR-214 or nivolumab or other anti-cancer therapy. A TEAE is considered 
as leading to treatment delay, reduction or interruption if reported as leading to either NKTR-214 or 
nivolumab or anti-cancer dose delay, reduction or interruption. A TEAE is considered as leading to 
death if the severity grade is 5 or the outcome is fatal. A patient reporting the same TEAE multiple times 
will be counted only once within each SOC and PT under the highest severity and closest relationship. 
Adverse events will be presented by summary tables and listings as outlined below: 
The TEAE summary tables will include: 
• 
Overall summary of TEAEs 
• 
Overall summary ofTEAE presented by worst CTC grade (any grade, grade 3-4, grade 5) by SOC 
andPT 
• 
Overall summary of any AEs that required immune modulating medication by worst CTC grade (any 
grade, grade 3-4, grade 5) by SOC and PT 
• 
Serious TEAE presented by worst CTC grade (any grade, grade 3-4, grade 5) by SOC and PT 
• 
TEAE presented by worst CTC grade (any grade, grade 3-4, grade 5) leading to any treatment dose 
delay, reduction, and interruption by SOC and PT 
• 
TEAE presented by worst CTC grade (any grade, grade 3-4, grade 5) leading to discontinuation of 
any treatment by SOC and PT 
• 
Related TEAE presented by worst CTC grade (any grade, grade 3-4, grade 5) by SOC and PT 
Additionally, TEAEs will be also be summarized in tables as follows: 
• 
Grade 3 or above TEAE by PT 
• 
Grade 3 or above related TEAE by PT 
• 
Serious related TEAE by PT 
• 
Related TEAE leading to discontinuation by PT 
• 
Related TEAE leading to death by PT 
For the following drug-related TEAE summary, 
• 
Related TEAE presented by worst CTC grade (any grade, grade 3-4, grade 5) by SOC and PT 
treatment-emergent period based on time from the date of the first dose of study drug administration 
until the earlier date of the two dates will also be used: 
• 
Date of initiation of new antineoplastic regimen- 1 day 
• 
100 days after the date of the last dose of all study drug 
All AEs will be presented in listing as follows: 
• 
SAEs, 
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• 
Grade 3 or above TEAEs, 
• 
TEAE leading to any treatment dose delay, reduction, or interruption, 
• 
TEAE leading to any treatment discontinuation, 
• 
Fatal TEAEs 
7.13.3 
Adverse Events of Special Interest for Checkpoint Inhibitors 
7.13.3.1 
Select Adverse Events (to Support EU MAA) 
The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific category 
(e.g. pulmonary events, gastrointestinal events categories, etc.). Select AEs are identified based on the 
following 4 guiding principles: 
• 
AEs that may differ in type, frequency, or severity from AEs caused by non-immunotherapies 
• 
AEs that may require immunosuppression ( eg, corticosteroids) as part of their management 
• 
AEs whose early recognition and management may mitigate severe toxicity 
• 
AEs for which multiple event terms may be used to describe a single type of AE, thereby necessitating 
the pooling of terms for full characterization. 
Based on these guiding principles and taking into account the types of AEs already observed across studies 
of nivolumab monotherapy, endocrinopathies, diarrhea/colitis, hepatitis, pneumonitis, interstitial 
nephritis, and rash are currently considered to be select AEs. Multiple event terms that may describe each 
of these are grouped into endocrine, gastrointestinal (GI), hepatic, pulmonary, renal, and skin select AE 
categories, respectively. 
Hypersensitivity/infusion reactions are analyzed along with the select AE categories because multiple 
event terms may be used to describe such events and pooling of terms was therefore necessary for full 
characterization. Hypersensitivity/infusion reactions do not otherwise meet criteria to be considered select 
AEs. 
The list ofMedDRA preferred terms used for the selection at the time of the database lock will be provided 
by categories/subcategories. 
In addition to the frequency and worst severity of select AEs, time-to onset, time-to resolution, and time-
to resolution where immune modulating medication was initiated will be analyzed for each specific 
category/subcategory of drug-related select AEs when applicable. 
Further details on the definitions of select adverse event, time-to onset and time-to resolution are described 
in Appendix 3. 
Unless otherwise specified, analyses will be performed by select AE category. Analyses will also be 
repeated by subcategory of endocrine events. 
1) Incidence of Select AE 
Select AEs will be summarized by treatment group for each category/subcategory. 
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• 
Overall summaries of any select AEs by worst CTC grade (any grade, grade 3-4, grade 5) presented 
by Category or Subcategory/PT. 
• 
Overall summaries of any drug-related select AEs by worst CTC grade (any grade, grade 3-4, grade 
5) presented by Category or Subcategory/PT. 
• 
Overall summaries of any serious select AEs by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by Category or Subcategory /PT. 
• 
Overall summaries of drug-related serious select AEs by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT. 
• 
Overall summaries of any select AEs leading to discontinuation by worst CTC grade (any grade, grade 
3-4, grade 5) presented by Category or Subcategory /PT. 
• 
Overall summaries of drug-related select AEs leading to discontinuation by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category or Subcategory /PT. 
• 
Summary of frequency of unique select AEs by Category or subcategory /PT (after duplicates have 
been eliminated and overlapping and contiguous occurrences of the same event (i.e. same PT) have 
been collapsed). 
A by-subject select AE listing will be provided. 
2) Time-to Onset of Select AE 
Time-to onset of drug-related select AEs (any grade, grade 3-5) will be summarized for each 
category/subcategory by treatment group. 
Time-to onset analyses are restricted to treated participants who experienced at least one drug-related 
select AE in the category/subcategory. 
3) Time-to Resolution of Select AE 
Time-to resolution of the following specific events will be summarized separately for each 
category /subcategory. 
• 
Time-to resolution of drug-related select AE (any grade, grade 3-5) 
• 
Time-to resolution of drug-related select AE (any grade, grade 3-5) where immune modulating 
medication was initiated 
Time-to resolution analyses are restricted to treated participants who experienced the specific events. 
Time-to resolution where immune modulating medication was initiated analyses are restricted to treated 
participants who experienced the specific events and who received immune modulating medication during 
the longest select AE. 
The following summary statistics will be reported: percentage of participants with resolution of the longest 
select AE, median time-to resolution along with 95% CI (derived from Kaplan-Meier estimation) and 
ranges. 
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Statistical Analysis Plan 
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7.13.3.2 
Immune Mediated Adverse Events (imAEs) (to Support US BLA) 
In order to further characterize AEs of special clinical interest, analysis of immune-mediated AEs 
(IMAE) will be conducted. The following imAEs will be grouped as potential non-endocrine or 
endocrine immune mediate adverse events: 
• 
Non-endocrine imAEs include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, 
rash , and/or other specific events 
• 
Endocrine imAEs include adrenal insufficiency, hypothyroidism/thyroiditis, hypothyroidism, 
thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis 
Non-endocrine imAEs must also meet the following criteria: 
• 
Taking systemic steroid or immune-modulating medication on or after the onset of the AE and 
before the AE resolution date or 
• 
The indication for a systemic steroid or immune-modulating medication is the AE 
• 
Taking systemic corticosteroid or selected IMM or hormone replacement initiation was on or after 
the AE onset date and before the AE resolution date 
All endocrine AEs will be considered as potential imAEs regardless ifiMM and/or steroids are 
administered given these events may be treated with other medications outside of IMM and/or steroids. 
All potential non-endocrine or endocrine imAEs along with concomitant medication information will be 
reviewed by Drug Safety, and Drug Safety will manually determine and provide a final list of non-
endocrine or endocrine imAEs for the imAE summaries. 
For imAE, treatment-emergent period based on period of time from the date/time of the first dose of 
study drug administration until the earlier date of the following two dates will be used: 
• 
Date of initiation of new antineoplastic regimen- 1 day 
• 
100 days after the date of the last dose of all study drug 
lmAEs will be summarized by safety population and for each immune-mediated category: 
• 
Overall summary of non-endocrine imAEs by worst CTC grade (any grade, grade 3-4, grade 5) where 
immune modulating medication was initiated presented by Category I PT. 
• 
Overall summary of endocrine imAEs by worst CTC grade (any grade, grade 3-4, grade 5) presented 
by Category I PT. 
• 
Overall summary of non-endocrine imAEs leading to discontinuation by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by Category I PT. 
• 
Overall summary of endocrine imAEs leading to discontinuation by worst CTC grade (any grade, 
grade 3-4, grade 5) presented by Category I PT. 
• 
Overall summary of non-endocrine imAEs leading to dose delay or reduction by worst CTC grade 
(any grade, grade 3-4, grade 5) presented by Category I PT 
• 
Overall summary of endocrine imAEs leading to dose delay or reduction by worst CTC grade (any 
grade, grade 3-4, grade 5) presented by Category I PT. 
• 
Summaries of time-to onset and time-to resolution of non-endocrine imAEs presented by Category. 
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• 
Summaries of time-to onset and time-to resolution of endocrine imAEs presented by Category. 
All imAEs including time to resolution will be listed. 
Final selection and grouping of PTs and medications will be based on study team review prior to the 
final analysis. 
7.13.3.3 
Other Events of Special Interest 
Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific category 
(e.g. Myositis Event, Myocarditis Event, Demyelination Event, Guillain-Barre Syndrome, Pancreatitis 
Event, Uveitis Event, Encephalitis Event, Myasthenic Syndrome, Rhabdomyolysis Event, Graft Versus 
Host Disease). The same treatment-emergent period for imAE will be used for OEOSI. 
The list ofMedDRA preferred terms used to identify OEOSI is revisited quarterly and updated 
accordingly. The preferred terms used for the selection at the time of the database lock by categories will 
be provided. 
• 
Overall summary ofOEOSI by worst CTC grade (any grade, grade 3-4, grade 5) presented by Category 
/PT 
• 
Overall summary of drug-related OEOSI by worst CTC grade (any grade, grade 3-4, grade 5) 
presented by Category I PT 
7.13.4 
Adverse Events of Special Interest to Bempegaldesleukin 
7.13.4.1 
Adverse Events of Special Interest 
Adverse events of special interest for NKTR-214 consists of cerebrovascular accident (CVA) adverse 
events. 
All analyses will be conducted for all patients in the safety analysis population, Part 1 and 2 RP2D 
doublet patients in the safety analysis population, and Part 3 and 4 patients in the safety analysis 
population. 
Treatment-emergent period based on period of time from the date/time of the first dose of study drug 
administration until the earlier date of the following two dates will be used: 
• 
Date of initiation of new antineoplastic regimen- 1 day 
• 
30 days after the date of the last dose of all study drug 
Search list used to identify CV A events will be provided. 
The following analyses will be conducted for Cerebrovascular accident (CVA) adverse events: 
o Treatment-emergent adverse events of cerebrovascular accident (CVA) presented by PT (any 
grade, grade 5, serious). 
o Subject incidence of cerebrovascular accident (CV A) by tumor type 
o Medical history for subjects without and with treatment emergent adverse events of 
cerebrovascular accident (CVA) 
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Statistical Analysis Plan 
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7.13.4.2 
Other AEs oflnterest 
Other AEs of interest (OAEOI) for NK1R-214 consists of the following: 
• 
Hypotension (Ho1N) 
• 
IL-2 mediated AEs 
o Flu-like symptoms 
o Rash and pruritus 
o Fatigue/asthenia 
o Elevated hepatic transaminases 
o Elevated serum creatinine 
• 
Infusion-related reaction (IRR, same day or next day post NK1R-214 administration) 
• 
Eosinophilic disorder 
• 
Thyroid dysfunction 
• 
Arthralgia 
• 
Syncope 
• 
Cytokine release syndrome/cytokine storm (CRS) 
• 
Capillary leak syndrome (CLS) 
• 
Atrial fibrillation and ventricular tachycardia (AF Nl) 
• 
Torsade de pointes/QT prolongation (TdP) 
• 
Seizure 
All analyses will be conducted for all patients in the safety analysis population, and Part 1 and 2 RP2D 
doublet patients in the safety analysis population. 
Treatment-emergent period based on period of time from the date/time of the first dose of study drug 
administration until the earlier date of the following two dates will be used: 
• 
Date of initiation of new antineoplastic regimen- 1 day 
• 
30 days after the date of the last dose of all study drug 
Collapsing and clustering of records will be implemented when applicable. For time to resolution 
analysis, record with the longest duration after event collapsing and clustering will be used for each 
patient (Appendix 3). 
Search list used to identify OAEOI will be provided. 
Lab values within 30 days oflast dose of all study drug received or date of initiation of new 
antineoplastic regimen- I day, whichever is earlier, will be included in the analysis. 
For HoTN, Syncope, Flu-like symptoms, Rash and pruritus, Fatigue/asthenia, Arthralgia, CRS, CLS, the 
following analyses will be conducted: 
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• 
Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any grade, 
grade 3-4, grade 5). 
• 
NKTR-214 Related Treatment-Emergent Adverse Events ofOAEOI by Worst CTC Grade presented 
by PT (any grade, grade 3-4, grade 5). 
• 
Serious Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any 
grade, grade 3-4, grade 5). 
• 
Treatment-Emergent Adverse Events of OAEOI Leading to NKTR-214 Discontinuation by Worst 
CTC Grade presented by PT (any grade, grade 3-4). 
• 
Time to the First Onset of Treatment Emergent Adverse Events ofOAEOI (any grade) 
• 
Time to Resolution of Treatment Emergent Adverse Events ofOAEOI (any grade) 
• 
Frequency of Treatment Emergent Adverse Events of OAEOI by Cycle by Worst CTC Grade (any 
grade, grade 3-5) 
In addition, the following will be conducted for HoTN and Syncope: 
• 
Medical history of subjects without and with Grade 3 and Above Treatment Emergent Adverse Events 
of OAEOI presented by SOC and PT 
In addition, the following will be conducted for Arthralgia: 
• 
Medical history of subjects without and with Treatment Emergent Adverse Events of OAEOI 
presented by SOC and PT 
For AFNT, TdP and seizure, the following analyses will be conducted: 
• 
Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any grade, 
grade 3-4, grade 5). 
• 
NKTR-214 Related Treatment-Emergent Adverse Events ofOAEOI by Worst CTC Grade presented 
by PT (any grade, grade 3-4, grade 5). 
• 
Serious Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any 
grade, grade 3-4, grade 5). 
• 
Treatment-Emergent Adverse Events of OAEOI Leading to NKTR-214 Discontinuation by Worst 
CTC Grade presented by PT (any grade, grade 3-4). 
• 
Time to the First Onset of Treatment Emergent Adverse Events ofOAEOI (any grade) 
For IRR, events that start after NKTR-214 administration on the same day or next day will be included. 
If AE onset time is available, the time information will be used to exclude events that start before 
NKTR-214 administration; otherwise, AEs that start on the same day as NKTR-214 administration will 
be included. 
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• 
Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any grade, 
grade 3-4, grade 5). 
• 
NKTR-214 Related Treatment-Emergent Adverse Events ofOAEOI by Worst CTC Grade presented 
by PT (any grade, grade 3-4, grade 5). 
• 
Serious Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any 
grade, grade 3-4, grade 5). 
• 
Treatment-Emergent Adverse Events of OAEOI Leading to NKTR-214 Discontinuation by Worst 
CTC Grade presented by PT (any grade, grade 3-4). 
• 
Time to Resolution of Treatment Emergent Adverse Events ofOAEOI 
• 
Frequency of Treatment Emergent Adverse Events ofOAEOI by Cycle by Worst CTC Grade 
• 
Medical history of subjects without and with Grade 3 and Above Treatment Emergent Adverse Events 
of OAEOI presented by SOC and PT 
For Elevated hepatic transaminases, Elevated serum creatinine and Eosinophilic disorder, the following 
analyses will be conducted based on AE data: 
• 
Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any grade, 
grade 3-4, grade 5). 
• 
NKTR-214 Related Treatment-Emergent Adverse Events ofOAEOI by Worst CTC Grade presented 
by PT (any grade, grade 3-4, grade 5). 
• 
Serious Treatment-Emergent Adverse Events of OAEOI by Worst CTC Grade presented by PT (any 
grade, grade 3-4, grade 5). 
• 
Treatment-Emergent Adverse Events of OAEOI Leading to NKTR-214 Discontinuation by Worst 
CTC Grade presented by PT (any grade, grade 3-4). 
In addition, the following analysis will be conducted based on laboratory data: 
• 
Frequency of Post-Baseline ALT/AST Laboratory Abnormal Elevations by Cycle and by Worst CTC 
Grade 
• 
Figure of Central Tendency of Serum Creatinine Ratio (vs Baseline) by Baseline Grade 
• 
Summary of Acute Kidney Injury KDIGO Staging based on Serum Creatinine Values 
• 
Summary of Post-Baseline Eosinophil Elevations 
• 
Treatment Emergent AEs for Subjects with Post-Baseline Eosinophil Elevations presented by SOC 
and PT (any grade, grade 3-5, serious) 
For thyroid dysfunction, AE based analyses are referred to imAE relevant subcategories. In addition, the 
following analysis will be conducted: 
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• 
Summary of Hypothyroidism Identified by Laboratory Abnormalities or Thyroid Therapy Use 
• 
Listing of Thyroid Therapy use for Subjects with Baseline Normal TSH!f4FR Lab Values and Prior 
Thyroid Therapy Use 
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Table 5: 
Summary of AE Based Analyses for Other AESI 
Title 
Treatment-Emergent Adverse Events 
ofOAEOI by Worst CTC Grade 
presented by PT (any grade, grade 3-
4, grade 5). 
NKTR-214 Related Treatment-
Emergent Adverse Events of OAEOI 
by Worst CTC Grade presented by 
PT (any grade, grade 3-4, grade 5). 
Serious Treatment-Emergent 
Adverse Events of OAEOI by Worst 
CTC Grade presented by PT (any 
grade, grade 3-4, grade 5). 
Treatment-Emergent Adverse Events 
ofOAEOI Leading to NKTR-214 
Discontinuation by Worst CTC 
Grade presented by PT (any grade, 
grade 3-4). 
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Flu-like 
HoTN; 
Symptom; 
Syncope 
Arthralgia 
Rash; 
y 
y 
y 
y 
y 
y 
y 
y 
y 
y 
y 
y 
Fatigue; 
CRS; 
CLS; 
y 
y 
y 
y 
AFNT; 
TdP; 
Seizure 
IRR[a] 
y 
y 
y 
y 
y 
y 
y 
y 
Page46 of72 
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Elevated Hepatic 
Transaminases; 
Elevated sCr; 
Eosinophilic 
disorder; [b] 
y 
y 
y 
y 
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Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Protocol16-214-02 
Time to the First Onset of Treatment 
Emergent Adverse Events of OAEOI 
any grade) 
y 
y 
y 
y 
y 
N 
N 
Time to Resolution of Treatment 
Emergent Adverse Events of OAEOI 
any grade) [c] 
y 
y 
y 
y 
N 
y 
N 
Frequency of Treatment Emergent 
Adverse Events ofOAEOI by Cycle 
by Worst CTC Grade (any grade, 
grade 3-5)[c] 
y 
y 
y 
y 
N 
y 
N 
Medical history of subjects without 
and with (Grade 3 and Above) 
Treatment Emergent Adverse Events 
of OAEOI presented by SOC and 
PT[c] [d] 
y 
y 
N 
N 
N 
y 
N 
[a] For IRR, events that start afterNKTR-214 administration on the same day or next day will be included. If AE onset time is available, the time 
information will be used to exclude events that start before NKTR-214 administration; otherwise, AEs that start on the same day as NKTR-214 
administration will be included. 
[b] Additional analyses based on laboratory data will be conducted for Elevated hepatic transaminases, Elevated serum creatinine, Eosinophilic 
disorder, and thyroid disfunction. AE based thyroid disfunction analyses refer to imAE analysis subcategories. 
[c]Collapsing and clustering of records will be implemented when applicable. For time to resolution analysis, record with longest duration after 
event collapsing and clustering will be used (APPENDIX 3). 
[d] MH analysis with be summarized for patients by Grade 3 and Above AEs ofHolN, Syncope, and IRR (within defined window); MH analysis 
with be summarized by any grade AEs of arthralgia. 
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Statistical Analysis Plan 
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7.13.5 
Deaths 
Deaths will be summarized by treatment group: 
• 
All deaths, reasons for death. 
• 
Deaths within 30 days of last dose received or date of initiation of new antineoplastic regimen- 1 
day, whichever is earlier, and reasons for death. 
• 
Deaths within 100 days of last dose received or date of initiation of new antineoplastic regimen- 1 
day, whichever is earlier, and reasons for death. 
A by-patient listing of deaths will be provided for the all enrolled participants. 
7.13.6 
Clinical Laboratory Evaluation 
7.13.6.1 
Hematology 
Hematology analytes include hemoglobin, platelet counts, and white (total leukocyte) blood cell counts 
and differentials (neutrophils and lymphocytes). Lab values within 30 days oflast dose of all study drug 
received or date of initiation of new antineoplastic regimen-! day, whichever is earlier, will be 
included in the analysis. Worst CTC grade and shift table of worst CTC grade compared to baseline 
CTC grade will be summarized. 
7.13.6.2 
Serum chemistry 
Serum chemistry analytes include aspartate aminotransferase (AST), alanine aminotransferase (AL T), 
alkaline phosphatase (ALP), ganuna-glutamyl transferase (GOT), lipase, amylase, albumin, creatinine, 
urate, and total bilirubin. Lab values within 30 days of last dose of all study drug received or date of 
initiation of new antineoplastic regimen- 1 day, whichever is earlier, will be included in the analysis. 
Worst CTC grade and shift table of worst CTC grade compared to baseline CTC grade will be 
summarized. 
7.13.6.3 
Electrolytes 
The following will be summarized by treatment group as worst CTC grade and as shift table of worst 
CTC grade compared to baseline CTC grade per subject: sodium (high and low), potassium (high and 
low), calcium (high and low), and glucose. Lab values within 30 days oflast dose of all study drug 
received or date of initiation of new antineoplastic regimen-! day, whichever is earlier, will be 
included in the analysis. 
7.13.6.4 
Additional Analyses 
In addition, further analyses on specific laboratory parameters will be performed: 
Abnormal Hepatic Function Test 
The number of patients with the following laboratory abnormalities will be summarized: 
• 
ALTor AST> 3 xULN,>5 xULN,> lOxULN and>20xULN 
• 
Total bilirubin> 2 x ULN 
• 
ALP > 1.5 x ULN 
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Statistical Analysis Plan 
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• 
Concurrent (within 7 days) ALT or AST > 3 x ULN and total bilirubin> 1.5 x ULN 
• 
Concurrent (within 7 days) ALT or AST > 3 x ULN and total bilirubin> 2 x ULN 
The window for this analysis is defined as the period of time after the first dose of study drug 
administration until the earlier date of the two dates: 
• 
Date of initiation of new antineoplastic regimen- 1 day 
• 
30 days after the date of the last dose of all study drug. 
A by-subject listing of these specific abnormalities will be provided. 
7.13.6.5 
Pregnancy Tests 
The number and percentage of patients with positive result based on serum or urine pregnancy tests will 
be provided. Listing of pregnancy tests will be provided. 
7.13.7 
Vital Signs 
Vital signs include height, weight, heart rate, respiratory rate, temperature, supine systolic blood 
pressure, supine diastolic blood pressure and oxygen saturation. Descriptive statistics will be provided 
for each vital sign at baseline, and maximum change from baseline during the study. 
All vital sign data will be listed by patient. 
7.13.8 
Electrocardiogram 
Electrocardiogram (ECG) assessment include PR, RR, QRS, QT, corrected QT interval using 
Fridericia's formula (QTcF), corrected QT interval using Bazett's formula (QTcB), and heart rate. 
The number and percentage of patients in each of the following categories based on PR, QRS and HR 
will be provided for all Part 1 patients and all RP2D doublet patients in the safety population: 
• 
PR outliers (PR > 200 msec and a 25% or greater increase from baseline) 
• 
QRS outliers (QRS > I 00 msec and a 25% or greater increase from baseline) 
• 
HR outliers (HR <50 beats/min and a 25% or greater decrease from baseline) 
• 
HR outliers (HR > 100 beats/min and a 25% or greater increase from baseline) 
The number and percentage of patients in each of the following categories based on QTcB and QTcF 
will be provided for all Part 1 patients and all RP2D doublet patients in the safety population: 
• 
QTc interval:<:: 450 vs > 450 ms, 
• 
QTc interval:<:: 450 vs > 480 ms, 
• 
QTc interval:<:: 450 vs > 500 ms, 
• 
QTc interval change from baseline:<:: 30 ms,> 30 ms and<= 60 ms, > 60 ms. 
All ECG and echocardiogram data will be listed. A QTc exposure response analysis was conducted 
under a separate analysis plan and was summarized in a separate report which will be included in the 
CSR. 
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Statistical Analysis Plan 
Protocol16-214-02 
8.0 
IMMUNOGENICITY 
8.1 
General Analysis Considerations 
Validated methods to detect anti-PEG, anti-NKTR-214, anti-IL-2, anti-nivolumab, and anti-ipilimumab 
anti-drug antibodies (ADA) will be used to analyze immunogenicity samples. Immunogenicity sample 
testing will be done in tiers. Samples will be frrst tested with screening electrochemiluminescence 
assays (ECLA). Putative positive samples for anti-nivolumab, anti-ipilimumab, anti-NKTR-214 or anti-
IL-2 ADAs will then be analyzed in a competition ECLA to confirm positivity. Confirmed anti--NKTR-
214 ADA-positive samples will be tested further in a polyethylene glycol (PEG) immuno-competition 
assay to determine the antibody specificity of the reactivity to the PEG or non-PEG (IL-2, linker) moiety 
ofNKTR-214. Confirmed positive samples from each assay (anti-nivolumab, anti-ipilimumab, anti-
NKTR-214 and anti-IL-2) will then be tested to obtain a titer. Samples confirmed to be positive for anti-
NKTR-214, anti-IL-2 and anti-nivolumab ADA will also be tested for neutralizing activity for IL-2 and 
nivolumab using validated cell-based assays. 
8.2 
Immunogenicity Measurements and Endpoints 
The immunogenicity analysis will be performed separately for NKTR-214, nivolumab and ipilimumab. 
The data will be summarized for anti-NKTR-214, anti-PEG, anti-IL-2, anti-nivolumab and 
anti-ipilimumab antibodies and will be reported by sample and patient status. 
For sample status, immunogenicity data will be summarized by the number and percentage of confirmed 
anti-drug antibodies to NKTR-214, PEG, IL-2, nivolumab and ipilimumab by analyte and visit. The 
samples will be classified as baseline ADA-positive, if ADA is detected in the immunogenicity sample 
collected before initiation of the treatment and baseline ADA-negative, if ADA is not detected in the 
immunogenicity sample collected before initiation of the treatment. ADA samples will be classified as 
positive if after initiation of the treatment, the ADA is detected (positive seroconversion) in a sample 
from a patient who was baseline negative, or if there is at least 4-fold or greater (2:) increase in ADA 
titer in comparison to the baseline positive titer. 
For patient status, immunogenicity will be reported by summarizing the number and percentage of 
ADA-positive patients and ADA-negative patients at baseline and after drug administration with 
positive status of anti-NKTR-214, anti-PEG, anti-1L2, anti-nivolumab and anti-ipilimumab ADA. In the 
immunogenicity evaluable population, the patients will be classified as treatment-induced ADA-positive 
if they were ADA-negative at baseline and became ADA-positive at any time after starting the 
treatment, or if they were ADA-positive at baseline and had a post-baseline ADA-positive titer that was 
at least 4-fold or greater (2:) than baseline positive titer (also known as Treatment-boosted). Treatment-
emergent ADA-positive patients will be the sum of treatment- induced and treatment- boosted ADA-
positive patients. The patients with an ADA-positive sample at 2 or more consecutive time points, where 
the first and last ADA-positive samples are at least 16 weeks apart will be classified as persistent 
positive. Patients that are not persistent positive but have an ADA-positive sample at the last sampling 
time point will be classified as not persistent last-sample positive. Non persistent positive patients with 
an ADA-negative sample at the last sampling time point will be classified as transiently positive or other 
positive. Patients with at least 1 ADA-positive sample with neutralizing activity will be classified as 
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Statistical Analysis Plan 
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neutralizing positive. All other ADA-evaluable patients are considered as treatment-emergent ADA 
negative. 
All ADA-positive patients will be included in the ADA titer kinetics analysis. Summary statistics of 
patient-level ADA titers using the maximum titer value within an ADA-positive patient will be presented 
for baseline ADA-negative patients and baseline ADA-positive patients. The median, interquartile range, 
and range of the maximum titers will be reported. For ADA-positive patients with baseline ADA-positive 
sample, the median and interquartile range of the fold increase from baseline in titer (ratio of maximum 
post-baseline titer to baseline titer) will also be reported. For sample-level ADA titers, boxplots of ADA 
titers at each assessment timepoint will be provided, as appropriate, to demonstrate whether the ADA 
levels tend to change over time during the treatment, along with ADA incidence at each assessment 
timepoint. 
Analyses of ADA kinetics on onset and duration will include only those ADA-positive patients that were 
ADA-negative at baseline. ADA-positive patients with baseline ADA-positive sample and an increased 
titer post-baseline will be excluded since this type of immune response differs mechanistically. 
Onset of ADA refers to the time period between the first dose of the treatment and the first instance of 
ADA detection. The median, interquartile range, and range of time to ADA development will be provided. 
The median and range of the number of treatment doses to before and after the first detection of ADA as 
well as the total number of doses received will also be provided. 
Duration of ADA refers to the longevity of ADA and is defined as the time from the first on-study ADA-
positive date to the first ADA-negative date after the last on-study ADA-positive date. Duration of ADA 
will be estimated by Kaplan-Meier method. Subjects who do not have an ADA-negative date after the last 
on-study ADA-positive date will be censored on the date of their last ADA-evaluable assessment. The 
median together with 95% confidence interval (using log-log transformation method) and range (min, 
max) will be provided. 
8.3 
Safety Evaluation of ADA 
All patients with ADA as mentioned above will be assessed for infusion related reactions (including 
hypersensitivity/angioedema/anaphylaxis) and will be compared against ADA negative patients. 
8.4 
Defmitions 
There are two sets of definitions: one for categorizing individual samples (Error! Referen£e sour£e not 
found.) and another for categorizing patient responses (Table 7: 
ADA Response Categories: Patient 
Level 
). 
Table 6: 
ADA Status: Individual Samples 
ADA Status 
Baseline Negative 
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Def'mition 
ADA is not detected in the last sample before initiation of treatment 
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Statistical Analysis Plan 
ADA Status 
Baseline positive 
Anti-NKTR-214 
ADA-positive sample 
Anti-PEG ADA-positive 
sample 
Anti-IL-2 ADA-positive 
sample 
Anti-Nivolumab 
ADA-positive sample 
Anti-lpilimumab 
ADA-positive sample 
ADA-Negative 
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Protocol16-214-02 
Dermition 
ADA is detected in the last sample before initiation of treatment 
After initiation of treatment, (I) an ADA detected (positive seroconversion) sample in a 
patient for whom anti-NKTR-214 ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-NKTR-214 titer to be at least 4-fold or greater~) 
than baseline positive titer 
Sample with a positive result in PEG -specificity assay. 
After initiation of treatment, (I) an ADA detected (positive seroconversion) sample in a 
patient for whom anti-IL-2 ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-IL2 titer to be at least 4-fold or greater~) than 
baseline positive titer 
After initiation of treatment, (I) an ADA detected (positive seroconversion) sample in a 
patient for whom anti-Nivolumab ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-Nivolumab titer to be at least 4-fold or greater ~) 
than baseline positive titer 
After initiation of treatment, (I) an ADA detected (positive seroconversion) sample in a 
patient for whom anti-lpilimumab ADA is not detected at baseline, or 
(2) an ADA detected sample with anti-Ipilimumab titer to be at least 4-fold or greater~) 
than baseline positive titer 
After initiation of treatment, assay result is not a positive sample relative to baseline, i.e., 
increase from baseline is <4-fold 
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Table 7: 
ADA Response Categories: Patient Level 
ADA status 
Description 
Baseline ADA-positive 
A patient wi1h baseline ADA-positive sample 
ADA-Negative Patient 
Patient wi1h no ADA-positive sample after 1he initiation of treatment. 
Note: due to 1he definition of an ADA positive sample for a patient testing positive at baseline 
(see sample status table, above), it is possible (but highly unlikely) for a patient wi1h a stable 
anti-drug titer 1hrougbout 1he study to be classified as 'ADA-negative' 
ADA-Positive Patient 
(Treatment emergent 
Patient wi1h at least 1 ADA positive-sample (relative to baseline) at any time after initiation of 
positive) 
treatment 
Persistent positive 
ADA-positive sample at 2 or more consecutive time points, where 1he frrst and last ADA-
positive samples are at least 16 weeks apart (Endogenous buman IgG 1, IgG2, and IgG4 have 
approximate half-lives in the range of21-25 days, and 5 half-lives are approximately equal to 
16 weeks) 
Not PP-Last Sample 
Not persistent positive wi1h ADA-positive sample at the last sampling time point 
Positive 
Transiently positive or 
Patient not persistently positive but has 1 or more ADA positive samples wi1h 1he last sample 
Other positive 
being ADA-negative. 
Neutralizing positive 
At least 1 ADA-positive sample wi1h neutralizing antibodies detected 
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Statistical Analysis Plan 
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10.0 
PHARMACOKINETICS 
10.1 
Objectives of the Pharmacokinetic Analysis 
In addition to the objectives described in this section, PK data obtained in this study may also be 
combined with data from other studies to develop population PK models. These models may be used to 
evaluate the effects of intrinsic and extrinsic covariates on the PK ofNKTR-214 related molecules 
and/or nivolumab and to determine measures of individual exposure for nivolumab (such as single dose 
and steady state peak, trough and time averaged concentration, CL volume, half-life) and for NKTR-214 
(such as AUC, clearance, volume, half-life, Cmax, Cmin, and Cavg). Model predicted exposures may 
be used for exposure-response analyses of selected efficacy and safety endpoints. Population PK 
analysis will be specified in a separate analysis plan and results of any population PK and/or exposure-
response analyses will be reported separately. 
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Statistical Analysis Plan 
Protocol16-214-02 
10.1.1 
Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set (PKAS) will consist of 5 different analyses. The PKAS includes all 
patients who received at least 1 dose ofNK.TR-214 and at least 1 measurable concentration of: 
• 
NK.TR-214-RC (related cytokine) PKAS: NK.TR-214-RC 
• 
NK.TR-214-AC (active cytokine) PKAS: NKTR-214-AC 
• 
Total-PEG PKAS: Total-PEG 
• 
Nivolumab PKAS: Nivolumab 
• 
lpilimumab PKAS: lpilimumab 
10.2 
General Analysis Considerations and Definitions 
10.2.1 
Pharmacokinetic Parameters 
For Cycle 1 (all patients) and Cycle 2 (Part 1 only), PK parameters will be derived by Phoenix 
WinNonlin (version 8.3 or higher) based on noncompartmental (NCA) methods. PK parameters 
(Table 11) will include Cmax, Tmax, AUCtast, AUCinf(for Cycle 1 only), Vz, CL, and ttnforNKTR-214-
RC, NK.TR-214-AC, and Total-PEG. For NKTR-214-RC and NK.TR-214-AC, AUCo-96h, AUCo-168b 
may also be derived. Time zero will be defined as the start time of the infusion. Linear-up/log-down 
NCA methods will be used to estimate AUC. For Cycle 2 and beyond, the predose concentration may be 
duplicated as the last time point in the previous cycle for the calculation of PK parameters. 
NCA PK parameters will only be derived when all requirements are met per Table 12. Where 
requirements are not met, PK parameter values will be reported as "not determinable". 
Table 11: 
Pharmacokinetic Parameter Def'mitions 
PK Parameter 
Description 
AUC;m 
Area under the concentration-time curve calculated from time 0 to infinity 
AUC~ut 
Area under the concentration-time curve calculated from time 0 to the last measurable concentration 
AUCo-96h 
Area under the concentration-time curve calculated from time 0 to 96 hours after dosing 
AUCo-t68h 
Area under the concentration-time curve calculated from time 0 to 168 hours after dosing 
CL 
Systemic clearance 
Cm.x 
Maximum observed concentration following drug administration 
tv'2 
Half-life: the time required for the concentration to reach half of its original value 
Tmu 
Time to reach maximum concentration 
Vz 
Volume of distribution during the terminal elimination phase following intravenous administration 
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Statistical Analysis Plan 
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Table 12: 
Noneompartmental Analysis Requirements 
PK Parameter 
Requirement 
A minimum of 3 time points should be used for determining lambda_ z, not including the Cmax time 
point. 
t112, AUCmr, CL, V, The span of the terminal phase must be at least 2 times the half-life for lambda_z to be determined. 
Where Rsq_adj < 0.75, lambda_z will not be determined 
If lambda_ z is not determined then tl/2, AUCinf, CLIF, or Vz will not be reported 
AUC;m 
The extrapolated area should not contribute more than 20% to the total AUC;m for the estimation of 
AUC;m 
10.3 
Pharmaeokinetie Measurements and Endpoints 
10.3.1 
Presentation oflndividual and Mean Data 
Graphical presentations of concentration data by sampling time, including individual and group mean 
values, will be provided. For all cycles, summary statistics of concentration data by scheduled sampling 
time will be provided. PK samples that were collected outside the protocol accepted time windows will 
be excluded from summary tables and summary figures. Descriptive statistics of all PK parameters will 
include geometric and arithmetic means, sample size (n), standard deviation, CV% and CV% geometric 
mean, median, minimum and maximum. 
10.3.1.1 
Handling of Missing Values, BLQ Values, and Outliers 
• 
NKTR-214-RC, NKTR-214-AC, and Total-PEG 
Missing concentration values will not be imputed. When summarizing concentrations, zero values will 
be excluded from the calculation of geometric means and CV% geometric mean, however, they will be 
included for all other summary statistics and the number of non-zero concentrations will be reported. 
Missing values for any PK parameters will not be imputed and will be handled as missing. 
When calculating PK parameters, all Cycle 1 pre-dose concentrations that are below the limit of 
quantification (BLQ) will be set to 0; all other concentrations that are BLQ will be set to missing. 
Cycle 1 pre-dose concentrations >50% of Cycle 1 Cmax, will be excluded from concentration statistics 
and the individual patient PK parameter calculation. Cycle 1 PK parameters for this subject may also be 
excluded from summary tables. 
• 
Nivolumab and ipilimumab 
Missing pre-dose concentration values (except for pre-dose C1D1) will be imputed as LLOQ/2. Listings 
for pre-dose concentrations values (except for pre-dose C 1 D 1) will list these concentrations as <LLOQ. 
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11.0 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
No changes from the protocol specified analyses are planned. 
12.0 
REFERENCES 
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Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial ofnanoparticle albumin-bound paclitaxel 
compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin 
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Guidance for Industry, Immunogenicity Assessment Therapeutic Protein Products, FDA, 2014. 
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Harris LN, Broadwater G, Lin NU, et al. Molecular subtypes of breast cancer in relation to paclitaxel 
response and outcomes in women with metastatic disease: results from CALGB 9342. Breast 
Cancer Research. 2006;8(6):R66. 
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, 
PD-Ll-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet. 2016;387:1540-50. 
Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal 
junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens 
(ON0-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 
trial. Lancet. 2017;390:2461-71. 
Kaufinan PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate 
versus capecitabine in patients with locally advanced or metastatic breast cancer previously 
treated with an anthracycline and a taxane. J Clin Oncol. 2015;33:594-601. 
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J 
Med. 2015;372:2509-20. 
Mcintyre K, O'Shaughnessy J, Schwartzberg L, et al. Phase 2 study of eribulin mesylate as first-line 
therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative 
breast cancer. Breast Cancer Res Treat. 2014;146:321-8. 
Mizuki, Nishino., et al. Cancer immunotherapy and immune-related response assessment: The role of 
radiologists in the near arena of cancer treatment. Eur J Radiology. 2015; 84: 1259-1268. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 
Nomura M, Otsuka A, Kondo T, et al. Efficacy and safety ofretreatment with nivolumab in metastatic 
melanoma patients previously treated with nivolumab. Cancer Chemother Pharmacol. 
2017;80:999-1004. 
Overman MJ, McDermott R,Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch 
repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-
label, multicentre, phase 2 study. 2017;18:1182-91. 
Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum 
failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, 
phase 1 trial. Lancet Oncol. 2018;19:51-64. 
Rizvi NA, Hellmann MD, Brahmer JR, et al. Nivolumab in Combination With Platinum-Based Doublet 
Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin 
Oncol. 2016;34:2969-79. 
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF 
mutation. N Engl J Med. 2015;372:320-30. 
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Statistical Analysis Plan 
Protocol16-214-02 
Rugo HS, Delord JP, 1m SA, eta!. Safety and Antitumor Activity ofPembrolizumab in Patients with 
Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced 
Breast Cancer. Clinical Cancer Research. 2018;24(12):2804-11. 
Shankar G, Arkin S, Cocea L, eta!. Assessment and Reporting of the Clinical Immunogenicity of the 
Therapeutic Proteins and Peptides - Harmonized Terminology and Tactical Recommendations. 
The AAPS Journal2014; DOI:10.1208/s12248-014-9599-2. 
Therneau 1M, Atkinson EJ. An introduction to recursive partitioning using the RPART routines. Mayo 
clinic technical report, 2019. 
Topalian S, Hodi F, Brahmer J, eta!. Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Eng! J Med 2012;366:2443-2454. 
Twelves C, Cortes J, Vahdat L, eta!. Efficacy of eribulin in women with metastatic breast cancer: a 
pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 2014;148(3):553-61. 
Wolchok, J. D., eta!. Guidelines for evaluation for immune therapy activity in solid tumors: immune-
related response criteria. Clin Cancer Res. 2009; 15 (23): 7412-7420. 
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Statistical Analysis Plan 
Protocol16-214-02 
13.0 
APPENDICES 
APPENDIX 1: EVALUATION OF OVERALL RESPONSE USING RECIST 1.1 
Overall Response Subsequent Time 
Overall Response First Time Point 
Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
PR• 
CR 
SD: 
SD provided minimum criteria for SD 
duration met, otherwise, PD. 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD. 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE. 
PR 
CR 
PR, except if next time point is CR, then 
overall CR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD. 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise, NE. 
NE 
NE 
NE 
Abbreviations CR, complete response, PR, partial response, SD, stable disease, PD, progressive disease, and NE, not 
evaluable. 
a. 
If a CR is truly met at fll"St time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However, sometimes 'CR' may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time 
point. Under these circumstances, the original CR should be changed to PR and the best response is PR 
Source: Eisenhauer, 2009 
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16.1.9 Documentation of Statistical Methods 
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Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
APPENDIX 2: COHORT GROUPS IN THE FINAL ANALYSIS 
Cancer Diagnosis in EDC 
[Cohort#, if applicable] 
Melanoma 
MEL (IL) [lA] 
MEL IL [] 
MEL IL ADJ [ID] 
MEL 2-3L, I-0 RELAPSE/ 
REFRACTORY [IB] 
MEL 2L ANTI-PD(L)I RR 
BRAFWT[IC] 
RENAL CELL CARCINOMA 
RENAL CELL CARCINOMA 
RCC IL [2A] 
RCC 2-3L ANTI-PD(L)I RR 
[2B]' 
RCC (2-3L, I-0 RELAPSE/ 
REFRACTORY) [2B]' 
RCC OTHER [2C] 
RCC IL [] 
RCC IL [IOA.3] 
UROTHELIAL IL [4A.2] 
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Phase 
Part I 
Part2 
Part3 
Part2 
Part2 
Part2 
Part I 
Part I 
Part2 
Part2 
Part2 
Part2 
Part3 
Part4 
Part2 
Final Analysis and 
Reporting Cohort 
ILMEL 
ILMELRP2D 
Triplet IL Melanoma 
Schedule2 
MEL ILADJ 
MEL 2-3L Anti-
PD(L)I 
MEL 2L Anti-PD(L)I 
BRAFWT 
ILRCC 
2L RCC I-0 Naive 
(If the patient 
received prior 
systemic therapy in 
locally advanced or 
metastatic setting) 
ILRCCR2PD 
RCC 2-3L ANTI-
PD(L)I RR 
RCC 2-3L ANTI-
PD(L)I RR 
RCC-Other 
Triplet IL RCC 
Triplet IL RCC 
Schedule 3 
UCC IL REFUSED 
soc 
Protocol16-214-02 
Treatment 
NKTR 0.006 Q2W/NIVO 240 Q2W, 
NKTR 0.006 Q3W/NIVO 240 Q2W, 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO IMG 
Q3WIIP1L 3 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.003 Q2W/NIVO 240 Q2W, 
NKTR 0.006 Q2W/NIVO 240 Q2W, 
NKTR 0.006 Q3W/NIVO 360 Q3W, 
NKTR 0.009 Q3W/NIVO 360 Q3W 
NKTR 0.003 Q2W/NIVO 240 Q2W, 
NKTR 0.006 Q2W/NIVO 240 Q2W, 
NKTR 0.006 Q3W/NIVO 240 Q2W, 
NKTR 0.006 Q3W/NIVO 360 Q3W, 
NKTR 0.009 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
NKTR 0.006 Q3W/NIVO 360 
Q3WIIP1L I Q6W, NKTR 0.006 
Q3W/NIVO 3MG Q3WIIP1L I Q3W 
NKTR 0.006 Q3W/NIVO 3MG 
Q3WIIP1L I Q3W 
NKTR 0.006 Q3W/NIVO 360 Q3W 
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Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Cancer Diagnosis in EDC 
[Cohort#, if applieable] 
UROTHELIAL IL CIS-
INELIGffiLE [4A.I] 
UROTHELIAL 3L, 1-0 
RELAPSE! REFRACTORY 
[4B]' 
UCC 2-3L ANTI-PD(L)I RR 
[4B]' 
UROTHELIAL 3L, 1-0 
RELAPSE/ REFRACTORY 
[4C] 
UCC IL [] 
TNBC 1-2L 1-0 NAIVE [5A]b 
TNBC I-2L, 1-0 THERAPY 
NAIVE [5A]b 
HR POS BC 1-0 NAIVE 
CHEM0[6B] 
GC 2-3L 1-0 NAIVE [7] 
CRC 2-3L 1-0 NAIVE MSI-
HIGH[8A] 
CRC 3L 1-0 NAIVE MSI-NON 
HIGH[8B] 
NON-SMALL CELL LUNG 
CANCER 
NON-SMALL CELL LUNG 
CANCER 
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Phase 
Part2 
Part2 
Part2 
Part2 
Part3 
Part2 
Part2 
Part2 
Part2 
Part2 
Part2 
Part I 
Part 1 
Final Analysis and 
Reporting Cohort 
UCC IL CIS-INEL 
UCC 2-3L ANTI-
PD(L)I RR 
UCC 2-3L ANTI-
PD(L)I RR 
UCC-Other 
Triplet IL UCC 
Schedule2 
TNBC I-2L 1-0 
NA1VE(5a) 
TNBC I-2L 1-0 
NA1VE(5a) 
HRPOSBCI-0 
NANECHEMO 
GC2-3LI-ONA1VE 
CRC2-3LI-O 
NAivE MSI-HIGH 
CRC 3L 1-0 NAIVE 
MSI-NONHIGH 
Depeoding oo PD-LI 
Ceotral Test assigoed 
to ooe of the 
following cohorts 
NSCLC IL PD-LI 
<1% 
NSCLC IL PD-LI 
~I%- <50% 
NSCLC lL PD-LI 
~50% 
NSCLC lL PD-LI 
Missing 
NSCLC2LI-O 
NAivE 
FOLLOWING PLAT 
(If the patieot 
received prior 
systemic therapy in 
Protocol16-214-02 
Treatment 
NK1R 0.006 Q3W/NIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3W/NIVO 360 Q3W 
NK1R 0.006 Q3WINIVO IMG 
Q3W/IPIL 3 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
NK1R 0.003 Q2WINIVO 240 Q2W, 
NK1R 0.006 Q3WINIVO 360 Q3W, 
NK1R 0.009 Q3WINIVO 360 Q3W 
NK1R 0.006 Q3WINIVO 360 Q3W 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Cancer Diagnosis in EDC 
[Cohort#, if applieable] 
NSCLC IL [IIA.I] 
NSCLC IL [IIA.I] 
NSCLC 1L NONSQ PLAT/ 
PEMMAlN [3D.1] 
NSCLC 1LPD-L1 < 1% [3A.1] 
NSCLC 1L PD-Ll >= 1% - < 
50% [3A.2] 
NSCLC 1L PD-L1 >= 50% 
[3A.3] 
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Phase 
Part3 
Part4 
Part2 
Part2 
Part2 
Part2 
Final Analysis and 
Reporting Cohort 
locally advanced or 
metastatic settiog) 
Triplet IL NSCLC 
Schedule I 
Triplet 1L NSCLC 
Schedule 1 
NSCLC 1L NONSQ 
PLAT/PEM MA1N 
Depeoding on PD-L1 
Ceotral Test assigoed 
to one of the 
followiog cohorts 
NSCLC 1L PD-Ll 
<1% 
NSCLC 1L PD-Ll 
~1%- <50% 
NSCLC 1L PD-Ll 
~50% 
NSCLC 1L PD-Ll 
Missiog 
Depeoding on PD-L1 
Ceotral Test assigoed 
to one of the 
followiog cohorts 
NSCLC 1L PD-Ll 
<1% 
NSCLC 1L PD-Ll 
~1%- <50% 
NSCLC 1L PD-Ll 
~50% 
NSCLC 1L PD-Ll 
Missing 
Depeoding on PD-Ll 
Ceotral Test assigoed 
to one of the 
followiog cohorts 
NSCLC 1L PD-Ll 
<1% 
NSCLC 1L PD-Ll 
~1%- <50% 
NSCLC 1L PD-Ll 
~50% 
NSCLC 1L PD-Ll 
Missing 
Protocol16-214-02 
Treatment 
NKTR 0.006 Q3W/NNO 360 
Q3W/IPIL I Q6W 
NKTR 0.006 Q3W/NNO 360 
Q3W/IPIL 1 Q6W 
NKTR 0.006 Q3W/NNO 360 
Q3W+Cbemo 
NKTR 0.006 Q3W/NNO 360 Q3W 
NKTR 0.006 Q3W/NNO 360 Q3W 
NKTR 0.006 Q3W/NNO 360 Q3W 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Protocol16-214-02 
Cancer Diagnosis in EDC 
Name Used in Study 
Final Analysis and 
[Cohort#, if applieable] 
Phase 
Reporting Cohort 
Treatment 
NSCLC, I-0 RELAPSE/ 
Part2 
NSCLC 2-3L ANTI-
NKTR 0.006 Q3W/NNO 360 Q3W 
REFRACTORY [3C]' 
PD(L)I RR 
NSCLC 2-3L ANTI-PD(L)I RR 
Part2 
NSCLC 2-3L ANTI-
NKTR 0.006 Q3W/NNO 360 Q3W 
[3C]' 
PD(L)I RR 
NSCLC2LFOLLOWING 
Part2 
NSCLC2L 
NKTR 0.006 Q3W/NNO 360 Q3W 
PLATDBLT/ ANTI-PD-1 [3H] 
FOLLOWING 
PLAT/DBLT/ANTI-
PD-1 
NSCLC 2L, I-0 THERAPY 
Part2 
NSCLC2LI-O 
NKTR 0.006 Q3W/NNO 360 Q3W 
NAIVE [3B] 
NAivE 
FOLLOWING PLAT 
NSCLC IL SQ PLAT/ TAX 
Part2 
NSCLC ILSQ 
NKTR 0.006 Q3W/NNO 360 
[3E] 
PLAT/TAX 
Q3W+Chemo 
NSCLC OTHER [31] 
Part2 
NSCLC - Other 
NKTR 0.006 Q3W/NNO 360 Q3W 
a. 
Name for these cohorts (2b, 3c, 4b) IS changed from 'I-0 RELAPSE/ REFRACTORY' to 'ANTI-PD(L)I RR' m 
Protocol Amendment 5 and oowards. 
b. 
Name in EDC was updated from 'TNBC 1-2L I-0 NAIVE [5A]' to 'TNBC 1-2L I-0 THERAPY NAIVE [5A]' in 
the middle of the study. 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
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Statistical Analysis Plan 
Protocol16-214-02 
APPENDIX 3: TIME-TO ONSET AND TIME-TO RESOLUTION DEFINITION AND 
CONVENTIONS FOR SELECT ADVERSE EVENTS, IMMUNE-MEDIATED 
ADVERSE EVENTS AND EVENTS OF INTEREST 
Time-to onset def'mition 
Time-to onset of AE (any grade) for a specific category is defined as the time between the day of the first 
dose of study treatment and the onset date of the earliest AE (of any grade) in this category. 
The time-to onset of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE. 
Time-to onset of drug-related AE (any grade or grade 3-5) for a specific category is defmed similarly but 
restricted to drug-related AE. 
Time-to onset for a specific subcategory is defmed similarly but restricted to event of this subcategory. 
Time-to resolution defmition 
In order to derive the time-to resolution, overlapping or contiguous AEs within a specific category or 
subcategory will be collapsed into what will be termed "clustered" AEs. For example, if a subject (without 
pre-treatment AE) experienced an AE from 1st to 5th January, another AE (with different PT but within 
same category) from 6th to 11th January and same AE from 1Oth to 12th January, these will be collapsed 
into one clustered AE from 1st to 12th January. Table 13: 
Derivation of Clustered AE is summarizing 
key derivation steps for each type of clustered AEs. 
Time-to resolution of AE (any grade) for a specific category is defmed as the longest time from onset to 
complete resolution among all clustered AEs experienced by the subject in this category per adverse event 
criteria category. Events which worsened into grade 5 events (death) or have a resolution date equal to the 
date of death are considered unresolved. If a clustered AE is considered as unresolved, the resolution date 
will be censored to the last known alive date. This measure is defmed only for subjects who experienced 
at least one AE in the specific category. 
The time-to resolution of AE (grade 3-5) for a specific category is defined similarly with an onset date 
corresponding to a grade 3-5 AE. 
Time-to resolution of drug-related AE (any grade or grade 3-5) for a specific category is defined similarly 
but restricted to drug-related AE. 
The time-to resolution of AE (any grade or grade 3-5. drug-related or all) where immune modulating 
medication was initiated is defined similarly. For data presentation not restricted to IMAE, the additional 
condition that the subject started an immune modulating medication during the longest AE resolution 
period will be applied. 
Time-to resolution for a specific subcategory is defined similarly but restricted to event of this 
subcategory. 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214) 


Statistical Analysis Plan 
Protocol16-214-02 
Table 13: 
Derivation of Clustered AE 
Type of clustered AE 
Any grade 
Drug-related of any grade 
Grade 3-5 
Drug-related of Grade 3-5 
Derivation 
Collapse any on-treatment AE from the same category 
Collapse any on-treatment drug-related 
AE from the same category 
Collapse any on-treatment AE from the same category. 
Resolution will be based on the onset date of the earliest grade 3-
5 records (if no grade 3-5 record, clustered AE is excluded) 
Collapse any on-treatment drug-related AE from the same 
category 
Resolution will be based on the onset date of the earliest grade 3-
5 record (if no Grade 3-5 record, clustered AE is excluded) 
The algorithm for collapsing adverse event records is using the following conventions: 
For each subject and specified category, the corresponding adverse event records will be collapsed when: 
1) Multiple adverse event records have the same onset date. 
2) The onset date of an event record is either the same day or 1 day later than the resolution date of a 
preceding event record (contiguous events). 
3) The onset date of an event record is after the onset date and prior to or on the resolution date of a 
preceding event record (overlapping events). 
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16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
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Docu~ 
 
16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)


16.1.9 Documentation of Statistical Methods 
Bempegaldesleukin (NKTR-214)


16.1.9 Documentation of Statistical Methods 
Clinical Study Report 16-214-02 (PIVOT-02)
Bempegaldesleukin (NKTR-214)