Clinical trial NCT04616196
Conditions: Head and Neck Squamous Cell Carcinoma Colorectal Cancer
Keywords: HNSCC Head and Neck Squamous Cell Carcinoma CRC Colorectal Cancer NKTR-255 Cetuximab Erbitux®
Sponsor: Nektar Therapeutics
Start date: 2020-10-30; Completion date: 2023-03-30
Enrollment: 25 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1b/2, open-label multicenter study evaluating NKTR-255 as a monotherapy and together with cetuximab in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal carcinoma (CRC).

Detailed description:
NKTR-255 is a cytokine that is designed to regulate T and natural killer cell activation, proliferation and promote their anti-tumor effects.

In the dose escalation (Phase 1/b) phase patients with HNSCC or CRC will be treated with ascending doses of NKTR-255 in combination with cetuximab, until the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) is reached.

Arms: arm 1: Establish RP2D, of NKTR-255 with cetuximab.
Interventions: intervention 1: NKTR-255 intervention 2: Cetuximab
Intervention descriptions: intervention 1: NKTR-255 IV every 21 days intervention 2: Cetuximab will be given at specified doses on specified days

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol 19-255-03 
 
 
A PHASE 1B/2, OPEN-LABEL, MULTICENTER, 
DOSE ESCALATION AND DOSE EXPANSION 
STUDY OF NKTR-255 MONOTHERAPY OR IN 
COMBINATION WITH CETUXIMAB AS A 
SALVAGE REGIMEN FOR SOLID TUMORS 
 
NCT04616196 
 
Approval Date: 08 October 2021 


Protocol No. 19-255-03 Amendment 2.0 
 
NKTR-255 
Nektar Therapeutics 
 
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Nektar Therapeutics 
CLINICAL STUDY PROTOCOL 
A PHASE 1B/2, OPEN-LABEL, MULTICENTER, DOSE ESCALATION, AND DOSE 
EXPANSION STUDY OF NKTR-255 MONOTHERAPY OR IN COMBINATION WITH 
CETUXIMAB AS A SALVAGE REGIMEN FOR SOLID TUMORS 
Protocol Number: 
19-255-03 
Protocol Date:   
08 October 2021  
Protocol Amendment Number: 
2.0  
Supersedes: 
Amendment 1.0 dated 07 August 2020 
Original Protocol dated 19 June 2020 
US IND Number: 
146,184 
Ex US: 
Non-IND 
Eudra CT No.:  
2021-002177-25 
Investigational Products: 
NKTR-255 and NKTR-255 in combination with 
cetuximab 
Indication: 
Relapsed or refractory advanced solid tumors 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
Sponsor’s Medical Contact and 
Study Medical Monitor: 
 
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. 
PPD
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INVESTIGATOR SIGNATURE PAGE 
Nektar Therapeutics 
TITLE: 
A PHASE 1B/2, OPEN-LABEL, MULTICENTER, DOSE 
ESCALATION, AND DOSE EXPANSION STUDY OF 
NKTR-255 MONOTHERAPY OR IN COMBINATION 
WITH CETUXIMAB AS A SALVAGE REGIMEN FOR 
SOLID TUMORS  
PROTOCOL NUMBER: 
19-255-03 
PHASE OF STUDY: 
1B/2 
PROTOCOL DATE: 
08 October 2021 
PROTOCOL 
AMENDMENT NO: 
2.0  
SUPERSEDES: 
Amendment 1.0 dated 07 August 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 
Institution: 
Address: 
 
Date 
 
 


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LIST OF STUDY CONTACTS 
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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .......................................................................................................................10 
LIST OF FIGURES .....................................................................................................................10 
LIST OF APPENDICES .............................................................................................................11 
ABBREVIATIONS ......................................................................................................................12 
1.0 
STUDY SYNOPSIS .........................................................................................................17 
1.1 
Study Schematic.....................................................................................................24 
1.2 
Schedules of Events ...............................................................................................27 
2.0 
INTRODUCTION............................................................................................................59 
2.1 
Background ............................................................................................................59 
2.1.1 
Expansion of NKTR-255 Clinical Development Plan for the 
Treatment of Solid Tumors ...................................................................60 
2.2 
NKTR-255 .............................................................................................................63 
 
 
 
 
 
 
2.2.3 
Clinical Experience with NKTR-255 ....................................................65 
 
 
 
 
2.2.6 
Selection of NKTR-255 Recommended Phase 2 Dose (RP2D) ...........66 
2.2.6.1 
Safety Considerations for NKTR-255 and Cetuximab 
Combination ..................................................................................66 
 
 
3.0 
OBJECTIVES ..................................................................................................................69 
3.1 
Primary Objectives .................................................................................................69 
3.2 
Secondary Objectives .............................................................................................69 
 
 
4.0 
SELECTION OF STUDY POPULATION ...................................................................71 
4.1 
Inclusion Criteria ...................................................................................................71 
4.1.1 
Inclusion Criteria for All Patients .........................................................71 
4.1.2 
Inclusion Criteria for Specific Tumor Types ........................................71 
4.2 
Exclusion Criteria ..................................................................................................73 
5.0 
INVESTIGATIONAL PLAN .........................................................................................77 
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5.1 
Overview ................................................................................................................77 
5.1.1 
Phase 1b – Dose Escalation ..................................................................77 
 
 
5.2 
Study Periods .........................................................................................................80 
5.2.1 
Screening Period ...................................................................................80 
5.2.2 
Assigning Patient Numbers ...................................................................80 
5.2.3 
Treatment Period ...................................................................................80 
5.2.3.1 
Criteria for Discontinuation from Treatment .................................81 
5.2.3.2 
End of Treatment Visit...................................................................81 
5.2.3.3 
Criteria for Discontinuation from Study ........................................82 
5.2.3.4 
Replacement of Patients .................................................................82 
5.2.4 
Maintenance Period ...............................................................................82 
5.2.5 
Treatment Beyond Progression .............................................................82 
5.2.6 
Safety Follow-up ...................................................................................83 
5.2.7 
Survival Follow-up ...............................................................................83 
5.2.8 
End of Study ..........................................................................................83 
5.3 
Administration of Study Drug(s) ...........................................................................84 
5.3.1 
NKTR-255 Dosing ................................................................................84 
 
 
 
 
 
 
5.3.1.4 
NKTR-255 Monotherapy with Cetuximab Add-On ......................85 
5.3.1.5 
NKTR-255 Dose Delay and Adjustment Criteria ..........................85 
5.3.1.6 
Criteria to Resume NKTR-255 ......................................................86 
5.3.2 
Cetuximab Dosing .................................................................................86 
5.4 
Determination of Dose-Limiting Toxicities (DLTs) ..............................................87 
5.5 
Dose-Limiting Toxicity Observation Period .........................................................87 
5.5.1 
Dose-Limiting Toxicities Related to NKTR-255 and Cetuximab ........87 
5.5.2 
Grade 3 or 4 AEs that Should Not be Considered a DLT .....................88 
5.5.3 
Delayed Dose-Limiting Toxicities ........................................................88 
5.5.4 
Proposed Stopping Rules ......................................................................88 
5.6 
Safety Review and Data Monitoring ......................................................................90 
5.7 
Permanent Treatment Discontinuation Criteria .....................................................90 
5.8 
Dose Escalation Decision Criteria .........................................................................91 
5.9 
Determination of MTD ..........................................................................................92 
5.10 
Prior and Concomitant Medications ......................................................................92 
5.10.1 
Permitted Medications ..........................................................................92 
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5.10.2 
Permitted Cetuximab Pre-/Post-Infusion Medication ...........................93 
5.10.3 
Prohibited Medications .........................................................................93 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.12 
Management of Potential Risks Associated with Cetuximab ..............................100 
5.13 
Study Assessments ...............................................................................................101 
5.13.1 
Tumor and Radiographic Assessments ...............................................101 
5.13.2 
Pharmacokinetic Measurements..........................................................101 
 
 
 
 
 
 
 
 
5.13.5 
Electrocardiogram ...............................................................................103 
5.13.6 
Serology ..............................................................................................104 
6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ............................................105 
6.1 
NKTR-255 ...........................................................................................................105 
6.1.1 
Drug Description and Formulation .....................................................105 
6.1.2 
Drug Packaging and Labeling .............................................................105 
6.1.3 
Drug Reconstitution and Handling......................................................105 
6.1.4 
Drug Storage .......................................................................................105 
6.1.5 
Drug Shipment ....................................................................................105 
6.2 
Cetuximab ............................................................................................................105 
6.3 
Study Drug Accountability and Reconciliation ...................................................106 
7.0 
ASSESSMENT OF SAFETY OR AES AND SERIOUS AES ...................................107 
7.1 
AE Definition and Assessment ............................................................................107 
7.2 
Monitoring AEs ...................................................................................................107 
7.3 
Grading of AEs ....................................................................................................108 
7.4 
Causality Relationship of AEs .............................................................................109 
7.5 
AE Reporting and Follow-up ...............................................................................109 
7.6 
Serious AE Definition ..........................................................................................109 
7.7 
Serious AE Reporting ..........................................................................................110 
7.7.1 
Electronic Serious Adverse Event (eSAE) Reporting Process ...........110 
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7.8 
Serious AE Follow-up..........................................................................................111 
7.9 
Disease Progression and Death Due to Disease Progression – Not Reportable 
as an AE/SAE ......................................................................................................112 
7.10 
Pregnancy .............................................................................................................112 
7.10.1 
Pregnancies in Female Patients ...........................................................112 
7.10.2 
Pregnancies in Female Partners of Male Patients ...............................113 
7.11 
Pregnancy Tests ...................................................................................................113 
7.12 
Clinical Laboratory Tests .....................................................................................113 
7.13 
Physical Examinations .........................................................................................114 
7.14 
Vital Signs ............................................................................................................114 
7.15 
Electrocardiograms ..............................................................................................114 
7.16 
Cardiac Function ..................................................................................................115 
8.0 
ASSESSMENT OF EFFICACY ...................................................................................116 
8.1 
Treatment Response Assessment .........................................................................116 
8.2 
Tumor Imaging (Computed Tomography or Magnetic Resonance Imaging) .....116 
 
 
9.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE ....................................................................118 
9.1 
General Considerations ........................................................................................118 
9.2 
Determination of Sample Size .............................................................................118 
9.3 
Safety Stopping Rules ..........................................................................................119 
9.4 
Interim Analyses ..................................................................................................119 
9.5 
Analysis Sets ........................................................................................................119 
9.6 
Planned Analyses .................................................................................................120 
9.6.1 
Safety ..................................................................................................120 
9.6.2 
Demographics and Baseline Characteristics .......................................121 
9.6.3 
Efficacy ...............................................................................................121 
 
 
 
 
9.7 
Concomitant Medications ....................................................................................122 
9.8 
Missing Data ........................................................................................................122 
10.0 
STUDY OR STUDY SITE TERMINATION ..............................................................123 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...........................................124 
11.1 
Changes to the Protocol .......................................................................................124 
11.2 
Monitoring ...........................................................................................................124 
11.3 
Direct Access to Source Data/Documents for Audits and Inspections ................125 
12.0 
ETHICAL CONSIDERATIONS ..................................................................................126 
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12.1 
IRB/IEC Approval ...............................................................................................126 
12.2 
Written Informed Consent ...................................................................................126 
13.0 
DATA HANDLING AND RECORD KEEPING ........................................................128 
13.1 
Data Collection Instruments and Source Documents ..........................................128 
13.1.1 
Study Records .....................................................................................128 
13.1.2 
Data Collection Instruments ................................................................128 
13.2 
Retention of Essential Documents .......................................................................128 
13.3 
Confidentiality .....................................................................................................129 
13.4 
Security Measures ................................................................................................129 
13.5 
Publication Plan ...................................................................................................129 
14.0 
REFERENCES ...............................................................................................................130 
 




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LIST OF APPENDICES 
Appendix 1: 
Prior Calibration and On-Study Dose Escalation Recommendations of 
the Bayesian Logistic Regression Model .................................................135 
Appendix 2: 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ................146 
 
 
Appendix 4: 
Clinical Laboratory Tests (Only Tests Done via Central Laboratory) ....149 
Appendix 5: 
ECOG Performance Scale ........................................................................150 
Appendix 6: 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
Creatinine Equation .................................................................................151 
Appendix 7: 
Acceptable Methods of Contraception .....................................................152 
 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
5-FU 
5-fluorouracil 
 
 
ADCC 
antibody-dependent cellular cytotoxicity  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
absolute neutrophil count 
anti-HBc 
antibodies to hepatitis B core antigens  
anti-HBs 
antibodies to hepatitis B surface antigens  
anti-PD-1 
antibody to programmed cell death protein 1 
anti-PD-L1 
antibody to programmed death-ligand 1  
anti-PD-(L)1 
anti-PD-1 antibody or anti-PD-L1 antibody  
ASBMT 
American Society for Blood and Marrow Transplantation 
 
 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
area under the concentration-time curve 
β 
beta  
β-HCG 
beta subunit of human chorionic gonadotropin 
BiPAP 
bilevel positive airway pressure 
BLRM 
Bayesian logistic regression model 
BOR 
best overall response  
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CK 
creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CL 
clearance 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum peak concentration 
CnDn 
Cycle n Day n (eg, Cycle 1 Day 1 = C1D1) 
CO2 
carbon dioxide 
COVID-19 
coronavirus disease 2019 
CPAP 
continuous positive airway pressure 
CR 
complete response 
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Abbreviation or Term 
Definition 
CRC 
colorectal carcinoma or colorectal cancer 
CRS 
cytokine release syndrome  
 
 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DCI 
data collection instrument 
DLT  
dose-limiting toxicity 
dMMR 
mismatch repair deficient  
DOR 
duration of response 
DSMC 
Data Safety Monitoring Committee 
EBV 
Epstein-Barr virus 
EC50 
half maximal effective concentration  
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor  
EMA 
European Medicines Agency 
EOI 
end of infusion 
EOT 
end of treatment 
eSAE 
electronic serious adverse event 
ESS 
effective sample size 
EWOC 
escalation with overdose control 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
γ 
gamma 
GCP 
Good Clinical Practice (guidelines) 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice (guidelines) 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCG 
human chorionic gonadotropin 
HCT 
hematocrit 
HCV 
hepatitis C virus 
HCV-RNA 
hepatitis C virus ribonucleic acid  
Hep B 
hepatitis B 
Hep C 
hepatitis C 
HER2 
human epidermal growth factor receptor 2 
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Abbreviation or Term 
Definition 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous cell carcinoma 
HPV 
human papillomavirus  
hr 
hour 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IEC 
independent ethics committee 
IFNα 
interferon alpha  
IgG1 
immunoglobulin gamma-1 
IHC 
immunohistochemistry 
IL-2 
interleukin-2  
IL-15 
interleukin-15  
IL-15Rα 
IL-15 receptor alpha  
IL-n 
interleukin-n (eg, interleukin 2 = IL-2) 
IND 
Investigational New Drug (application) 
IRB 
institutional review board 
IRR 
infusion-related reaction 
 
 
IV 
intravenous(ly) 
JAK-STAT5  
Janus kinase/signal transducer and activator of transcription-5  
kDa 
kilodalton 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog  
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCMC 
Markov chain Monte Carlo 
MCP-1 
monocyte chemoattractant protein-1  
mCRC 
metastatic colorectal carcinoma 
MCV 
mean corpuscular volume 
MM 
multiple myeloma 
mmHg 
millimeters of mercury 
MMR 
mismatch repair 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
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Abbreviation or Term 
Definition 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer 
NKT 
natural killer T cells 
NRAS 
neuroblastoma RAS viral oncogene homolog 
ORR 
objective response rate  
OS 
overall survival 
PaO2 
oxygen saturation 
PD 
pharmacodynamic(s) 
PD-1 
programmed cell death protein 1  
PD-L1 
programmed death ligand 1  
PEG 
polyethylene glycol 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
q21d 
every 21 days  
q28d 
every 28 days  
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-15 
recombinant human interleukin-15 
RP2D 
recommended Phase 2 dose 
R/R 
relapsed or refractory 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2  
SCC 
squamous cell carcinoma 
sCD25 
soluble CD25 
SD 
stable disease 
sIL-15Rα 
soluble IL-15 receptor alpha  
SOI 
start of infusion 
SOP 
standard operating procedure 
SRC 
Safety Review Committee  


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Abbreviation or Term 
Definition 
STAT5 
signal transducer and activator of transcription-5 
sTNF RI 
soluble tumor necrosis factor receptor I  
sTNF RII 
soluble tumor necrosis factor receptor II  
t1/2 
half-life 
T3 
triiodothyronine 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TGA 
Therapeutic Goods Administration 
TNF 
tumor necrosis factor 
TP 
total protein 
TSH 
thyroid-stimulating hormone 
TTR 
time to response 
UDP 
uridine diphosphate 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
V 
volume of distribution 
WBC 
white blood cell 
WCBP  
women of childbearing potential 
 






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The first patient (a sentinel patient) of each escalating NKTR-255 dose level will be 
monitored for safety and tolerability for 7 days after the first dose of NKTR-255 before 
additional patients are dosed at the same dose level. 
A composite of clinical information will be used to select the RP2D based on safety and 
tolerability, PK, PD, and optimal biological response. Additional patients may be enrolled to 
refine the RP2D, and a minimum of 6 patients will be required to define the RP2D. 
The dose-limiting toxicity (DLT) window is 21 days after the first dose of NKTR-255. 
Patients who achieve optimal response (partial response [PR] or complete response [CR] per 
RECIST 1.1) after at least 1 tumor assessment, as determined by the Investigator and in 
consultation with the Medical Monitor, will be given the option to continue treatment with 
NKTR-255 as single agent for maintenance every 28 days (q28d) at the same dose as the 
patient’s originally assigned dose. 
• 
Intermediate doses may be evaluated. 
• 
No intra-patient dose escalation will be allowed. 
• 
Enrollment into a new dose level with an escalating dose of NKTR-255 cannot begin 
until the DLT window has closed for at least 3 patients in the prior dose level. 
• 
The SRC will assess safety before opening dose escalation to the next level. 
• 
The Sponsor’s decision to declare the RP2D of NKTR-255 can occur at any given dose 
level prior to reaching the MTD based on safety, PK, 
 effects. 
• 
Data from a minimum of 6 evaluable patients are required to define the RP2D. 
• 
Dose reduction of NKTR-255 is not allowed during dose escalation within the DLT 
window. Outside of the DLT window in the dose escalation phase, and during dose 
expansion, dose levels of NKTR-255 may be reduced depending on the severity, 
duration, and frequency of toxicities observed at the previous dose level tested (the dose 
level may be de-escalated in order to characterize RP2D for a specific dose level). 
• 
The cetuximab dose may be reduced or adjusted based on review of available safety and 
tolerability data. Dose adjustment or discontinuation for cetuximab may be required 
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based on emerging toxicities, and should follow the guidelines specified in this protocol 
and in the current local prescribing information for cetuximab. 
Key Eligibility 
Criteria:   
Each patient must meet all of the following criteria to be enrolled in the study (for both dose 
escalation and dose expansion phases): 
• 
Histologically confirmed diagnosis of a locally-advanced (not amenable to curative 
therapy such as surgical resection or radiotherapy) or metastatic cancer of the following 
histologies: HNSCC, CRC, 
 
• 
Life expectancy > 12 weeks as determined by the Investigator. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
• 
Measurable disease per RECIST 1.1. 
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• 
Patients who have received systemic interferon alpha (IFNα) within the previous 
6 months prior to enrollment in the study are not eligible. 
• 
Patients who have been previously treated with interleukin-2 (IL-2) or IL-15 are not 
eligible. 
• 
Demonstrated adequate organ function within 14 days before C1D1. 
• 
Patients with other active malignancy are not eligible, with the exception of: basal cell 
carcinoma of the skin, SCC of the skin that has undergone potentially curative therapy, 
in situ cervical cancer, or prostate cancer under certain circumstances. Patients with 
simultaneous diagnosis of cSCC and hematologic malignancy (eg, chronic lymphocytic 
leukemia [CLL]) are allowed.   
• 
Patients who have previously received cetuximab or other epidermal growth factor 
receptor (EGFR)-directed therapies are excluded from Phase 2 of the trial, unless 
cetuximab was given as part of a primary treatment approach, with no progressive 
disease for at least 4 months following the end of prior cetuximab treatment. 
Head and Neck Squamous Cell Carcinoma  
• 
Patients must have histologically or cytologically confirmed advanced, recurrent, or 
metastatic HNSCC that could not be treated with curative intent. “Advanced” is defined 
as either locally advanced HNSCC not amenable to curative surgery or radiotherapy or 
with distant metastases. 
• 
Patients who have undergone treatment with antibody to programmed cell death protein 
1 (anti-PD-1) or antibody to programmed death-ligand 1 (anti-PD-L1) (together termed 
"anti-PD-(L)1") must have had the last dose of antibody at least 4 weeks prior to 
receiving any study drug and evidence of tumor progression before they can be enrolled 
into this study. 
• 
Patients must have known status by pathology for human papillomavirus (HPV) and 
Epstein-Barr virus (EBV) in HNSCC, either metastatic or recurrent disease. 
• 
Patients must have experienced progression (or toxicity precluding additional treatment) 
on any first- or second-line platinum-based chemotherapy and anti-PD-(L)1 antibody, 
unless they are ineligible for such treatment, OR, 
• 
Patients must be ineligible for platinum-based (either cisplatin or carboplatin) 
chemotherapy or chemoradiation due to decline in renal function and/or patient's 
intolerance. 
Colorectal Cancer 
• 
Patients must have a histologically or cytologically confirmed diagnosis of advanced 
CRC; patients in Phase 2 must have confirmed KRAS (US) or RAS (ex-US) wild type 
EGFR-expressing advanced CRC. “Advanced” is defined as either locally advanced 
unresectable cancer or metastatic disease. 
• 
Patients must have received at least 2 prior cancer therapy regimens administered for 
metastatic disease including fluoropyrimidine, irinotecan, and oxaliplatin, unless 
ineligible or intolerant for such treatment. 
• 
Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient 
(dMMR) tumors must have been exposed to checkpoint inhibitors such as anti-PD-1. 
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Efficacy: 
Tumor measurements will be performed every 9 weeks + 7 days. 
The primary efficacy measurement will be ORR by RECIST 1.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical 
Methods: 
Safety: 
Safety assessments will include AEs, including incidence of SAEs, clinical laboratory tests, 
vital signs, physical examinations, cardiac function tests, and ECGs. The incidence of DLTs 
will be evaluated for each dose level. All treatment-emergent adverse events (TEAEs) will be 
summarized by system organ class and preferred term for each dose level or cohort in the 
dose escalation and dose expansion phases of the study separately. All TEAEs will be 
summarized by incidence, severity, and relationship to study drug(s). 
Clinical laboratory tests and vital signs will be summarized descriptively for each dose level 
in the dose escalation phase and separately for the dose expansion phase of the study. All 
abnormal findings in clinical laboratory test results, vital signs, physical examination, cardiac 
function tests, and ECGs will be listed. 
Efficacy: 
Objective response rate, CBR, and each BOR category will be calculated along with the 95% 
confidence intervals (CIs) based on the exact method. The Kaplan-Meier method will be 
used for the analyses of PFS, OS, and DOR. Time to response will be summarized among 
responders. 
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1.2 
Schedules of Events 
Table 1: 
Schedule of Visits and Assessments – Phase 1b (CRC and HNSCC; NKTR-255 Dose Escalation) 
Eventa  
Screening 
Period 
Treatment Period 
Post-treatment 
Period 
Run-in 
(1 week) 
Day 
Cycle 1 
(21-day cycle) 
Day 
Cycle 2 
(21-day cycle) 
Day 
Cycle 3 
(21-day 
cycle) 
Day 
Cycle 4+ 
(21-day 
cycles) 
Day 
≤ 28d prior to 
Day 1 of Run-
in Period 
-7 
-6 
-4 
1 2 3 4 5 8 10 15 1 2 3 4 8 10 15 1 4 8 15 1 
8 
15 EOTb 
60-day 
Follow
-upc 
Survival 
Follow-
upc 
Windows (days) 
 
+1 
 
 
+1  
 
 
 
 
 
 +1  
 
 
 
 
 
+1  
 
 +1 
 
 
+7 
±14 
Every 
3 months  
±14 days 
Screening Assessments 
Informed consent  
X 
 
Inclusion/exclusion 
criteria 
X 
 
Demographics 
X 
 
Medical/cancer history 
X 
 
Medication/cancer 
therapy historyd 
X 
 
HBV, HCV, HIV 
serologye 
X 
 
MRIf 
X 
 
General and Safety Assessments 
Physical examinationg 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Weight (kg)h  
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Vital signsi  
X 
X 
 
 
X X X X X X X X X X X X X X X X 
 
 
 
X 
 
 
X 
X 
 
 


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Table 1: 
Schedule of Visits and Assessments – Phase 1b (CRC and HNSCC; NKTR-255 Dose Escalation) (Contd) 
Eventa  
Screening 
Period 
Treatment Period 
Post-treatment 
Period 
Run-in 
(1 week) 
Day 
Cycle 1 
(21-day cycle) 
Day 
Cycle 2 
(21-day cycle) 
Day 
Cycle 3 
(21-day 
cycle) 
Day 
Cycle 4+ 
(21-day 
cycles) 
Day 
≤ 28d prior to 
Day 1 of Run-
in Period 
-7 
-6 
-4 
1 2 3 4 5 8 10 15 1 2 3 4 8 10 15 1 4 8 15 1 
8 
15 EOTb 
60-day 
Follow
-upc 
Survival 
Follow-
upc 
Windows (days) 
 
+1 
 
 
+1  
 
 
 
 
 
 +1  
 
 
 
 
 
+1  
 
 +1 
 
 
+7 
±14 
Every 
3 months  
±14 days 
General and Safety Assessments 
ECOG performance 
status 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Echocardiogram or 
MUGA or nuclear scanj  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECGk 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Adverse events review  
Continuous from time of ICF until 60 days after last study treatment dose (refer to Sections 7.5 and 7.7) 
 
Laboratory Assessments 
Pregnancy testl 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Hematologym 
X 
X 
X 
X 
X X  X  X  X X X  X X 
 
X X 
 X X X 
 
 
X 
X 
 
Serum chemistrym 
X 
X 
 
X 
X 
 
 X  X  X X  
 X X 
 
X X 
 X X X 
 
 
X 
X 
 
PT/PTT 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
TSH, T4, lipase, 
amylase, CKn 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
Urinalysis 
X 
X 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 


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Table 1: 
Schedule of Visits and Assessments – Phase 1b (CRC and HNSCC; NKTR-255 Dose Escalation) (Contd) 
Eventa  
Screening 
Period 
Treatment Period 
Post-treatment 
Period 
Run-in 
(1 week) 
Day 
Cycle 1 
(21-day cycle) 
Day 
Cycle 2 
(21-day cycle) 
Day 
Cycle 3 
(21-day 
cycle) 
Day 
Cycle 4+ 
(21-day 
cycles) 
Day 
≤ 28d prior to 
Day 1 of Run-
in Period 
-7 
-6 
-4 
1 2 3 4 5 8 10 15 1 2 3 4 8 10 15 1 4 8 15 1 
8 
15 EOTb 
60-day 
Follow
-upc 
Survival 
Follow-
upc 
Windows (days) 
 
+1 
 
 
+1  
 
 
 
 
 
 +1  
 
 
 
 
 
+1  
 
 +1 
 
 
+7 
±14 
Every 
3 months  
±14 days 
PK 
 Assessments 
PK (NKTR-255)o 
(See Table 7 for 
sampling times) 
 
 
 
 
X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
 
PK (cetuximab)o 
(See Table 7 for 
sampling times) 
 
X 
 
 
X X X X X X X X X X X X X X X X X X X X X 
X 
X 
X 
 
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Table 1: 
Schedule of Visits and Assessments – Phase 1b (CRC and HNSCC; NKTR-255 Dose Escalation) (Contd) 
Eventa  
Screening 
Period 
Treatment Period 
Post-treatment 
Period 
Run-in 
(1 week) 
Day 
Cycle 1 
(21-day cycle) 
Day 
Cycle 2 
(21-day cycle) 
Day 
Cycle 3 
(21-day 
cycle) 
Day 
Cycle 4+ 
(21-day 
cycles) 
Day 
≤ 28d prior to 
Day 1 of Run-
in Period 
-7 
-6 
-4 
1 2 3 4 5 8 10 15 1 2 3 4 8 10 15 1 4 8 15 1 
8 
15 EOTb 
60-day 
Follow
-upc 
Survival 
Follow-
upc 
Windows (days) 
 
+1 
 
 
+1  
 
 
 
 
 
 +1  
 
 
 
 
 
+1  
 
 +1 
 
 
+7 
±14 
Every 
3 months  
±14 days 
Study Drug Administration 
NKTR-255 
administrationu 
 
 
 
 
X 
 
 
 
 
 
 
 X  
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Cetuximab 
administrationv 
 
X 
 
 
X 
 
 
 
 X  X X  
 
 X 
 
X X 
 X X X X 
X 
 
 
 
Concomitant 
medications review 
Continuous from time of ICF until 60 days after last study treatment dose  
 
Efficacy Assessments 
Tumor measurements 
and RECIST 1.1 and 
irRECIST response 
assessmentsw 
Tumor assessments at Screening and every 9 weeks from C1D1 + 7 days until patients meet one of the criteria for  
discontinuation of treatment in Section 5.2.3.1. 
 
 
Subsequent therapy/ 
survival/secondary 
malignancy information 
 
X 
X 
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m. See Appendix 4. Central safety laboratory results must be used to determine patient eligibility, with the exception that pregnancy tests are done locally (see 
Section 7.11); thereafter, central laboratory samples must be obtained prior to each cycle. If local laboratory results are used for retreatment decisions due to 
timing issues (eg, predose, treatment-related AE management, dose delays, etc.), duplicate central safety laboratory tests must be submitted to the central 
laboratory. 
n. Tests include free or total triiodothyronine (T3) reflex testing if TSH is abnormal. 
o. Refer to the Laboratory Manual for sample processing. See Table 7 for detailed sampling timepoints. 
u. NKTR-255 will be administered q21d starting C1D1. 
v. Cetuximab will be administered at the recommended dose according to the current local prescribing information, ie, IV weekly. A loading dose of 
400 mg/m2 IV is given as an initial dose, then weekly doses of 250 mg/m2 IV. On days that NKTR-255 and cetuximab are both dosed, cetuximab should be 
administered first, 
 
w. Patients will remain on treatment until meeting one of the criteria for discontinuation of treatment in Section 5.2.3.1. 
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2.0 
INTRODUCTION 
2.1 
Background 
Activating the immune system has been demonstrated to produce durable efficacious responses 
in human cancers (Hodi, 2010). Targeted monoclonal antibodies (mAbs) that bind to 
tumor-associated antigens and recruit a patient’s immune system to kill the tumor cells via 
antibody-dependent cellular cytotoxicity (ADCC) are mainstay treatments in oncology. Research 
on enhancing the immune system to enable functional and numerical capacity of the patient’s 
immune system to synergize with the mAb are coming to focus more recently 
(Messaoudene, 2017). Because interleukin-15 (IL-15) was initially identified through its ability 
to mimic interleukin-2 (IL-2)-induced T cell proliferation, the biochemical and functional 
relation between these cytokines was quickly investigated. The results validated the concept that 
stimulating T cell and natural killer (NK) cell responses could yield effective and durable 
responses. IL-15 is a cytokine that has many overlapping functions with IL-2, including the 
ability to promote anti-tumor responses. IL-15 signaling has been shown in the clinic to stimulate 
an array of downstream pathways in immune cells leading to increased cellular growth, 
decreased apoptosis, and enhanced activation and migration of specific immune cells 
(Conlon, 2015). Endogenous IL-15 plays a crucial role in the development, function, and 
survival of NK cells, NK T cells, CD8+ T cells, and intestinal intraepithelial lymphocytes 
(Grabstein, 1994; Berard, 2003; Schluns, 2004). 
IL-15 is constitutively expressed by a large number of cell types and tissues, including 
monocytes, macrophages, dendritic cells, keratinocytes, fibroblasts and nerve cells 
(Grabstein, 1994). The receptor for IL-15 consists of the α subunit and a common βγ subunit that 
shares the IL-2 receptor responsible for signal transduction (Giri, 1995). In addition, IL-15 
receptor alpha (IL-15Rα) is expressed on antigen-presenting dendritic cells, monocytes, 
macrophages and lymphocytes. IL-15 signaling also enhances the cytolytic activity of CD8+ 
T cells and induces long-lasting antigen-experienced CD8+CD44hi memory T cells. 
NKTR-255 is a novel immunotherapeutic anti-cancer drug candidate 
 
 The PEG moiety of NKTR-255 serves to extend the effective 
half-life (t1/2) relative to unconjugated rhIL-15. As a result, NKTR-255 is expected to provide 
sustained IL-15 biological activity without the need for daily dosing. Unlike other engineered 
IL-15 agents (eg, ALT-803 [Han, 2011]), NKTR-255 binds to IL-15Rα and IL-2/IL-15R βγ 
subunits and has the potential to maintain the full spectrum of IL-15 biology, including sustained 
pharmacodynamic (PD) effects of both NK cells and CD8+ memory T cells. 
NKTR-255 is being evaluated in hematological malignancies as a salvage regimen in a Phase 1 
dose escalation/expansion trial (NCT04136756), testing the safety and efficacy of NKTR-255. 
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2.1.1 
Expansion of NKTR-255 Clinical Development Plan for the Treatment of Solid 
Tumors 
Natural killer cells are innate lymphoid cells endowed with cytolytic activity and a capacity to 
secrete cytokines and chemokines. Several lines of evidence suggest that NK cells play an 
important role in anti-tumor immunity by directly lysing tumor cells or through participating in 
ADCC in conjunction with a tumor targeted monoclonal antibody. High levels of NK cell 
infiltration have been associated with a better prognosis for some tumors, including solid tumors. 
However, NK cells are often underappreciated in solid tumors, leading to speculation that these 
cells might only be involved in the control of hematological malignancies and tumor metastasis 
(Brittenden, 1996; Halama, 2011). Several studies have shown that the natural cytotoxicity of 
peripheral blood is significantly lower in patients with solid tumors than in healthy individuals 
(Brittenden, 1996). More recently, colorectal tumors have been shown to be almost devoid of 
NK cells, despite efficient T cell infiltration (Halama, 2011). 
Squamous cell carcinoma (SCC) accounts for more than 90% of all head and neck cancers and is 
ranked the sixth most common cancer worldwide, with more than 650,000 new cases and 
330,000 deaths reported in 2018 (Vigneswaran, 2014; Bray, 2018). In the United States (US), 
head and neck squamous cell carcinoma (HNSCC) accounts for 3% of malignancies, with 
approximately 53,000 Americans developing head and neck cancer annually and 10,800 dying 
from the disease (Siegel, 2019). The 2 broad approaches to treatment include primary surgery 
and upfront definitive radiation therapy, either alone or in combination with chemotherapy 
(Gilbert, 2009). Pembrolizumab has become the new standard first-line treatment either alone or 
in combination with chemotherapy for patients with metastatic or unresectable, recurrent 
HNSCC (Rischin, 2019; Keytruda US package insert, 2020). Successful outcomes with 
pembrolizumab have garnered interest in other immunotherapy modalities as treatment options 
for HNSCC. Head and neck squamous cell carcinoma is an immunosuppressive disease 
associated with low absolute lymphocyte count, altered NK cell function, and impairment of 
tumor-infiltrating T lymphocytes with an important impact on clinical outcome (Ferris, 2004; 
Kuss, 2004; Dasgupta, 2005). It is therefore of interest to promote NK cell infiltration of tumors 
and to develop immunotherapeutic approaches designed to harness NK cell functions in the 
tumor bed, including those that aim to reinforce conventional anti-tumor therapies to increase the 
chances of successful treatment (Habif, 2019). 
Colorectal carcinoma (CRC) is the third most common cancer affecting both males and females 
in the US; approximately 70% of CRC cases arise in the colon (Siegel, 2019). Globally, CRC is 
the third leading cause of cancer and cancer-related deaths worldwide (Demb, 2019). The last 
15 years have seen major advances in the treatment of metastatic colorectal carcinoma (mCRC). 
The median survival duration is now approaching 2 years, and 5-year survival rates as high as 
15% are reported in some trials of patients treated with chemotherapy alone (Masi, 2011). 
Cetuximab has emerged as a core agent, along with 5-fluorouracil, irinotecan, oxaliplatin, and 
bevacizumab, for overall mCRC management and to prolong survival (Lenz, 2007). More 
recently, antibody to programmed cell death protein 1 (anti-PD-1) agent pembrolizumab received 


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accelerated approval for the treatment of mismatch repair (MMR)-deficient (dMMR) or 
microsatellite instability-high (MSI-H) colorectal cancer that has progressed following treatment 
with a fluoropyrimidine, oxaliplatin, and irinotecan. However, microsatellite instability (MSI) is 
present only in a small subset of CRC patients and has an even lower incidence in the metastatic 
setting (4%-5%) (Battaglin, 2018). While there is clear clinical evidence for a therapeutic role of 
immune checkpoint inhibitors such as pembrolizumab, the vast majority of patients with 
proficient MMR or microsatellite stable tumors do not benefit from immunotherapy 
(Ciardiello, 2019). Thus, many patients exhaust standard treatment options without deriving 
benefit and are subsequently transitioned to palliative care even though they still have good 
performance status. 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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2.2 
NKTR-255 
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2.2.3 
Clinical Experience with NKTR-255 
NKTR-255 is being evaluated in hematological malignancies as a salvage regimen in a Phase 1 
dose escalation /expansion trial (Nektar Study 18-255-02; NCT04136756), testing the safety and 
tolerability of NKTR-255. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.2.6 
Selection of NKTR-255 Recommended Phase 2 Dose (RP2D) 
A composite of clinical information will be used to select the RP2D based on safety and 
tolerability, PK, PD, and optimal biological response. Additional patients may be enrolled to 
refine the RP2D and a minimum of 6 patients will be required to define the RP2D. 
2.2.6.1 
Safety Considerations for NKTR-255 and Cetuximab Combination 
Cetuximab is a targeted monoclonal antibody to EGFR and has been part of the treatment 
backbone for metastatic CRC since its approval in 2004 and for HNSCC since approval in 2006. 
The safety of cetuximab as monotherapy has been well characterized and summarized by several 
multicenter clinical studies (Fakih, 2010; Erbitux US package insert, 2021). In this study, the 
loading dose of cetuximab will be given as monotherapy. 
Infusion-related reactions occurred within minutes of administration of cetuximab (median: 
15 minutes, range: 2 to 140 minutes). The time from start of cetuximab to onset of IRR 
correlated inversely with the grade of the IRR, whereby the onset of the IRR occurred much 
earlier with Grade 4 IRR and later with lower grades of IRR (median to onset of Grades 4, 3, 2, 
and 1 IRR were 5, 13.5, 22, and 25 minutes, respectively, p = 0.04). Pharmacologic prophylaxis 
with antihistamines IV 30 to 60 minutes prior to the first dose has been shown to be effective in 
reducing IRR incidence (Touma, 2014). 
 
 
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3.0 
OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives are: 
Phase 1b (Dose Escalation): 
• To evaluate the safety and tolerability, as well as define the MTD and/or RP2D, of 
NKTR-255 in combination with cetuximab in relapsed or refractory (R/R) HNSCC CRC 
Phase 2 (Dose Expansion): 
• To evaluate the safety and tolerability of NKTR-255 monotherapy and NKTR-255 in 
combination with cetuximab in R/R HNSCC, CRC, 
 
• To evaluate the efficacy of NKTR-255 in combination with cetuximab in R/R HNSCC or 
CRC by assessing the ORR by Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) 
3.2 
Secondary Objectives 
The secondary objectives are: 
• To evaluate the efficacy of NKTR-255 monotherapy in R/R 
 
 by assessing the ORR by RECIST 1.1 
• To evaluate the efficacy of NKTR-255 in combination with cetuximab and NKTR-255 
monotherapy by assessing progression-free survival (PFS) and overall survival (OS) 
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4.0 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion Criteria 
4.1.1 
Inclusion Criteria for All Patients 
Each patient must satisfy all of the following criteria to be enrolled in the study (for both dose 
escalation and dose expansion phases): 
1. Patients must be at least 18 years of age at study entry, and of any gender, race, or ethnicity. 
2. Patients must be capable of understanding and providing a written informed consent. 
3. Women of childbearing potential (WCBP) must have a negative serum pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) 
at Screening and a negative serum or urine pregnancy test within 24 hours prior to dosing. 
Women of childbearing potential and men who are sexually active with WCBP must commit 
to use contraception as described in Appendix 7, for the duration of the study and for 1 
month after the last dose of NKTR-255 and 2 months after the last dose of cetuximab. 
4. Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy 
such as surgical resection or radiotherapy) or metastatic cancer of the following histologies: 
HNSCC, CRC, 
 
5. Patients who have previously received cetuximab or other EGFR-directed therapies are 
excluded from Phase 2 of the trial, unless cetuximab was given as part of a primary treatment 
approach, with no progressive disease for at least 4 months following the end of prior 
cetuximab treatment. 
6. Life expectancy > 12 weeks as determined by the Investigator 
7. Eastern Cooperative Oncology Group performance status 0 or 1 (Appendix 5) 
8. Measurable disease per RECIST 1.1 
9. Patients must have demonstrated adequate organ function within 14 days before Cycle 1  
Day 1 (C1D1): 
a. Estimated glomerular filtration rate ≥ 40 mL/min/1.73 m2 calculated using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (see 
Appendix 6) 
4.1.2 
Inclusion Criteria for Specific Tumor Types 
A patient may be entered into this study only if he/she meets all of the following additional 
criteria specific to that patient’s tumor type: 
• Head and Neck Squamous Cell Carcinoma  
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1. Patients must have histologically or cytologically confirmed advanced, recurrent, or 
metastatic HNSCC that could not be treated with curative intent. “Advanced” is defined as 
either locally advanced HNSCC not amenable to curative surgery or radiotherapy or with 
distant metastases. 
2. Patients who have undergone treatment with anti-PD-1 or antibody to programmed 
death-ligand 1 (anti-PD-L1) (together termed "anti-PD-(L)1") must have had the last dose of 
antibody at least 4 weeks prior to receiving any study drug and evidence of tumor 
progression before they can be enrolled into this study. 
3. Patients must have known status by pathology for HPV and Epstein-Barr virus (EBV) in 
HNSCC, either metastatic or recurrent disease.  
4. Patients must have experienced progression (or toxicity precluding additional treatment) on 
any first- or second-line platinum-based chemotherapy and anti-PD-(L)1 antibody, unless 
they are ineligible for such treatment, OR, 
5. Patients must be ineligible for platinum-based (either cisplatin or carboplatin) chemotherapy 
or chemoradiation due to decline in renal function and/or patient's intolerance. 
• Colorectal Cancer 
1. Patients must have a histologically or cytologically confirmed diagnosis of advanced CRC; 
patients in Phase 2 must have confirmed KRAS (US) or RAS (ex-US) wild type EGFR-
expressing advanced CRC. “Advanced” is defined as either locally advanced unresectable 
cancer or metastatic disease. 
2. Patients must have received at least 2 prior cancer therapy regimens administered for 
metastatic disease including fluoropyrimidine, irinotecan, and oxaliplatin, unless ineligible or 
intolerant for such treatment. 
3. Patients with MSI-H or dMMR tumors must have been exposed to checkpoint inhibitors such 
as anti-PD-1. 
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4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are ineligible: 
1. 
Use of an investigational agent or an investigational device within 28 days before 
administration of first dose of study drug(s)  
2. 
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 corticosteroids 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, chronic 
graft-versus-host disease, Graves’ disease, Hashimoto's disease, alopecia areata, eczema, 
psoriasis, or with Medical Monitor approval). 
3. 
History of allergy or known hypersensitivity to murine protein or study drug components 
4. 
History of organ transplant that requires ongoing use of immunosuppressive agents 
5. 
Patients who have been previously treated with IL-2 or IL-15 
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6. 
Patients with HNSCC who require treatment with anticoagulation therapy are not 
eligible. Use of warfarin for CRC, 
patients within 
14 days of initiating study drug(s) is not permitted. Additional information about 
anti-coagulant therapy on treatment can be found in Section 5.10.3. 
7. 
Known Grade 3 or 4 hypersensitivity reaction to cetuximab, history of allergy to red meat 
or tick bites, or history of positive test results for immunoglobulin E antibodies against 
cetuximab 
8. 
Patient has had prior Grade 4 IRR to cetuximab 
9. 
Unresolved toxicity from previous anti-cancer therapy, unless resolved to Grade ≤ 1 or 
baseline; or resolved to Grade 2 (with the exceptions outlined in the inclusion criteria or 
deemed clinically not significant, and approved by the Sponsor); or resulting from 
incomplete recovery from recent surgery (major) 
10. 
Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must 
have recovered from all acute radiation-related toxicities, not require corticosteroids, and 
have not had radiation pneumonitis. 
11. 
Patients participating in observational studies should be discussed with the Medical 
Monitor to confirm eligibility. 
12. 
Patients who have had < 28 days since the last anti-cancer treatment, chemotherapy, or 
biological therapy, or < 14 days from approved tyrosine kinase inhibitor therapy 
(sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib), 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(s) 
13. 
Patients who have received systemic interferon alpha (IFNα) within the previous 
6 months prior to enrollment in the study are not eligible. 
14. 
Active infection requiring systemic therapy within 7 days prior to dosing 
15. 
Evidence of clinically significant interstitial lung disease or active, noninfectious 
pneumonitis 
16. 
Known immunodeficiency or active HIV (antibodies to HIV-1 or HIV-2). However, 
HIV-associated ASCC patients on effective anti-retroviral therapy with CD4+ count 
≥ 300/µL and undetectable viral load are eligible. 
17. 
Known to be seropositive or active for hepatitis B or hepatitis C as defined in 
Section 5.13.6. Patients who had hepatitis B but have received an antiviral treatment and 
show non-detectable viral DNA for 3 months are eligible. Patients who are seropositive 
because of hepatitis B virus vaccine are eligible. 
18. 
Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for 
women at Screening 
19. 
History of unstable or deteriorating cardiac disease within the previous 6 months prior to 
Screening including but not limited to the following: 
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a. Unstable angina or myocardial infarction 
b. Congestive heart failure (New York Heart Association Class III or IV) 
c. Uncontrolled clinically significant arrhythmias 
20. 
Has a known additional malignancy that is progressing or requires active treatment; 
exceptions include basal cell carcinoma of the skin, SCC 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 below lower limit of normal by local laboratory. 
 
21. 
Patient has any of the following laboratory test results during Screening: 
a. Aspartate aminotransferase or ALT level ≥ 2.5 × the upper limit of normal (ULN) 
b. Alkaline phosphatase level ≥ 2.5 × ULN 
c. Total bilirubin level ≥ 2 × ULN (except for Gilbert Syndrome: direct bilirubin 
≥ 2 × ULN) 
d. Potassium level < 3.0 mEq/L; or > 10 mEq/L 
e. Corrected serum calcium > 14.0 mg/dL (3.5 mmol/L) 
f. Magnesium level < 1.0 mg/dL 
22. 
Patient is a woman who is pregnant or breastfeeding or planning to become pregnant 
while enrolled in this study or within 1 month after the last dose of NKTR-255 or within 
2 months after the last dose of cetuximab. 
23. 
Active brain metastases or leptomeningeal metastases patients with brain metastases are 
eligible if these have been treated and there is no radiographic evidence of progression 
for at least 4 weeks after treatment is complete (confirmed by the head imaging obtained 
within 28 days prior to study treatment). There must also be no requirement for 
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone 
equivalents) for at least 4 weeks prior to study treatment. Stable dose of anticonvulsants 
is required within 14 days prior to study treatment. Treatment for central nervous system 
metastases may include stereotactic radiosurgery (eg, GammaKnife, CyberKnife, or 
equivalent) or neurosurgical resection. Patients who received whole brain radiation 
therapy are not eligible. 
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24. 
History of unstable hypertension and/or Screening blood pressure > 150/90 millimeters of 
mercury (mmHg) (systolic/diastolic) with or without end organ damage; Screening blood 
pressure must be < 150 mmHg for systolic blood pressure and < 90 mmHg for diastolic 
blood pressure (by at least 1 and up to 3 observations taken during the Screening period). 
25. 
Live, attenuated vaccines are prohibited within 30 days before the first dose of study drug 
(exception is made for vaccines against severe acute respiratory syndrome coronavirus 2 
[SARS-CoV-2]; coronavirus disease 2019 [COVID-19]). For details, refer to 
Section 5.10.3. 
26. 
Known current drug, alcohol, or tobacco abuse 
27. 
Any condition including medical, emotional, psychiatric, or logistical that, in the opinion 
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5.0 
INVESTIGATIONAL PLAN 
5.1 
Overview 
This study is a Phase 1b/2, open-label, multicenter, dose escalation, and dose expansion study in 
patients with R/R HNSCC, CRC, 
. 
5.1.1 
Phase 1b – Dose Escalation 
The NKTR-255 starting dose will be 1.5 µg/kg, which had no safety concerns as defined by 
pre-specified dose-limiting toxicities (DLTs) in the first cohort of the FIH study Protocol 
18-255-02. The starting dose is based on the safety data from escalation cohorts and the RP2D 
determination from the FIH study. The starting dose will not be greater than the highest dose 
determined by the Safety Review Committee (SRC) to have no safety concerns in the FIH study. 
After an initial cetuximab loading dose, patients will receive IV NKTR-255 q21d in combination 
with cetuximab weekly (Figure 2). Beginning with Dose Level 1, successive dose levels of at 
least 3 patients each will receive ascending doses of NKTR-255 until the MTD and/or RP2D is 
determined. Approximately 30 patients may be enrolled in the dose escalation phase of the study. 
A 2-parameter Bayesian logistic regression model (BLRM) employing the escalation with 
overdose control (EWOC) principle (Neuenschwander, 2008) will be used as a guide during the 
escalation phase of the study for dose level selection and for determination of the MTD and/or 
RP2D. Additional dose levels may also be opened to further explore the MTD and/or RP2D. For 
details, refer to Sections 5.8 and 5.9. 
The first patient (a sentinel patient) of each escalating NKTR-255 dose level will be monitored 
for safety and tolerability for 7 days after the first dose of NKTR-255 before additional patients 
are dosed within the same dose level. 
A composite of clinical information will be used to select the RP2D based on safety and 
tolerability, PK, 
and optimal biological response. Additional patients may be enrolled to 
refine the RP2D, and a minimum of 6 patients will be required to define the RP2D. 
Eligible patients will receive cetuximab 400 mg/m2 IV as a loading dose during the study run-in 
period (Day -7). Thereafter, cetuximab 250 mg/m2 IV will be administered weekly and 
NKTR-255 will be administered q21d. The DLT window is 21 days after the first dose of 
NKTR-255. Patients who achieve optimal response (partial response [PR] or complete response 
[CR] as determined by RECIST 1.1) after at least 1 tumor assessment, as determined by the 
Investigator and in consultation with the Medical Monitor, will be given the option to continue 
treatment with NKTR-255 as single agent for maintenance every 28 days (q28d) at the same 
dose as the patient’s originally assigned dose. 
 
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• Intermediate doses may be evaluated. 
• No intra-patient dose escalation will be allowed. 
• Enrollment into a new dose level with an escalating dose of NKTR-255 cannot begin until 
the DLT window has closed for at least 3 patients in the prior dose level. The DLT window is 
21 days after the first dose of NKTR-255. 
• The SRC will assess safety before opening dose escalation to the next level. 
• The Sponsor’s decision to declare the RP2D of NKTR-255 can occur at any given dose level 
based on safety, PK or 
effects without reaching the MTD. 
• Data from a minimum of 6 evaluable patients are required to define the RP2D. 
• Dose reduction of NKTR-255 is not allowed during dose escalation within the DLT window. 
Outside of the DLT window in the dose escalation phase, and during dose expansion, dose 
levels of NKTR-255 may be reduced depending on the severity, duration, and frequency of 
toxicities observed at the previous dose level tested (the dose level may be de-escalated in 
order to characterize RP2D for a specific dose). 
• The cetuximab dose may be reduced or adjusted based on review of available safety and 
tolerability data. Dose adjustment or discontinuation for cetuximab may be required based on 
emerging toxicities, and should follow the guidelines specified in this protocol and in the 
current local prescribing information for cetuximab. 
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5.2 
Study Periods 
5.2.1 
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 of 
care. Procedures that were performed for standard of care prior to signing informed consent may 
be used for screening purposes (eg, full physical examination) as long as the procedures were 
completed within the window of that assessment during the Screening period  
(Section 1.2). After signing the informed consent form (ICF), patients will be evaluated for all 
eligibility criteria during the Screening period before administration of study drug(s). 
Rescreening after screen failure will be allowed after consultation with the Medical Monitor. The 
Screening window is 28 days. Baseline scan(s) available up to 14 days prior to signing the ICF 
are acceptable. 
5.2.2 
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. 
5.2.3 
Treatment Period 
Patients will remain on treatment until meeting one of the criteria for discontinuation of 
treatment in Section 5.2.3.1. 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 (EOT) procedures 
specified in the Schedule of Events (Section 1.2). Patients will continue to be followed for safety 
and survival as per Sections 5.2.6 and 5.2.7, respectively. 
If scheduled visits or assessments coincide with a weekend or holiday, schedule at the next 
feasible date. Please contact the Medical Monitor to discuss any concerns about study visits or 
assessments that may fall out of the protocol-specified window because of unforeseen delays or 
other patient-specific circumstances. The allowable windows for PK and immunogenicity 
sampling, and vital signs on PK collection days is provided in Table 6. All out-of-window visits 
and procedures will incur a protocol deviation. 
Patients will remain on study until meeting one of the criteria for discontinuation of study in 
Section 5.2.3.3. Patients may choose to discontinue the trial at any time, for any reason, and 
without prejudice to further treatment.  
Patients in Phase 1b (dose escalation) or Phase 2 Cohorts A, B, C1, D1, and/or E1 who achieve 
an optimal response (CR or PR per RECIST 1.1) after at least 1 tumor assessment, as determined 
by the Investigator and in consultation with the Medical Monitor, may transition to a q28d 
schedule of single-agent NKTR-255 as maintenance at the same dose as the patient’s originally 
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Patients receiving monotherapy NKTR-255 who do not achieve optimal response will have the 
option to receive cetuximab add-on. 
See Section 5.2.5 for information about treatment beyond progression. 
5.2.3.1 
Criteria for Discontinuation from Treatment 
Study treatment may be discontinued for any of the following reasons: 
• Any clinical AE, laboratory abnormality, or intercurrent illness that would, in the judgment 
of the Investigator, affect assessments of clinical status to a significant degree 
• Toxicity that, despite maximum medical management, in the judgment of the Investigator, 
compromises the ability to continue study-specific procedures or is considered to not be in 
the patient’s best interest 
• Disease progression (based on Investigator assessment of baseline and post-baseline scans as 
per RECIST 1.1). In some circumstances patients may be treated beyond disease progression. 
Details are provided in Section 5.2.5. 
• Patient request to discontinue treatment for any reason 
• Patient noncompliance 
• Initiation of systemic antineoplastic therapy other than treatments per protocol in the absence 
of progression 
• Discontinuation of the study treatment at the request of Nektar, a regulatory agency or an 
institutional review board (IRB) or independent ethics committee (IEC) 
• Pregnancy during treatment 
• Death 
• Investigator’s decision, in consultation with the Medical Monitor 
If a patient discontinues NKTR-255, the patient may continue on cetuximab alone, at the 
discretion of the Investigator, until disease progression or initiation of systemic anti-tumor 
therapy (whichever is earlier).  
If a patient discontinues study drug(s), every attempt should be made to continue tumor 
assessment at every 9 weeks until disease progression or initiation of systemic anti-tumor 
therapy. The patient will be asked to attend the 60-day post-treatment follow-up assessment visit 
when discontinuing from the study treatment. 
5.2.3.2 
End of Treatment Visit 
Patients will remain on study until meeting one of the criteria for discontinuation of study in 
Section 5.2.3.3. Patients who are discontinued will complete the EOT visit and all safety 
follow-up procedures as per the Schedule of Events (Section 1.2). The EOT visit should occur 


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within 7 days after study treatment is discontinued, and before a new antineoplastic regimen has 
been initiated. 
5.2.3.3 
Criteria for Discontinuation from Study 
Patients who discontinue study treatment due to any of the treatment discontinuation criteria in 
Section 5.2.3.1 will continue to be followed for survival per Section 5.2.7. 
In the event of an unscheduled study termination by the Sponsor, patients who are on-treatment 
at the time of the end of the study will be followed for safety for 60 days post EOT as per 
Section 5.2.6. 
Criteria for study discontinuation may include: 
• Withdrawal of consent from study 
• Loss to follow-up 
• Death 
• Discontinuation of the study at the request of Nektar, a regulatory agency or an IRB/IEC 
• Principal Investigator’s decision 
• Medical Monitor’s assessment due to lack of adherence to protocol 
 
5.2.3.4 
Replacement of Patients 
In the dose escalation portion, patients who do not complete the DLT observation period for 
reasons other than a DLT may be replaced to provide a sufficient number of patients for adequate 
evaluation of each dose escalation level. 
Patients will not be replaced during the dose expansion portion of the study. 
5.2.4 
Maintenance Period 
Patients in Phase 1b (dose escalation) 
 who 
achieve optimal response (PR or CR per RECIST 1.1) after at least 1 tumor assessment, as 
determined by the Investigator and in consultation with the Medical Monitor, will be given the 
option to continue treatment with NKTR-255 as single agent for maintenance q28d at the same 
dose as the patient’s originally assigned dose. 
5.2.5 
Treatment Beyond Progression 
Accumulating evidence indicates that some patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease. Patients will be permitted to 
continue on treatment beyond progressive disease as long as they meet the following criteria: 
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• Investigator-assessed clinical benefit. 
• Continue to meet all other study protocol eligibility criteria. 
• Patient tolerates study drug(s). 
• No clinical signs or symptoms of disease progression or clinical deterioration.  
• Patient has stable ECOG performance status of ≤ 2. 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, 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 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 
patient records. Patient will sign a "treatment beyond progression ICF" prior to continuing. 
5.2.6 
Safety Follow-up 
The Safety Follow-up visit should occur 60 days after the last dose of study treatment unless the 
patient withdraws consent to treat, initiates new anti-cancer therapy, is lost to follow up, or death 
occurs. In case of a clinically significant AE, the patient will be followed for safety until 
resolution, return to baseline values, or permanent sequelae of all toxicities attributable to study 
drug(s). If the patient discontinues study drug for a clinically significant AE, the patient will be 
followed until resolution of the AE or until the event is considered to be stable and/or chronic. 
5.2.7 
Survival Follow-up 
Following discontinuation of study treatment, patients will be contacted approximately every 
3 months ± 14 days after the EOT by clinic visit or telephone, or other alternate methods such as 
email, contact with family, or public records (if allowed per local regulations), to obtain the 
information about alternative anti-cancer therapy and assess survival information until the patient 
meets the criteria for study discontinuation in Section 5.2.3.3. 
5.2.8 
End of Study 
End of study is defined as no more than 2 years after the last patient received his or her last dose 
of NKTR-255 or Sponsor decision to terminate the study, whichever comes first. 
At the conclusion of the study, patients who continue to demonstrate clinical benefit may be able 
to receive Nektar-supplied study treatment for a maximum treatment duration of 2 years. 
NKTR-255 may be provided via an extension of the study, a rollover study requiring approval by 
the responsible health authority and ethics committee, or through another mechanism, at the 
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Nektar reserves the right to terminate access to Nektar-supplied study treatment if any of the 
following occur: 1) a study is terminated due to safety concerns; 2) the development of 
NKTR-255 is terminated for other reasons, including but not limited to, lack of efficacy and/or 
not meeting the study objective; 3) the patient can obtain medication from a government 
sponsored or private health program. In all cases Nektar will follow local regulations. 
5.3 
Administration of Study Drug(s) 
5.3.1 
NKTR-255 Dosing 
Dose administration is shown in Figure 2 and Figure 3. NKTR-255 will be administered as a 
30-minute infusion, q21d as monotherapy and in combination with cetuximab, and q28d as 
single-agent maintenance at the same dose as the patient’s originally assigned dose. For 
applicable dose levels or cohorts (Phase 1b 
), 
cetuximab will be given weekly. 
 
 
The dose does not need to be recalculated for weight changes that are < 10% from baseline 
(Day -7). 
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5.3.1.4 
NKTR-255 Monotherapy with Cetuximab Add-On 
Patients in Cohorts C, D, E, A1, and B1 (monotherapy cohorts) who, after at least 1 tumor 
assessment, do not experience PR or CR per RECIST 1.1, will have the option to receive 
cetuximab as “add-on” therapy. Patients opting to receive NKTR-255 in combination with 
cetuximab will maintain their original cohort assignment.  
Patients will receive a loading dose of cetuximab 400 mg/m2 IV 7 days prior to their next 
scheduled cycle of NKTR-255 and thereafter cetuximab will be administered at a dose of 
250 mg/m2 IV weekly.  
Patients in the “add-on” treatment group will be assessed, monitored, and treated as per Table 5. 
All other portions of the protocol applicable to patients receiving NKTR-255 in combination 
with cetuximab are applicable to these cetuximab add-on patients as well. 
5.3.1.5 
NKTR-255 Dose Delay and Adjustment Criteria 
NKTR-255 dose adjustments may only be performed with approval of the Sponsor’s Medical 
Monitor. Dose adjustments of NKTR-255 within a single patient are not permitted within the 
DLT window. Outside of the DLT window in the dose escalation phase and during dose 
expansion, dose levels of NKTR-255 may be reduced depending on the severity, duration, and 
frequency of toxicities observed at the previous dose level tested (the dose level may be 
de-escalated in order to characterize RP2D for a specific cohort). 
NKTR-255 doses may be delayed or reduced per the recommendation of the Investigator and 
approval of the Sponsor’s Medical Monitor, based on observed drug-related toxicities for the 
following reasons: 
• Grade 1 or 2 toxicity: No requirement for dose delay or dose reduction. If the toxicity persists 
at Grade 2 following completion of the cycle, a dose delay or dose reduction may be 
implemented in consultation with the Medical Monitor. 
• Grade 3 toxicity: NKTR-255 may be withheld if toxicity cannot be managed by adequate 
medical intervention. NKTR-255 dosing may resume at one dose level lower 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. 
• Grade 4 non-hematological toxicity that is not considered by the Investigator to be 
attributable to another identifiable cause: dosing should be permanently discontinued. 
• For specific severe or medically important toxicities that require permanent treatment 
discontinuation, refer to Section 5.7. 
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Tumor assessments for all patients should continue as per protocol even if dosing is delayed. 
Grading of AEs is described in Section 7.3. 
5.3.1.6 
Criteria to Resume NKTR-255 
Patients will be permitted to resume study drug(s) at the same dose level(s) following resolution 
of the AE to Grade ≤ 1 or to baseline within 2 weeks after the completion of the prior cycle, with 
the exception of patients who meet criteria for permanent discontinuation as specified in 
Section 5.7. 
Patients may resume treatment when the drug-related AE(s) resolve(s) to Grade ≤ 1 or baseline, 
with the following exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue. 
• 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. 
• Patients with combined Grade 2 AST/ALT and total bilirubin values meeting discontinuation 
parameters (see Section 5.7) should have treatment permanently discontinued. 
A dosing delay lasting more than 2 weeks should be discussed with the Medical Monitor and the 
patient may resume the study if approved based on clinical assessment. 
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. 
If the decision is 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. 
5.3.2 
Cetuximab Dosing 
In Phase 2 (Dose Expansion), cetuximab will only be administered in Cohorts A, B, C1, D1, and 
E1, and in patients in the monotherapy cohorts (Cohorts C, D, E, A1, and B1) who, after at least 
1 tumor assessment, do not experience PR or CR per RECIST 1.1. In these patient groups, 
cetuximab 400 mg/m2 IV will be given alone as a loading dose 7 days before the start of Cycle 1 
(Day -7). Starting C1D1, cetuximab 250 mg/m2 IV will be administered once weekly.
 
Body surface area used in calculating cetuximab dose should be the same as the Day -7 value, 
unless there is a ≥ 10% change in weight or height of the patient in which case the body surface 
area will be re-calculated based on the new weight and height of that patient within a cycle. 
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For current information about administration and dose modification of cetuximab refer to the 
current local prescribing information, published on the local applicable website (eg, http://base-
donnees-publique.medicaments.gouv.fr). 
The cetuximab dose may be reduced or adjusted based on review of available safety and 
tolerability data. Dose adjustment or discontinuation for cetuximab may be required based on 
emerging toxicities and should follow the guidelines specified in this protocol and in the current 
local prescribing information for cetuximab. 
For Grade 1 or 2 IRRs, the infusion rate may be reduced by 50%. For Grade 3 or 4 IRRs, 
cetuximb must be immediately and permanently discontinued. 
For additional information about cetuximab administration, refer to the current local prescribing 
information. 
5.4 
Determination of Dose-Limiting Toxicities (DLTs) 
Clinically relevant toxicities will be those assessed as unrelated to disease, disease progression, 
intercurrent illness, or concomitant medications. These will be evaluated according to the 
National Cancer Institute/National Institutes of Health Common Terminology Criteria for 
Adverse Events (CTCAE). Dose-limiting toxicities will be assessed during the predefined DLT 
window (Section 5.5). 
5.5 
Dose-Limiting Toxicity Observation Period 
Dose-limiting toxicities will be assessed during the dose escalation and dose expansion portions 
of the study. The DLT window will be 21 days after the first dose of NKTR-255. 
Enrollment into a new dose level with an escalating dose of NKTR-255 may not begin until the 
DLT window has closed for at least 3 patients in the prior dose level. The dose escalation scheme 
is described in Section 5.1. 
5.5.1 
Dose-Limiting Toxicities Related to NKTR-255 and Cetuximab 
Examples of AEs related to NKTR-255 or NKTR-255 combined with cetuximab that are defined 
as a DLT include the following: 
1. 
Any Grade ≥ 3 non-hematological AE except those listed in Section 5.5.2 
2. 
Any Grade 4 hematological AE, including neutropenia, leukopenia, thrombocytopenia, 
and anemia, except those listed in Section 5.5.2 
3. 
Any Grade 3 thrombocytopenia with bleeding  
4. 
Any case meeting the Hy’s law criteria 
(https://www.fda.gov/downloads/Guidances/UCM174090.pdf) 
5. 
Any Grade ≥ 3 (> 5x ULN) AST/ALT elevation  


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6. 
Any Grade ≥ 3 (> 3x ULN) total bilirubin elevation  
7. 
Any Grade 4 nausea or vomiting 
8. 
Any Grade 4 amylase or lipase elevation  
9. 
Death not clearly due to underlying disease or extraneous causes or disease progression 
Laboratory findings indicating a DLT should be reconfirmed by the local laboratory within 
24 hours. 
5.5.2 
Grade 3 or 4 AEs that Should Not be Considered a DLT 
The following Grade 3 or 4 AEs should not be considered DLTs: 
1. 
Lymphopenia < 14 days in duration or not associated with clinical manifestations 
2. 
Grade 3 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
3. 
Tumor flare defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor 
4. 
Grade 3 nausea or vomiting that can be medically managed to Grade ≤ 2 within 72 hours 
5. 
Fatigue that improves to Grade ≤ 2 within 7 days 
6. 
Grade 3 rash that improves to Grade ≤ 2 within 7 days 
7. 
Grade 3 amylase or lipase not associated with symptoms or clinical manifestations of 
pancreatitis.  
5.5.3 
Delayed Dose-Limiting Toxicities 
Delayed DLTs are AEs as defined in Section 5.5.1 that occur after the predefined DLT window. 
Delayed DLTs will be collected and evaluated by the Investigator and the Medical Monitor on an 
ongoing basis and also reviewed by the SRC. Delayed DLTs will also be reviewed in context of 
the determination of the MTD. 
5.5.4 
Proposed Stopping Rules 
Dose-limiting toxicities will be monitored by the SRC during the dose escalation and dose 
expansion. Study enrollment may be suspended based on calculated DLT rate listed below. 
Table 11 below is provided as a reference for the suspension boundaries. Patients will be 
monitored across doses and cohorts after a minimum of 6 patients have been treated. The 
reference suspension boundaries due to toxicity are based on a Bayesian sequential monitoring 
design (Thall, 1995) with the following criterion: 
Pr [prob(NKTR-255 related DLT) > 0.33 | data] > 0.95 


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A beta (0.66, 1.34) prior distribution is assumed for the toxicity rate, which has a mean of 
0.33 corresponding to the 33% target toxicity rate. If there is a greater than 95% chance that the 
DLT rate is greater than 33%, accrual will be suspended and the SRC will meet to review safety 
data including aggregated safety summaries. Table 12 below presents the operating 
characteristics of the above monitoring rule. 
Table 11: 
Suspension Boundaries for Toxicity 
Number of Safety 
Evaluable Patients 
Suspending Accrual if  
≥ Number of Patients  
Observed with  
NKTR-255-related DLTs 
Number of Safety 
Evaluable Patients 
Suspending Accrual if 
≥ Number of Patients  
Observed with  
NKTR-255-related DLTs 
1–5 
Not Applicable 
42–44 
20 
6–7 
5 
45–46 
21 
8–9 
6 
47–49 
22 
10–12 
7 
50–51 
23 
13–14 
8 
52–54 
24 
15–16 
9 
55–57 
25 
17–19 
10 
58–59 
26 
20–21 
11 
60–62 
27 
22–23 
12 
63–65 
28 
24–26 
13 
66–67 
29 
27–28 
14 
68–70 
30 
29–31 
15 
71–73 
31 
32–33 
16 
74–75 
32 
34–36 
17 
76–78 
33 
37–38 
18 
79-81 
34 
39–41 
19 
82-83 
35 
— 
— 
84 
36 
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Table 12: 
Operating Characteristics of Suspension Boundaries for Toxicity 
 
True Toxicity Incidence 
Early Stopping Probability 
0.15 
0.25 
0.30 
0.33 
0.45 
0.60 
N < 84 
0.00 
0.04 
0.11 
0.21 
0.86 
1.00 
N < 60 
0.00 
0.03 
0.11 
0.19 
0.76 
1.00 
N < 48 
0.00 
0.03 
0.10 
0.17 
0.68 
0.99 
N < 24 
0.00 
0.03 
0.08 
0.13 
0.46 
0.90 
Average Sample Size 
83.9 
81.6 
77 
71.8 
36.1 
12.6 
 
5.6 
Safety Review and Data Monitoring 
An SRC will be used for the dose escalation and dose expansion phases of the study. The SRC 
will be comprised of at least one site Investigator and the Sponsor’s Medical Monitor. Additional 
patients may include representatives from the Sponsor’s Clinical Development, Drug Safety, 
Biostatistics, and Clinical Pharmacology divisions as well as other functional representatives as 
needed to review safety data. For dose escalation levels, the SRC will jointly assess safety before 
opening dose escalation to each level. The exact dose will be confirmed based on review of 
safety data after at least 3 patients have been enrolled in each level. 
An independent, external, and multidisciplinary Data Safety Monitoring Committee (DSMC) 
composed of 3 to 5 members will be established and include at least 1 clinician knowledgeable in 
the field of the trial and at least 1 statistician. The DSMC will operate according to a prespecified 
charter and make recommendations on study conduct related to patient safety. The DSMC will 
review the progress of the study and perform reviews of safety data and provide recommendation 
to whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the patients, whether the study 
should continue as planned, or whether the study should continue with modifications. 
5.7 
Permanent Treatment Discontinuation Criteria 
Patients meeting any of the following criteria will be required to permanently discontinue all 
assigned study drug(s). However, with Medical Monitor approval, NKTR-255 treatment may 
continue if the toxicities listed below are considered related to cetuximab only. 
• Progressive disease per RECIST 1.1 (see details regarding continuing treatment beyond 
initial assessment of progression, Section 5.2.5) 
• Clinical deterioration, as assessed by the Investigator 
• Grade 3 or 4 CRS (Lee, 2014) 
• Grade 3 or 4 IRR  
• Grade 4 rash 


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• Grade 3 laboratory abnormalities require treatment discontinuation for the following: 
o Grade 3 thrombocytopenia > 7 days associated with clinically significant bleeding 
requires discontinuation. 
• Any Grade 4 AE or laboratory abnormality, except for the following events, which do not 
require discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset 
• Any AE, laboratory abnormality, or intercurrent illness, which, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued treatment. 
• Any dosing delay lasting > 2 weeks after completion of the prior cycle, with the following 
exceptions (see Section 5.3.1.5 for dose delay and adjustment criteria): 
o Patient has not started any new therapy. 
o Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Tumor assessments should continue as per protocol even if dosing is delayed. 
o The Investigator and the Medical Monitor may agree to a longer dose delay following a 
clinically significant AE if the patient is deriving clinical benefit from the regimen as 
defined by CR, PR, or stable disease, up to 6 weeks from last dose of either of the 
2 investigational agents, per RECIST 1.1. Any delay beyond 6 weeks must be discussed 
with the Medical Monitor and approval documented. 
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 (see Section 5.11). 
5.8 
Dose Escalation Decision Criteria 
After the completion of the DLT observation period of the last patient enrolled in a dose 
escalation level, the BLRM will be re-run to obtain updated posterior probabilities of 
under-dosing, targeted toxicity, and excessive toxicity (see Appendix 1) for all doses. The 
model-recommended dose for the next dose level of patients will thus be computed in steps (a) 
through (c) below: 
a) identify the range of doses that satisfy the EWOC criteria and are ≤ 100% increment 
from the current dose 
b) identify the dose that has the highest posterior probability of targeted toxicity from the 
range of doses from a) above 


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c) adjust the dose from b) above based on criteria C1–C8 as defined in Appendix 1. 
The dose recommended by the adaptive Bayesian logistic model will be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at the 
time of the analysis in determining the next dose level to be investigated. Generally, the study 
will not treat patients at a dose higher than the model-recommended dose. However, the study 
may escalate to or stay at a dose higher than the model-recommended dose if such a decision is 
consistent with accepted clinical practice (eg, standard 3+3 escalation rules serving as guidance). 
The dose given to the next dose level in the study will be based on considerations of the MTDs 
estimated by the BLRM. The overall clinical assessment of all available safety and tolerability, 
PK, and PD data may also be taken into consideration for the determination of dose given to the 
next dose level. 
5.9 
Determination of MTD 
Definition of MTD: 
The MTD is the highest NKTR-255 dosage in combination with cetuximab that is not expected 
to cause a DLT in more than 33% of the treated patients in the DLT window of NKTR-255. 
Adverse events and laboratory abnormalities considered to be DLTs are defined in Section 5.5. 
Estimation of MTD: 
A 2-parameter BLRM employing the EWOC principle (Babb, 1998; Neuenschwander, 2008) 
will be used during the escalation phase for selection of NKTR-255 doses to investigate and for 
estimation of the MTD of NKTR-255 when used in combination with cetuximab. The general 
plan is that dose levels of patients will receive escalating doses of NKTR-255 in combination 
with cetuximab until the MTD or approximately 30 patients are dosed (see Section 5.1). 
Estimation of the MTD during the escalation phase of the study will be based upon the 
estimation of the probability of DLT in Cycle 1. The corresponding methodology is described in 
Section 5.1 and Appendix 1. 
5.10 
Prior and Concomitant Medications 
5.10.1 
Permitted Medications 
Premedication for IRRs is not permitted for the first dose of NKTR-255. 
Treatment for flu-like symptoms with either acetaminophen or ibuprofen (or equivalent) is 
permitted for patients receiving NKTR-255 per the Investigator’s discretion. 
Treatment for flu-like symptoms with antihistamines is permitted for patients receiving 
NKTR-255 per the Investigator’s discretion. 
Patients are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). A brief (less than 3 weeks) course of 


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corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
conditions (eg, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
5.10.2 
Permitted Cetuximab Pre-/Post-Infusion Medication 
Premedication for IRRs is allowed at the Investigator's discretion for cetuximab. If used, 
premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) IV 30 to 60 minutes prior to 
the first dose; premedication may be administered for subsequent cetuximab doses based upon 
clinical judgment and presence/severity of prior IRRs. Post-infusion medications are permitted at 
the Investigator's discretion. 
5.10.3 
Prohibited Medications 
• Immunosuppressive agents, including disease-modifying anti-rheumatic drugs  
(eg, anti-tumor necrosis factor [TNF]) 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 5.10.1) 
• Any antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, extensive 
non-palliative radiation therapy, investigational agent, or radiation therapy) is prohibited 
during the study. 
Consideration should be given to withholding antihypertensive medications including diuretics, 
as well as other drugs with hypotensive properties (eg, alpha blockers for benign prostatic 
hypertrophy), prior to each dose of NKTR-255, particularly when therapy involves multiple 
anti-hypertensive drugs and classes other than thiazide diuretics. Antihypertensive medications 
should be withheld no less than 12 hours and no more than 48 hours prior to each dose of 
NKTR-255. Antihypertensive medications may be reinstituted in between doses of NKTR-255 if 
the diastolic pressure exceeds 90 mmHg and/or the systolic pressure exceeds 160 mmHg. 
Drugs known to cause QTc interval prolongation must be used with precaution. Refer to 
https://crediblemeds.org for the list of drugs. 
Concomitant use of hematopoietic growth factors such as erythropoietin, granulocyte 
colony-stimulating factor (filgrastim, pegfilgrastim), granulocytes/macrophage 
colony-stimulating factor (sargramostim), or thrombopoietin (oprelvekin, eltrombopag) should 
not be initiated or increased in dose from the start of the Screening period until the completion of 
the DLT assessment window in the absence of a DLT. After the DLT assessment windows have 
been completed or after a DLT has been documented, initiation or dose and schedule 
modifications are allowed in accordance with instructions provided in the package inserts, 
institutional practice, and/or published guidelines. 
Investigators should follow their institutional guidelines for discontinuation of anti-coagulant 
therapy (eg, aspirin and Plavix [clopidogrel]) before injections. Investigators should understand 
current best-practice recommendations for pre- and post-procedure management of 


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antithrombotic therapy, balancing the risk/benefit of modifying antithrombotic therapy in 
patients. 
Live, attenuated vaccines are prohibited within 30 days before the first dose of study drug and 
while participating in the study. Note: Acceptable vaccines include killed vaccines. 
All vaccines against SARS-CoV-2 (including live, attenuated vaccines) are acceptable. 
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5.12 
Management of Potential Risks Associated with Cetuximab 
The most frequently reported adverse reactions in patients receiving cetuximab are provided in 
the current local prescribing information. Instructions for pre- and post-infusion medication are 
provided in Section 5.10.2. 
To monitor for neutropenia and thrombocytopenia, complete blood cell counts will be done 
periodically during treatment (Section 1.2). Patients with neutropenia should be monitored for 
signs of infection. Dose delay may be required to allow recovery of neutrophils or platelets 
(Section 5.3.2). 
To date, no studies evaluating the toxicity of NKTR-255 in combination with cetuximab have 
been conducted. The toxicity profile of NKTR-255 (systemic inflammation due to expected 
pharmacology) is not expected to overlap substantially with that of cetuximab (infusion 
reactions, skin and ocular effects, hypomagnesemia) (Thomas, 2005; Fakih, 2010). However, 
based on PD studies (Nektar data on file; Chen, 2016), enhancement of cetuximab-mediated 
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ADCC is possible due to increases in NK cells induced by NKTR-255. While the enhanced 
ADCC is anticipated to be primarily directed at tumor cells that overexpress EGFR, effects on 
non-tumor cells expressing lower levels of EGFR may also occur. Therefore, adverse effects of 
cetuximab may be enhanced and/or encountered when combined with NKTR-255. Clinical 
manifestations may include rash, erythema, pain, and swelling at the tumor site. Necrosis, pain, 
ulceration, or bleeding of tumor tissue may occur during and/or after combination therapy. 
5.13 
Study Assessments 
5.13.1 
Tumor and Radiographic Assessments 
Tumor assessments for all patients will be performed at Screening and every 9 weeks from C1D1 
until the patient withdraws consent or starts a new antineoplastic regimen. Tumor response will 
be evaluated using RECIST 1.1 as the primary (Phase 2) and irRECIST as an exploratory 
measure. Efficacy assessments are further described in Section 8.0. 
5.13.2 
Pharmacokinetic Measurements 
Blood samples for PK analyses will be collected from all patients (Section 1.2). Serial PK 
samples will be collected at multiple scheduled sampling times. Concentrations of NKTR-255 
and cetuximab will be measured using validated method(s). Concentrations of additional analytes 
such as total PEG may also be analyzed in plasma samples. Pharmacokinetic parameters such as 
maximum peak concentration (Cmax), area under the concentration-time curve (AUC), CL, V, 
and t1/2 will be estimated from plasma concentration-time data where possible. 
Blood samples for quantification of NKTR-255 and cetuximab concentrations will be drawn at 
times listed in the Schedule of Events (Section 1.2) 
. Blood samples for 
PK analysis will be processed as outlined in the Laboratory Manual. All on-treatment timepoints 
are intended to align with days on which study drug is administered. If a decision is made to 
delay dosing after collection of a predose sample, a second predose sample should not be 
collected. However, all postdose 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. Please refer to the Laboratory Manual for details. 
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5.13.5 
Electrocardiogram 
Electrocardiograms will be performed according to the Schedule of Events (Section 1.2). 
Patients must be resting quietly in the supine position for ≥ 5 minutes prior to the specified ECG 
timepoints. If the ECG assessments coincide close to mealtime, obtain ECG and PK sample prior 
to meal, if possible. 
Interpretation of ECGs and interval duration measurements will be performed locally by the 
study sites. 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. 
See Section 7.15 for monitoring of safety by ECGs. 
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5.13.6 
Serology 
Seropositivity for hepatitis B is defined by a positive test for hepatitis B surface antigen (HBsAg) 
or antibodies to hepatitis B surface and core antigens (anti-HBs and anti-HBc, respectively); 
hepatitis C (anti-hepatitis C virus [HCV] antibody positive or hepatitis C virus ribonucleic acid 
[HCV-RNA] quantitation positive). 
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6.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS 
6.1 
NKTR-255 
NKTR-255 will be supplied to the Investigator by Nektar Therapeutics or its designee. Study 
drug supplies must be kept in an appropriate, secure locked area, and stored in accordance with 
the conditions specified on the labels. 
6.1.1 
Drug Description and Formulation 
NKTR-255 Drug Product is provided as a sterile, lyophilized powder.
 
 
 
 The vials are preservative free. 
6.1.2 
Drug Packaging and Labeling 
NKTR-255 will be packaged and labeled according to current Good Manufacturing Practices. 
 
 
 
 
6.1.3 
Drug Reconstitution and Handling 
The instructions for reconstitution, dilution, storage, and administration of NKTR-255 Drug 
Product are described in the Pharmacy Manual.  
6.1.4 
Drug Storage 
NKTR-255 Drug Product should be stored at -
 in its original packaging. 
6.1.5 
Drug Shipment 
Supply of NKTR-255 Drug Product will be shipped at 
 to the site pharmacy. 
6.2 
Cetuximab 
Cetuximab will be supplied to the Investigator by Nektar Therapeutics or its designee. With 
Sponsor approval and, depending on local health authority guidelines and drug availability, 
cetuximab may be obtained through commercial supply, the site pharmacy, or through a central 
depository.  Information regarding the packaging, labeling, formulation, storage, and handling of 
commercial cetuximab can be found in the current local prescribing information for cetuximab. 
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6.3 
Study Drug Accountability and Reconciliation  
The Investigator, pharmacist, or designee must maintain an accurate record of dispensing the 
study drug(s) in a Drug Accountability Log, a copy of which must be given to Nektar 
Therapeutics at the end of the study. 
The Drug Accountability Log may record specifics to study drug dispensation such as: 
• Records of product delivery, inventory, temperature monitoring, destruction, and return as 
per Sponsor’s instructions 
• Dosages prepared, time prepared, doses dispensed 
• Doses and/or vials destroyed 
• The Drug Accountability Log will be reviewed by the monitor during site visits and at the 
completion of the study 
Please refer to the Pharmacy Manual for details. 


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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 patient administered a pharmaceutical 
product in a clinical investigation, at any dose, not necessarily related to the treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can also arise from any use of the drug and from any route of 
administration, formulation, dose, or overdose. This definition includes intercurrent illnesses or 
injuries, and exacerbation of pre-existing conditions. Clinical laboratory, vital sign, or physical 
examination abnormalities will only be reported as AEs if they are deemed clinically significant 
by the Investigator (eg, associated with signs and symptoms, require treatment, or require 
follow-up). 
An AE does not include: 
• A medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, or transfusion); 
an AE is the underlying condition that leads to the procedure 
• Pre-existing diseases or conditions present or detected before start of study drug(s) 
administration which do not worsen or increase in severity or frequency after the 
administration of study drug(s) 
• 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, or other 
situations where an untoward medical occurrence has not occurred 
• 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). Adverse 
events will be reported starting immediately after the patient has been administered the first dose 
of study drug(s) until 60 days after the last dose of study treatment, unless the patient withdraws 
consent to treat, initiates new anti-cancer therapy, is lost to follow up, or death occurs, whichever 
comes earlier. 
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. 


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Under the latter 2 circumstances, the event will be considered an AE and will be captured as 
such. 
Example 1: 
Thrombophlebitis associated with a blood draw for assessments required prior to dosing per 
protocol is an event that is related to protocol-mandated procedures. In this scenario, the event 
of “thrombophlebitis” will be captured as an AE, and it will be documented as being 
“unrelated” to study drug(s) as applicable. 
Example 2: 
An ankle sprain following an unexpected fall from a flight of stairs while at home, after the 
patient has provided informed consent, but before the first dose of study drug(s), is clearly 
unrelated to any protocol-mandated procedures and would therefore be captured as medical 
history. 
7.3 
Grading of AEs 
The severity of an event and the seriousness are not to be considered synonymous. The severity 
is grading the intensity of an event. The seriousness of an event is based on the patient/event 
outcome or action criteria. All AEs will be assessed for severity using the National Cancer 
Institute (NCI)-CTCAE (Version 5.0) guidelines,
 
. If a particular AE is 
not listed in the NCI-CTCAE, the following criteria will be used: 
• Grade 1 = Mild (event results in mild or transient discomfort, not requiring or needing only 
minimal intervention or treatment; does not limit or interfere with daily activities 
[eg, insomnia, mild headache]). 
• Grade 2 = Moderate (event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment [eg, fever requiring antipyretic medication]). 
• Grade 3 = Severe (event results in significant symptoms that prevent normal daily activities; 
may require hospitalization or invasive intervention). 
• Grade 4 = Life-threatening or disabling. 
• Grade 5 = Death. 
AEs will be reported with an individual start and stop date for each level of severity. 
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7.4 
Causality Relationship of AEs 
The relationship of each AE to each study drug (NKTR-255 and cetuximab) as applicable will be 
evaluated by the Investigator using the following definitions: 
• Not related:  The AE is considered not related to the study drug(s). The AE can be reasonably 
explained by other factors such as the patient’s pre-existing medical condition, underlying 
disease, concurrent illness, or concomitant medications/therapies. 
• Related:  The AE is considered related to the study drug(s). A plausible temporal sequence 
exists between the time of administration of the study drug and the development of the AE, 
or it follows a known response pattern to the investigational product. The AE cannot be 
reasonably explained by the known characteristics of the patient’s clinical state or other 
concomitant therapies or interventions administered to the patient. 
7.5 
AE Reporting and Follow-up 
All AEs, except for SAEs (Section 7.7) and AEs attributed to protocol-mandated procedures 
(Section 7.2), will be reported from the time of first study drug(s) administration until 60 days 
after the last dose of study treatment, unless the patient withdraws consent to treat, initiates new 
anti-cancer therapy, is lost to follow up, or death occurs. All ongoing AEs will be followed until 
resolution, the patient is lost to follow-up, patient death, or until 60 days after the last dose of 
study treatment. In case the AE has not completely resolved up to 60 days after the last dose of 
study treatment or until a new antineoplastic regimen has been initiated, the final outcome of 
these ongoing AEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable. 
For specific instructions on identifying and reporting SAEs, see Sections 7.6 and 7.7. 
7.6 
Serious AE Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening, ie, in the opinion of the Investigator, the 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.  
Note:  the following are not considered SAEs: 
o A surgery or procedure that was planned before the patient entered the study and which is 
part of the planned study procedure 
o Nonmedical reasons, in the absence of an AE 


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o A visit to the emergency room or other hospital department for less than 24 hours that 
does not result in admission (unless considered an important medical or life-threatening 
event) 
• 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 (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. 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.  
All SAEs, regardless of causality attribution, with an onset within 60 days after the last dose of 
study treatment (EOT), unless the patient withdraws consent to treat, initiates new anti-cancer 
therapy, is lost to follow up, or death occurs, will be reported to Nektar Therapeutics Drug Safety 
within 24 hours after the site becomes aware of the event. 
All AEs and SAEs will be recorded in the electronic case report form (eCRF) database within the 
timelines outlined in the eCRF completion guidelines. At the time of study start, SAEs may be 
reported using a paper SAE reporting form. During the study conduct, sites may transition to an 
electronic SAE (eSAE) system. Nektar or designee will provide training and account information 
prior to implementing an eSAE system at each site.  
7.7.1 
Electronic Serious Adverse Event (eSAE) Reporting Process 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Nektar Drug Safety within 24 hours of the Investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. If for any reason it is not 
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record the SAE on the paper SAE reporting form and submit within 24 hours of the 
Investigator’s knowledge of the event to Nektar Therapeutics Drug Safety via email or Safety 
Fax as listed at the beginning of this protocol.  
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the eCRF 
database according to instructions in the eCRF completion guidelines. If an SAE has been 
reported via a paper form because the eCRF database has been locked, no further action is 
necessary.  
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by email or fax when requested and applicable. Transmission 
of such documents should occur without personal patient identification, maintaining the 
traceability of a document to the patient identifiers. Additional information may be requested to 
ensure the timely completion of accurate safety reports. Any medications necessary for treatment 
of the SAE must be recorded onto the concomitant medication section of the patient’s eCRF and 
the event description section of the SAE form. 
All SAEs will be followed as described in Section 7.8. 
Reporting of SAEs to the IRB/IEC will be done in accordance with the standard operating 
procedures (SOPs) and policies of the IRB/IEC. Adequate documentation must be provided to 
Nektar Therapeutics, showing that the IRB/IEC was properly notified. Serious AEs will be 
reported by Nektar Therapeutics or designee to the Regulatory Authorities, per local regulations. 
7.8 
Serious AE Follow-up 
All study treatment-related SAEs that have not resolved within 60 days after the last dose of 
study treatment, until a new antineoplastic regimen has been initiated, loss to follow-up, 
withdrawal of consent, or death, will be followed until any of the following occurs (whichever 
comes first): 
• The event resolves 
• The event has stabilized 
• The event returns to baseline, if a baseline value is available 
• It is unlikely that any additional information can be obtained (eg, patient or health care 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
• The patient dies or is lost to follow-up 
All ongoing SAEs assessed as “unrelated” to study drug(s) will be followed until resolution or 
until 60 days after the last dose of study treatment or until a new antineoplastic regimen has been 
initiated. In the case where an unrelated SAE has not completely resolved up to 60 days after the 
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outcome of these ongoing SAEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable. 
7.9 
Disease Progression and Death Due to Disease Progression – Not Reportable as an 
AE/SAE 
It is anticipated that during this study a proportion of patients will experience disease progression 
prior to study discontinuation. Disease progression should not be reported as an AE or SAE. In 
some patients disease progression may result in clinical manifestations (eg, pleural effusion) that 
meet “seriousness” criteria (eg, hospitalization). These clinical manifestations may be reported as 
non-fatal SAEs. 
For all SAEs assessed as clinical manifestations associated with fatal disease progression, the 
following criteria will apply: 
• Seriousness Criteria = Cannot equal to Death 
• Severity = Cannot equal to Grade 5 
• Outcome = Ongoing at time of Death 
Deaths that are attributed by the Investigator solely to disease progression should not be reported 
as SAEs. 
7.10 
Pregnancy 
7.10.1 
Pregnancies in Female Patients 
The Sponsor must be notified within 24 hours of the initial report and any follow-up reports of a 
female study patient becoming pregnant during the course of the study 
 
 via the Pregnancy 
Notification Form for any pregnancy. The patient, once becoming aware of pregnancy, should 
reach out to the study Investigator for confirmation and consultation. In order for the Sponsor or 
designee to collect any pregnancy surveillance information, the pregnant patient will be asked to 
sign a Pregnancy Follow-up ICF. Pregnancy, although reportable, is not considered an AE/SAE 
unless a female patient experiences signs or symptoms of pregnancy complications (in which 
case the AE is the complication, not the pregnancy); however, the contact information for 
pregnancy reporting is the same as for SAE reporting and listed in Section 7.7 and the List of 
Study Contacts. Female patients 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 (Section 5.2.3.1, Section 5.2.3.2). 
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7.10.2 
Pregnancies in Female Partners of Male Patients 
The Sponsor must be notified within 24 hours of the initial report of a female partner of a male 
study patient becoming pregnant during the course of the study
 
via the Pregnancy Notification 
Form. A female partner of the male patient will be asked to sign a Pregnancy ICF for follow-up 
of the pregnancy. The contact information for pregnancy reporting is the same as for SAE 
reporting and listed in Section 7.7 and the List of Study Contacts. Attempts should be made to 
collect and report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drugs with the authorization from the pregnant partner. 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. 
7.11 
Pregnancy Tests 
Appendix 7 describes acceptable methods of contraception. Patients must follow these guidelines 
while on study.  
Serum pregnancy tests will be performed on WCBP during Screening, and serum or urine 
pregnancy test on Day 1 prior to each dose of study drug and at EOT. Serum pregnancy tests 
should have a minimum sensitivity of 25 IU/L or equivalent units of HCG. A negative pregnancy 
test result must be obtained before the administration of the study drug(s). 
A pregnancy test does not need to be performed on women who are postmenopausal for at least 
1 year or surgically sterile for at least 3 months before signing the ICF. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. 
7.12 
Clinical Laboratory Tests 
Clinical laboratory tests will be conducted according to the Schedule of Events (Section 1.2). 
Clinical safety laboratory tests (Appendix 4) will be performed by a designated central 
laboratory. Central laboratory results must be used to determine patient eligibility, unless 
otherwise stated. In situations where central laboratory results are unavailable for eligibility 
determination, the Medical Monitor may approve of substitution of local laboratory results 
(a repeat full set of central laboratory results must be obtained prior to dosing). Clinical 
laboratory test data will be reviewed by the Investigator or Sub-Investigator. Additional clinical 
laboratory tests may be ordered at the Investigator’s or qualified Sub-Investigator’s discretion. 
For treatment decisions at Cycle 2 and beyond, blood draw for the central laboratory may be 
obtained up to 5 days prior to the scheduled day of treatment. Depending on the turn-around time 
for the central laboratory, the results of these safety laboratory tests may not be available prior to 
the scheduled treatment. If the results are not available, or, at the discretion of the Investigator, 
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local laboratory results may be used to determine eligibility for retreatment. In all cases, if local 
laboratory results are used for retreatment decisions, duplicate central laboratory tests must be 
submitted to the central laboratory. 
Treatment decisions require results for the following tests:  hemoglobin, absolute neutrophil 
count (ANC), platelets, bicarbonate/carbon dioxide (CO2), calcium, chloride, potassium, sodium, 
and serum creatinine. 
The Investigator or designee will review all laboratory results for clinical significance. Any 
laboratory result deemed clinically significant (ie, associated with signs and symptoms, requires 
treatment, or requires follow-up) will be recorded as an AE as described in Section 7.1. 
7.13 
Physical Examinations 
Physical examinations should be conducted according to the Schedule of Events (Section 1.2). 
Full physical examinations should 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. Weight is to be reported on Day 1 of each 
cycle, and height at Screening visit only. 
7.14 
Vital Signs 
Vital sign measurement will be recorded according to the Schedule of Events (Section 1.2). Vital 
signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, oxygen saturation 
(oxygen saturation at Screening and on dosing days only), and temperature (oral). It is preferred 
that the same arm be used for all blood pressure readings, if possible. Where feasible, vital signs 
should be measured before having blood drawn for laboratory evaluations. 
The study site must be equipped for medical emergencies and have access to an intensive care 
unit. 
If the patient experiences a Grade > 2 IRR 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. 
7.15 
Electrocardiograms 
The Investigator or designee 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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7.16 
Cardiac Function 
An echocardiogram, nuclear scan, or multigated acquisition (MUGA) scan will be performed for 
all patients as per schedule of assesments, within 60 days prior to dosing and at EOT to assess 
cardiac function and left ventricular ejection fraction (LVEF). The same assessment method 
should be used for the same patient throughout the study, if feasible. 


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8.0 
ASSESSMENT OF EFFICACY 
8.1 
Treatment Response Assessment 
Tumor response will be evaluated using RECIST 1.1 criteria (Eisenhauer, 2009; Appendix 2). 
Tumor burden will be characterized prior to enrollment, and response assessments will be 
performed approximately every 9 weeks starting from C1D1. 
8.2 
Tumor Imaging (Computed Tomography or Magnetic Resonance Imaging) 
Computed tomography (CT) with contrast or magnetic resonance imaging (MRI) (for patients 
who cannot tolerate CT contrast) will be obtained to document metastatic disease, identify target 
lesions as described in RECIST 1.1, and to assess response and disease progression. Imaging by 
CT scan with contrast or MRI will be performed at Screening, and approximately every 9 weeks 
during the treatment period regardless of cycle number or dose interruption. 
Scans taken as part of standard medical practice up to 42 days prior to first dose of study 
treatment can be used for Screening. During the treatment, scans may be performed at timepoints 
other than every 9 weeks as clinically indicated to assess tumor progression. A standard-of-care 
brain MRI occurring prior to the 28-day screening window may be acceptable based on 
consultation with the Medical Monitor. 
At Screening, a brain MRI is only required for patients with a history of brain metastases and 
should be followed as clinically indicated. Other scans may be included as clinically indicated. 
For patients who stop study treatment in the absence of disease progression (eg, due to 
unexpected toxicity), scans should continue to be collected approximately every 9 weeks until 
disease progression or initiation of systemic anti-tumor therapy other than the study treatment 
(whichever is earlier) or unless patient withdraws consent. 
The same imaging procedure and specifications (eg, contrast agent, scanner, slice thickness, etc.) 
used to define measurable target and non-target lesions must be used throughout the study for 
each patient. 
Computed tomography scans may not be performed at sites or in countries where additional 
radiology approval is required, unless that approval is sought and granted. 
 
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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. 
A description of analysis methods and detailed definitions for efficacy and safety endpoints will 
be provided in the statistical analysis plan (SAP). The potential impact of COVID-19 on this trial 
will be assessed. Any changes to the analyses that are required due to COVID-19 will be detailed 
in the SAP. 
9.2 
Determination of Sample Size 
This is a Phase 1b/2 dose escalation and dose expansion study. During dose escalation 
(Phase 1b), successive groups of at least 3 patients will be treated at each dose level until the 
MTD and/or RP2D is determined. Additional patients may be added to each dose level based on 
the scheme and rules outlined in Section 5.2.3.4 or Sponsor determination of the need for 
additional data to further evaluate the benefit/risk profile. It is estimated that approximately 
30 patients will be enrolled in the dose escalation. 
A Bayesian design will be used 
.  
For HNSCC and CRC cohorts, an initial 12 patients will be enrolled into stage 1 of Cohorts A 
and B, respectively, and the enrollment will continue to a maximum of 24 patients or until the 
criteria of Pr(ORR > 0.25 | Data) > 30% is met. Patient enrollment to Cohorts A1 and B1 will be 
gated by the Bayesian criteria. After the initial 5 patients’ first tumor assessment, subsequent 
patients will be randomized to the second stage of Cohort A versus Cohort A1, and the second 
stage of Cohort B versus Cohort B1 using adaptive randomization.  
With adaptive randomization, patients will be adaptively assigned proportional to weighted 
clinical utility function based on available response data. Higher scores are assigned to better 
responses: [CR ≥ 6m = 6], [CR = 5], [PR ≥ 6m = 4], [PR = 3], [stable disease (SD) ≥ 6m = 2], 
[SD = 1], [progressive disease = 0], thus a new patient will have higher chance to be assigned to 
the cohort with better responses. A minimum of 0.1 allocation probability will be retained for 
each cohort. A maximum of 50 patients each will be enrolled into Cohort A and Cohort B, and a 
maximum of 26 patients each will be enrolled into Cohort A1 and Cohort B1. 
Prior for ORR is set to be Beta(0.25,0.75) corresponding to a prior belief of ORR = 0.25 with 1 
effective sample. The following Bayesian decision rules will be applied to Cohort A, Cohort A1, 
Cohort B, and Cohort B1, respectively, to guide the Go/No-Go decision: 
• Select an arm as superior if  
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o Pr(ORR > 0.25 | Data) > 80% and Pr(ORR > 0.10 | Data) > 90% 
• Suspend accrual to an arm if Pr(ORR ≤ 0.10 | Data) > 85% 
• Achieve maximum sample size  
 
 
 
 
 
With adaptive randomization, patients will be adaptively assigned proportional to weighted 
clinical utility function based on available response data. Higher scores are assigned to better 
responses: [CR ≥ 6m = 6], [CR = 5], [PR ≥ 6m = 4], [PR = 3], [SD ≥ 6m = 2], [SD = 1], 
[progressive disease = 0], thus a new patient will have higher chance to be assigned to the cohort 
with better responses. A minimum of 0.1 allocation probability will be retained for each cohort. 
 
Prior for ORR is set to be Beta(0.25, 0.75) corresponding to a prior belief of ORR = 0.25 with 1 
effective sample. The following Bayesian decision rules will be applied to Cohort C, Cohort C1, 
Cohort D, Cohort D1, Cohort E, and Cohort E1, respectively, to guide the Go/No-Go decision: 
• Select an arm as superior if  
o Pr(ORR > 0.25 | Data) > 80% and Pr(ORR > 0.10 | Data) > 90% 
• Suspend accrual to an arm if Pr(ORR ≤ 0.10 | Data) > 85% 
• Achieve maximum sample size  
9.3 
Safety Stopping Rules 
A Bayesian sequential monitoring design (Thall, 1995) will be employed to monitor safety of all 
patients enrolled in the study after 6 patients have been treated. See Section 5.5.4 for details. 
9.4 
Interim Analyses 
No interim analyses are planned for this study. 
9.5 
Analysis Sets 
Safety Population:  All patients who receive at least 1 dose (or partial dose) of NKTR-255  
Cetuximab-only Population: All patients who receive at least 1 dose (or partial dose) of 
cetuximab but without any dose of NKTR-255 
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DLT Population:  All patients who receive at least 1 dose of the combination treatment of 
NKTR-255 and cetuximab and who complete the DLT observation period or discontinue from 
the study treatment due to a DLT will be included, where DLT window is 21 days since the first 
dose of NKTR-255. 
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:  The Response-evaluable Population is defined as patients who 
have measurable disease (per RECIST 1.1) at baseline, receive at least 1 dose (or partial dose) of 
study drug, and have at least 1 post-baseline assessment of tumor response. 
9.6 
Planned Analyses 
9.6.1 
Safety 
Safety assessments will include Safety Population with treatment-emergent AEs with 
categorization of treatment related with incidences of serious and severe (≥ Grade 3) AEs, 
clinical laboratory tests including cardiac function tests, vital signs, physical examinations, and 
ECGs. 
Adverse events and toxicity severity will be evaluated according to NCI-CTCAE Version 5.0 
toxicity grading system. Safety assessments will be performed by medical review of AEs, vital 
signs, and laboratory results. 
The incidence rate of DLTs will be evaluated by dose level for the DLT Population. 
Treatment-emergent AEs will be summarized by preferred term, system organ class, 
NCI-CTCAE grade of severity, and relationship to the study treatment by dose level for Phase 1b 
(Dose Escalation), 
 for the Safety Population. All 
TEAEs will be summarized by incidence, severity, and relationship to study drug(s). 
A TEAE is defined as (regardless of intensity), any AE that occurs after initiation of study 
treatment on C1D1 until 60 days (inclusive) after the last dose of study treatment. Adverse 
events with a starting date after the start of new anti-cancer therapy are not considered TEAEs. 
Vital signs (including change in weight) and clinical laboratory test results will be summarized 
descriptively by dose level in Phase 1b (Dose Escalation) 
 
 for the Safety Population. A listing and summary of patients who discontinued study 
drug(s) due to an AE will be provided. 
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A data listing for deaths will be provided. 
9.6.2 
Demographics and Baseline Characteristics 
Demographic data (age, sex, ethnicity, body weight) and baseline disease characteristics will be 
summarized and presented in data listings for the Phase 1b (Dose Escalation) and Phase 2 
(Dose Expansion) portions separately for each disease type. 
9.6.3 
Efficacy 
The primary efficacy measurement will be ORR by RECIST 1.1. Other efficacy outcomes will 
include: 
• BOR 
• DOR 
• CBR 
• TTR 
• PFS 
• OS 
• ORR by irRECIST 
Objective response rate, BOR, DOR, CBR, TTR, PFS, and OS efficacy endpoints will be 
assessed in the Response-evaluable Population, where DOR and TTR will be analyzed among 
responders. In addition, OS will be presented for the Safety Population. 
Objective response rate, CBR, and each BOR category will be calculated along with the 95% 
confidence intervals (CIs) based on the exact method. The Kaplan-Meier method will be used for 
the analyses of PFS, OS, and DOR. Summary statistics will be provided for time since C1D1 to 
first response among responders. 
Final statistical considerations and analyses will be detailed in the SAP. 
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9.7 
Concomitant Medications 
All reported concomitant medications will be mapped using the World Health Organization Drug 
Dictionary. Concomitant medications will be tabulated in summary tables and data listings. 
9.8 
Missing Data 
Statistical considerations and methodology for handling missing data will be detailed in the SAP. 
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10.0 
STUDY OR STUDY SITE TERMINATION 
The Sponsor has the right to suspend or terminate the study. Sponsor reasons for suspension or 
termination of the study may include, but are not limited to the following: 
• Study is terminated due to safety concerns (ie, the benefit-risk balance is unacceptable) 
• Lack of efficacy or not meeting the study objectives 
• Development of NKTR-255 is terminated 
If an Investigator suspends or terminates their study site, the Investigator will promptly (if 
possible, within 24 hours) 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, summaries, and other documentation as required by 
health authorities, IRB/IEC, and other regulatory requirements. 


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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/IEC and the regulatory agency, as required 
by regulations, 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 and reported to 
the Sponsor promptly. 
11.2 
Monitoring 
In accordance with Code of Federal Regulations 21 CFR 312.56, International Council for 
Harmonisation (ICH) GCP, and local regulations, the clinical monitor will periodically inspect 
all 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, 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 
(IND) Application regulations and ICH GCP guidelines also require the Investigator to allow 
authorized representatives of the Sponsor, IRB/IEC, FDA, and other relevant regulatory 
authorities direct access to study source records, and to inspect and make copies of the same 
records. The names and identities of the patients need not be divulged to the Sponsor; however, 
the records must nevertheless be available to be inspected for review. This can be accomplished 
by blacking out the patient’s name and replacing the name with the patient’s study identification 
number. If these requirements are in conflict with local regulatory restrictions or institutional 
requirements, the Investigator must inform the Sponsor of these restrictions before initiation of 
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11.3 
Direct Access to Source Data/Documents for Audits and Inspections 
The Sponsor or designees may conduct 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 shall notify the Sponsor immediately. The Investigator will ensure 
that the inspectors and auditors have access to the clinical supplies, study site facilities, and 
laboratory, and that all data (including original source documentation) and all study files are 
available, if requested. 


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12.0 
ETHICAL CONSIDERATIONS 
This study will be conducted to be consistent with the principles that have their origin in 
Declaration of Helsinki and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, 
and 312), with ICH GCP, 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, regulatory authority requirements, and local regulations, the current protocol, 
Investigator’s Brochure, and ICF will be reviewed and approved by the applicable regulatory 
authority and/or competent IRB/IEC. A letter documenting the IRB/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 in accordance with 
Section 11.1. 
The Investigator, Sponsor, or their designees will submit a progress report at least once yearly to 
the IRB/IEC, or more frequently if required by the IRB/IEC. As soon as possible after 
completion or termination of the study, the Investigator will submit a final report to the IRB/IEC 
per the IRB/IEC requirements, and in compliance with FDA regulations, applicable regulatory 
authority requirements, and ICH GCP. 
The Investigator, the Sponsor, or their designees shall promptly notify the IRB/IEC of any SAEs, 
suspected unexpected serious adverse reactions, or any other information that may affect the safe 
use of the study drug(s) during the study, per the IRB/IEC local requirements, and in compliance 
with FDA regulations, regulatory authority regulations, and ICH GCP. 
12.2 
Written Informed Consent 
A freely and voluntarily written documentation of informed consent must be obtained from each 
patient, or if the patient is an incapacitated person or a minor, their legal representative before 
entering the study. The content and approval of the ICF must meet requirements of regulations 
and ICH GCP. Patients will be informed of all aspects of the study that are relevant to the 
patient’s decision to participate, and the ICF must be presented to each patient in the language in 
which the patient is fluent. 
Informed consent will be obtained from, and documented for, each patient prior to the conduct of 
any protocol-specific procedures. Signed and dated ICFs will be retained by the Investigator with 
the study records. Each patient will be given a copy of the signed and dated ICF. 
Any pregnancy that occurs in a study patient or the female partner of a male study patient should 
be reported to the Sponsor or designee. Only if a pregnant patient or partner has signed an ICF 
for disclosure information will the Sponsor or designee be able to collect any pregnancy 


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surveillance information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form (see Section 7.10). 


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13.0 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Collection Instruments and Source Documents 
13.1.1 
Study Records 
During the study, the Investigator/institution should maintain adequate and accurate source 
documents and trial records that include all pertinent observations on each of the site’s trial 
patients. Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, and 
should be explained if necessary (eg, via an audit trail). The Investigator should ensure the 
accuracy, completeness, legibility, and timeliness of the data reported to the Sponsor in the case 
report forms and in all required reports. The Investigator/institution should, at a minimum, 
maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical 
Trial (ICH E6 Section 8) and as required by the applicable regulatory requirement(s). The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
13.1.2 
Data Collection Instruments 
Data collection instruments (DCIs) (eg, eCRFs, electronic clinical outcomes assessments, 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 
The Essential Documents contained in the clinical trial master files shall be retained for 25 years 
or per local and regional regulations and guidelines, whichever is longer. These documents 
should be retained for a longer period, however, if required by an agreement with the Sponsor. 
At all times, the retention must meet applicable data protection laws. It is the responsibility of the 
Sponsor to inform the Investigator/institution in writing as to when these documents no longer 
need to be retained. 
The Investigator shall archive the clinical trial master file securely and in a way that ensures that 
it is readily available and accessible, upon request, to the regulatory authorities. Sites must 
inform the Sponsor in writing if documents will be disposed of per Institutional Policy. 
The Investigator will contact the Sponsor before transferring or destroying any study records. 
The Investigator will also promptly notify the Sponsor in writing 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 legal and regulatory requirements and ICH GCP. 
To comply with GCP guidelines and requirements, patient records will be reviewed during 
monitoring visits and audits conducted by the Sponsor, Sponsor's representatives, or health 
authorities. During these activities, every reasonable effort will be made to keep medical 
information, including patient identifying information, as confidential as possible as required by 
law. 
Study data given to, and used by, Nektar are protected by the use of a patient identification 
number. The assignment of unique patient identification number to each patient by Interactive 
Response Technology system enables de-identification. 
Demographic identifiers that will be collected as part of Study Data include year of birth, age, 
gender, race, and ethnicity provided this is permitted under applicable laws. Exact date of birth 
and patient name/initials are not collected. 
The study site is not to attach the names or other directly identifying information of the patients 
to any Study Data or biological samples that will be transferred to Nektar. Only pseudonymised / 
key-coded Study Data and biological samples will be transferred to Nektar, and only the study 
site will be able to connect the patient identification number to a patient’s personal data. 
13.4 
Security Measures 
Sites will employ both technical and organizational measures (such as, but not limited to, 
controlling access to personal patient data to only those with a need to know such data, data 
encryption, data anonymization and pseudonymization, and so forth) to ensure patient and 
patient data privacy. Sites will adhere to a “privacy by design” and “privacy by default” 
approach in collecting, storing, and processing personal patient data. 
In the event of a breach of the security measures used by the site to ensure patient and patient 
data privacy, the site will immediately notify the Sponsor. 
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APPENDIX 1: 
PRIOR CALIBRATION AND ON-STUDY DOSE ESCALATION 
RECOMMENDATIONS OF THE BAYESIAN LOGISTIC 
REGRESSION MODEL 
1. 
INTRODUCTION 
An adaptive Bayesian Logistic Regression Model (BLRM) for dose escalation with overdose 
control (EWOC) similar to that proposed by Babb et al. (1998) will be used to guide dose 
escalation in this study. 
As indicated in the Protocol Section 5.8, “the dose recommended by the adaptive Bayesian 
logistic model will be regarded as guidance and information to be integrated with a clinical 
assessment of the toxicity profiles observed at the time of the analysis in determining the next 
dose level to be investigated. Generally, the study will not treat patients at a dose higher than the 
model-recommended dose. However, the study may escalate to or stay at a dose higher than the 
model-recommended dose if such a decision is consistent with accepted clinical practice 
(eg, standard 3+3 escalation rules serving as guidance). The dose given to the next dose group in 
the study will be based on considerations of the MTDs estimated by the BLRM, and on an 
overall clinical assessment of all available safety, tolerability, PK, and PD data from all cycles at 
all different dose levels tested.” 
The purpose of this document is to describe the statistical details of the BLRM for dose 
escalation with EWOC and decision criteria. The performance metrics (operating characteristics) 
that illustrate the precision of the design in estimating the MTD under various dose-toxicity 
relationships through computer simulation are also presented. In addition, recommendations of 
the next dose level by BLRM with overdose control principle are also provided under various 
hypothetical outcome scenarios in early groups to show how it facilitates on-study dose-
escalation decisions. 
2. 
STATISTICAL DETAILS OF BAYESIAN LOGISTIC REGRESSION MODEL 
2.1. 
Statistical Model 
The dose-toxicity relationship in the dose escalation part of the study is described by the 
following model: 
logit(π(d)) = log(α) + β log(d/d*), α > 0, β > 0 
where logit(π(d)) = ln(π (d)/(1- π (d))), π(d) is the probability of a DLT at dose d. 
Doses are rescaled as d/d* with reference dose d*=6µg/kg. As a consequence, α is equal to the 
odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity is zero. 


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2.3 
Prior Specification 
A vague bivariate normal prior for the model parameters (log(α), log(β)) is elicited based on 
prior guesses (medians) from preclinical data and wide confidence intervals. The parameters of 
the prior distributions of model parameters and the assigned weights are provided in Table 1. 
Figure 1 illustrates the resulting prior distribution of DLT rate derived from the prior given in 
Table 1. 
Table 1. 
Prior Parameters for Bivariate Normal Distribution of Model 
Parameters 
Parameters  
Mean 
Standard deviation 
Correlation 
log(α), log(β) 
(0, -0.017)  
(2.841, 0.515)  
0 
 
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• The approximate effective sample size (ESS) of the prior is between 0.9 and 1 for all doses 
considered. For prior DLT rate π, and approximation of ESS can be obtained by moment-
matching of prior mean (m) and standard deviation (s) to that of a beta distribution with 
parameters (a, b), so that: 
 
ESS = a + b = m(1-m) / s2 – 1 
 
2.4. 
Toxicity Intervals and EWOC Criteria 
Dose recommendation will be based on posterior summaries for each dose, primarily the 
posterior probabilities for the following three toxicity intervals: 
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1. [0,16%) under-dosing 
2. [16%,33%) targeted toxicity 
3. [33%,100%] excessive toxicity 
The EWOC criteria for a dose level d µg/kg is specified as Prob(DLT rate ≥ 33% | data) < 25%, 
ie, the posterior probability that the dose level d µg/kg is excessively toxic (with a DLT rate of 
33% or higher) must be low (less than 25%). 
2.5. 
Dose Escalation Procedures and Decision Criteria 
After each group of patients has passed their DLT observation window, the posterior distribution 
for the model parameters will be obtained. Based on the posterior distribution of all model 
parameters, the corresponding posterior distributions for the probabilities of DLT at different 
dose levels are obtained. 
The recommended dose is the one with the highest posterior probability of the DLT rate falling 
in the target toxicity interval [16%, 33%) among the doses fulfilling EWOC, ie, it is unlikely 
(< 25% posterior probability) that the DLT rate at the dose falls in the excessive toxicity interval. 
Note that the dose that maximizes the posterior probability of targeted toxicity is the best 
estimate of the MTD, but it may not be an admissible dose according to the overdose criterion if 
the amount of data is insufficient. If vague prior information is used for the probabilities of DLT, 
in the early stages of the study this escalation procedure will reflect a conservative strategy. 
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The MTD will be declared when the posterior probability of targeted toxicity is at least 60% for 
a dose and at least 6 patients are treated at that dose. An RP2D may be identified without 
identification of MTD.
 
 
3. 
OPERATING CHARACTERISTICS FROM SIMULATION 
This section presents the operating characteristics that illustrate the precision of the design in 
estimating the MTD under various assumed true dose-toxicity relationships. 
3.2. 
Decision Rules 
Each group consisted of 3 patients. Dose escalation followed the following rule: 
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• escalate to the dose which maximizes the probability of the targeted toxicity region and 
satisfies the overdose criteria if it is a ≤ m% increase from the current dose 
• if the recommended dose satisfying the overdose criteria is a > m% increase in dose, then 
escalate to the highest dose level which is a ≤ m% increase from the current dose 
Intermediate dose levels have been added so that the above can be implemented in by restricting 
dose increments to a maximum of 2 dose levels among the doses described previously. 
The MTD stopping rule is that at least 6 patients have been evaluated at a dose level for which 
the posterior probability of targeted toxicity is at least 60%. All simulations were conducted 
under the assumption of a maximum sample size of 30. 
 
 
The protocol also states that the study may escalate or stay at a dose higher than the model-
recommended dose if such a decision is consistent with accepted clinical practice (eg, standard 
3+3 escalation rules serving as guidance).
 
However, there may be other less likely situations not being accounted for in the simulations. 
In addition, the study will include a sentinel patient who will be treated at the introduction of 
each dose (and if no patients have been treated at higher doses) before treating more patients. 
This requirement has also not been accounted for in the simulations. 
3.3. 
Dose Chosen if MTD Stopping Criteria Are Not Achieved 
In the simulation study, when MTD cannot be identified within 30 patients using the above 
outlined BLRM methodology, dose chosen for summary of operating characteristics is the 
highest dose which meets all of the following criteria: 
1. Selected dose satisfies EWOC 
2. Selected dose is less than or equal to the last dose that was tested 
3. There are at least 3 patients treated at that dose 
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4. Selected dose must be less than or equal to highest dose at which observed proportion of 
DLTs is 33% or less (upper limit of targeted toxicity interval) 
 
3.4. 
Assumed True Dose-toxicity Relationships 
Simulations are performed for the BLRM under a total of 5 scenarios of true dose-DLT 
relationship (Figure 2; Table 2): 
a. Dose-DLT relationship is a steep curve and MTD is reached at middle dose level 
b. Dose-DLT relationship is a steep curve and MTD is reached at early dose level 
c. Dose-DLT relationship is a flat curve and MTD is reached at middle dose level 
d. Dose-DLT relationship is a flat curve and MTD is reached at late dose level 
e. Dose-DLT relationship is a steep curve and MTD is reached at late dose level 
 
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3.5. 
Simulation Results 
Operating characteristics are reviewed to investigate overall performance of the BLRM under 
each true scenario. 
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4. 
HYPOTHETICAL DOSE ESCALATION SCENARIOS IN EARLY GROUPS 
Aside from the overall operating characteristics studied above, the design should make 
reasonable decisions during a study based on the observed toxicities. After completion of a given 
group, the decision to dose escalate and actual dose chosen for the subsequent group will depend 
on the recommendation of the BLRM per EWOC principle and medical review of available 
clinical, PK/PD, and laboratory data. 
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5. 
DISCUSSION 
The Bayesian Logistic Regression Model for the dose-escalation enables us to incorporate the 
preclinical information, as well as to update the recommended dose based on all safety data in 
the study. 
On-study recommendations based on the model are consistent with the clinical decision-making 
process and should be considered in conjunction with other available clinical information by the 
Nektar Clinical Trial Team and study Investigators in deciding the dose levels to be tested in 
order to determine the MTD/RP2D. 
6. 
REFERENCES 
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials:  efficient dose escalation with 
overdose control. Stat Med. 1998;17(10):1103–1120. 
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APPENDIX 2: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST 1.1)  
Response 
Assessment 
RECIST Guideline, Version 1.1 
Target Lesions 
CR 
Disappearance of all target lesions and reduction in the short axis measurement of all 
pathologic lymph nodes to ≤ 10 mm 
PR 
≥ 30% decrease in the sum of the longest diameter of the target lesions compared with baseline 
PD 
≥ 20% increase of at least 5 mm in the sum of the longest diameter of the target lesions compared with 
the smallest sum of the longest diameter recorded 
OR 
The appearance of new lesions, including those detected by FDG-PET 
SD 
Neither PR nor PD 
Non-target Lesions 
CR 
Disappearance of all non-target lesions and normalization of tumor marker levels 
SD 
Persistence of 1 or more non-target lesions and/or the maintenance of tumor marker levels above normal 
limits 
PD 
The appearance of 1 or more new lesions or unequivocal progression 
If patient has measurable disease, an increase in the overall level or substantial worsening in non-target 
lesions, such that tumor burden has increased, even if there is SD or PR in target lesions 
If no measurable disease, an increase in the overall tumor burden comparable in magnitude with the 
increase that would be required to declare PD in measurable disease (eg, an increase in pleural effusions 
from trace to large, or an increase in lymphangitic disease from localized to widespread) 
CR = complete response; FDG-PET = fluorodeoxyglucose (FDG)-positron emission tomography; PD = progressive 
disease; PR = partial response; SD = stable disease 
Reproduced from Eisenhauer, 2009. 


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APPENDIX 4: 
CLINICAL LABORATORY TESTS (ONLY TESTS DONE VIA 
CENTRAL LABORATORY) 
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) 
• 
Albumin 
• 
Creatinine 
• 
Calculated creatinine clearance 
• 
Calcium 
• 
Ferritin 
• 
Gamma-glutamyl transferase 
(GGT) 
• 
Glucose 
• 
Total protein (TP) 
• 
Total and direct bilirubin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Magnesium 
• 
Carbon dioxide (CO2) content 
or bicarbonate 
• 
Blood urea nitrogen (BUN) 
• 
Lactate dehydrogenase (LDH) 
• 
Uric acid 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis B core antigens (anti-HBc) 
• 
Hep B DNA 
• 
Hepatitis C virus antibody 
(anti-HCV) 
• 
Hepatitis C virus ribonucleic acid 
(HCV-RNA) 
• 
Human immunodeficiency virus 
(HIV) antibody 
Additional Labs 
• 
Creatine kinase (CK) 
• 
Thyroid-stimulating hormone (TSH) 
• 
Free thyroxine (free T4) 
• 
Free or total triiodothyronine (T3)a 
• 
Lipase 
• 
Amylase 
Coagulation 
• 
Partial thromboplastin time (PTT) 
• 
Prothrombin time (PT) 
• 
International normalized ratio (INR) 
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 
Minimal acceptable laboratory safety tests for local laboratory to assess suitability for retreatment of 
NKTR-255 
Hematology 
Chemistry 
• 
Hemoglobin 
• 
Platelet count 
• 
Neutrophils including bands (absolute) 
• 
Creatinine 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Calcium 
• 
Bicarbonate/CO2 
a. 
T3 should be tested in case of an abnormal TSH and normal T4. See the Laboratory Manual for further 
information. 


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APPENDIX 5: 
ECOG PERFORMANCE SCALE 
ECOG Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
ECOG = Eastern Cooperative Oncology Group 
Source:  Oken, 1982. 
 


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APPENDIX 6: 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) CREATININE EQUATION 
eGFR = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 
0.993Age x 
1.018 [if female] x 
1.159 [if Black] 
where: 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2 
SCr (standardized serum creatinine) = mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
Source:  Levey, 2009. 


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APPENDIX 7: 
ACCEPTABLE METHODS OF CONTRACEPTION 
Highly Effective 
Methods of 
Contraception 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
Hormonal methods of contraception including oral contraceptive pills (combination of 
estrogen and progesterone), vaginal ring, injectables, implants, transdermal and 
intrauterine hormone-releasing system (IUS) 
Bilateral tubal ligation 
Vasectomized partner 
Intrauterine devices (IUD)  
Complete abstinence 
 
Local laws and regulations may require use of alternative and/or additional contraception 
methods 
Additional Method for 
Male Patients 
Condom 
NOTE: Partners of male patients are to use one highly effective method of contraception 
Unacceptable Methods 
for Contraception 
Vaginal sponge with spermicide 
Progestin only pills 
Cervical cap with spermicide 
Diaphragm with spermicide 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
Withdrawal (coitus interruptus) 
Spermicide only 
Lactation amenorrhea method (LAM) 
Male condoms with or without spermicide for partners of female patients, as the only 
method of contraception 
Female condoms 
A male and a female condom used together 
 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan Version 1.0 19-255-03  
 
 
A PHASE 1B/2, OPEN-LABEL, MULTICENTER, 
DOSE ESCALATION AND DOSE EXPANSION 
STUDY OF NKTR-255 MONOTHERAPY OR IN 
COMBINATION WITH CETUXIMAB AS A 
SALVAGE REGIMEN FOR SOLID TUMORS 
 
NCT04616196 
 
Approval Date: 24 March 2023 


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Nektar Therapeutics 
STATISTICAL ANALYSIS PLAN 
A PHASE 1B/2, OPEN-LABEL, MULTICENTER, DOSE ESCALATION AND DOSE 
EXPANSION STUDY OF NKTR-255 MONOTHERAPY OR IN COMBINATION WITH 
CETUXIMAB AS A SALVAGE REGIMEN FOR SOLID TUMORS 
 
Protocol Number: 
19-255-03, Amendment 2.0 
SAP Version: 
Final 1.0 
Date: 
Mar 24, 2023 
 
 
 
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. 


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PREPARED BY: 
 
Biostatistician 
Approved by: 
Approved by: 
Approved by: 
Approved by: 
PPD
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .............................................................................................1
PREPARED BY: ............................................................................................................................2
TABLE OF CONTENTS ..............................................................................................................3
LIST OF TABLES .........................................................................................................................5
LIST OF FIGURES .......................................................................................................................5
LIST OF ABBREVIATIONS .......................................................................................................6
1.0
ADMINISTRATIVE STRUCTURE ................................................................................8
2.0
INTRODUCTION..............................................................................................................9
3.0
STUDY OBJECTIVES ....................................................................................................10
3.1
Primary Objectives .................................................................................................10
3.2
Secondary Objectives .............................................................................................10
4.0
STUDY ENDPOINTS ......................................................................................................11
4.1
Primary Endpoints .................................................................................................11
4.2
Secondary Endpoints .............................................................................................11
5.0
OVERALL STUDY DESIGN AND PLAN ...................................................................13
6.0
STATISTICAL CONSIDERATIONS ...........................................................................18
6.1
General Considerations ..........................................................................................18
6.2
Determination of Sample size ................................................................................18
6.2.1
Sample Size Determination in Phase 1b ...............................................18
6.3
Analysis Populations ..............................................................................................20
6.4
Handling of Missing Data ......................................................................................21
6.5
Conversion between Day, Month and Year ...........................................................23
6.6
Definitions..............................................................................................................23
6.6.1
Definitions Related to Endpoints ..........................................................24
7.0
STATISTICAL ANALYSIS ...........................................................................................27
7.1
Patient Disposition .................................................................................................27
7.2
Protocol Deviations ................................................................................................27
7.3
Study Population ....................................................................................................27
7.3.1
Demographic and Other Baseline Disease Characteristics ...................27
7.3.2
Cancer History and Prior Cancer Treatment .........................................28
7.3.3
Surgical History and Prior Radiotherapy ..............................................29
7.3.4
Medical History .....................................................................................29
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7.4
Treatments and Medications ..................................................................................29
7.4.1
Prior and Concomitant Medications .....................................................29
7.4.2
Subsequent Anti-Cancer Therapy .........................................................29
7.4.3
Study Drug Exposure and Dose Modification ......................................29
7.5
Efficacy Analysis ...................................................................................................30
7.5.1
Best Overall Response, Objective Response Rate, Clinical Benefit 
Rate .......................................................................................................30
7.5.2
Duration of Response and Time to Response .......................................30
7.5.3
Progression Free Survival (PFS) ...........................................................31
7.5.4
Overall Survival ....................................................................................31
7.5.5
Subgroup Analysis ................................................................................31
7.6
Safety Analyses ......................................................................................................31
7.6.1
Dose Limiting Toxicities ......................................................................31
7.6.2
Adverse Events .....................................................................................32
7.6.3
Death .....................................................................................................34
7.6.4
Clinical Laboratory Evaluation .............................................................34
7.6.4.1
Hematology ....................................................................................35
7.6.4.2
Chemistry .......................................................................................35
7.6.5
Additional Safety Analyses ...................................................................37
7.6.5.1
Vital Signs ......................................................................................37
7.6.5.2
Electrocardiogram ..........................................................................37
7.6.6
Listing of safety ECG Parameters will be Provided. COVID-19 
Related Analyses ...................................................................................38
8.0
DATA MONITORING COMMITTEE AND SAFETY REVIEW .............................39
9.1.4
Missing Data Imputation and Handling of Values Outside the 
Limits of Quantitation ...........................................................................42
10.0
PHARMACOKINETIC ANALYSIS .............................................................................44
10.1
Objectives of the Pharmacokinetic Analysis .........................................................44
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10.3.2
Handling of Missing Values, BLQ Values, and Outliers ......................46
12.0
CHANGES FROM PROTOCOL ...................................................................................51
13.0
REFERENCES .................................................................................................................52
LIST OF TABLES 
Table 2: 
Partial Dates Imputation Rules for Initial Diagnosis and Diagnosis of 
Disease .......................................................................................................22
Table 3: 
PFS Censoring Rules .................................................................................26
Table 4: 
Cancer History and Prior Cancer Treatment ..............................................28
Table 5: 
Vital Sign Abnormality Definition ............................................................37
Table 6: 
ECG Outlier Criteria ..................................................................................38
 
 
 
 
 
LIST OF FIGURES 
Figure 1:
Study Schema.............................................................................................13
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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
 
 
AE 
Adverse Event 
 
 
AST 
Aspartate Aminotransferase  
AUC 
Area Under the Curve 
BLRM 
Bayesian logistic regression model 
BMI 
Body Mass Index 
BOR 
Best Overall Response Rate 
C1D1 
Cycle 1 Day 1 
CC 
Cervical Cancer 
CBR 
Clinical Benefit Rate 
CI 
Confidence Interval 
CL/calCrCL 
Calculated Creatinine Clearance 
CM 
Concomitant Medication 
Cmax  
Maximum Peak Concentration 
CnDn 
Cycle n Day n (e.g., Cycle 1 Day 1 = C1D1) 
CR 
Complete Response 
CRC 
Colorectal Carcinoma or Colorectal Cancer 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Cytokine Release Syndrome 
 
 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
DSMC 
Data Safety Monitoring Committee 
EC50 
Half Maximal Effective Concentration (EC50)  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
EWOC 
Escalation With Overdose Control 
FDA 
Food and Drug Administration 
FIH 
First in Human 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HPV 
Human Papillomavirus 
hr 
Hour 
IRT 
Interactive Response Technology 
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Abbreviation or Term 
Definition 
mAb 
Monoclonal Antibody 
MTD 
Maximum Tolerated Dose 
NA 
Not Applicable 
NCI 
 National Cancer Institute 
ORR 
Objective Response Rate  
OS 
Overall Survival  
PD 
Pharmacodynamic(s) 
PD1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death Ligand 1 
PEG 
Polyethylene Glycol 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
q21d 
Every 21 Days 
q28d 
Every 28 Days 
QTcB 
Corrected QT interval using Bazett formula  
QTcF 
Corrected QT interval using Fridericia formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
R/R 
Relapsed or Refractory 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFU 
Survival Follow-up 
sIL-15Rα 
Soluble IL-15 Receptor Alpha 
SOP 
Standard Operating Procedure 
SRC 
Safety Review Committee 
TEAE 
Treatment Emergent Adverse Event 
TP 
Total Protein 
TTR 
Time to Response 
TRTSDT 
Treatment Start Date 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
 


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1.0 
ADMINISTRATIVE STRUCTURE 
This study will be managed via partnership between Nektar Therapeutics and a contract research 
organization (CRO). Central clinical laboratories will be used for processing of safety specimens, 
 pharmacokinetic (PK),
 samples. An 
interactive response technology (IRT) service provider will manage the patient enrolment, study 
drug(s) distribution and inventory management. Data for this trial will be entered into an 
Electronic Data Capture (EDC) system, using a Medidata Rave platform. An independent data 
monitoring committee (DMC) is established to review the safety data on a periodic basis. 
Response and progression will be determined using Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1). 
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2.0 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Nektar Therapeutics Protocol 19-255-03 “A Phase 1b/2, open-label, 
multi-center, dose escalation and dose expansion study of NKTR-255 monotherapy or in 
combination with cetuximab as a salvage regimen for solid tumors”, protocol amendment 2.0 
dated 08 October 2021.  The purpose of this plan is to describe the statistical analyses according 
to Section 9.0 of the study protocol along with any additional analyses, specifications or 
deviations from the protocol planned. Because only Phase 1b patients were enrolled for the 
study, this plan will focus on Phase 1b part. Any deviations from these guidelines will be 
documented in the clinical study report (CSR). All analyses will be conducted by Nektar 
Statistical Programming & Analysis (SPA) using SAS£ Version 9.4 or later.  




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4.0 
STUDY ENDPOINTS 
This section shows planned primary, secondary, and exploratory endpoints which are related to 
Phase 1b only. 
4.1 
Primary Endpoints 
x Incidence of dose limiting toxicity (DLT), treatment emergent adverse events (AEs) in 
Phase 1b 
4.2 
Secondary Endpoints 
x ORR by investigator assessment (per RECIST 1.1) in R/R cSCC, ASCC, and cervical 
cancer 
x PFS and OS in NKTR-255 monotherapy and in combination with cetuximab 
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Phase 1b – Dose Escalation 
The NKTR-255 starting dose will be 1.5 μg/kg, which had no safety concerns as defined by pre-
specified dose limiting toxicities in the first cohort of the first-in-human (FIH) study Protocol  
18-255-02. The starting dose is based on the safety data generated from the escalation cohorts 
and the RP2D determination from the FIH study. The starting dose will not be greater than the 
highest dose determined by the Safety Review Committee (SRC) to have no safety concerns in 
the FIH study.  
After an initial cetuximab loading dose, patients will receive IV NKTR-255 every 21 days 
(q21d) in combination with cetuximab weekly. Beginning with Dose Level 1, successive cohorts 
of at least 3 patients each will receive ascending doses of NKTR-255 until the MTD and/or 
RP2D is determined. Approximately 30 patients may be enrolled in the dose escalation phase of 
the study. A 2-parameter Bayesian logistic regression model (BLRM) employing the escalation 
with overdose control (EWOC) principle (Neuenschwander, 2008) will be used as a guide during 
the escalation phase of the study for dose level selection and for determination of the MTD 
and/or RP2D. Additional dose levels may also be opened to further explore the MTD and/or 
RP2D.  
The first patient (a sentinel patient) of each escalating NKTR-255 dose level will be monitored 
for safety and tolerability for 7 days after the first dose of NKTR-255 before additional patients 
are dosed within the same dose level. A composite of clinical information will be used to select 
the RP2D based on safety and tolerability, PK, 
and optimal biological response. Additional 
patients may be enrolled to refine the RP2D, and a minimum of 6 patients will be required to 
define the RP2D 
The dose limiting toxicity (DLT) window is 21 days after the first dose of NKTR-255. Patients 
who achieve optimal response (partial response [PR] or complete response [CR] as determined 
by RECIST 1.1) after at least 1 tumor assessment, as determined by the Investigator and in 
consultation with the Medical Monitor, will be given the option to continue treatment with 
NKTR-255 as single agent for maintenance every 28 days (q28d) at the same dose as the 
patient’s originally assigned dose. 
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x Intermediate doses may be evaluated.  
x No intra-patient dose escalation will be allowed.  
x Enrollment into a new dose level with an escalating dose of NKTR-255 cannot begin 
until the DLT window has closed for the last patient in the prior dose cohort. The DLT 
window is 21 days after the first dose of NKTR-255. 
x The SRC will assess safety before opening dose escalation to the next level.  
x The Sponsor’s decision to declare the RP2D of NKTR-255 can occur at any given dose 
level prior to reaching the MTD based on safety, PK 
. 
x Data from a minimum of 6 evaluable patients are required to define the RP2D.  
x Dose reduction of NKTR-255 is not allowed during dose escalation within the DLT 
window. Outside of the DLT window in the dose escalation phase, and during dose 
expansion, dose levels of NKTR-255 may be reduced depending on the severity, 
duration, and frequency of toxicities observed at the previous dose level tested (the dose 
level may be de-escalated in order to characterize RP2D for a specific cohort).  
x The cetuximab dose may be reduced or adjusted based on review of available safety and 
tolerability data. Dose adjustment or discontinuation for cetuximab may be required 
based on emerging toxicities and should follow the guidelines specified in the protocol 
and in the current Prescribing Information for Erbitux® (cetuximab).  
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6.0 
STATISTICAL CONSIDERATIONS 
6.1 
General Considerations 
The statistical analyses will be reported using summary tables, data listings and graphics as 
appropriate.   
Unless otherwise specified, data collected during the dose escalation phase will be presented by 
dose level groups and overall. Continuous variables will be summarized with means, standard 
deviations, medians, minimums, and maximums. The means 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 summarized by counts and by percentage of subjects in 
corresponding categories. A row or column denoted ‘Missing’ will be included in count 
tabulations where necessary to account for dropouts and missing values. Percentages will be 
rounded to 1 decimal place and the percent will be suppressed when the count is zero. The 
denominator will be the number of subjects in the cohort of interest unless otherwise noted.  
Unless specified otherwise, all 95% confidence interval for proportions will be two-sided and be 
based on the exact (Clopper-Pearson) method and confidence interval for the quartiles of time to 
event variables will be based on the Brookmeyer and Crowley method using log-log 
transformation (1982). 
For analyses by visit, only data of scheduled visits will be reported, and nominal visits will be 
used. For analyses up to a certain time point, data of both scheduled visits and unscheduled visits 
up to that time point will be considered. For analyses of worst post-baseline value, both 
scheduled and unscheduled measurements will be included. 
For BOR and PFS, both scheduled and unscheduled assessments will be included. The actual 
investigator response assessment dates will be used.  
6.2 
Determination of Sample size 
6.2.1 
Sample Size Determination in Phase 1b 
This is a Phase 1b/2 dose escalation and dose expansion study. During dose escalation (Phase 
1b), successive cohorts of at least 3 patients will be treated at each dose level until the MTD 
and/or RP2D is determined. A 2-parameter adaptive Bayesian Logistic Regression Model 
(BLRM) with overdose control (EWOC) similar to that proposed by Babb et al. (1998) will be 
used to guide dose escalation in this study. After the completion of the DLT observation period 
of the last patient enrolled in a dose escalation level, the BLRM will be re-run to obtain updated 
posterior probabilities of under-dosing, targeted toxicity, and excessive toxicity  
(see Appendix 1 of Protocol Amendment 2.0) for all doses. 


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The dose recommended by the adaptive Bayesian logistic model will be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at the 
time of the analysis in determining the next dose level to be investigated. Generally, the study 
will not treat patients at a dose higher than the model-recommended dose. However, the study 
may escalate to or stay at a dose higher than the model-recommended dose if such a decision is 
consistent with accepted clinical practice (eg, standard 3+3 escalation rules serving as guidance). 
The dose given to the next dose level in the study will be based on considerations of the MTDs 
estimated by the BLRM. The overall clinical assessment of all available safety and tolerability, 
PK, and PD data may also be taken into consideration for the determination of dose given to the 
next dose level. 
Additional patients may be added to each cohort based on the scheme and rules outlined in 
protocol Section 5.2.3.4 or Sponsor determination of the need for additional data to further 
evaluate the benefit/risk profile. 
 
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6.3 
Analysis Populations 
Enrolled Population: All patients who receive at least 1 dose (or partial dose) of cetuximab or 
NKTR-255. 
Safety Population: All patients who receive at least 1 dose (or partial dose) of NKTR-255. 
Cetuximab-only Population: All patients who receive at least 1 dose (or partial dose) of 
cetuximab but without any dose of NKTR-255. 
DLT Population: All patients who receive at least 1 dose of the combination treatment of 
NKTR-255 and cetuximab and who complete the DLT observation period or discontinue from 
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the study treatment due to a DLT will be included, where DLT window is 21 days since the first 
dose of NKTR-255.  
Response-evaluable Population: The Response-evaluable Population is defined as patients who 
have measurable disease (per RECIST 1.1) at baseline, receive at least 1 dose (or partial dose) of 
NKTR-255, and have at least 1 post-baseline assessment of tumor response. 
Pharmacokinetic Population: All patients in the Safety Population who receive at least 1 dose 
of treatment and have at least one evaluable PK concentration.  
 
 
 
  
6.4 
Handling of Missing Data 
Every effort will be made to avoid missing/partial on-study data. 
Missing baseline data will not be imputed. This includes variables which are not allowed to be 
collected according to local regulations (e.g. race in France).  
For post-baseline data, observations with values ‘not done’, ‘not evaluable’, ‘not applicable’ will 
be treated as missing values. For descriptive analyses, missing values will not be imputed. 
Number and percentage of missing values will be described separately. For analyses involve 
modeling, handling of missing values will be explicitly specified. 
Detailed approaches for the imputation of missing information in death dates, AE start and end 
dates, cancer history diagnosis dates, and prior and concomitant medications start, and end dates 
are described below. Missing dates for surgery or procedures will use the same rules as for 
concomitant medications.  
The general approach to handle partial dates are as follows: 
x Dates with missing year information will not be imputed. 
x Dates with missing month or day information will be imputed. Conservative imputation 
approaches will be adopted when applicable. For example, imputation rules for AE start 
and end dates are designed such that AEs with partially missing start dates will be 
included as TEAE if available information is not sufficient to decide whether AE starts 
before C1D1. 
x Last known alive date, C1D1, the end of study follow-up date, informed consent date, 
etc. are used as reference dates to guide the imputation when applicable. 
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1) For the subsequent anti-cancer therapy start date: 
x If only the day is missing then: if the end date of the subsequent anti-cancer therapy is 
complete, impute to the minimum of (the last day of the month, end date of subsequent 
anti-cancer therapy); otherwise impute to the last day of the month. 
x If the month or year is missing, then leave missing. 
2) For time from diagnosis of disease to treatment start date (TRTSDT), partial dates for initial 
diagnosis and diagnosis of disease will be imputed as follows:  
Table 2:  
Partial Dates Imputation Rules for Initial Diagnosis and Diagnosis of 
Disease 
Parameter 
Missing 
Additional Conditions 
Imputation 
Initial Diagnosis 
Date 
D 
M and Y the same as M and Y of 
first dose date of study drug 
Date of the first day of month of 
TRTSDT 
M and/or Y not same as first 
dose date of study drug 
Day 15 of the month of diagnosis 
D and M 
Y the same as Y of first dose 
date of study drug(s) 
Date of the first day of month of 
TRTSDT 
Y prior to Y of first dose date of 
study drug 
01 July of the year of diagnosis 
D, M and Y 
None 
No imputation 
 
3) Partial or missing dates for Concomitant Medication  
x If missing the 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 + 30 days 
or (date of initiation of subsequent anti-cancer therapy -1 day), whichever is earlier 
x 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  
x A medication with completely missing start and end dates will be classified as 
concomitant. 
4) For death date, the following conventions will be used: 
x If the death date is completely missing but reason for death is present, it will be imputed 
as the last known alive date 


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x If the death date is partially missing (missing day only, or missing both day and month), 
the death date and corresponding last known alive date will be imputed in 2 steps: 
x 1. Imputed as the 1st of the month (missing day only) or January 1st of the year 
(missing both day and month) 
x 2. The imputed death date from step 1 will be compared to the latest alive date 
captured from multiple sources (unimputed), and the later of the two will be 
considered as the imputed death date and last known alive date 
6.5 
Conversion between Day, Month and Year 
Conversions between different time unit will be based on days. For conversion to month and 
year, the following formula are used: month=days/30.4375, year=days/365.25. 
Days of duration and time to events are calculated with the following formula: 
(later assessment or study treatment [or follow-up] end date) – (earlier assessment or study 
treatment start date) +1.  
6.6 
Definitions 
Run-in period: 
Eligible patients on combination therapy will receive cetuximab 400mg/m2 IV as a loading dose 
during the study run-in period (Day -7). The run-in period therefore starts from the time the 
patient receives cetuximab and ends when the patient receives combination treatment of  
NKTR-255 +cetuximab.  
Study drug or study treatment: Study drug or study treatment refers to NKTR-255 or 
cetuximab.  
Study day: Study Day 1 (C1D1) is the first day that the combination treatment of  
NKTR-255 +cetuximab begins. 
Baseline: Unless otherwise specified, the baseline value for each variable is the last non-missing 
value collected at the time (if collected) closest to, but prior to, the start of NKTR-255 
administration. For triplicate ECG data, the record with three non-missing value will be 
considered as non-missing. If multiple measurements occur on the same day at the same time, or 
on the same day but the time is not available, the average of the measurements (for continuous 
data) will be considered the baseline value. When dosing times and/or observation times are not 
collected, it is assumed that protocol planned in-office assessments obtained on the day of the 
first dose of study drug are prior to administration of the first dose of study drug and therefore 
considered baseline values. 
Last known alive date: The date of last known alive date will be derived for patients unknown 
to have died or known alive at the analysis cut-off by using following dates:  


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x Patient assessment dates (blood draws 
, vital signs, performance 
status, ECG, tumor assessments, ECOG, or tumor biopsy dates) 
x Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
x AE start or end date 
x Concomitant medication start or end dates 
x Last date of contact collected on the ‘Survival follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’) 
x Study treatment start or end date 
x Date of discontinuation for study participation on disposition eCRF pages (do not use if 
reason for discontinuation is lost to follow-up) 
Only dates associated with actual examinations of the patient will be used in the derivation. 
Dates associated with a technical operation unrelated to patient status such as the date a blood 
sample was processed will not be used.  
End of Study: End of study is defined as no more than 2 years after the last patient received his 
or her last dose of NKTR-255 or Sponsor decision to terminate the study, whichever comes first. 
6.6.1 
Definitions Related to Endpoints 
Absolute value (and/or percent) change from baseline: Absolute value change and or percent 
change from baseline will only be summarized for patients with both baseline and post-baseline 
values for the relevant visit and will be calculated as: 
Change from baseline = post-baseline value ̢ baseline value 
Percent change from baseline = (post-baseline value ̢ baseline value)/baseline value*100 
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Treatment-emergent adverse events (TEAE):  
x Any AE that occurs after study treatment initiation. 
x An AE that was present at the time of study treatment initiation but worsened after study 
treatment initiation. 
x An AE that was present and resolved prior to treatment and reappeared after treatment 
initiation. 
x Any treatment-related AE will always be considered treatment-emergent. 
NKTR-255 Treatment-emergent adverse events (TEAE) period: Start of NKTR-255 through 
30 days post last dose NKTR-255, or until a new antineoplastic regimen has been initiated, 
whichever comes first. 
Extended treatment-emergent adverse events (TEAE) period: Start of any study drug 
through 60 days post last dose of study drug, or until a new antineoplastic regimen has been 
initiated, whichever comes first. 
Prior medications: Prior medications are defined as medications with start date prior to C1D1. 
Concomitant medications: Concomitant medications are defined as medications with stop date 
after C1D1, or medications with start date on or after C1D1 and up to 30 days after the last dose 
of NKTR-255. Medications with a start date after the initiation of any subsequent anticancer 
treatment will not be considered concomitant medications. 
Medications with start date prior to C1D1 and end date after C1D1 will be classified as both 
prior and concomitant medications. 
Best overall response (BOR): The BOR is defined as the confirmed best response designation 
over post-baseline response assessments. Disease assessments beyond progression or after start 
of subsequent therapy will not be considered for BOR. 
Overall response rate (ORR): The ORR is defined as the proportion of subjects who have 
achieved PR or better as their BOR. 
Complete response rate (CRR): The CRR is defined as the proportion of subjects who have 
achieved CR as their BOR.  
Responders: Responders are defined as subjects with a confirmed BOR of PR or better. 
Ongoing responders are defined as responders who have not progressed, not died, not been off 
study and not started a subsequent therapy. 


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Duration of response (DOR): DOR is defined as the time from first response (PR or better) to 
the date of disease progression or death due to any cause, whichever occurs first. Subjects who 
remain alive and have not progressed are censored on the last evaluable disease assessment date 
(prior to subsequent cancer therapy). Same censoring rules for PFS apply to DOR. This endpoint 
is only defined for subjects with a confirmed BOR of PR or better.  
Time to response (TTR): TTR is defined as the time from treatment start date (i.e. first dose of 
Cetuximab) to first response (PR or better). This endpoint is only applied for subjects with a 
confirmed BOR of PR or better. 
Progression free survival (PFS): The PFS is defined as the time between the first dose date of 
Cetuximab to the date of disease progression or death, whichever is earlier. For patients without 
PD or death, those patients will be censored following the rules specified below. 
Table 3:  
PFS Censoring Rules  
Situation  
Date of Disease Progression or Censoring  Outcome  
No post-baseline tumor assessments and no 
death  
first dose date of Cetuximab 
Censored  
No progression and no death, and no new 
anti-cancer therapy started  
Date of last assessment showing no 
evidence of disease progression  
Censored  
New anti-cancer therapy started without 
progression before  
Date of last assessment before the start of 
anti-cancer therapy showing no evidence of 
disease progression  
Censored  
Disease progression reported on one or 
multiple response assessments without new 
anti-cancer therapy before  
Date of earliest evidence of PD  
Progressed  
Death without PD or new anti-cancer therapy 
before  
Date of death  
Death  
Two or more consecutive missing tumor 
assessments, and no progression before the 
missing assessment  
Date of the last assessment prior to the 
missing assessment showing no evidence of 
disease progression  
Censored  
 
Overall Survival (OS): OS is defined as the time from the first dose date of Cetuximab to death 
from any cause. Patients will be followed until their date of death, loss to follow-up, or 
withdrawal of consent for further follow-up for survival, regardless of the start of anti-cancer 
therapy. Patients who are lost to follow-up will be censored at their last date known to be alive.  
Patients who do not have date of death at data cut-off date will be censored at their last date 
known to be alive. Patients who do not have any follow-up since first dose date of Cetuximab 
will be censored on the first dose date of Cetuximab.   


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7.0 
STATISTICAL ANALYSIS 
Starting from this section, this statistical analysis plan will only focus on Phase 1b part of the 
study where patients were enrolled. 
7.1 
Patient Disposition 
The summary for subject disposition will include number of subjects enrolled in the dose 
escalation phases, number of subjects in each study population, number of subjects who 
discontinue from study treatment and reason for treatment discontinuation, and number of 
subjects who discontinue from study and reasons for study discontinuation.  
All patients in enrolled population will be included in the summary table, additional summary 
tables will be generated for HNSCC and CRC enrolled population separately. All disposition data 
will be presented in a data listing. 
7.2 
 Protocol Deviations 
Protocol deviations will be classified as significant/major or non-significant/minor and grouped 
into categories. A protocol deviation that affects primary efficacy and safety assessments (as 
applicable), the safety or mental integrity of a subject, or the scientific value of the trial is 
considered as significant protocol deviation.  
The number and percentage of patients with significant protocol deviations in each category will 
be summarized. Significant protocol deviations will be provided in listings. 
7.3 
Study Population 
7.3.1 
Demographic and Other Baseline Disease Characteristics 
Demographic and baseline characteristics will be summarized and listed for the safety 
population, additional summary tables will be generated for HNSCC and CRC safety population 
separately. 
Demographic variables include the following:  
x Age  
x Age categorization I (< 65, ≥ 65 years)  
x Age categorization II (<65, ≥ 65 and < 75, ≥ 75 years)  
x Age categorization III (<65, ≥ 65 and < 75, ≥ 75 and <85, ≥ 85 years) 
x Sex 
x Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
x Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, and Unknown, Race not reported) 


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Baseline characteristics include:  
x Height (cm)  
x Weight (kg)  
x Body mass index (BMI) (kg/m2)  
x ECOG status 
7.3.2 
Cancer History and Prior Cancer Treatment 
The following prior cancer history and cancer treatment history will be summarized and listed 
for HNSCC and CRC safety population separately. 
Table 4:  
Cancer History and Prior Cancer Treatment 
Cancer Type 
Parameters 
All 
x 
Time from initial primary cancer diagnosis to first dose of NKTR-255 (months) 
x 
Stage at initial diagnosis 
x 
Stage at most recent recurrence 
x 
Current status 
x 
Number of lines of prior systemic cancer therapy 
x 
Time since start of most recent line of systemic cancer therapy 
x 
Best response of most recent line of systemic cancer therapy 
x 
Sites of metastasis 
x 
EGFR Mutational Status 
x 
Prior EGFR experience 
x 
Prior PD-1/L1 experience 
HNSCC 
x 
Histological type 
x 
Human papillomavirus infection (HPV) status 
x 
Epstein-Barr virus (EBV) status 
x 
P16 status 
x 
PD-L1 combined positive score (CPS) 
CRC 
x 
History of brain metastases  
x 
Mutational status (BRAF status, NRAS/KRAS Status) 
x 
MSI status 
 


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7.3.3 
Surgical History and Prior Radiotherapy 
The number and percent of patients who had prior cancer-related surgery will be summarized by 
type of surgery. 
The number and percent of patients who had prior radiotherapy will be summarized by site of 
radiotherapy. 
All prior radiotherapy and cancer related surgery history will be listed. 
7.3.4 
Medical History 
Medical history collected at screening will be coded by the Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class (SOC) and preferred term (PT) for 
HNSCC and CRC safety population separately. For summary tables, patient will be counted only 
once within each SOC and PT. All medical history will also be provided in a listing 
7.4 
Treatments and Medications 
7.4.1 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded by the World Health Organization Drug 
Dictionary Enhanced (WHODrug) using Anatomical Therapeutic Chemical (ATC) level 2 term 
and preferred Term (PT).  The number and percentage of subjects who have received each prior 
medication and who have received each concomitant medication will be summarized by ATC 
level 2 term and PT. Subjects will be counted only once under each ATC level 2 term and 
preferred term.  
Prior or concomitant medications are defined in Section 6.6.1 and will be classified based on 
recorded or imputed start dates of medication taking with rules specified in and Sections 6.4. 
All prior and concomitant medications will be listed. 
7.4.2 
Subsequent Anti-Cancer Therapy 
Subsequent cancer therapy will be coded by the WHODrug using ATC level 2 term and PT. The 
number and percentage of subjects who have subsequent cancer therapy will be summarized by 
ATC level 2 term and PT. Subjects will be counted only once under each ATC level 2 term and 
preferred term.  
All subsequent cancer therapy will be listed. 
7.4.3 
Study Drug Exposure and Dose Modification  
The number and percentage of subjects with at least one dose delays, dose reductions, and dose 
interruptions, and the reasons will be summarized respectively for HNSCC and CRC safety 
population.  


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The following variables will also be summarized for NKTR-255 and cetuximab respectively for 
HNSCC and CRC safety population: 
x Exposure duration (days):  Date of last administration – date of first administration +1, 
regardless of any delay of dosing between the first and the last dose. 
x Actual number of infusions: Total number of infusions for which the patient received 
non-zero doses.  
x Planned number of infusions: The cycle number for which the patient received last non-
zero doses. 
x Cumulative dose (ug): The summation of actual dose a patient received across all cycles. 
The units ug/kg used for NKTR-255 and mg/m2 for cetuximab.  
x Average dose per infusion (ug): Cumulative dose / Actual number of infusions. 
All study exposure summary data will be presented in a data listing. 
7.5 
Efficacy Analysis 
Tumor response will be evaluated using RECIST 1.1 criteria (Eisenhauer, 2009). Tumor burden 
will be characterized prior to enrollment, and response assessments will be at approximately 
every 9 weeks starting from C1D1. A confirmed BOR of CR or PR requires the confirmation 
occurring at least 4 weeks after initial documentation. A BOR of SD requires a minimum of 63 
days on study from C1D1 to the date of the first imaging assessment., Disease assessment at both 
scheduled and unscheduled visits will be used for efficacy endpoints. Disease assessments after 
new systemic anti-cancer therapy, surgical procedures or radiotherapy on target lesions will be 
excluded. Treatment beyond progression is allowed for qualified subjects. However, tumor 
assessment beyond progression will not be considered for response endpoints.  
For efficacy endpoints including ORR, CBR, BOR summary will be based on the response-
evaluable population. DOR and TTR will be summarized among confirmed responders. PFS, OS 
will be analyzed in the safety population. In addition, swimmer plot of tumor response and 
waterfall plot of best tumor size change will be generated based on safety population. Separate 
summary table and figures for efficacy analyses will be generated for HNSCC and CRC patients. 
7.5.1 
Best Overall Response, Objective Response Rate, Clinical Benefit Rate  
BOR will be summarized by response category. Number and percentage of subjects who 
achieved CR, or PR (ORR) and who achieved CR, PR or SD (CBR) will the summarized with 
95% CIs.  
7.5.2 
Duration of Response and Time to Response 
The DOR will be summarized for subjects who achieve confirmed PR or better determined by 
investigators. Median and 95% CI for DOR among responders will be estimated. The quartiles 


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(25%, median, and 75%) of DOR and 95% CI for median DOR will be provided by Kaplan-
Meier method. Along with DOR statistics, the number and percentage of subjects who have 
events or censored will also be presented. Among the responders, subjects who remain alive and 
have not progressed are continued responders and are censored on the last evaluable disease 
assessment date (prior to subsequent cancer therapy). The number and percentage of continued 
responders will be presented. Summary statistics of TTR will also be provided for responders. A 
listing instead of summary tables may be provided for DOR and TTR if there are not sufficiently 
large number of confirmed responders. 
7.5.3 
Progression Free Survival (PFS) 
PFS will be analyzed in the safety population. Investigator-assessed PFS will be summarized 
descriptively using the Kaplan-Meier (KM) product-limit method. KM estimate of PFS rates at 
6, 9 and 12 months will be calculated. PFS rates at 18, and 24 months may also be estimated 
depending on whether minimum follow-up will be longer than timepoint to generate the rate. 
Quartiles (25%, median and 95% confidence interval, and 75%) of PFS, along with two-sided 
95% CIs (based on the log-log transformation) for median PFS will be calculated. The reasons of 
PFS events (death vs. progression) will be summarized. PFS KM curve will be plotted. 
7.5.4 
Overall Survival 
OS will be analyzed in the safety population. OS will be summarized descriptively using the 
Kaplan-Meier (KM) product-limit method. KM estimate of OS rates at 6, 9 and 12 months will 
be calculated. OS rates at 18, and 24 months may also be estimated depending on whether 
minimum follow-up will be longer than timepoint to generate the rate. Quartiles (25%, median 
and 95% confidence interval, and 75%) of OS, along with two-sided 95% CIs (based on the log-
log transformation) of median OS, will be calculated. OS KM curve will be plotted. 
7.5.5 
Subgroup Analysis 
No subgroup analysis is planned for efficacy endpoints other than summarizing separately for 
HNSCC and CRC patients. 
7.6 
Safety Analyses 
Unless otherwise specified, all safety analyses except for incidence of DLTs will be based on the 
Safety Population. All summaries will be provided by dose groups in Phase 1b. 
7.6.1 
Dose Limiting Toxicities 
DLTs will be evaluated in the DLT evaluation window of 21 days following NKTR-255 
administration in Cycle 1 Day 1 as specified in the protocol. Delayed DLTs are AEs that meet 
criteria of DLT defined in the protocol but occur after the DLT evaluation window. DLTs and 
delayed DLTs will be summarized separately by system organ class (SOC) and preferred term 
(PT) in the DLT population. All DLTs and delay DLTs will be listed by patient.  


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7.6.2 
Adverse Events 
Verbatim AE terms on case report forms will be mapped to PTs and SOCs using the Medical 
Dictionary for Regulatory Activities (MedDRA) (version 22.0). CRS events are graded based 
upon ASBMT 2018 criteria. All other Adverse Events and toxicity will be evaluated according to 
CTCAE Version 5.0.  
TEAEs will be summarized by SOC, PT, CTCAE grade of severity, and relationship to the study 
treatment. For patient level summaries, patients with multiple occurrences of events of the same 
PT and SOC will be counted once.   
TEAE period defined in Section 6.6.1 will be applied if AEs are summarized in safety 
population, extended TEAE period will be applied if AEs are summarized in enrolled population. 
All AE tables by worst CTCAE grade will includes 4 categories, which are Grade 1-2,  
Grade 3-4, Grade 5 and all Grades. 
The following AE summaries will be provided in safety population with NKTR-255 TEAE 
period 
x Overall summary of TEAEs  
x TEAEs by SOC, PT and Worst CTC Grade  
x Grade 3 and above TEAEs by SOC and PT  
x TEAE Related to NKTR-255 by SOC, PT and Worst CTC Grade 
x Serious TEAE by SOC, PT and Worst CTC Grade 
x Serious TEAE Related to NKTR-255 by SOC, PT and Worst CTC Grade 
x Grade 3 and above TEAEs related to NKTR-255 by SOC and PT  
x TEAE Leading to NKTR-255 Dose Delay by SOC and PT 
x TEAE Leading to NKTR-255 Dose Reduction by SOC and PT 
x TEAE Leading to NKTR-255 Dose Interruption by SOC and PT 
x TEAE Leading to Discontinuation of NKTR-255 by SOC and PT 
x TEAE Leading to Death by SOC and PT 
Other safety observations (OSO) will be summarized in following categories: 
Ͳ 
AEs associated with increased cytokine levels in blood 
o 
Arthralgia 
o 
Asthenic conditions/Fatigue 
o 
Flu like symptoms 


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o 
Elevated hepatic transaminases 
o 
Hypotension 
o 
Rash and pruritus 
Ͳ 
Cytokine release syndrome (CRS) 
Ͳ 
Elevated hepatic transaminase 
Ͳ 
ICANs (this is an individual PT which is Immune Effector Cell-Associated Neurotoxicity 
Syndrome and is included in TEAE summary tables) 
Ͳ 
Infections 
Ͳ 
Infusion related reaction (IRR, 48-hour window post NKTR-255 administration) 
Ͳ 
Neutropenia 
Ͳ 
QT/QTc Prolongation 
Ͳ 
Thrombocytopenia 
For IRR (except for the PT of infusion related reaction), events that start within 48 hours after 
NKTR-255 drug administration will be included. If AE onset time is available, the time 
information will be used to exclude events that start before dosing and include events that start 
on day 3 relative to dosing day but within 48 hours of start of NKTR-255 administration; 
otherwise, AEs that start on the same and next day of dosing will be included. Analysis on IRR 
will only be performed for patients who receive at least one NKTR-255 dose.  
The following summaries will be performed for OSO using safety population with TEAE period. 
A listing of how OSO is categorized will also be provided. 
x Treatment-emergent Other Safety Observations (OSO) by Category/PT and Worst CTC 
Grade 
x Grade 3 and above Treatment-emergent Other Safety Observations (OSO) by 
Category/PT 
x Treatment-emergent Other Safety Observations (OSO) Related to NKTR-255 by 
Category/PT and Worst CTC Grade 
x Serious Treatment-emergent Other Safety Observations (OSO) by Category/PT and 
Worst CTC Grade 
x Serious Treatment-emergent Other Safety Observations (OSO) Related to NKTR-255 by 
Category/PT and Worst CTC Grade 
Additionally, site identified Treatment-emergent CRS events will also be summarized and listed 
by PT and Worst CTC Grade.  


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The following AE summaries will be provided in enrolled population with extended TEAE 
period: 
x Overall summary of Extended TEAEs  
x Extended TEAE Related to any Study Drug by SOC, PT and Worst CTC Grade 
x Serious Extended TEAE Related to any Study Drug by SOC, PT and Worst CTC Grade 
x Grade 3 and above Extended TEAEs related to any Study Drug by SOC and PT  
x Extended TEAE Leading to Discontinuation of any Study Drug by SOC and PT 
x Extended TEAE Leading to death by SOC and PT  
The following data listings will be provided in enrolled population: 
x All TEAEs 
x Serious TEAEs 
x Grade 3 or Higher TEAEs 
x Other Safety Observations (OSO) 
x TEAEs Leading to Study Drug Discontinuation 
x TEAEs Leading to Dose delay, Reduction, and Interruption 
x TEAE leading to death  
7.6.3 
Death 
All cause deaths will be summarized by dose level in the enrolled population: 
x All deaths, reasons for death 
x Deaths within treatment-emergent period, and reasons for death 
x Deaths within extended treatment-emergent period, and reasons for death 
A by-patient listing of deaths will be provided for all enrolled patients. 
7.6.4 
Clinical Laboratory Evaluation 
Clinical laboratory tests will be conducted according to the Schedule of Assessments and 
performed by the designated central laboratories.  Analyses of laboratory parameters include 
values collected until 30 days after the last dose of NKTR-255, but before the initiation of 
subsequent anticancer treatment. 
Below are the selected laboratory parameters with the direction of interest to be summarized: 


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7.6.4.1 
Hematology 
x Absolute neutrophil count (ANC) (Decrease) 
x Hemoglobin (Hgb) (Both directions) 
x Hematocrit (HCT) (Both directions) 
x Platelet count (Decrease) 
x White blood cell (WBC) count (Both directions) 
x Lymphocyte count (Both directions) 
7.6.4.2 
Chemistry 
x AST (Increase) 
x ALT (Increase) 
x Alkaline phosphatase (ALP) (Increase) 
x Albumin (Both) 
x Total Bilirubin (TBL) (Increase) 
x Creatinine (Increase) 
x Blood urea nitrogen (BUN) (Both directions) 
x Calcium (absolute, albumin-corrected) (Both directions) 
x Gamma-glutamyl transferase (GGT) (Increase) 
x Sodium (Both directions) 
x Potassium (Both directions) 
x Chloride (Both directions) 
x Lactate dehydrogenase (LDH) (Increase) 
x Lipase (Increase) 
x Amylase (Increase) 
x Magnesium (Decrease) 
A table presenting number and percentage of patients with post-baseline CTC grade increased 
from baseline (any grade, grade 3-4) will be generated for the above selected laboratory 
parameters. If lab parameters do not have toxicity grade in CTCAE v5.0, it will not be presented 
in the table. In addition, a table presenting hepatic impairment evaluation and a table presenting 
renal impairment evaluation will be generated. The hepatic and renal impairment evaluation 
criteria can be found below: 


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x Hepatic impairment evaluation 
Normal: TBL ≤ ULN and AST ≤ ULN 
Mild: ULN < TBL ≤ 1.5 x ULN or AST > ULN 
Moderate: 1.5 x ULN < TBL ≤ 3 x ULN 
Severe: TBL > 3 x ULN 
x Renal impairment evaluation based on baseline estimated glomerular filtration rate 
(eGFR, mL/min/1.73 m2) (Levey et al., 2009) 
Normal: eGFR ≥ 90 mL/min/1.73 m2 
Mild: eGFR between 60 to 89 mL/min/1.73 m2 (inclusive) 
Moderate: eGFR between 30 and 59 mL/min/1.73 m2 (inclusive) 
Severe: eGFR < 30 mL/min/1.73 m2 
x Where eGFR =141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 灤 0.993Age × 1.018 [if female] × 
1.159 [if black] 
o Scr is serum creatinine in mg/dL, 
o κ is 0.7 for females and 0.9 for males, 
o α is -0.329 for females and -0.411 for males 
o min indicates the minimum of Scr/κ or 1 
o max indicates the maximum of Scr/κ or 1 
o age = years 
x Renal impairment evaluation based on Cockcroft and Gault equation (calculated 
creatinine clearance) 
Severe: calCrCL <30 
Moderate: 30 ≤ calCrCL ≤ 59 
Mild/Normal: calCrCL ≥ 60 


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Where calCrCl (male) = ([140-age] × weight in kg)/(serum creatinine in mg/dLh 72); 
calCrCl (female) = calCrCl (male) × 0.85 
A listing of patients who met Hy’s Law criteria will be provided. Hy’s Law criteria are defined 
as follows:  
x ALT >= 3xULN or AST >= 3xULN 
x Total bilirubin TBL >= 2xULN 
x ALP <= 2xULN or missing 
7.6.5 
Additional Safety Analyses 
7.6.5.1 
Vital Signs 
Vital signs visits will be included in listings. Vital sign abnormality will be summarized by 
maximum and minimum post-baseline value. Abnormal values are defined as an absolute value 
outside the defined range in Table 5. 
Table 5:  
Vital Sign Abnormality Definition 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 160 mmHg 
< 90 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 60 mmHg 
Heart rate 
> 100 bpm 
< 60 bpm 
Temperature 
> 38ºC 
< 35ºC 
Respiratory rate 
> 24/min 
< 12/min 
 
7.6.5.2 
Electrocardiogram 
ECG (safety) parameters (numeric) will be summarized at baseline. Worst post-baseline and 
Worse post baseline change from baseline will also be summarized 
Categorical outliers will be summarized in frequency tables. ECG finding at any timepoint will 
be determined as an outlier if the following criteria (which are assessed separately) are met for 
the ECG intervals (ie, QTcF, PR, QRS, HR). 


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Table 6:  
ECG Outlier Criteria 
ECG 
Interval 
Categorical Outlier Criteria  
QTcF 
Male: Treatment-emergent value of > 450 and ≤480 ms when not present at baseline (new onset)  
Male: Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline (new onset)  
Male:Treatment-emergent value of > 500 ms when not present at baseline (new onset)  
Increase of QTc from baseline of > 30 and ≤ 60 ms  
Increase of QTc from baseline > 60 ms  
Female: Treatment-emergent value of > 470 and ≤ =480 ms when not present at baseline (new onset)  
Female: Treatment-emergent value of > 480 and ≤ = 500 ms when not present at baseline (new onset)  
Female:Treatment-emergent value of > 500 ms when not present at baseline (new onset)  
Increase of QTc from baseline of > 30 and ≤ 60 ms  
Increase of QTc from baseline > 60 ms  
PR  
Increase of PR from baseline > 25% resulting in PR > 200 ms  
QRS  
Increase of QRS from baseline > 25% resulting in QRS > 120 ms  
HR  
Decrease of HR from baseline >25% resulting in HR < 50 bpm  
Increase of HR from baseline >25% resulting in HR > 100 bpm  
 
Number and percentages of categorical outliers will be summarized for each treatment group. A 
patient will be counted only once for a particular outlier event if the patient experiences more 
than 1 episode of that event. 
7.6.6 
Listing of safety ECG Parameters will be Provided. COVID-19 Related Analyses 
A listing of patients who missed study visit(s) or study procedure(s) due to COVID-19 will be 
provided. 


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8.0 
DATA MONITORING COMMITTEE AND SAFETY REVIEW 
An SRC will be used for the dose escalation and dose expansion phases of the study. The SRC 
will be comprised of at least one site Investigator and the Sponsor’s Medical Monitor. Additional 
participants may include representatives from the Sponsor’s Clinical Development, Drug Safety, 
Biostatistics, and Clinical Pharmacology divisions as well as other functional representatives as 
needed to review safety data. For dose escalation cohorts, the SRC will jointly assess safety 
before opening dose escalation to each level. The exact dose will be confirmed based on review 
of safety data after a minimum of 3 patients have been enrolled in each level.  
An independent, external, and multidisciplinary Data Safety Monitoring Committee (DSMC) 
composed of 3 to 5 members will be established and include at least 1 clinician knowledgeable in 
the field of the trial and at least 1 statistician. The DSMC will operate according to a prespecified 
charter and make recommendations on study conduct related to patient safety. The DSMC will 
review the progress of the study and perform reviews of safety data and provide recommendation 
to whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. 


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CCI


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CCI


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9.1.4 
Missing Data Imputation and Handling of Values Outside the Limits of 
Quantitation 
Missing values due to a missing sample or failed test will not be imputed. For cytokine 
assessment only, values reported as below the limit of quantitation (BLQ) at baseline, will be 
imputed as LLOQ (lower limit of quantitation). If LLOQ is not available, the minimum value 
across all samples will be used in place of the LLOQ to impute the values reported as BLQ. This 
imputation approach with LLOQ is only for baseline cytokine values, and not for post-baseline 
values. 
CCI


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Values reported as above the limit of quantitation (ALQ) post-baseline, will be imputed as 
ULOQ (upper limit of quantitation). If ULOQ is not available, the maximum value across all 
samples will be used in place of the ULOQ to impute the values reported as ALQ. The 
imputation approach is for post-baseline values only, and not for any baseline cytokine values. 


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10.0 
PHARMACOKINETIC ANALYSIS 
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 of NKTR-255 and to 
determine measures of individual exposure for NKTR-255. Model predicted exposures may be 
used for exposure-response analyses of selected efficacy and safety endpoints. Population PK 
and/or exposure-response analyses will be specified in a separate analysis plan and the results 
will be reported separately. 
CCI


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10.3.2 
Handling of Missing Values, BLQ Values, and Outliers 
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. 
Predose concentration for Cycle 2 and onward will be duplicated as D22 (504 hr, trough) for the 
previous cycle and predose on Day 1 for the scheduled cycle for the calculation of PK 
parameters. Concentration value of BLQ will be treated as missing for D22 (504 hr) of previous 
cycle and as 0 for the predose on Day 1 for the scheduled cycle. 
CCI


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12.0 
CHANGES FROM PROTOCOL 
Below are changes of this plan from Nektar Therapeutics Protocol 19-255-03 “A Phase 1b/2, 
open-label, multi-center, dose escalation and dose expansion study of NKTR-255 in combination 
with cetuximab as a salvage regimen for solid tumors”, protocol amendment 2.0 dated  
08 October 2021. 
x All analyses methods related to expansion phase of the study are removed as only Phase 
1b patients were enrolled 
x PFS analysis is based on safety population 
x 
 
x Updated definition for TEAE period  
x Updated definition for Response-evaluable population 
CCI


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13.0 
REFERENCES 
1. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol. 2014;32(27):3059. 
2. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247 
3. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Statistics in medicine. 2008;27(13):2420-39. 
4. 
Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med. 1995;14(4):357-379. 
5. 
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management 
of cytokine release syndrome. Blood. 2014;124(2):188̽195. 


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