Clinical trial NCT04969861
Conditions: Metastatic Head and Neck Cancer Recurrent Head and Neck Cancer
Keywords: Head and Neck Cancer Head and Neck Squamous-Cell Carcinoma HNSCC BEMPEG Bempegaldesleukin NKTR-214 Keytruda Pembrolizumab PROPEL-36
Sponsor: Nektar Therapeutics
Start date: 2022-03-09; Completion date: 2022-04-22
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, randomized, open-label, Phase 2/3 study that will evaluate the efficacy and safety of bempegaldesleukin (BEMPEG; NKTR-214) combined with pembrolizumab compared with pembrolizumab monotherapy in patients with recurrent or metastatic HNSCC with positive PD-L1 expression (CPS ≥ 1).

Detailed description:

Arms: arm 1: Bempegaldesleukin plus pembrolizumab every 3 weeks (q3w) for up to 35 cycles (approximately 2 years). arm 2: Pembrolizumab monotherapy q3w for up to 35 cycles (approximately 2 years).
Interventions: intervention 1: Bempegaldesleukin intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Pembrolizumab (anti-PD-1) will be dosed as per the pharmacy manual.

Protocol documents:
Prot_000.pdf: 


Protocol No. 20-214-36 
 
bempegaldesleukin (NKTR-214) and pembrolizumab 
Nektar Therapeutics 
 
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PRINCIPAL INVESTIGATOR COMMITMENT 
 
Protocol Number: 20-214-36 
Title: 
A Phase 2/3, Randomized, Open-label Study to Compare 
Bempegaldesleukin Combined with Pembrolizumab Versus 
Pembrolizumab Alone in First-Line Treatment of Patients with Metastatic 
or Recurrent Head and Neck Squamous-Cell Carcinoma with PD-L1 
Expressing Tumors (PROPEL-36) 
Version: 
Original 
Date: 
14 June 2021 
Sponsor: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
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 Signature 
 
Date 
Printed Name: 
 
 
 
Institution: 
 
Address 
 
 
 
 




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LIST OF STUDY CONTACTS 
Study Contact 
Name 
Contact Information 
Medical Monitor 
 
 
 
 
Nektar Medical Monitor 
 
 
 
  
 
  
 
Serious AEs, AEs of Special 
Interest, Events of Clinical 
Interest, and Pregnancy 
Reporting 
 
 
 
  
 
 


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TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR COMMITMENT ....................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................8 
LIST OF APPENDICES ...............................................................................................................8 
ACRONYMS AND ABBREVIATIONS ......................................................................................9 
1.0 
STUDY SYNOPSIS .........................................................................................................14 
1.1 
Study Schematic.....................................................................................................22 
1.2 
Schedule of Events .................................................................................................23 
2.0 
INTRODUCTION............................................................................................................31 
2.1 
Background ............................................................................................................31 
2.2 
Benefit/Risk Assessment .......................................................................................40 
3.0 
INVESTIGATIONAL PLAN .........................................................................................43 
3.1 
Study Design ..........................................................................................................43 
3.2 
Rationale for Study Design ....................................................................................44 
4.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................49 
4.1 
Primary Objectives and Endpoints .........................................................................49 
4.2 
Secondary Objectives and Endpoints .....................................................................49 
 
 
5.0 
SELECTION OF STUDY POPULATION ...................................................................51 
5.1 
Inclusion Criteria ...................................................................................................51 
5.2 
Exclusion Criteria ..................................................................................................54 
6.0 
TREATMENT PLAN ......................................................................................................58 
6.1 
Screening Period ....................................................................................................58 
6.2 
Treatment Period ....................................................................................................58 
6.3 
Long-Term Follow-Up...........................................................................................65 
6.4 
End of Study ..........................................................................................................66 
6.5 
Dose Modification and Management of Specific Adverse Events ........................66 
6.6 
Discontinuation Criteria .........................................................................................79 
6.7 
Prior and Concomitant Medications/Procedures ...................................................81 
6.8 
Adverse Events ......................................................................................................85 
7.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ..............................................86 
7.1 
Bempegaldesleukin (NKTR-214) ..........................................................................86 


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7.2 
Pembrolizumab Preparation, Storage, and Packaging ...........................................87 
7.3 
Study Drug Accountability and Reconciliation .....................................................87 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................89 
8.1 
Tumor Imaging and Assessment of Disease ..........................................................89 
8.2 
Pharmacokinetic and Immunogenicity Measurements ..........................................91 
 
 
8.4 
Health-Related Quality of Life (HRQoL) ..............................................................97 
9.0 
ASSESSMENT OF EFFICACY .....................................................................................98 
9.1 
Assessment of Tumor Response and Progression .................................................98 
9.2 
Patient-Reported Outcomes ...................................................................................98 
10.0 
ASSESSMENT OF SAFETY ........................................................................................100 
10.1 
AE Definition and Assessment ............................................................................100 
10.2 
Monitoring AEs ...................................................................................................101 
10.3 
Grading of AEs ....................................................................................................101 
10.4 
Causality Relationship of AEs .............................................................................102 
10.5 
AE Reporting and Follow-up ...............................................................................102 
10.6 
Serious AE Definition ..........................................................................................104 
10.7 
Serious AE Reporting ..........................................................................................104 
10.8 
Serious AE Follow-up..........................................................................................106 
10.9 
Disease Progression and Death due to Disease Progression– Not Reportable as 
an AE or SAE.......................................................................................................106 
10.10 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ........................................................................................................107 
10.11 Immune-Mediated Adverse Events......................................................................107 
10.12 Adverse Events of Special Interest for Bempegaldesleukin ................................107 
10.13 Potential Drug-Induced Liver Injury for Bempegaldesleukin .............................108 
10.14 Events of Clinical Interest for Pembrolizumab ....................................................108 
10.15 Treatment of Overdose ........................................................................................108 
10.16 Pregnancy Tests/Pregnancy .................................................................................109 
10.17 Emergency Medical Support and Patient Card ....................................................110 
10.18 Clinical Laboratory Tests .....................................................................................111 
10.19 Physical Examinations .........................................................................................111 
10.20 Vital Signs ............................................................................................................111 
10.21 Electrocardiograms ..............................................................................................111 
10.22 Echocardiograms..................................................................................................111 
11.0 
STATISTICAL PLAN ...................................................................................................113 
11.1 
General Considerations ........................................................................................113 




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Table 8: 
Phase 2 Portion of the Study: Pharmacokinetic and Immunogenicity 
Sampling (for Arm A [Bempegaldesleukin plus Pembrolizumab]) ..........92 
Table 9: 
Phase 3 Portion of the Study: Pharmacokinetic and Immunogenicity 
Sampling (for Arm A [Bempegaldesleukin plus Pembrolizumab]) ..........93 
Table 10: 
Tumor Tissue 
 Sampling ....................................................94 
Table 11: 
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events ...............................................................103 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic.........................................................................................22 
Figure 2: 
Statistical Testing Procedure ....................................................................114 
 
LIST OF APPENDICES 
Appendix 1: 
CLINICAL LABORATORY TESTS ......................................................135 
Appendix 2: 
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM FOR PATIENTS IN ARM A 
RECEIVING BEMPEGALDESLEUKIN ...............................................138 
Appendix 3: 
PERFORMANCE STATUS CRITERIA ................................................139 
Appendix 4: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) (VERSION 1.1) FOR EVALUATING RESPONSE IN 
SOLID TUMORS ....................................................................................140 
Appendix 5: 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ......................................................141 
Appendix 6: 
CYTOKINE-RELEASE SYNDROME (CRS) MANAGEMENT 
MEASURES/ALGORITHM FOR PATIENTS IN ARM A 
RECEIVING BEMPEGALDESLEUKIN ...............................................144 


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ACRONYMS AND ABBREVIATIONS 
Abbreviation or Term 
Definition 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT (SGPT) 
alanine transaminase (serum glutamic pyruvic transaminase) 
AST (SGOT) 
aspartate transaminase (serum glutamic oxaloacetic transaminase) 
bempeg, BEMPEG 
abbreviation for bempegaldesleukin, the International Nonproprietary Name 
(INN) for NKTR-214 
bempegaldesleukin 
International Nonproprietary Name (INN) for NKTR-214 
BICR 
blinded independent central review 
BTLA 
B- and T-lymphocyte attenuator 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMH 
Cochran Mantel Haenszel 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019, caused by the severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) 
CPS 
combined positive score 
CR 
complete response 
CRF 
case report form 
CRR 
complete response rate 
CRS 
cytokine-release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
  
CTLA-4 
cytotoxic T lymphocyte-associated protein 4 
CVA 
cerebrovascular accident 
DCI 
data collection instrument 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid  


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Abbreviation or Term 
Definition 
DOAC 
direct oral anticoagulant 
DOR 
duration of response 
DRESS 
drug reaction with eosinophilia and systemic symptoms 
DVT 
deep vein thrombosis 
DWI 
diffusion-weighted imaging 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECI 
event of clinical interest 
ECLA 
electrochemiluminescence assays 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EOI 
end of infusion 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D 
EuroQol-5D 
EQ-5D-5L 
5-level EuroQol-5D 
eSAE 
electronic serious adverse event 
FA 
final analysis 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GEP 
gene expression profile 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HNSCC 
head and neck squamous-cell carcinoma 
HPV 
human papillomavirus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
IA1 
first interim analysis (Interim Analysis 1) 
IA2 
second interim analysis (Interim Analysis 2) 


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Abbreviation or Term 
Definition 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICOS 
inducible T-cell co-stimulator  
IEC 
independent ethics committee 
IFN-γ 
interferon-γ  
IHC 
immunohistochemistry 
IL-2 
interleukin-2 
IL-2Rαβγ 
interleukin-2 receptor alpha beta gamma 
IL-2Rβγ 
interleukin-2 receptor beta gamma 
imAE 
immune-mediated adverse event (also referred to as immune-related AEs 
[irAEs] in this document) 
IMG 
immunogenicity 
IND 
Investigational New Drug application 
INN 
International Nonproprietary Name 
INR 
international normalized ratio 
irAE 
immune-related adverse event (also referred to as immune-mediated AEs 
[imAEs] in this document) 
IRB 
institutional review board 
IRT 
Interactive Response Technology  
ITT 
intent-to-treat 
IV 
intravenous 
kg 
kilogram 
L 
liter 
LDH 
lactate dehydrogenase 
LMWH 
low molecular weight heparin 
LVEF 
left ventricular ejection fraction 
mg 
milligram 
min 
minute(s) 
mL 
milliliter 
MRI 
magnetic resonance imaging 
msec 
millisecond 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition  


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Abbreviation or Term 
Definition 
NCI 
National Cancer Institute 
NK 
natural killer 
NKTR-214 
bempegaldesleukin (International Nonproprietary Name) 
NSAE 
nonserious adverse event 
NSAID 
nonsteroidal anti-inflammatory drugs 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate  
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PD-L2 
programmed cell death ligand 2 
PEG 
polyethylene glycol 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response  
PRO 
patient-reported outcomes 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QLQ-H&N35 
Quality of Life Questionnaire head and neck cancer specific module 
QTcF 
Fridericia’s corrected QT interval 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rhIL-2 
recombinant human interleukin-2 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
rtPA 
recombinant tissue plasminogen activator 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 


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Abbreviation or Term 
Definition 
SJS 
Stevens-Johnson Syndrome 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TIA 
transient ischemic attack 
TIL 
tumor infiltrating lymphocyte 
TME 
tumor microenvironment 
TNBC 
triple-negative breast cancer 
Treg 
regulatory T cell 
TTR 
time to response 
ULN 
upper limit of normal 
US, USA 
United States (of America) 
VAS 
visual analog scale 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
 


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1.0 
STUDY SYNOPSIS 
Title of Study: 
A Phase 2/3, Randomized, Open-label Study to Compare Bempegaldesleukin Combined 
with Pembrolizumab Versus Pembrolizumab Alone in First-Line Treatment of Patients with 
Metastatic or Recurrent Head and Neck Squamous-Cell Carcinoma with PD-L1 Expressing 
Tumors (PROPEL-36) 
Sponsor: 
Nektar Therapeutics 
Name of Finished 
Product(s): 
Bempegaldesleukin (NKTR-214 drug product) 
Keytruda® 
Name of Active 
Ingredient(s): 
Bempegaldesleukin (NKTR-214) drug substance 
Pembrolizumab (anti-programmed cell death protein 1 [anti-PD-1] antibody) 
Phase of 
Development: 
Phase 2/3 
Objectives and 
Endpoints: 
In patients who are aged 18 years and older with recurrent or metastatic head and neck 
squamous-cell carcinoma (HNSCC) and positive programmed cell death ligand 1 (PD-L1) 
expression (defined by combined positive score [CPS] ≥ 1) who have not received prior 
therapy for the treatment of recurrent or metastatic HNSCC, the primary objectives and 
endpoints are: 
Primary Objective 
Endpoint 
To compare the overall survival (OS) of 
bempegaldesleukin plus pembrolizumab 
versus pembrolizumab monotherapy.  
OS, defined as the time from randomization 
to death due to any cause. 
To compare the objective response rate 
(ORR) of bempegaldesleukin plus 
pembrolizumab versus pembrolizumab 
monotherapy. 
ORR, defined as the rate of confirmed 
complete response (CR) or partial response 
(PR) per Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1) as 
assessed by blinded independent central 
review (BICR).  
 
The secondary objectives and endpoints listed below involve comparison of 
bempegaldesleukin plus pembrolizumab versus pembrolizumab monotherapy in first-line 
patients with recurrent or metastatic HNSCC and positive PD-L1 expression (defined by 
CPS ≥ 1) who have not received prior therapy for the treatment of recurrent or metastatic 
HNSCC: 
Secondary Objective 
Endpoint 
To compare progression-free survival 
(PFS). 
PFS, defined as the time from randomization 
to the first documented disease progression 
(per RECIST 1.1 by BICR) or death due to 
any cause, whichever occurs first. 






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survival events have been observed. At the second interim analysis, if the OS efficacy 
boundary is crossed, the trial will be stopped for efficacy. Otherwise, conditional power 
will be calculated to determine the overall survival event size for final analysis. 
Patients will be randomized at a 1:1 ratio to receive one of two treatments: 
• 
Arm A:  Bempegaldesleukin plus pembrolizumab every 3 weeks (q3w) for up to 
35 cycles (approximately 2 years). 
• 
Arm B:  Pembrolizumab monotherapy q3w for up to 35 cycles (approximately 
2 years). 
Randomization will be stratified according to the following factors: 
1.  Disease status (metastatic vs recurrent only). 
2.  PD-L1 tumor expression determined by PD-L1 immunohistochemistry (IHC) 22C3 
PharmDx (CPS ≥ 20 vs CPS 1-19) at either a local or the central laboratory. 
Note: CPS is the number of PD-L1 staining cells (tumor cells, lymphocytes, 
macrophages) divided by the total number of viable tumor cells, multiplied by 100. The 
specimen should be considered to have PD-L1 expression if CPS ≥ 1. 
3. Human papillomavirus (HPV) status for oropharyngeal cancer determined by p16 IHC 
(positive vs negative). For patients with cancers of the oral cavity, hypopharynx, and 
larynx, HPV status is considered HPV negative. 
Patients who attain a complete response may consider stopping study drug if they meet 
criteria for holding therapy. Patients who stop study drug after receiving 35 cycles 
(approximately 2 years) of study drug for reasons other than disease progression or 
intolerability, or patients who attain a complete response and stop study drug may be 
eligible for up to 17 cycles (approximately 1 year) of retreatment upon experiencing 
Investigator-determined radiographic disease progression. The decision to retreat will be at 
the discretion of the Investigator only if the patient meets the criteria for retreatment and the 
trial is ongoing.  
After the end of treatment, each patient will be followed for 90 days after the last dose of all 
study drug(s) for AE monitoring, including serious AEs [SAEs] and AEs of special interest 
[AESI]. Patients who discontinue for reasons other than centrally verified disease 
progression will have post-treatment follow-up for disease status until disease progression 
is verified by the central imaging vendor, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up. All patients will be followed for 
overall survival until death, the patient withdraws consent, the patient is lost to follow-up, 
or the study is terminated by the Sponsor. 
The Sponsor estimates that the study will be fully enrolled within approximately 25 months. 
Analyses are anticipated at the following times (relative to the first patient’s randomization 
date): approximately 14 months for the first interim analysis, approximately 32 months for 
the second interim analysis, and approximately 38 to 52 months for the final analysis for 
overall survival. 
Key Eligibility 
Criteria: 
The following list contains key eligibility criteria only; a full list of eligibility criteria is 
provided in Section 5.0. 
Key Inclusion Criteria: 
• 
Provide written, informed consent to participate in the study and follow the study 
procedures. 
• 
Male or female patients, age 18 years or older on the day of signing the informed 
consent form. 


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• 
Have histologically or cytologically-confirmed recurrent or metastatic HNSCC that is 
considered incurable by local therapies. 
o 
No prior systemic therapy for recurrent or metastatic disease. Systemic therapy 
given as part of multimodal treatment for locally advanced disease is allowed if 
completed more than 6 months prior to signing consent. 
o 
The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, 
and larynx. 
o 
Patients may not have a primary tumor site of nasopharynx (any histology) and/or 
unknown primary. 
• 
Have measurable disease based on RECIST 1.1 as determined by the local site 
Investigator. Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been shown in such lesions since irradiation. 
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 
• 
Tumor tissue from a core, incisional, or excisional biopsy (fine needle aspirates are not 
acceptable) to the central laboratory for determination of PD-L1 status (if not 
determined at local laboratory) 
. A newly obtained 
biopsy is strongly preferred, but archival tumor biopsy may be used and provided (see 
Section 8.3.1). 
• 
The tumor must have positive PD-L1 expression (ie, CPS ≥ 1) as determined with the 
PD-L1 IHC 22C3 PharmDx diagnostic kit at either a local or central laboratory. 
• 
Patients with oropharyngeal cancer: must have results from testing of HPV status 
defined as p16 IHC testing using CINtec® p16 Histology assay (Ventana Medical 
Systems Inc., Tucson AZ). If HPV status was previously tested using this method, no 
additional testing is required. Note: 
o 
If local p16 testing results are not available, or cannot be assessed by the specified 
method, a tumor tissue sample may be submitted to the central laboratory for p16 
testing. 
Patients with oral cavity, hypopharynx, or larynx cancers:  HPV testing by p16 IHC is 
not required as by convention these tumor locations are assumed to be HPV negative. 
Key Exclusion Criteria: 
• 
Has disease that is suitable for local therapy administered with curative intent. 
• 
Has progressive disease within 6 months of completion of curatively intended systemic 
treatment for locoregionally advanced HNSCC. 
• 
Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to 
initiation of study drug, or patient has not fully recovered (ie, ≤ Grade 1 or at baseline) 
from AEs due to a previously administered treatment. A 1-week washout is permitted 
for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system 
(CNS) disease. Note: 
o 
Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and qualify for the study. 
o 
If patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
• 
Has a life expectancy of less than 3 months and/or has rapidly progressing disease 
(eg, tumor bleeding, uncontrolled tumor pain) as determined by Investigator. 
• 
Has a known additional malignancy that is progressing or has required active treatment 
within 5 years prior to the first dose of study drug with the exception of:  curatively 
treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
curatively resected in situ cervical cancer, and curatively resected in situ breast cancer. 




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to first onset of PRO deterioration with confirmation), is based on the swallowing multi-
item scales of the EORTC QLQ-H&N35. 
Opioid analgesic use will be measured based on reported concomitant medications. 
Safety Evaluation: 
Assessment of safety will be determined by an ongoing review of the following: 
• 
Treatment-emergent AEs, including treatment-related AEs, serious AEs (SAEs), AEs 
of special interest for bempegaldesleukin, events of clinical interest (ECIs) for 
pembrolizumab, and AEs leading to drug discontinuation. 
• 
Clinical laboratory tests (see Appendix 1). 
• 
Vital signs. 
• 
Physical examination. 
Statistical Methods: 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. 
Efficacy: 
As a primary efficacy endpoint, ORR will be tested at an alpha level of 0.001 The Cochran 
Mantel Haenszel (CMH) test statistic will be used to compare the proportion of patients 
with an objective response between the 2 treatment arms. 
As a primary efficacy endpoint, OS will be evaluated at an alpha level of 0.049 if ORR is 
not significant and 0.05 if ORR is significant. The stratified log-rank test statistic with 
prespecified weights will be used to compare OS between the 2 treatment arms. A stratified 
Cox proportional hazards model with treatment as the single covariate will be used to 
estimate the hazard ratio and corresponding 95% confidence interval (CI). The Kaplan-
Meier method will be used to further summarize OS, including Kaplan-Meier curves, 
medians with corresponding 95% CIs, etc. 
The first interim analysis will occur at least one month after the last patient of the Phase 2 
portion has been randomized into the study. At the first interim analysis, ORR will be 
assessed for futility:  
• 
ORR futility assessment (ie, difference in ORR proportions is ≥ 0% 
[bempegaldesleukin plus pembrolizumab minus pembrolizumab monotherapy]) will 
serve as a gate to proceed to the Phase 3 portion of the study. 
If the DMC determines that the study should continue based on the prespecified futility 
boundary, Phase 3 of the study will begin following an expected 4-month enrollment pause 
for the first interim analysis readout. At the second interim analysis when 
approximately 500 patients have been randomized and about 231 OS events have been 
observed, the following tests will be conducted (if the actual number of events at the time 
of the analysis is different from the planned one, the actual alpha and statistical significance 
level will be adjusted using O’Brien and Fleming alpha spending function): 
• 
If ORR is not significant at the second interim analysis, OS will be tested at an overall 
alpha level of 0.049 and at α = 0.021 at the second interim analysis. 
• 
If ORR is significant at the second interim analysis, the fallback method will be used 
and OS will be tested at an overall alpha level of 0.05 at α = 0.022 at the second 
interim analysis. 
For the final analysis, the adaptive method in Liu and Hu (Liu 2016) and Mehta and Pocock 
(Mehta 2011) will be used to determine the number of OS events needed to target 
approximately 85% to 90% conditional power for the final analysis. The minimum and 
maximum number of OS events for the final analysis are 298 and 393, respectively.  
At the final analysis, the primary analysis of OS to claim statistical significance will be 
based on the weighted combination version of the stratified log-rank test with prespecified 
weights (Lehmacher 1999). Statistical significance level for the final analysis is 0.043 or 
0.044 depending on whether ORR is significant at the second interim analysis. Prespecified 


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weights for the primary OS are 𝑤= √231/345 and 1-w for events occurring before and 
after the second interim analysis, respectively. The middle point, 345, of minimum and 
maximum event sizes is chosen to set up the weights. The conventional stratified log-rank 
test with equal weights for every patient will be conducted as a sensitivity analysis. Details 
will be provided in the Statistical Analysis Plan. 
Safety: 
Overall safety and tolerability of bempegaldesleukin plus pembrolizumab will be measured 
by the incidence of AEs, AESIs, SAEs, deaths, and laboratory abnormalities. Safety 
analyses will be summarized for the Safety population using descriptive statistics by 
treatment arm. 


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1.1 
Study Schematic 
Figure 1: 
Study Schematic 
  
Abbreviations:  ~ = approximately; CPS = combined positive score; DMC = Data Monitoring Committee; HNSCC = head and neck squamous-cell carcinoma; 
HPV = human papillomavirus; IV = intravenous; ORR = objective response rate; OS = overall survival; PD = progressive disease; PD-L1 = programmed cell 
death ligand 1; q3w = every 3 weeks; RR = randomization ratio 
Note:  The study schematic describes the initial treatment (ie, First Course). See Section 6.2.6 for information regarding eligibility for a Second Course. 
a. 
Additional reasons for discontinuing imaging are withdrawal of consent and the end of the study (see Section 8.1.2). 
 


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1.2 
Schedule of Events  
Table 1: 
Schedule of Events (Excluding Pharmacokinetic, Immunogenicity, 
 Sampling) 
Procedure / Period: 
Screening 
Treatment Cycles (3-Week Cycles) 
Post-treatment 
Cycle 1 Only 
Cycle 2 and Beyond  
Follow-up 
Visit 1y 
Follow-up 
Visit 2y 
Survival 
Follow-upz 
Study Daysa: 
Day  
−28 to −1 
Day 1  
Day 3 
(− 1 day) 
Phase 3 only: 
Day 5 
(± 1 day) 
Day 1  
(± 3 days) 
Day 3 
(+ 2 days) 
30 days from  
last dose 
(± 7 days) 
90 days from 
last dose 
(± 7 days) 
Every 
12 weeks 
(± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographics and medical historyb 
X 
 
 
 
 
 
 
 
 
Tumor biopsyc 
X 
 
 
 
 
 
 
 
 
Randomization 
 
Xd 
 
 
 
 
 
 
 
Physical examinatione 
X 
Predose 
 
 
Predose 
 
X 
X 
 
Vital signsf 
X 
Xf 
X 
 
Xf 
 
X 
X 
 
ECOG performance statusg 
X 
Predose 
 
 
Predose 
 
X 
X 
 
ECGh 
X 
 
 
 
 
 
 
 
 
ECHO/MUGAi 
X 
 
 
 
 
 
 
 
 
Pregnancy testj 
Xj 
Predosej 
 
 
Predose 
 
X 
X 
 
Hematology and serum chemistryk 
X 
Predose 
 
 
Predose 
 
X 
 
 
Coagulationk 
X 
 
 
 
 
 
 
 
 
Thyroid function tests (T3 [total or 
free], free T4, TSH)l 
X 
 
 
 
Predosel 
 
X 
 
 
 


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Table 1: 
Schedule of Events (Excluding Pharmacokinetic, Immunogenicity, 
 Sampling) 
(Contd) 
Procedure / Period: 
Screening 
Treatment Cycles (3-Week Cycles) 
Post-treatment 
Cycle 1 Only 
Cycle 2 and Beyond  
Follow-up 
Visit 1y 
Follow-up 
Visit 2y 
Survival 
Follow-upz 
Study Daysa: 
Day  
−28 to −1 
Day 1  
Day 3 
(− 1 day) 
Phase 3 only: 
Day 5 
(± 1 day) 
Day 1  
(± 3 days) 
Day 3 
(+ 2 days) 
30 days  
from last dose 
(± 7 days) 
90 days  
from last dose 
(± 7 days) 
Every 
12 weeks 
(± 14 days) 
Additional lab assessmentsm 
X 
 
 
 
Predosem 
 
 
 
 
Urinalysis (dipstick)n 
X 
Predose 
 
 
Predose 
 
 
 
 
Serologyo 
X 
 
 
 
 
 
 
 
 
Tumor HPV statusp 
X 
 
 
 
 
 
 
 
 
PK and immunogenicity 
assessments 
 
Phase 2 portion of the study:  refer to Table 8 
Phase 3 portion of the study:  refer to Table 9 
 
 
 
 
 
 
Tumor assessmentq 
X 
First year from date of randomization, imaging every 6 weeks 
(± 7 days), or more frequently if clinically indicated. After 1 year 
from randomization, imaging every 9 weeks (± 14 days) for 
patients who remain on treatment. 
For patients who discontinue study drug 
without progression, monitor every 6 weeks 
(± 7 days) (or every 9 weeks ± 14 days 1 year 
after randomization) until:  
1) Start of new anticancer treatment, 
2) Disease progression by BICR, 
3) Death,  
4) Withdrawal of consent, or 
5) End of the study, whichever occurs first. 
The first follow-up assessment should occur 
6 weeks (± 7 days) from the last scheduled 
on-treatment imaging time point (or 9 weeks 
±14 days from the last scheduled on–treatment 
imaging time point 1 year after randomization). 
 




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a. 
Cycle intervals less than 21 days (eg, 21 days - 3 days) should only occur if the Investigator believes there are no safety concerns with dosing the patient 1 to 
3 days prior to a 21-day cycle. All procedures and examinations should be performed before the administration of study drug(s), except as indicated. 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, the coronavirus disease 2019 
(COVID-19) public health emergency, or other patient-specific circumstances. All out of window visits and procedures will incur a protocol deviation. 
Following randomization, Investigators may choose to perform study visits via telemedicine or at alternate locations if needed during periods of global 
pandemics (eg, COVID-19); however, any protocol-mandated procedures that cannot be performed via telemedicine or at alternate locations will be 
documented as a protocol deviation. 
b.  A medical history will be obtained by the Investigator or qualified designee. Medical history will include all active conditions, and any condition diagnosed 
within the prior 10 years that is considered to be clinically significant by the Investigator. The patient’s history of tobacco use will also be collected. Details 
regarding the patient’s head and neck cancer will be recorded separately and not listed as medical history.  
c.  Tumor tissue requirements: formalin-fixed paraffin-embedded (FFPE) tumor tissue block (obtained within 12 months of randomization) or unstained FFPE 
tumor tissue sections on slides (a minimum of 8 slides, preferably 15 to 25, obtained within 4 months [if stored in the dark at room temperature up to 25°C] 
or 6 months [if stored in the dark at 2°C–8°C] of randomization) collected from a recurrent lesion without intervening therapy and irradiation, are acceptable 
in lieu of a newly obtained excisional, incisional, or core tumor biopsy prior to treatment. Recurrent lesions in a previously irradiated area can be biopsied if 
progression has been shown in such lesions since irradiation. See Section 8.3.1. Newly obtained biopsies are preferred to archived tissue. 
PD-L1 expression: PD-L1 expression testing will be determined by a local or central laboratory. PD-L1 testing will use the PD-L1 IHC 22C3 PharmDx 
diagnostic kit.  
d.  Within 5 calendar days following randomization, the patient should receive the first dose of study treatment.  
e. 
Physical examinations must occur within 5 days prior to administering study drug(s). A full physical examination should be conducted during Screening; 
targeted physical examinations should be conducted on Day 1 of Cycles 1 and beyond and at the post-treatment follow-up visits. See Section 10.19 for 
additional details. 
f. 
See Section 10.20. Weight is to be reported at each vital sign visit, height at screening only. On dosing days, vital signs are to be taken and recorded as 
follows: 
• 
For Arm A (bempegaldesleukin/pembrolizumab): prior to bempegaldesleukin infusion and 30 (± 10) minutes following the end of pembrolizumab 
infusion. 
• 
For Arm B (pembrolizumab monotherapy): prior to pembrolizumab infusion and 30 (± 10) minutes following the end of pembrolizumab infusion.  
g. ECOG performance status assessments for Day 1 of each cycle must occur within 5 days prior to administering study drug(s) (see Appendix 3). If the 
Cycle 1 Day ECOG assessment will be performed within 7 days of the Screening assessment, the ECOG assessment will not need to be repeated. 
h. ECG must be done within 14 days of the date of randomization. See Section 10.21. 
i. 
A standard echocardiogram or MUGA must be performed for all patients within 60 days prior to randomization to assess for cardiac function and left 
ventricular ejection fraction (LVEF). See Section 10.22. 
j. 
Pregnancy test information is provided in Section 10.16.1. Women of childbearing potential (WOCBP) must have a screening negative serum or urine 
pregnancy test within 28 days prior to randomization. A negative highly sensitive pregnancy test (urine or serum as required by local regulations) is required 
within 24 hours for urine or within 72 hours for serum before the first dose of study treatment. 
k. Screening hematology and chemistry and coagulation must be drawn within 10 days of the date of randomization. Hematology and chemistry assessments 
for Day 1 of each cycle must be drawn within 5 days prior to administering study drug(s). See Section 10.18 and Appendix 1. 


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l. 
See Appendix 1. Screening thyroid function tests must be drawn within 28 days of the date of randomization. Thyroid function tests may be obtained within 
5 days of administration of study drugs. 
m. See Appendix 1. Screening additional laboratory tests must be drawn within 28 days of the date of randomization. For Cycle 2 and beyond, the sampling for 
additional laboratory tests can be drawn within 5 days prior to administration of study drug(s). Any patient receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the study via local laboratories per institutional guidelines. 
n. See Appendix 1. Urinalysis assessment for Day 1 of each cycle must be provided within 5 days prior to administering study drug(s). 
o. Screening serology laboratory tests can be drawn within 28 days of the date of randomization. See Appendix 1. 
p.  For patients with oropharyngeal cancer only:  tumor tissue collection for HPV status is described in Section 8.3.1.1. 
q. Section 8.1 describes tumor imaging (including confirmation of tumor response) and assessment of disease. All tumor assessments will be sent to the 
imaging vendor. For patients who continue to receive treatment beyond progression, see Section 6.2.5. For assessments in long-term follow-up, see 
Section 6.3. 
Arm A (bempegaldesleukin plus pembrolizumab) only: 
r. 
See Appendix 1B for the list of local laboratory tests that require evaluation within 24 hours prior to bempegaldesleukin administration or as soon as 
locally feasible. 
s. 
Hydration guidelines provided in Section 6.2.3.2. 
t. 
See Section 6.7.1 for premedication guidance before study drug infusion(s). 
u. In Cycles 1 and 2, site personnel must contact the patient (by telephone or clinic visit) once between Days 3 and 5 (inclusive) following infusion, to 
remind the patient of the oral hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and document the results of 
the discussion (see Section 6.2.3.2). In Cycles 3 and beyond, the oral hydration follow-up is conducted as clinically indicated for patients in Arm A 
receiving bempegaldesleukin and pembrolizumab. 
v. Within 5 calendar days following randomization, the patient should receive the first dose of study treatment. Study drug infusion timing should be as close to 
30 minutes as possible; however, a window between −5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes −5 min/+10 min). See 
Sections 6.2.2.1 and 6.2.2.2 for additional details. 
w. At each visit specified, health-related quality of life assessments should be performed in the following order:  EQ-5D first, then European Organization for 
the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and finally the EORTC Quality of Life 
Questionnaire-head and neck cancer specific module (QLQ-H&N35). The questionnaires will be completed prior to dosing at Cycle 1, Cycle 2, Cycle 3, 
Cycle 4 and every 2 cycles thereafter (eg, Cycle 6, Cycle 8, Cycle 10) up to 1 year from treatment initiation or End of Treatment, whichever occurs first, and 
at the Follow-up Visit 1. See Section 9.2. 
x. Additional subsequent cancer therapy details such as regimen, setting of the regimen, line of therapy, start date and end date of each regimen, best response 
to the regimen, and date of progression to subsequent anticancer therapies will be collected. 
y. For Follow-up visits, see Section 6.3.1.  
z. 
For Survival Follow-up, see Section 6.3.2. 
 


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Table 2: 
Second Course Phase – Retreatment with Study Drug:  Schedule of Events 
 
Treatment Cycles (3-Week Cycles) 
Post-treatment 
Procedure / Period: 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
To be repeated beyond 
6 cycles 
Follow-up 
Visit 1p 
Follow-up 
Visit 2p 
Survival 
Follow-upq 
Cycle 5 
Cycle 6 
Study Daysa: + 3 days 
± 3 days ± 3 days 
± 3 days 
± 3 days 
± 3 days 
30 days from  
last dose 
(± 7 days) 
90 days from 
last dose 
(± 7 days) 
Every 
12 weeks 
(± 14 days) 
Eligibility criteriab 
X 
 
 
 
 
 
 
 
 
Physical examinationc 
Predose 
Predose 
Predose 
Predose 
Predose 
Predose 
X 
X 
 
Vital signsd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
X 
X 
 
ECOG performance statuse 
Predose 
Predose 
Predose 
Predose 
Predose 
Predose 
X 
X 
 
Pregnancy testf 
Predosef 
Predose 
Predose 
Predose 
Predose 
Predose 
X 
X 
 
Hematology and serum chemistryg 
Predose 
Predose 
Predose 
Predose 
Predose 
Predose 
X 
 
 
Thyroid function tests (T3 [total 
or free], free T4, TSH)h 
Predose 
 
Predose 
 
Predose 
 
X 
 
 
Coagulationh 
Predose 
 
 
 
 
 
 
 
 
Additional lab assessmentsh 
Predose 
Predose 
Predose 
Predose 
Predose 
Predose 
 
 
 
Tumor assessmenti 
Imaging should continue to be performed every 6 weeks (± 7 days) from the first dose of study drug(s) in the Second Course 
or more frequently if clinically indicated. 
 
 




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c. 
Physical examinations must occur within 5 days prior to administering study drug(s). A full physical examination should be conducted in Cycle 1; targeted 
physical examinations should be conducted on Day 1 of Cycles 2 and beyond and at the posttreatment follow-up visits. See Section 10.19 for additional 
details. 
d. See Section 10.20. Weight is to be reported at each vital sign visit. On dosing days, vital signs are to be taken and recorded as follows: 
• 
For Arm A (bempegaldesleukin/pembrolizumab): prior to bempegaldesleukin infusion and 30 (± 10) minutes following the end of pembrolizumab 
infusion. 
• 
For Arm B (pembrolizumab monotherapy): prior to pembrolizumab infusion and 30 (± 10) minutes following the end of pembrolizumab infusion. 
e. 
ECOG performance status assessments for Day 1 of each cycle must occur within 5 days prior to administering study drug(s) (see Appendix 3). 
f. 
Pregnancy test information is provided in Section 10.16.1. A negative highly sensitive pregnancy test (urine or serum as required by local regulations) is 
required within 24 hours for urine or within 72 hours for serum before the first dose of study treatment. 
g. Hematology and chemistry assessments for Day 1 of each cycle must be drawn within 5 days prior to administering study drug(s). See Section 10.18 and 
Appendix 1. 
h. See Appendix 1. The sampling for thyroid function, coagulation, and additional laboratory tests can be drawn within 5 days prior to administration of study 
drug(s). Any patient receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study via local laboratories per 
institutional guidelines. 
i. 
Section 8.1 describes tumor imaging (including confirmation of tumor response) and assessment of disease. A scan must be performed within 28 days prior 
to restarting treatment. Imaging should continue to be performed every 6 weeks (± 7 days) from the first dose of Second Course trial treatment or more 
frequently if clinically indicated. All tumor assessments will be sent to the imaging vendor. For patients who continue to receive treatment beyond 
progression, see Section 6.2.5. For assessments in long-term follow-up, see Section 6.3. 
Arm A (bempegaldesleukin plus pembrolizumab) only: 
j. 
See Appendix 1B for the list of local laboratory tests that require evaluation within 24 hours prior to bempegaldesleukin administration or as soon as 
locally feasible. 
k. Hydration guidelines provided in Section 6.2.3.2. 
l. 
See Section 6.7.1 for premedication guidance before study drug infusion(s). 
m. In Cycles 1 and 2, site personnel must contact the patient (by telephone or clinic visit) once between Days 3 and 5 (inclusive) following infusion, to 
remind the patient of the oral hydration guidelines, to assess for any symptomatology and compliance with the guidelines, and document the results of 
the discussion (see Section 6.2.3.2). In Cycles 3 and beyond, the oral hydration follow-up is conducted as clinically indicated for patients in Arm A 
receiving bempegaldesleukin and pembrolizumab. 
n. Patients who restart treatment should resume with the same study drug(s) and at the same dose that they were receiving prior to discontinuation. Study drug 
infusion timing should be as close to 30 minutes as possible; however, a window between −5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes −5 min/+10 min). See Sections 6.2.2.1 and 6.2.2.2 for additional details.  
o. Additional subsequent cancer therapy details such as regimen, setting of the regimen, line of therapy, start date and end date of each regimen, best response 
to the regimen, and date of progression to subsequent anticancer therapies will be collected. 
p. For Follow-up visits, see Section 6.3.1.  
q. For Survival Follow-up, see Section 6.3.2. 
 


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2.0 
INTRODUCTION 
This is a Phase 2/3, randomized study of bempegaldesleukin combined with pembrolizumab or 
pembrolizumab monotherapy in patients with recurrent or metastatic head and neck cancer that is 
previously untreated. Approximately 500 patients with first-line recurrent or metastatic head and 
neck squamous cell carcinoma (HNSCC) will be randomized in a 1:1 ratio between the 2 arms of 
the study to examine the efficacy and safety of bempegaldesleukin plus pembrolizumab (Arm A) 
versus pembrolizumab monotherapy (Arm B). 
2.1 
Background 
2.1.1 
HNSCC / Current Therapies 
Head and neck cancer describes a range of tumors that arise in the head and neck region, which 
includes the oral cavity, oropharynx, hypopharynx, and larynx. The worldwide incidence of head 
and neck cancer approaches 750,000 cases annually, ranking it as the eighth most common 
cancer, accounting for nearly 4% of all malignancies in the world (Sung 2021) and 3.5% of all 
malignancies in the United States (Siegel 2021). Although the head and neck region has a wide 
diversity of structures and cell types, the vast majority of head and neck cancers arise from the 
mucosa of the upper aerodigestive tract and are predominantly squamous cell in origin. 
A large number of patients with head and neck cancer initially present with locally advanced, 
Stage 3 or 4 disease that is initially treated with combinations of chemotherapy, radiation and/or 
surgery. This initial treatment is generally designated as “definitive” therapy, which typically 
combines chemoradiation and surgery and can result in disease control rates ranging between 
33% and 86% of patients. Patients who progress after initial definitive therapy require 
subsequent treatment for recurrent disease. Patients who initially present with metastatic disease 
generally receive the same therapy as those with recurrent disease after definitive treatment. 
Based on the results of the Phase 3 KEYNOTE-048 study, pembrolizumab was established as an 
appropriate first-line treatment for patients with recurrent or metastatic HNSCC and tumors with 
programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (see 
Section 2.1.2.2). 
2.1.2 
Pembrolizumab 
Pembrolizumab (Keytruda®) is approved for the treatment of several types of cancer in multiple 
regions including the United States (US; September 2014) and the European Union (EU; 
July 2015). Pembrolizumab is also being investigated in various other types of cancer as 
monotherapy or in combination with other therapies. 
2.1.2.1 
Pembrolizumab Mechanism of Action 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 


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cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses 
(Pardoll 2003; Zitvogel 2006; Dunn 2002). Current immunotherapy efforts attempt to break the 
apparent tolerance of the immune system to tumor cells and antigens by either introducing cancer 
antigens by therapeutic vaccination or by modulating regulatory checkpoints of the immune 
system. T-cell stimulation is a complex process involving the integration of numerous positive as 
well as negative co-stimulatory signals in addition to antigen recognition by the T-cell receptor 
(TCR) (Greenwald 2005). Collectively, these signals govern the balance between T-cell 
activation and tolerance. 
Programmed cell death protein 1 (PD-1) is a member of the CD28 family of T-cell 
co-stimulatory receptors that also includes CD28, CTLA-4 (cytotoxic T lymphocyte-associated 
protein 4), inducible T-cell co-stimulator (ICOS), and B- and T-lymphocyte attenuator (BTLA; 
Freeman 2000). PD-1 signaling has been shown to inhibit CD-28-mediated upregulation of 
interleukin-2 (IL-2), IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also has 
been noted to inhibit T-cell activation, and expansion of previously activated cells. Evidence for 
a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes (Sharpe 2007). These results suggest that PD-1 blockade has 
the potential to activate anti-self T-cell responses, but these responses are variable and dependent 
upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a 
universal loss of tolerance to self-antigens. 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 
and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab 
has high affinity and potent receptor blocking activity for PD-1. 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (Disis 2010). Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies (Dong 2002; Sharpe 2002; Brown 2003; Francisco 2010; 
Thompson 2007). In particular, the presence of CD8+ T cells and the ratio of CD8+ effector 
T cells / FoxP3+ regulatory T cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in multiple models of squamous cell carcinoma, pancreatic 
carcinoma, melanoma and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 


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effector T-cell function in vivo (Ropponen 1997; Dudley 2005; Hunder 2008; Polcher 2010; 
Okazaki 2001; Greenwald 2005; Chow 2015). Experiments have confirmed the in vivo efficacy 
of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in syngeneic 
mouse tumor models (see the pembrolizumab Investigator’s Brochure). 
2.1.2.2 
Pembrolizumab in Clinical Trials in Patients with HNSCC 
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung cancer 
(NSCLC), a number of advanced solid tumor indications (including head and neck cancer), and 
hematologic malignancies. For study details, please refer to the pembrolizumab Investigator’s 
Brochure. 
The Phase 3 KEYNOTE-048 study established pembrolizumab as an appropriate first-line 
treatment for patients with recurrent or metastatic HNSCC and tumors with PD-L1 CPS ≥ 1. In 
this study, pembrolizumab monotherapy (200 mg every 3 weeks [q3w]) improved overall 
survival (OS) versus cetuximab and chemotherapy in patients with CPS ≥ 20 (median 
14.9 months vs 10.7 months, hazard ratio [HR] 0.61 [95% CI 0.45–0.83] p-value = 0.0007) and 
in patients with CPS ≥ 1 (12.3 vs 10.3, HR 0.78 [95% CI: 0.64–0.96], p-value = 0.0086) and was 
non-inferior in the total population (11.6 vs 10.7, 0.85 [0.71−1.03]). At the final analysis, the 
objective response rate (ORR) in the PD-L1 CPS ≥ 20 population was 23% and 36% in the 
pembrolizumab monotherapy and cetuximab with chemotherapy groups, respectively, and the 
ORR in the CPS ≥ 1 population was 19% and 35%, respectively (Burtness 2019). 
Other trials evaluating pembrolizumab in head and neck cancer have demonstrated clinical 
activity in patients with recurrent and/or metastatic disease, including those with poor prognosis.  
• KEYNOTE-012 was a Phase 1b study of pembrolizumab in 4 indications, one of which 
included patients with head and neck cancer. Single-agent pembrolizumab demonstrated 
clinically meaningful anti-tumor activity in patients with PD-L1-positive, (ie, any level of 
PD-L1 expression, defined as ≥ 1% of tumor cells or stroma that were PD-L1-positive by 
immunohistochemistry [IHC]), recurrent or metastatic HNSCC, with an overall response of 
18% (8 of 45 patients; 95% CI 8-32) and 25% (4 of 16; 7-52) in human papillomavirus 
(HPV)-positive patients and 14% (4 of 29; 4-32) in HPV-negative patients (Seiwert 2016). 
• KEYNOTE-040 was a Phase 3, multicenter, randomized trial of pembrolizumab (200 mg 
q3w) versus standard of care in subjects with recurrent or metastatic HNSCC. Results from 
KEYNOTE-040 showed that pembrolizumab imparted a greater benefit in subjects with 
PD-L1 expressing tumors. In the CPS ≥ 1 population, the ORR was 17.3% for the 
pembrolizumab arm compared to 9.9% for the standard of care arm (CI: 0.6% to 14.6%). The 
median OS was 8.7 months for the pembrolizumab arm compared to 7.1 months for the 
standard of care arm (HR=0.75, CI: 0.59-0.95) (Cohen 2017). 


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• KEYNOTE-055 was a Phase 2 study of 171 patients with recurrent or metastatic HNSCC 
who were previously treated with platinum and cetuximab. In this population with poor 
prognosis, pembrolizumab 200 mg q3w exhibited clinically meaningful antitumor activity, 
including an ORR of 16% (95% CI 11% to 23%), a median response duration of 8 months 
(range, 2+ to 12+ months), a median progression-free survival (PFS) of 2.1 months, and 
median OS of 8 months (Bauml 2017). 
2.1.3 
Bempegaldesleukin (NKTR-214) 
Bempegaldesleukin is the International Nonproprietary Name (INN) for NKTR-214. 
2.1.3.1 
Mechanism of Action 
Bempegaldesleukin (NKTR-214) is a prodrug of a conjugated cancer immunotherapy cytokine 
that exerts its biological activity by binding to the IL-2 receptor and subsequent activation of 
effector T cells. As a PEGylated human recombinant IL-2 molecule of aldesleukin with an 
average of six releasable polyethylene glycol (PEG) chains, bempegaldesleukin can be 
administered conveniently in the outpatient setting using an antibody-like dosing regimen. The 
polymer conjugation renders the cytokine initially inactive. Upon intravenous (IV) 
administration, the PEG chains slowly release to generate the active cytokine species (mainly 
2-PEG-IL-2 and 1-PEG-IL-2) that have a peak plasma concentration of 24 to 48 hours after 
infusion. The slow generation of the 2-PEG-IL-2 and 1-PEG-IL-2 significantly mitigates the 
rapid-onset, systemic cytokine-related toxicities associated with high dose IL-2. 
The polymer conjugation of bempegaldesleukin promotes biased signaling through the IL-2 
receptor beta gamma (IL-2Rβγ). Specifically, the location of the bempegaldesleukin PEG chains 
interferes with the binding to the IL-2 alpha receptor subunit responsible for the undesirable 
effect of activating regulatory T cells (Tregs) in the tumor while continuing to permit binding to 
the IL-2Rβγ (CD122) receptor. Upon infusion, bempegaldesleukin preferentially increases the 
proliferation, activation, and effector function of tumor antigen-specific CD8+ T cells and 
natural killer (NK) cells within the tumor microenvironment (TME) over expansion of unwanted 
intra-tumoral Tregs that are activated through the IL-2 receptor alpha beta gamma (IL-2Rαβγ) 
(Charych 2016a; Charych 2016b). Consistent with this mechanism of action, recent nonclinical 
studies demonstrate strong synergy of bempegaldesleukin with adoptive T-cell therapy (ACT), 
with PD-1 checkpoint blockade, and with tumor antigen-specific vaccination, in a variety of 
mouse models (Parisi 2020; Sharma 2020). This synergy was mediated by expansion of 
tumor-specific CD8+ T cells in the periphery and tumor, without strong expansion of Tregs in 
the tumor tissue. 
Bempegaldesleukin also correspondingly promotes expression of PD-1 on the surface of CD8+ 
T cells and induction of a Type II interferon gene signature in the TME, driving cell surface 
expression of PD-L1 on tumor cells (Diab 2017). 
The immunological properties of bempegaldesleukin with the induction of TILs and upregulation 
of the PD-1/PD-L1 axis makes bempegaldesleukin a potentially promising combination therapy 


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for use with checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway. Moreover, the 
safety profile of bempegaldesleukin generally does not overlap with that of checkpoint 
inhibitors, further supporting the use of bempegaldesleukin as a potentially complimentary 
combination partner with checkpoint inhibitors. 
2.1.3.2 
Clinical Experience with Bempegaldesleukin 
2.1.3.2.1 
Study 15-214-01 (EXCEL) Bempegaldesleukin Monotherapy 
The bempegaldesleukin clinical development program started with the monotherapy study 
EXCEL (Study 15-214-01 [NCT02869295]; A Phase 1/2, Open-label, Multicenter, 
Dose-Escalation and Dose Expansion Study of NKTR-214 in Subjects with Locally Advanced or 
Metastatic Solid Tumor Malignancies). The first part of the study was a dose escalation phase, 
designed to evaluate the safety and tolerability, and define the maximum tolerated dose (MTD) 
or recommended Phase 2 dose (RP2D) of bempegaldesleukin. The second part of the study was 
an expansion phase following identification of the RP2D, designed to evaluate the safety and 
tolerability, as well as the efficacy of bempegaldesleukin in specific tumor types. 
Bempegaldesleukin at a dose of 0.009 mg/kg administered once every 3 weeks was deemed the 
MTD by pre-defined dose-limiting toxicity criteria. The RP2D was determined to be 
0.006 mg/kg q3w. Enrollment was closed after 28 patients were exposed to bempegaldesleukin 
in the dose-escalation phase and the dose expansion phase was not initiated. 
The safety of single-agent bempegaldesleukin has been assessed in 28 patients across 5 dose 
cohorts administered bempegaldesleukin q3w at doses ranging from 0.003 mg/kg to 0.012 mg/kg 
and a dosing frequency of every 2 weeks (q2w) was explored at 0.006 mg/kg. For the q3w 
dosing frequency, doses up to 0.009 mg/kg were well tolerated. One patient dosed at 
0.012 mg/kg experienced cytokine release syndrome and the dose-limiting toxicities (DLTs) of 
hypotension and syncope; this patient received 2 additional cycles of bempegaldesleukin at a 
lower dose of 0.006 mg/kg and tolerated treatment well. The bempegaldesleukin dose of 
0.009 mg/kg was determined to be the MTD. 
As of the final database lock date of 29 March 2018, 593 treatment-emergent adverse events 
(AEs) were reported among the 28 patients who received single-agent bempegaldesleukin. 
Overall, the most common treatment-emergent AEs were fatigue (82.1%), flu-like symptoms 
(also consisting of influenza-like illness, influenza, pyrexia, and chills, 71.4%), pruritus (67.9%), 
hypotension (64.3%), rash (consisting of erythema, rash, rash erythematous, rash maculo-
papular, rash papular, rash pruritic, rash pustular, rash vesicular, rash generalized, and rash 
macular, 53.6%), decreased appetite (53.6%), and arthralgia or cough (42.9% each). 
The most common AEs considered by the Investigator to be related to bempegaldesleukin were 
fatigue (71.4%), flu-like symptoms (67.9%), pruritus (64.3%), hypotension (57.1%), rash 
(50.0%), decreased appetite (46.4%), and arthralgia or cough (32.1% each). Such 
treatment-related AEs as flu-like symptoms, rash and pruritus were generally mild or moderate in 
severity, predictable, manageable, and short-lived. These cytokine-related AEs generally 


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occurred 3 to 4 days after dosing and corresponded to the time of peak plasma concentration of 
the active cytokines. The flu-like symptoms were managed with acetaminophen and nonsteroidal 
anti-inflammatory drugs (NSAIDs) and the cases of rash/pruritus were either self-limiting or 
treated with antihistamines (steroids were administered for occasional patients who had severe 
rash/pruritus). 
Six of 28 patients reported Grade 3 treatment-related AEs, which included hypotension, 
abdominal pain, infusion-related reaction, headache, and syncope. The cases of Grade 3 
hypotension were rapidly reversed with intravenous fluids, and a hydration management 
guideline was implemented during the study which mitigated the incidences of hypotension 
and/or severity. One patient, who had a prior history of an infusion reaction to a previously 
administered immunotherapy, discontinued treatment due to an infusion-related reaction 
following the first dose of bempegaldesleukin 0.009 mg/kg. With the exception of one event of 
hypothyroidism, no other known immune mediated AEs consistent with checkpoint inhibitors 
were reported. No patient experienced capillary leak syndrome and no Grade 4 treatment-related 
AEs or treatment-related deaths were reported on the study. 
Fifteen patients (53.6%) reported 31 serious AEs (SAEs) in monotherapy Study 15-214-01. 
Eleven SAEs reported among 7 (25.0%) patients were considered related to treatment. The only 
treatment-related SAE reported for more than 1 patient was hypotension (5 patients, 17.9%, 4 of 
5 were Grade 3 in severity). 
In the 28 patients evaluable for efficacy in Study 15-214-01, best overall response included 
stable disease in 14 patients (50%), 12 patients (42.9%) with progressive disease (PD) and 
2 patients (7.1%) were not evaluable (NE). While no objective responses were observed in Study 
15-214-01, 9 patients experienced tumor shrinkage between 1% and 30% and two patients, after 
progressing on multiple prior therapies, had durable stable disease over 1 year. One patient with 
metastatic melanoma, who was previously treated with ipilimumab and a BRAF inhibitor, 
received 25 cycles of bempegaldesleukin and had durable stable disease for 18 months. A second 
patient with metastatic renal cell carcinoma (RCC), who had progressed on high-dose IL-2 and 
was refractory to single-agent OX40 (ie, an antibody targeting the tumor necrosis factor receptor 
superfamily member 4) and nivolumab, was treated with 19 cycles of bempegaldesleukin and 
had durable stable disease for 14 months. Given the biological properties of bempegaldesleukin 
and nivolumab these observations further supported the rationale for combining these two 
agents. 
2.1.3.2.2 
Study 16-214-02 (PIVOT-02) Bempegaldesleukin and Nivolumab 
Combination Therapy 
The PIVOT-02 trial (NCT02983045) is an ongoing Phase 1/2 open-label, multicenter, dose 
escalation, and dose expansion study of bempegaldesleukin in combination with nivolumab and 
other anticancer therapies in patients with locally advanced or metastatic solid tumors. Part 1 of 
the study was a dose escalation phase to evaluate the safety and tolerability, and define the MTD 
or RP2D of bempegaldesleukin in combination with nivolumab. Following determination of the 


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RP2D (0.006 mg/kg bempegaldesleukin q3w plus 360 mg nivolumab q3w), Part 2 of the study is 
evaluating the safety and tolerability as well as the efficacy of the combination by assessing the 
ORR at the RP2D. The indications studied in Part 2 include melanoma, RCC, NSCLC, urothelial 
carcinoma, breast cancer, gastric cancer, colorectal carcinoma (CRC), and small cell lung cancer 
(SCLC). Parts 3 and 4 are schedule-finding and dose expansion for the triplet, studying the safety 
and tolerability of bempegaldesleukin in combination with nivolumab and ipilimumab in patients 
with metastatic RCC, urothelial carcinoma, melanoma, or NSCLC who are treatment-naïve. 
The bempegaldesleukin and nivolumab dose escalation portion of PIVOT-02 has completed, 
with the safety results of bempegaldesleukin at 0.006 mg/kg in combination with nivolumab 
360 mg every 3 weeks indicating no DLTs and no Grade ≥ 3 treatment-related AEs at the time of 
completion. Bempegaldesleukin 0.006 mg/kg in combination with nivolumab 360 mg every 
3 weeks was the recommended dose regimen to be taken forward into expansion cohorts in 
Part 2. 
As of 28 October 2019, a total of 541 patients have been treated with bempegaldesleukin in 
combination with nivolumab (488 patients with doublet [bempegaldesleukin and nivolumab]; 
43 patients with triplet [bempegaldesleukin, nivolumab, and ipilimumab]; and 10 patients with 
doublet [bempegaldesleukin and nivolumab] plus other anticancer study drug). The median 
duration of exposure was 115.0 days (doublet, 112.0; triplet, 151.0; doublet plus other anticancer 
drug, 137.5) (range:  6 to 815 days).  
Among the 488 patients who received the doublet, the most frequently reported 
treatment-emergent AEs were fatigue (52.9%), pyrexia (50.2%), nausea (39.5%), pruritus 
(38.5%), decreased appetite (36.3%), diarrhea or rash (each 28.5%), chills (28.3%), influenza-
like illness (27.5%), arthralgia (26.4%), and cough or vomiting (each 25.2%). 
The most frequently reported treatment-related AEs in the 488 patient doublet group were 
fatigue (47.3%), pyrexia (44.3%), pruritus (35.7%), nausea (29.7%), influenza-like illness 
(26.8%), decreased appetite (26.4%), chills (26.0%), and rash (25.8%). 
Among the 488 patients treated with the doublet, the most frequently reported 
treatment-emergent AEs Grade ≥ 3 were dyspnea (3.9%), anemia or hyponatremia (each 3.7%), 
hypotension or syncope (each 3.5%), fatigue or urinary tract infection (each 2.7%), and 
hypertension or lipase increased (each 2.5%). The Grade ≥ 3 treatment-related AEs experienced 
by 2.0% or more patients in the doublet group were syncope (2.9%), hypotension (2.7%), and 
lipase increased (2.0%). 
As of 28 October 2019, 44.7% of doublet patients have reported SAEs; the most frequently 
experienced SAEs were pyrexia (3.7%), dyspnea or hypotension (2.9%), and hyponatremia 
(2.0%). Treatment-related SAEs were reported for 17.2% of doublet patients, with the most 
frequently reported being pyrexia (3.1%), hypotension (2.0%), and pneumonitis (1.0%). 


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Tumor response data are available for 37 of the dose escalation patients, including 11 with 
metastatic melanoma, 21 with RCC, and 5 with NSCLC. Of these 37 response-evaluable 
patients, 24 were treated at 0.006 mg/kg bempegaldesleukin combined with nivolumab 360 mg 
flat dose every 3 weeks. As of 29 October 2018, 21 of 37 evaluable patients (56.8%) achieved a 
response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
For select tumors, additional efficacy data have been presented. PIVOT-02 has a 2-stage design 
and data for either the Stage 1 (N1) population alone or in combination with the Stage 2 (N2; 
expansion) population were presented depending on data maturity. Data presented for the 
efficacy evaluable population (defined as having received one dose of study treatment and 
having undergone at least one scan) were as follows: 
• In first-line RCC patients, a 46% (12 of 26 patients) ORR was observed (N = 48 enrolled; 
N = 26 in the N1 + N2 population; Diab 2018; 29 May 2018 cutoff). 
• In first-line melanoma patients, a 53% (20 of 38 patients, including 35% [13 of 38] with 
complete response) ORR via blinded independent central review (BICR) was observed 
(N = 41 enrolled; N = 38 included in the N1 + N2 population; Diab 2019; 25 Sep 2019 data 
cutoff). 
• In first-line metastatic urothelial carcinoma patients, a 48% (13 of 27 patients) ORR was 
observed (N = 41 enrolled; N = 27 in the efficacy evaluable population; 
Siefker-Radtke 2019; 03 Dec 2018 data cutoff). 
• In metastatic triple-negative breast cancer (TNBC) patients, a 13% (5 of 38 patients) ORR 
was observed (N = 43 enrolled; N = 38 in the efficacy evaluable population; Tolaney 2019; 
01 Jul 2019 data cutoff). 
Additional details on the clinical experience with bempegaldesleukin are provided in the 
bempegaldesleukin Investigator’s Brochure. 
2.1.3.2.2.1 
Observed Events of Cerebrovascular Accident in Study 16-214-02 
Serious events of cerebrovascular accident (CVA), including one fatal event, have been observed 
in patients who have received bempegaldesleukin in the triplet combination with nivolumab and 
ipilimumab, in the doublet combination with nivolumab, and in the combination of 
bempegaldesleukin, nivolumab, and other anticancer therapy. As of 28 October 2019, 3 of 
43 patients (7.0%) who received triplet therapy in Study 16-214-02 had CVA events, including 
one fatal event; all of these CVA events were considered by the Investigator to be related to 
treatment with bempegaldesleukin, nivolumab, and ipilimumab. Additionally, 9 of 488 patients 
(1.8%) who received doublet therapy (bempegaldesleukin and nivolumab) had 10 CVA events, 
which were considered by the Investigator to be related to at least one of the study treatments in 
4 patients (3 related to the doublet therapy and 1 related to nivolumab only); and one of 
10 (10.0%) patients who received the combination of bempegaldesleukin, nivolumab, and other 
anticancer therapy (platinum-based chemotherapy) had a CVA event, which was considered by 
the Investigator to be unrelated to study treatment. 


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Although hypercoagulable state is a known confounder in cancer patients with solid tumors, 
based on these events and a comprehensive assessment of CVA across all bempegaldesleukin 
clinical studies, CVA has been escalated to an adverse event of special interest (AESI) for close 
monitoring and mitigations have been put in place for early identification and to reduce the 
incidence and/or risk of CVA. These mitigations include implementation of a cerebrovascular 
accident adverse event management algorithm (Appendix 2) and updates to the exclusion 
criteria, renal function and hydration assessment, hydration guidelines, concomitant and 
prohibited medications, dose modification guidelines, and discontinuation criteria.  
Additional information on the clinical safety and risk of CVA is found in the bempegaldesleukin 
Investigator’s Brochure. 
2.1.3.2.3 
Study 16-214-05 (PROPEL) Bempegaldesleukin and Pembrolizumab 
Combination Therapy 
Study 16-214-05 is a Phase 1/2, open-label, multicenter study to investigate the safety and 
preliminary efficacy of bempegaldesleukin (0.006 mg/kg) in combination with atezolizumab 
(1200 mg q3w) or pembrolizumab (200 mg q3w) in patients with locally advanced or metastatic 
solid tumors, including HNSCC. Protocol Amendment 5.0 (dated 20 August 2019) ended 
enrollment to an atezolizumab arm. 
As of 28 October 2019, 36 patients have been enrolled and have received at least 1 dose of study 
treatment. A total of 23 patients were enrolled in the bempegaldesleukin plus atezolizumab 
combination cohort and 13 patients have been enrolled in the bempegaldesleukin plus 
pembrolizumab combination cohort.  
At least 1 treatment-related treatment-emergent AE (TEAE) was reported by 91.7% of patients 
(33 of 36 patients) overall, including 91.3% (21 of 23 patients) who received bempegaldesleukin 
plus atezolizumab and 92.3% (12 of 13 patients) who received bempegaldesleukin plus 
pembrolizumab. The most common treatment-related TEAEs were fatigue (19 of 36 patients, 
52.8%), pyrexia (11 patients, 30.6%), nausea (10 patients, 27.8%), decreased appetite or 
vomiting (each 9 patients, 25.0%), and influenza-like illness (8 patients, 22.2%). 
In the bempegaldesleukin plus atezolizumab cohort, the most frequently reported TEAEs 
assessed as related were fatigue (13 of 23 patients, 56.5%) pyrexia (8 of 23 patients, 34.8%), 
decreased appetite (7 of 23 patients, 30.4%), and influenza-like illness (5 of 23 patients, 21.7%). 
In the bempegaldesleukin plus pembrolizumab cohort the most frequently reported TEAEs 
assessed as related were fatigue or nausea (each: 6 of 13 patients, 46.2%), vomiting (5 patients, 
38.5%) and blood creatinine increased, chills, diarrhea, dizziness, dry mouth, influenza-like 
illness, myalgia, pruritus, pyrexia, or rash maculo-papular (each: 3 patients 23.1%).  
Thirteen of the 36 patients (36.1%) experienced TEAEs ≥ Grade 3 assessed as related (7/23, 
30.4% in the bempegaldesleukin plus atezolizumab group and 6/13, 46.2% in the 


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bempegaldesleukin plus pembrolizumab group). For each therapy cohort, all were single patient 
reports. Fatigue, anemia, arthralgia, or chills were reported by 2 patients each overall. 
One Grade 5 TEAE was reported: cardiac arrest, not-related, in an 84-year-old, male patient with 
bladder cancer and prior cardiac illness in the bempegaldesleukin plus atezolizumab cohort. The 
patient died 5 days after the first dose of study drug. The patient’s general condition was stated to 
be declining in the setting of disease progression. 
2.2 
Benefit/Risk Assessment 
2.2.1 
Bempegaldesleukin Safety Profile 
Bempegaldesleukin was designed to mitigate the severe toxicities associated with rapid systemic 
immune activation seen with administration of aldesleukin. The identified risks of 
bempegaldesleukin include hypotension, cytokine-related toxicities (eg, flu-like symptoms, rash, 
pruritus, fatigue, hepatic transaminase elevations, and serum creatinine elevations), infusion-
related reactions/hypersensitivity reactions, thyroid dysfunction, eosinophilic disorder (including 
cases of hypereosinophilic syndrome), and arthralgia. The majority of these AEs are mild to 
moderate in severity and can be monitored and managed in the clinical setting. The goal of 
engineering a PEGylated form of IL-2 that reduces the treatment-limiting toxicities of 
aldesleukin, that is, those necessitating in-hospital administration, appears to have been realized 
with bempegaldesleukin at the doses tested. 
Additional details on the clinical experience with bempegaldesleukin are provided in the 
bempegaldesleukin Investigator’s Brochure. 
2.2.2 
Pembrolizumab Safety Profile 
The safety profile of pembrolizumab in various approved indications is well established and 
consistent with other marketed check-point inhibitors. Extensive details on the safety profile of 
pembrolizumab are available in the pembrolizumab Investigator’s Brochure. 
The most common pembrolizumab adverse reactions (reported in ≥ 20% of patients) include 
pruritus, diarrhea, and cough. In the pembrolizumab monotherapy trials, the incidence of 
Grade 3-5 drug-related AEs across studies is 13.8%. Pembrolizumab immune-mediated AESIs 
are relatively uncommon. The most frequently reported AESI is hypothyroidism, with an overall 
incidence of 8.5%. Furthermore, most AESIs are mild to moderate in severity, and are generally 
readily manageable with appropriate care in the clinical setting.  


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In KEYNOTE-048, pembrolizumab monotherapy had a favorable safety profile compared with 
pembrolizumab with chemotherapy (ie, platinum and 5-fluorouracil) as first-line therapy for 
patients with recurrent or metastatic advanced HNSCC (Burtness 2019). Grade 3 or worse AEs 
occurred in 164 (55%) of 300 patients in the pembrolizumab monotherapy group and 235 (85%) 
of 276 in the pembrolizumab with chemotherapy group. AEs led to death in 25 (8%) patients in 
the pembrolizumab monotherapy group and 32 (12%) in the pembrolizumab with chemotherapy 
group. Pembrolizumab was discontinued for AEs in 12% of patients in the pembrolizumab 
monotherapy group and 16% of patients in the pembrolizumab with chemotherapy group; the 
most common AEs resulting in permanent discontinuation were (Merck 2020): 
• Pembrolizumab monotherapy: sepsis (1.7%) and pneumonia (1.3%). 
• Pembrolizumab with chemotherapy: pneumonia (2.5%), pneumonitis (1.8%), and septic 
shock (1.4%). 
2.2.3 
Bempegaldesleukin and Pembrolizumab Benefit and Risk Assessment 
Advanced cancer patients in clinical trials generally cannot expect to receive direct benefit from 
pembrolizumab and bempegaldesleukin during participation, as clinical trials are designed to 
provide information about the safety and effectiveness of an investigational medicine. 
Additional details regarding specific benefits and risks for patients participating in this clinical 
trial may be found in the accompanying pembrolizumab and bempegaldesleukin Investigator’s 
Brochures and informed consent form (ICF) documents. 
Pembrolizumab has a positive benefit-risk profile and is well tolerated in the approved 
indications. Publications of a significantly positive benefit/risk ratio have been reported for 
melanoma in a single arm study encompassing nearly 1000 patients (KEYNOTE-001), which led 
to US Food and Drug Administration (FDA) approval in September 2014. Pembrolizumab 
subsequently received approval across a broad range of cancers, including for the treatment of 
patients with NSCLC and for the treatment of patients with recurrent or metastatic HNSCC. The 
pembrolizumab Investigator’s Brochure provides additional details about these approvals. The 
US FDA approval to treat patients with recurrent or metastatic HNSCC with disease progression 
on or after platinum-containing chemotherapy was based on the favorable tumor response rate 
and durability of responses seen in KEYNOTE-012 and KEYNOTE-055. Finally, the Phase 3 
KEYNOTE-048 study established pembrolizumab as an appropriate first-line treatment for 
patients with recurrent or metastatic HNSCC and tumors with PD-L1 CPS ≥ 1 (Burtness 2019). 
The potential benefits for patients with HNSCC are addressed in Section 2.1.2.2. 
Bempegaldesleukin has been generally well-tolerated in the clinical studies to date, both as 
monotherapy as well as in combination with the PD-1 checkpoint inhibitor nivolumab, with 
promising evidence of clinical efficacy and a potentially favorable benefit-risk profile. 
Bempegaldesleukin has been safely administered in an outpatient setting supported by 
appropriate clinical monitoring. 


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Hypotension has been identified as a clinically significant adverse effect of bempegaldesleukin 
and can be effectively mitigated by prophylaxis and hydration guidelines. Other risks associated 
with bempegaldesleukin include cytokine-related toxicities (eg, flu-like symptoms, rash, pruritus, 
fatigue, hepatic transaminase elevations, and serum creatinine elevation), infusion-related 
reactions, thyroid dysfunction, eosinophilic disorder, and arthralgia; these AEs are generally mild 
or moderate in severity, and can be monitored and managed in the clinical setting. Cases of 
thyroid dysfunction (hypothyroidism, hyperthyroidism, thyroiditis), dermatitis, pneumonitis, 
hepatitis, myocarditis, myositis/myasthenia gravis, and vitiligo/hypopigmentation consistent with 
PD-L1/PD-1/CTLA-4 checkpoint immune-mediated mechanism have been observed in patients 
receiving bempegaldesleukin plus nivolumab; however, there is no evidence that 
bempegaldesleukin increases the frequency or severity of immune-mediated AEs (also referred 
to as immune-related AEs [irAEs] in this document) associated with nivolumab with the 
limitation of small sample size and relatively shorter treatment duration for bempegaldesleukin-
treated patients. 
The continued development of bempegaldesleukin in combination with PD-1 checkpoint 
inhibitors such as pembrolizumab for the treatment of various cancers is warranted based on a 
positive benefit-risk profile. In addition, the early efficacy data along with the correlative 
biomarker showing conversion of PD-L1 negative patients to PD-L1 positive patients suggests 
that the addition of bempegaldesleukin to a PD-1/PD-L1 checkpoint inhibitor may change the 
tumor microenvironment in PD-L1 negative patients such that the combination therapy may 
contribute to enhanced anti-tumor activity with an acceptable safety profile. Preliminary data 
from the PIVOT-02 study in the metastatic melanoma setting have suggested that this 
combination may improve upon the treatment effects of the checkpoint inhibitor nivolumab 
alone. The combination of bempegaldesleukin and nivolumab led to an ORR of 53% by 
independent radiology review, which included a 34% complete response (CR) rate (Diab 2019), 
and these data were the basis for the FDA granting a breakthrough therapy designation for the 
treatment of patients with previously untreated unresectable or metastatic melanoma. A Phase 3 
randomized clinical trial of bempegaldesleukin in combination with nivolumab versus nivolumab 
alone in patients with previously untreated unresectable or metastatic melanoma is ongoing 
(NCT03635983). 
2.2.4 
Data Monitoring Committee 
The study will use an independent, external Data Monitoring Committee (DMC) to monitor 
efficacy and safety. Safety will be evaluated by the DMC approximately twice a year. There will 
be 2 interim analyses evaluated by the DMC. The first interim futility analysis will occur at least 
one month after the last patient of the Phase 2 portion has been randomized into the study. The 
second interim efficacy analysis will be conducted when approximately 500 patients have been 
randomized and about 231 OS events have been observed. The DMC will also meet on an ad-hoc 
basis if needed (see Section 11.8). 


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3.0 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a multicenter, randomized, open-label, Phase 2/3 study that will evaluate the efficacy and 
safety of bempegaldesleukin combined with pembrolizumab compared with pembrolizumab 
monotherapy in patients with recurrent or metastatic HNSCC with positive PD-L1 expression 
(CPS ≥ 1). 
The study will use an adaptive design based on prespecified criteria and an independent, external 
Data Monitoring Committee (DMC) to monitor efficacy and safety. Safety will be evaluated by 
the DMC approximately twice a year. The first interim analysis will address futility. Enrollment 
will pause for approximately 4 months after approximately 200 patients have been randomized, 
and the first interim analysis will occur at least one month after the last patient of the Phase 2 
portion has been randomized into the study. If the ORR passes the prespecified futility boundary, 
the Phase 3 portion of the study will begin with an expected 300 additional patients to be 
randomized. The second interim analysis will be conducted when approximately 500 patients 
have been randomized and about 231 overall survival events have been observed. At the second 
interim analysis, if the OS efficacy boundary is crossed, the trial will be stopped for efficacy. 
Otherwise, conditional power will be calculated to determine the overall survival event size for 
final analysis. 
Patients will be randomized at a 1:1 ratio to receive one of two treatments: 
• Arm A: Bempegaldesleukin plus pembrolizumab every 3 weeks (q3w) for up to 35 cycles 
(approximately 2 years). 
• Arm B: Pembrolizumab monotherapy q3w for up to 35 cycles (approximately 2 years). 
Randomization will be stratified according to the following factors: 
1.  Disease status (metastatic vs recurrent only). 
2.  PD-L1 tumor expression determined by a local or the central laboratory using the PD-L1 IHC 
22C3 PharmDx diagnostic kit (CPS ≥ 20 vs CPS 1-19). 
Note: CPS is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) 
divided by the total number of viable tumor cells, multiplied by 100. The specimen should be 
considered to have PD-L1 expression if CPS ≥ 1. 
3. Human papillomavirus (HPV) status for oropharyngeal cancer determined by p16 IHC 
(positive vs negative). For patients with cancers of the oral cavity, hypopharynx, and larynx, 
HPV status is considered HPV negative. 
The Sponsor estimates that the study will be fully enrolled within approximately 25 months. 
Analyses are anticipated at the following times (relative to the first patient’s randomization date): 
approximately 14 months for the first interim analysis, approximately 32 months for the second 
interim analysis, and approximately 38 to 52 months for the final analysis for OS. 


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Section 1.1 provides the study schematic and Section 1.2 provides the Schedule of Events. 
3.2 
Rationale for Study Design 
3.2.1 
Open-Label Design 
The study will have an open-label design with a BICR. There are multiple reasons that would 
make blinding the trial impractical or impossible:  
1. The hydration guidelines, which only apply to patients in Arm A (bempegaldesleukin plus 
pembrolizumab).  
2. The withholding of anti-hypertensive medications, which only applies to patients in Arm A 
(bempegaldesleukin plus pembrolizumab). 
3. The unique adverse event profile of bempegaldesleukin may easily unblind the patient study 
drug assignment.  
Therefore, a placebo-controlled, double-blinded design is not appropriate for this study. 
3.2.2 
Choice of Endpoints 
3.2.2.1 
Primary Endpoints 
Overall survival is the gold standard endpoint to demonstrate efficacy of antineoplastic therapy.  
ORR per RECIST 1.1 criteria as assessed by blinded independent central radiology review will 
serve as an additional measure of efficacy. RECIST 1.1 will be used to determine the dates of 
progression as this methodology is accepted by regulatory authorities. Because the treatment 
assignment is unblinded, images will be read by independent radiologists blinded to treatment 
assignment to minimize bias in the response assessments. In addition, final determination of 
radiologic progression will be based on the central assessment of progression, rather than site 
assessment. Real-time determination of radiologic progression as determined by central review 
will be communicated to the site. 
3.2.2.2 
Safety 
Assessment of safety will be determined by an ongoing review throughout the study of 
treatment-emergent AEs, including treatment-related AEs, SAEs, AESIs, and AEs leading to 
drug discontinuation, clinical laboratory tests, and vital signs. All AEs will be assessed for 
severity using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) version 5.0 guidelines. 


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3.2.3 
Prospective Stratification 
Randomization will be stratified by 3 factors: 
• Disease status (metastatic vs recurrent only). In the KEYNOTE-048 trial, metastatic versus 
recurrent only disease status demonstrated a prognostic value for patient survival 
(Burtness 2019). 
• PD-L1 tumor expression determined by PD-L1 IHC (CPS ≥ 20 vs CPS 1-19). The 
KEYNOTE-048 trial demonstrated a statistically significant improvement in OS in the 
subgroup of patients with CPS ≥ 1 randomized to single-agent pembrolizumab. The median 
OS for CPS ≥ 1 in months was 12.3 (95% CI: 10.8, 14.9). The median OS for the CPS ≥ 20 
subgroup in months was 14.9 (95% CI: 11.6, 21.5) for single agent pembrolizumab 
(Burtness 2019). In an exploratory subgroup analysis, CPS 1 – 19 median OS was 
10.8 months (95% 9.0, 12.6) for single agent pembrolizumab (Merck 2020). 
• HPV status (positive or negative) for patients with head and neck cancer of the oropharynx. 
The favorable prognostic significance of HPV-positive head and neck cancers in the 
oropharynx has been increasingly established (Fakhry 2008). Preliminary data of single agent 
pembrolizumab in head and neck cancer patients in KEYNOTE-012 demonstrate efficacy in 
both HPV-positive and HPV-negative patients. Investigator site assessment of HPV using 
IHC staining for the p16 protein will be used for the patients with oropharyngeal cancer prior 
to randomization. 
3.2.4 
Duration of Treatment with Bempegaldesleukin/Pembrolizumab 
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long-term benefit. Study CA209003 (NCT00730639), a dose-escalation cohort expansion 
trial evaluating the safety and clinical activity of nivolumab in patients with previously treated 
advanced solid tumors (including 129 patients with NSCLC), specified a maximum treatment 
duration of 2 years. Among 16 patients with NSCLC who discontinued nivolumab after 
completing 2 years of treatment, 12 patients were alive > 5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to 
plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years (Brahmer 2017). 
These survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in which 
nivolumab treatment was continued until progression or unacceptable toxicity (2 year OS rates of 
23% and 29%, and 3 year OS rates of 16%-18% for squamous and nonsquamous NSCLC 
respectively) (Felip 2017). 
Similar results have been reported in clinical studies of pembrolizumab. KEYNOTE-010 
(NCT01905657) was a randomized Phase 3 trial of pembrolizumab (at either 2 mg/kg or 
10 mg/kg every 3 weeks) versus docetaxel in patients with previously treated, PD-L1-positive, 
advanced NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab. 
OS was significantly longer with both pembrolizumab 2 mg/kg (HR = 0.72, p-value = 0.00017) 
and pembrolizumab 10 mg/kg (HR = 0.60, p-value < 0.00001) compared to docetaxel, with an 


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OS plateau developing beyond 2 years in both pembrolizumab arms. Among 690 patients who 
received pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped 
treatment. Most were able to maintain their response, including those with stable disease, with 
only 2 patients (4%) having confirmed progression after stopping at 2 years (Herbst 2016). 
KEYNOTE-006 (NCT01866319) was a randomized Phase 3 study of pembrolizumab versus 
ipilimumab in patients with advanced melanoma, which also specified a maximum 2-year 
duration of pembrolizumab treatment. A total of 104 (19%) of 556 patients randomized to 
pembrolizumab completed 2 years of treatment. With a median follow-up of 9 months after 
completion of pembrolizumab, the estimated risk of progression or death was 9% in these 
patients (Robert 2017).  
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low. 
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153 (NCT02066636), patients with previously treated advanced 
NSCLC who completed 1 year of nivolumab therapy were randomized to either continue or stop 
treatment, with the option of retreatment upon progression. Among 163 patients still on 
treatment at 1 year and without progression, those who were randomized to continue nivolumab 
had significant improvement in PFS compared with those who were randomized to stop 
treatment, with median PFS (post-randomization) not reached vs 10.3 months, respectively; 
HR = 0.42 (95% CI, 0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, 
there also was a trend for patients on continued treatment to live longer (OS HR = 0.63 
[95% CI:  0.33, 1.20]). Of note, the PFS curves in both groups plateaued approximately 1 year 
after randomization (ie, 2 years after treatment initiation), suggesting that there may be minimal 
benefit in extending treatment beyond a total of 2 years (Spigel 2017).  
Collectively, these data suggest that there is minimal if any benefit derived from continuing 
immune-oncology treatment beyond 2 years in advanced tumors. However, even though 
immunotherapy is well tolerated, patients will be at risk for additional toxicity with longer term 
treatment. Therefore, in this study, the initial treatment will be given for a maximum of 35 cycles 
(approximately 2 years) following the date of the first dose of study drug. 
Given the hypothesis that co-administration of bempegaldesleukin with pembrolizumab will 
potentiate the pharmacological effects of pembrolizumab, the duration of bempegaldesleukin 
therapy will also be restricted to 35 cycles (approximately 2 years) to match the duration of 
pembrolizumab therapy. 


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3.2.5 
Justification for Dose 
3.2.5.1 
Bempegaldesleukin 
Bempegaldesleukin 0.006 mg/kg q3w was chosen as the RP2D in the PIVOT-02 study based on 
the observed clinical safety profile as well as the clinical evidence of a robust immune system 
activation. Refer to Section 2.1.3.2.2 for additional details regarding the PIVOT-02 study. 
3.2.5.2 
Pembrolizumab 
Pembrolizumab will be given at 200 mg q3w IV according to the label. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg q3w is the appropriate dose 
of pembrolizumab across all indications and regardless of tumor type. As outlined below, this 
dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg q3w to 10 mg/kg every 2 weeks (q2w). 
• Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg q3w 
across multiple indications. 
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically based PK analysis) at 
200 mg q3w. 
Among the 8 randomized dose-comparison studies, a total of 2262 patients were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naive, previously treated, 
PD-L1 enriched and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg q3w versus 10 mg/kg q3w 
(KEYNOTE-001 B2, KEYNOTE-001 D, KEYNOTE-002, KEYNOTE-010, and 
KEYNOTE-021), and three studies compared 10 mg/kg q3w versus 10 mg/kg q2w 
(KEYNOTE-001 B3, KEYNOTE-001 F2, and KEYNOTE-006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) q3w provided similar responses to the highest doses studied. Subsequently, flat 
dose-/exposure-response relationships were also observed in other tumor types including head 
and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, confirming 
200 mg q3w as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg q3w. First, PK data in 
KEYNOTE-001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg q3w. Secondly, a 
physiologically based PK analysis was conducted to predict tumor PD-1 saturation over a wide 


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range of tumor penetration and PD-1 expression. This evaluation concluded that pembrolizumab 
at 200 mg q3w achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other patient covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg q3w fixed dose and 2 mg/kg q3w dose. Supported by 
these PK characteristics, and given that a fixed dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg q3w fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
Additional details on dosing are provided in the pembrolizumab Investigator’s Brochure. 
3.2.5.3 
Rationale for Bempegaldesleukin/Pembrolizumab Combination 
Accumulating evidence suggests that patients with low baseline CD8+ T cells within the tumor 
microenvironment (tumor infiltrating lymphocytes [TILs]) predict poor response to checkpoint 
inhibitor immunotherapies (Daud 2016a; Daud 2016b); thus, agents designed to specifically 
activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. 
NKTR-214 targets the IL-2 pathway and is designed to provide biased sustained signaling 
through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate NK and 
effector CD8+ T cells over Treg cells. Preliminary analyses of patients’ blood and tumor by flow 
cytometry and IHC demonstrate that NKTR-214, as a single agent, increases activated CD4+ and 
CD8+ T cells in peripheral blood, with an increase in T-cell infiltrates within the tumor tissue 
after 1 dose of NKTR-214. In addition, there is an increase in programmed cell death receptor-1 
(PD-1) expression on T cells in the blood and tumor after treatment with NKTR-214. The ability 
to alter the immune environment and increase PD-1 expression on effector T cells may improve 
the effectiveness of anti-PD-1/anti-PD-L1 blockade. 


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4.0 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Primary Objectives and Endpoints 
In patients who are aged 18 years and older with recurrent or metastatic HNSCC and positive 
PD-L1 expression (CPS ≥ 1) who have not received prior therapy for the treatment of recurrent 
or metastatic HNSCC, the primary objectives and endpoints are: 
Primary Objective 
Endpoint 
To compare the overall survival (OS) of 
bempegaldesleukin plus pembrolizumab versus 
pembrolizumab monotherapy. 
OS, defined as the time from randomization to death due to 
any cause. 
To compare the objective response rate (ORR) of 
bempegaldesleukin plus pembrolizumab versus 
pembrolizumab monotherapy. 
ORR, defined as the rate of confirmed complete response 
(CR) or partial response (PR) per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1) as 
assessed by blinded independent central review (BICR). 
 
4.2 
Secondary Objectives and Endpoints 
The secondary objectives and endpoints listed below involve comparison of bempegaldesleukin 
plus pembrolizumab versus pembrolizumab monotherapy in first-line patients with recurrent or 
metastatic HNSCC and positive PD-L1 expression (defined by CPS ≥ 1) who have not received 
prior therapy for the treatment of recurrent or metastatic HNSCC: 
Secondary Objective 
Endpoint 
To compare progression-free survival (PFS). 
PFS, defined as the time from randomization to the first 
documented disease progression (per RECIST 1.1 by 
BICR) or death due to any cause, whichever occurs first. 
To compare time to deterioration in global health 
status/quality of life, pain, and swallowing. 
The time from baseline to a ≥ 10-point decrease from 
baseline with confirmation by the subsequent visit of a 
≥ 10-point deterioration from baseline in: 
• 
Global health status/quality of life assessment based on 
the global health status/quality of life scales of the 
European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire-
Core 30 (QLQ-C30). 
• 
Pain based on the pain multi-item scales of EORTC 
QLQ head and neck cancer specific module (EORTC 
QLQ-H&N35). 
• 
Swallowing based on the swallowing multi-item scales 
of EORTC QLQ-H&N35. 
To compare mean change from baseline in global 
health status/quality of life. 
Mean change from baseline in global health status/quality 
of life scales of EORTC QLQ-C30. 
To compare the overall safety and tolerability. 
Safety will be based on assessments of treatment-emergent 
adverse events (AEs) and serious AEs (SAEs). 
 




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5.0 
SELECTION OF STUDY POPULATION 
5.1 
Inclusion Criteria 
An eligible patient must meet all of the following criteria: 
1. 
Provide written, informed consent to participate in the study and follow the study 
procedures. The Investigator takes responsibility for ensuring that all vulnerable patients 
are protected and participate voluntarily in an environment free from coercion or undue 
influence. The patient may also provide consent for additional research (described in 
Section 8.3.3). However, the patient may participate in the study without participating in 
additional research. 
2. 
Male or female patients, age 18 years or older at the time of signing the informed consent 
form (ICF). 
3. 
Have histologically or cytologically-confirmed recurrent or metastatic HNSCC that is 
considered incurable by local therapies. 
a. 
No prior systemic therapy for recurrent or metastatic disease. Systemic therapy 
given as part of multimodal treatment for locally advanced disease is allowed if 
completed more than 6 months prior to signing consent. 
b. 
The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and 
larynx. 
c. 
Patients may not have a primary tumor site of nasopharynx (any histology) and/or 
unknown primary. 
4. 
Have measurable disease based on RECIST 1.1 as determined by the local site 
Investigator. Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been shown in such lesions since irradiation. 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see 
Appendix 3). 
6. 
Provide tumor tissue from a core, incisional, or excisional biopsy (fine needle aspirates 
are not acceptable) to the central laboratory for determination of PD-L1 status (if not 
determined at local laboratory) 
. Repeat samples may 
be required if adequate tissue is not provided for assessment of PD-L1 status. A newly 
obtained biopsy is strongly preferred, but archival tumor biopsy may be used and 
provided (see Section 8.3.1).  
7. 
The tumor must have positive PD-L1 expression (ie, CPS ≥ 1) as determined by a local or 
the central laboratory with the IHC 22C3 PharmDx diagnostic kit. 


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8. 
Patients with oropharyngeal cancer: must have results from testing of HPV status defined 
as p16 IHC testing using CINtec® p16 Histology assay. If HPV status was previously 
tested using this method, no additional testing is required. Note: 
a. 
Tumor p16 expression must be evaluated by assessment of IHC analysis with 
CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using 
‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and standard protocol. 
Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic 
staining in 70% or more of the tumor cells. 
b. 
If local p16 testing results are not available, or cannot be assessed by the specified 
method, a tumor tissue sample may be submitted to the central laboratory for p16 
testing. 
Patients with oral cavity, hypopharynx, or larynx cancers:  HPV testing by p16 IHC is not 
required as by convention these tumor locations are assumed to be HPV negative. 
9. 
Demonstrated adequate organ function as defined below (see Section 10.18 for clinical 
laboratory test information): 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥ 1500/μL (1.5 × 109/L) without myeloid growth factor support for 7 
days preceding the lab assessment 
Platelets 
Platelet count ≥ 100,000/μL (100 × 109/L) without platelet 
transfusions for 7 days preceding the lab assessment 
Hemoglobin 
Hemoglobin ≥ 9.0 g/dL (90 g/L) without erythropoietin-stimulating 
agents or transfusion for 14 days preceding the lab assessment 
Renal 
 
Serum creatinine OR measured or 
calculated creatinine clearancea  
(GFR can also be used in place of 
creatinine or creatinine clearance)  
≤ 1.5 × ULN OR 
≥ 60 mL/min for patients with creatinine levels > 1.5 × ULN 
Hepatic 
 
Total bilirubin  
≤ 1.5 × ULN OR  
Direct bilirubin ≤ ULN for patients with total bilirubin > 1.5 × ULN  
AST or ALT 
≤ 2.5 × ULN 
Digestive 
 
Lipase and amylase 
≤ 1.5 × ULN 
Patients with pancreatic metastases and lipase and/or amylase < 3× 
ULN may enroll. Patients may not enroll if there are clinical or 
radiographic signs of pancreatitis. 
Coagulation 
 
INR or PT  
aPTT 
≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy, as 
long as PT or aPTT is within the therapeutic range of intended use of 
anticoagulants 
Abbreviations:  ALT (SGPT) = alanine transaminase (serum glutamic pyruvic transaminase); aPTT = activated 
partial thromboplastin time; AST (SGOT) = aspartate transaminase (serum glutamic oxaloacetic transaminase); 
GFR = glomerular filtration rate; INR = international normalized ratio; PT = prothrombin time; ULN = upper 
limit of normal 
a. 
Creatinine clearance should be calculated according to institutional standard. 


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10. 
A documented left ventricular ejection fraction (LVEF) > 45% using standard 
echocardiogram or multigated acquisition (MUGA) scan test. 
11. 
Patients with hypertension must be on a stable antihypertensive regimen for the 14 days 
prior to the first dose of study drug. Need for ≤ 2 antihypertensive medications for 
management of hypertension (including diuretics) permitted (for patients randomized to 
Arm A receiving bempegaldesleukin: Section 6.7.2.2 provides additional on-treatment 
considerations regarding antihypertensive medications). 
12. 
Oxygen saturation ≥ 90% on room air. 
13. 
Clinically significant toxic effect(s) of the most recent prior anticancer therapy must be 
Grade 1 or resolved (except alopecia, neuropathy, adrenal insufficiency and 
hypothyroidism). Note: 
a. 
Patients with ≤ Grade 2 neuropathy are eligible. 
b. 
Patients with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone 
replacement may be eligible. Specifically, patients with Grade ≤ 2 adrenal 
insufficiency (defined as requiring medical intervention, such as concomitant 
steroids) or Grade ≤ 2 hypothyroidism (defined as requiring hormone replacement 
therapy) may be enrolled provided that clinical symptoms are adequately controlled 
and the daily dose is 10 mg or less of prednisone or equivalent.  
c. 
If the patient had a major operation, the patient must have recovered adequately 
from the procedure and/or any complications from the operation before starting 
study intervention. 
14. 
Reproductive Status 
a. 
Women of childbearing potential (WOCBP) must have a negative highly sensitive 
pregnancy test (urine or serum as required by local regulations) within 24 hours for 
urine or within 72 hours for serum before the first dose of study treatment.  
Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the patient must be excluded from 
participation if the serum pregnancy result is positive. 
b. 
Women must not be breastfeeding. 
c. 
WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study treatment and for at least 120 days after the last 
dose of study treatment or 30 days after cessation of study drug if the patient 
initiates a new anticancer treatment. Women should use an adequate method(s) of 
contraception as indicated in Appendix 5. WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements, and still must 
undergo pregnancy testing as described in this protocol. 


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Note: The Investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a woman with 
an early undetected pregnancy. 
d. 
For Arm A:  Males who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment with study 
treatment(s) and at least 3 months after the last dose of bempegaldesleukin. In 
addition, male patients must be willing to refrain from sperm donation during this 
time (Appendix 5). 
For Arm B:  For males receiving pembrolizumab monotherapy, there are no 
contraception requirements. 
15. 
Patients who are hepatitis B surface antigen (HBsAg) positive are eligible if they have 
received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have 
undetectable HBV viral load prior to randomization. 
Note:  Patients should remain on antiviral therapy throughout study intervention and 
follow local guidelines for HBV antiviral therapy post completion of study intervention. 
Hepatitis B screening tests are not required unless: 
• Known history of HBV infection 
• As mandated by local health authority 
16. 
Patients with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is 
undetectable at screening. 
Note:  Patients must have completed curative antiviral therapy at least 4 weeks prior to 
randomization. Hepatitis C screening tests are not required unless: 
• Known history of HCV infection 
• As mandated by local health authority 
17. 
Patients must be able and willing to comply with the study visit schedule and study 
procedures. 
5.2 
Exclusion Criteria 
A patient will be excluded from this study if he/she meets any of the following criteria: 
1. 
Has disease that is suitable for local therapy administered with curative intent. 
2. 
Has progressive disease within 6 months of completion of curatively intended systemic 
treatment for locoregionally advanced HNSCC.  


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3. 
Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to 
initiation of study drug, or patient has not fully recovered (ie, ≤ Grade 1 or at baseline) 
from AEs due to a previously administered treatment. A 1-week washout is permitted for 
palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) 
disease. Note: 
a. 
Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and qualify for the study. 
b. 
If patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
4. 
Has a life expectancy of less than 3 months and/or has rapidly progressing disease 
(eg, tumor bleeding, uncontrolled tumor pain) as determined by the Investigator. 
5. 
Has a known additional malignancy that is progressing or has required active treatment 
within 5 years prior to the first dose of study drug with the exception of:  curatively 
treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, curatively 
resected in situ cervical cancer, and curatively resected in situ breast cancer.  
6. 
Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed. 
7. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
Corticosteroid use as pre-medication for allergic reactions (eg, IV contrast) is allowed. 
The use of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor. 
8. 
Use of an investigational agent or an investigational device within 28 days before the first 
dose of study drug. 
Note: Patients who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.  
9. 
Prior treatment with an anti PD-1, anti PD-L1, anti-PD-L2, or anti CTLA-4 antibody, 
agents that target IL-2 pathway, or any other antibody or drug specifically targeting 
T-cell costimulation or checkpoint pathways. 


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10. 
Has known active CNS metastases and/or carcinomatous meningitis. 
Note:  Patients with previously treated brain metastases may participate provided they are 
radiographically stable (without evidence of progression by imaging [using the identical 
imaging modality for each assessment, either magnetic resonance imaging (MRI) or 
computed tomography (CT) scan] for at least 4 weeks prior to the first dose of study 
treatment and any neurologic symptoms have returned to baseline), have no evidence of 
new or enlarging brain metastases, and are not using steroids for at least 7 days prior to 
study treatment. This exception does not include carcinomatous meningitis, which is 
excluded regardless of clinical stability. 
11. 
History of severe hypersensitivity (≥ Grade 3) to study drug components (for 
pembrolizumab, bempegaldesleukin, or any of their excipients). 
12. 
History of severe hypersensitivity reaction to any monoclonal antibody. 
13. 
History of allogeneic tissue/solid organ transplant. 
14. 
Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a 
stable regimen at study entry. Symptomatic lesions (eg, bone metastases or metastases 
causing nerve impingement) amenable to palliative radiotherapy should be treated prior 
to the first dose of study drug. Patients should be recovered from the effects of radiation. 
There is no required minimum recovery period. 
15. 
Active infection requiring systemic therapy. 
16. 
Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
17. 
Has concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV 
deoxyribonucleic acid [DNA]) and hepatitis C virus (defined as anti-HCV antibody 
positive and detectable HCV ribonucleic acid [RNA]) infection. 
Note: Hepatitis B and C screening tests are not required unless: 
• Known history of HBV and HCV infection  
• As mandated by local health authority 
18. 
Known history of positive test for human immunodeficiency virus (HIV 1/2 antibodies). 
19. 
Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study within 2 weeks prior to the first dose 
of study drug. Refer to Section 6.7.2 for prohibited concomitant medications. 
20. 
Prolonged Fridericia’s corrected QT interval (QTcF) > 450 msec for men and > 470 msec 
for women at Screening. 
21. 
Known cardiovascular history, including unstable or deteriorating cardiac disease, within 
the previous 12 months prior to the first dose of study drug including, but not limited to, 
the following: 
a. 
Unstable angina or myocardial infarction. 


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b. 
Transient ischemic attack (TIA)/Cerebrovascular accident (CVA). 
c. 
Congestive heart failure (New York Heart Association [NYHA] Class III or IV). 
d. 
Uncontrolled clinically significant arrhythmias. 
22. 
Need for > 2 antihypertensive medications for management of hypertension (including 
diuretics). Patients with hypertension must be on a stable antihypertensive regimen 
(defined as no dose adjustments to antihypertensive medications) for the 14 days prior to 
the first dose of study drug. 
Note:  An antihypertensive medication that contains 2 drugs under one formulation is 
counted as 2 antihypertensive medications (eg, angiotensin-converting-enzyme [ACE] 
inhibitor plus diuretic, calcium channel blocker plus ACE inhibitor). 
23. 
History of pulmonary embolism, deep vein thrombosis (DVT), or prior clinically 
significant venous or non-CVA/TIA arterial thromboembolic event within 3 months prior 
to the first dose of study drug. 
• Patients with a history of a venous or arterial thromboembolic event must be 
asymptomatic for at least 2 weeks prior to enrollment and must be receiving a stable 
regimen of therapeutic anticoagulation (preferably low molecular weight heparin 
[LMWH] or direct oral anticoagulants [DOAC]; see Section 6.7.3.3). Note:  unless 
there is a new medical contraindication observed after Cycle 1 Day 1, a patient with a 
history of venous or arterial thromboembolic event must be willing to maintain 
therapeutic anticoagulation throughout participation in the treatment phase of the 
study. 
24. 
Patients who have received a live / attenuated vaccine within 30 days of the first dose of 
study drug. Note: Killed vaccines are allowed. 
25. 
Any contraindication or exclusions specific to pembrolizumab included in the current 
package insert, Summary of Product Characteristics, or the applicable country-specific 
prescribing guidelines. 
26. 
Any condition including medical, emotional, psychiatric, substance abuse, or logistical 
that, in the opinion of the Investigator, would preclude the patient from adhering to the 
protocol or would increase the risk associated with study participation or study drug 
administration or interfere with the interpretation of safety results (eg, a condition 
associated with diarrhea or acute diverticulitis). 


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6.0 
TREATMENT PLAN 
6.1 
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 
care. After signing the ICF, patients will be evaluated for entry criteria during the Screening 
period based on assessments outlined in Table 1. 
Furthermore, additional evaluations/testing may be deemed necessary by the Investigator and/or 
the Sponsor for reasons related to patient safety. In some cases, such evaluations/testing may be 
potentially sensitive in nature (eg, HIV, hepatitis C, etc.), and thus local regulations may require 
that additional informed consent be obtained from the patient. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
6.1.1 
Screening Failure 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements, as applicable, and to respond to queries from 
regulatory authorities. 
Re-screening will be allowed for a patient who has discontinued the study as a pretreatment 
failure (ie, patient has not been randomized). Results from assessments performed during the 
initial screening period are acceptable in lieu of a repeat screening test if performed within the 
specified time frame and the inclusion/exclusion criteria is met. If re-enrolled, the patient must 
be re-consented. 
Retesting of laboratory parameters and/or other assessments within any single Screening period 
will be permitted (in addition to any parameters that require a confirmatory value). The most 
current result prior to randomization is the value by which study inclusion will be assessed, as it 
represents the patient’s most current clinical state. 
Laboratory parameters and/or assessments that are included in the Schedule of Events 
(Section 1.2) may be repeated in an effort to find all possible well-qualified patients. 
Consultation with the Medical Monitor may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant. 
6.2 
Treatment Period 
Section 1.2 provides the study assessments to be performed during the treatment period. 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, the 


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coronavirus disease 2019 (COVID-19) public health emergency, or other patient-specific 
circumstances. All out of window visits and procedures will incur a protocol deviation and 
should be documented as described in Section 13.1. 
The duration of study treatment is described in Section 6.2.4. 
Patients with progressive disease per RECIST 1.1 but with otherwise stable or improved 
performance and clinical status may continue to be treated in the event of a perceived benefit per 
Investigator; see Section 6.2.5 for treatment beyond progression. Patients with a partial response 
(PR) or with stable disease will continue to receive study drugs until disease progression, or 
intolerability to therapy. It is at the discretion of the Investigator to continue treating patients 
with a confirmed CR for a maximum treatment of 35 cycles (approximately 2 years). 
6.2.1 
Treatment Assignment and Patient Number Assignment 
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.  
An Interactive Response Technology (IRT) will be employed to manage patient randomization 
and drug supply. 
Following Screening and confirmation of a patient’s eligibility, patients will be randomized in a 
1:1 ratio to Arm A (bempegaldesleukin in combination with pembrolizumab) or Arm B 
(pembrolizumab monotherapy) using the IRT system. Within 5 calendar days following 
randomization, the patient should receive the first dose of study treatment. 
6.2.2 
Administration of Study Drugs 
Table 3 provides the timing of study drug administration. Dosing visits are not skipped, only 
delayed. 
Study agent(s) should be administered in an area with access to resuscitation equipment. 
Table 3: 
Selection and Timing of Dose 
Study Treatment 
Starting dose 
Frequency  
of Administration 
Route  
of Administration 
Bempegaldesleukin (NKTR-214)a 
0.006 mg/kg 
q3w 
IV 
Pembrolizumab  
200 mg  
q3w 
IV 
Abbreviations:  IV = intravenous; q3w = every 3 weeks 
a. 
Bempegaldesleukin dose is based on IL-2 content. 
 


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6.2.2.1 
Arm A: Bempegaldesleukin Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients should be carefully monitored for infusion reactions during bempegaldesleukin 
administration. If an acute infusion reaction is noted, patients should be managed according to 
Section 6.5.1.1.1. If the patient experiences a Grade ≥ 2 infusion-related reaction or hypotension 
during the days after bempegaldesleukin dosing, 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. 
Treatment with bempegaldesleukin may be delayed or reduced as described in Section 6.5.1.2. 
No dose escalations of bempegaldesleukin above 0.006 mg/kg are allowed (see Section 6.5.1.2 
for information regarding patients with a bempegaldesleukin dose reduction). 
Bempegaldesleukin monotherapy may continue if pembrolizumab is permanently discontinued 
due to toxicities. 
Please refer to the Pharmacy Manual/current Investigator’s Brochure for details regarding 
bempegaldesleukin preparation, storage, and administration. 


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6.2.2.2 
Arm A and Arm B:  Pembrolizumab Dosing 
Pembrolizumab dosing will be as follows: 
• Arm A:  Patients in Arm A should receive pembrolizumab at least 30 minutes after the end 
of the bempegaldesleukin infusion. Do not co-administer pembrolizumab with the same IV 
line used for bempegaldesleukin; the pembrolizumab infusion must be administered using a 
separate infusion set with an in-line filter, which include add-on filters (also known as an 
in-line filter extension set). Pembrolizumab will be administered as a dose of 200 mg using a 
30-minute IV infusion on Day 1 of each treatment cycle q3w (± 3 days). Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible. However, given 
the variability of infusion pumps from site to site, a window between −5 minutes and 
+10 minutes is permitted (ie, infusion time is 30 minutes −5 min/+10 min). 
• Arm B:  Patients in Arm B will receive pembrolizumab as a dose of 200 mg using a 
30-minute IV infusion on Day 1 of each treatment cycle q3w (± 3 days). The pembrolizumab 
infusion must be administered using an infusion set with an in-line filter, which include 
add-on filters (also known as an in-line filter extension set). Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps from site to site, a window between −5 minutes and +10 minutes is 
permitted (ie, infusion time is 30 minutes −5 min/+10 min). 
No dose escalations or reductions of pembrolizumab are allowed. Patients may be dosed no less 
than 18 days from the previous dose during q3w cycles.  
Patients should be carefully monitored for infusion reactions during pembrolizumab 
administration. If an acute infusion reaction is noted, patients should be managed according to 
the directions in Section 6.5.2.1.1. 
Doses of pembrolizumab may be interrupted, delayed, or discontinued depending on how well 
the patient tolerates the treatment (see Section 6.5.2.1). Pembrolizumab monotherapy may 
continue if bempegaldesleukin is permanently discontinued due to toxicities. 
Flush the IV line with an appropriate amount of diluent to ensure that the total dose is completely 
administered over the appropriate time. Care must be taken to assure sterility of the prepared 
solution as the product does not contain any antimicrobial preservative or bacteriostatic agent. 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution. 
6.2.3 
Monitoring, Vital Signs, and Hydration Guidelines 
The study site must be equipped for medical emergencies. 


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6.2.3.1 
Frequent Vital Signs 
Refer to Section 10.20 for vital sign measurements, which are to be monitored according to the 
Schedule of Events (Section 1.2).  
6.2.3.2 
Arm A: Hydration Guidelines 
Important safety information and hydration instructions are to be provided to patients in Arm A 
receiving bempegaldesleukin and pembrolizumab. Hydration and renal function should be 
assessed within 24 hours prior to study drug administration or as soon as locally feasible (see 
Appendix 1B for the list of local laboratory tests that require evaluation prior to 
bempegaldesleukin administration). Underlying reasons for decreased oral intake (such as 
nausea) should be addressed and treatment (such as IV hydration) should be provided. Patients 
may receive additional hydration precautions in a patient card. 
For those patients receiving bempegaldesleukin and pembrolizumab, administer at least 1 liter of 
IV fluid on bempegaldesleukin dosing days (at any time on Day 1 of each cycle). For the next 
3 days (Days 2-4) after administration of bempegaldesleukin, patients are to be instructed to 
drink at least 2 liters per day (ie, 8–10 glasses) of self-administered oral hydration. Advise 
patients to avoid activity that may contribute to dehydration (including, but not limited to, 
strenuous activity, long hot showers, and saunas) for Days 1 to 4 of each cycle of 
bempegaldesleukin treatment. Advise patients with orthostatic symptoms to call their treating 
oncologist and consider increasing oral hydration. 
In Cycles 1 and 2, site personnel must contact the patient (by telephone or clinic visit) once 
between Days 3 and 5 (inclusive) following infusion, to remind the patient of the oral hydration 
guidelines, to assess for any symptomatology and compliance with the guidelines, and document 
the results of the discussion (Section 1.2). Following subsequent bempegaldesleukin 
administrations, the oral hydration follow-up should be conducted as clinically indicated for 
patients receiving bempegaldesleukin. 
Per clinical judgment, IV fluids may be administered at any time. The Investigator may decide to 
forego administering IV fluids to a patient or adjust the recommendation for self-oral hydration 
to a particular patient if this is deemed to be in the best interest of the patient (eg, evidence of 
fluid overload). 


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6.2.4 
Duration of Treatment 
In the initial treatment (ie, First Course), patients may remain on treatment for up to 35 cycles 
(approximately 2 years) of study drug (ie, bempegaldesleukin plus pembrolizumab or 
pembrolizumab monotherapy). Note: the number of cycles of study medication is calculated 
starting with the first dose. 
For patients who have attained a confirmed complete response and have received at least 
2 cycles of study drug beyond the initial complete response confirmation date, treatment may be 
stopped.  
These patients may be eligible for the Second Course as described in Section 6.2.6. 
6.2.5 
Treatment Beyond Progression 
Accumulating evidence indicates a minority of patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (Wolchok 2009; Nishino 2015). 
Patients will be permitted to continue assigned study drug beyond initial RECIST 1.1-defined 
progressive disease (confirmed by BICR) up to a maximum of 35 cycles (approximately 2 years) 
from the date of first study drug dose as long as they meet the following criteria: 
• Investigator-assessed clinical benefit. 
• Patient tolerates study treatment. 
• Stable ECOG performance status. 
• Absence of signs and symptoms indicating clinical disease progression (eg, increased pain or 
worsening laboratory values). 
• Absence of tumor progression at critical anatomical sites (eg, brain metastases or cord 
compression) requiring urgent intervention. 
• Patient provides written informed consent prior to receiving additional study treatment. All 
other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply. 
Radiographic assessment/scan(s) should continue in accordance with the Schedule of Events 
(Section 1.2) for the duration of the treatment beyond progression and should be submitted to the 
central imaging vendor.  
Treatment beyond progression should be stopped when the Investigator assesses a loss of clinical 
benefit. The criteria may include clinical disease progression, second progressive disease of 
target lesions per RECIST 1.1, radiographic progression of non-target lesions, or new lesions. 
Discussion with the Medical Monitor is encouraged. 


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6.2.6 
Second Course Phase 
All patients who have stable disease, partial response, or complete response may be eligible for 
up to an additional 17 cycles (approximately 1 year) of study treatment if there is 
Investigator-determined radiographic disease progression by RECIST 1.1 after the initial 
treatment (ie, First Course) has been completed or stopped for confirmed CR as specified in 
Section 6.2.4. This retreatment is the Second Course of this study. Patients who restart treatment 
will be retreated with the same study drug(s) and at the same dose as when they last received 
study drug. 
Patients may enter the Second Course if all of the following criteria are met: 
1. No new anticancer treatment was administered after the last dose of study intervention. 
2. The patient meets all of the inclusion criteria and none of the exclusion criteria (see 
Section 5.0). Initial screening results are acceptable and do not need to be repeated for the 
Second Course for the following Section 5.1 inclusion criteria 3a, 6, 7, 8, 10, 15, and 16 and 
the following in Section 5.2 exclusion criteria 2, 9, 17, 18, and 20. 
3. The study is ongoing. 
An objective response or disease progression that occurs during the Second Course will not be 
counted as an event for the primary analysis of either endpoint in this study. 
Visit requirements for the Second Course Phase are outlined in Section 1.2, Second Course 
Phase – Retreatment with Study Drug. 
6.2.7 
Lost to Follow-Up 
If a patient fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the patient, the following procedures are to be performed: 
• The site must attempt to contact the patient and reschedule the missed visit. If the patient is 
contacted, the patient should be counseled on the importance of maintaining the 
protocol-specified visit schedule. 
• The Investigator or designee must make every effort to regain contact with the patient at each 
missed visit (eg, telephone calls and/or a certified letter to the patient’s last known mailing 
address or locally equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
Note: A patient is not considered lost to follow-up until the last scheduled visit for the individual 
patient. The missing data for the patient will be managed via the prespecified statistical data 
handling and analysis guidelines. 


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6.3 
Long-Term Follow-Up 
Section 1.2 presents the long-term follow-up assessments. 
6.3.1 
Follow-Up Visits 
Both Follow-Up Visits should be conducted in person and should occur regardless of initiation of 
subsequent anticancer therapy as follows: 
• Follow-Up Visit 1 should occur 30 (± 7) days from the last dose of all study drug(s) or before 
a new antineoplastic regimen starts  
• Follow-Up Visit 2 occurs 90 (± 7) days from the last dose of all study drug(s). 
If the patient is unable to return to the clinic (eg, due to the COVID-19 public health emergency) 
for Follow-Up Visits, assessments and laboratory samples may be collected by research staff or 
designee at an alternate location or by phone as necessary; the location of the protocol-mandated 
visit (eg, real-time video conference) should be documented as described in Section 13.1. 
Per clinical judgment, the patient may come in earlier for additional follow up. 
Patients will also be followed for safety until resolution or permanent sequelae of all toxicities 
attributable to study drugs (bempegaldesleukin and/or pembrolizumab) as outlined in 
Sections 10.5 and 10.8. 
For AE and SAE reporting periods, please refer to Sections 10.5 and 10.7. 
6.3.2 
Survival Follow-Up 
All patients will be contacted for survival every 12 weeks (± 14 days) following Follow-Up 
Visit 2 (or following last contact with the patient, if Follow-Up Visit 2 is missed) as follows: 
• Survival visits may be conducted in person or by telephone. 
• The Sponsor may request that survival data be collected on all treated patients outside of the 
scheduled contacts. At the time of this request, each patient will be contacted to determine 
their survival status unless the patient has withdrawn consent for all contact or is lost to 
follow-up (as defined in Section 6.2.7). Alternative methods to determine survival status may 
be used (eg, access to medical records and public record searches) as allowed by local 
regulations and/or guidelines. 
• For patients who discontinue study treatment before BICR-confirmed disease progression, 
radiographic tumor assessments will continue to be collected every 6 weeks (± 7 days) or 
more frequently if clinically indicated. One year after randomization, radiographic tumor 
assessments will continue to be collected every 9 weeks (± 14 days) until BICR-confirmed 
disease progression, patient withdraws consent, death, initiation of subsequent anticancer 
therapy, or study termination by the Sponsor. 


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• Additional subsequent cancer therapy details such as regimen, setting of the regimen, line of 
therapy, start date and end date of each regimen, best response to the regimen, and date of 
progression after next line of therapy will be collected. 
• Survival follow up should continue until patient withdrawal of consent for survival 
follow-up, death, loss to follow-up, or study termination by the Sponsor. 
6.4 
End of Study 
End of study is defined as no more than 5 years after the last patient received their first dose of 
study drug or Sponsor decision to terminate the study, whichever comes first. 
6.5 
Dose Modification and Management of Specific Adverse Events 
Every effort should be made to follow planned dosing schedules for all study drugs in both 
treatment arms. Study drug administration may be delayed or modified for toxicity as described 
below and must be discontinued as required by criteria described in Section 6.6. 
For patients in Arm A (bempegaldesleukin plus pembrolizumab):  Dose modification for 
bempegaldesleukin in Arm A may be considered independently from pembrolizumab based on 
Investigator assessment of relationship of a toxicity to each of the study drugs. If only one of the 
study drugs meets the criteria for dose delay, then administration of the other study drug may be 
continued or delayed at the discretion of the Investigator. Likewise, in the event that one of the 
study drugs in Arm A is permanently discontinued due to toxicities, the other can continue to be 
administered.  
Patients who require a dose delay of pembrolizumab or bempegaldesleukin should be 
re-evaluated weekly or more frequently if clinically indicated and should resume treatment with 
combination of bempegaldesleukin and pembrolizumab when retreatment criteria are met. 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. 
Tumor assessments for all patients should continue as per protocol even if dosing is delayed. 
6.5.1 
Bempegaldesleukin 
6.5.1.1 
Monitoring and Management of Specific Adverse Events 
6.5.1.1.1 
Infusion Reactions 
Infusion reactions have been reported during infusions with bempegaldesleukin. If such a 
reaction were to occur with the bempegaldesleukin infusion, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other 
allergic-like reactions.  


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Dose modification and toxicity management guidelines for bempegaldesleukin infusions should 
follow those provided for pembrolizumab infusion reactions that are provided in Table 5 
(Section 6.5.2.1.1). For patients randomized to Arm A receiving bempegaldesleukin, note: 
• In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine or corticosteroids). 
• If a patient has experienced a previous infusion reaction to bempegaldesleukin, subsequent 
doses of bempegaldesleukin may be administered at a reduced rate (over longer duration) per 
Investigator discretion (eg, 50% of the initial rate of infusion). The investigator may also 
consider re-elevating the rate of infusion if the patient tolerates the subsequent dose(s) 
well. The Investigator may consult with the Medical Monitor for additional guidance, as 
needed. Completion of bempegaldesleukin administration must occur within accepted 
timeframes (eg, from reconstitution or from time bempegaldesleukin is brought to room 
temperature) as described in the Pharmacy Manual. 
6.5.1.1.2 
Elevated Hepatic Transaminases:  Monitoring and Management 
Elevated hepatic transaminases are a toxicity that can occur for bempegaldesleukin. The 
elevations in hepatic transaminases associated with bempegaldesleukin typically occur at the 
time of peak of bempegaldesleukin active metabolite concentrations in the blood (Days 4-8), and 
are often accompanied by other cytokine-related toxicities such as flu-like symptoms, rash or 
pruritus. The transient elevations in hepatic transaminases are usually mild or moderate in 
severity, not associated with increased total bilirubin, resolve spontaneously without treatment, 
and predominantly occur in Cycle 1 and Cycle 2. 
The following recommendations are for patients randomized to Arm A receiving 
bempegaldesleukin and apply to Cycle 1 only. Patients on subsequent cycles of 
bempegaldesleukin should follow the guidance in Table 6 (Section 6.5.2.1.2). These 
recommendations are not intended to serve as rigid guidelines or to replace clinical judgment, 
and do not apply to patients receiving pembrolizumab monotherapy. Hepatic events, including 
elevated liver function tests, have also been observed for pembrolizumab; for patients receiving 
pembrolizumab monotherapy, see Table 6 (Section 6.5.2.1.2). 
For patients experiencing elevated hepatic transaminases while receiving Cycle 1 of 
bempegaldesleukin alone or in combination with pembrolizumab, first rule out 
non-inflammatory etiologies. If non-inflammatory cause, treat accordingly and continue 
bempegaldesleukin. Consider imaging if obstruction is suspected. 
If during monitoring alanine transaminase (ALT)/aspartate transaminase (AST) increases, follow 
the guidance for the highest levels. 


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AST or ALT > 3.0 to ≤ 5.0 × upper limit of normal (ULN) 
Increase frequency of liver function test monitoring to approximately every 3 days and 
delay treatment until lab abnormalities resolve to Grade 0-1. 
If no improvement within 7 days, treat with 0.5 to 1 mg/kg/day prednisone equivalents, 
and taper steroids over at least 1 month before resuming treatment. 
ALT or AST > 5.0 to ≤ 8.0 × ULN 
Increase frequency of monitoring to approximately every 3 days until lab abnormalities 
resolve to Grade 0-1. 
Treatment must be delayed until lab abnormalities resolve to Grade 0-1. 
If no improvement within 7 days: 
o Discontinue bempegaldesleukin and pembrolizumab  
o 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 
one month 
o Consult gastroenterologist 
o Consider adding non-corticosteroid immunosuppressive medication if no 
improvement in > 3-5 days, worsens or rebounds while on steroids 
ALT or AST > 8.0 × ULN  
o Discontinue bempegaldesleukin and pembrolizumab  
o Increase frequency of monitoring to approximately 1-2 days 
o 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 
one month 
o Consult gastroenterologist 
o If no improvement in > 3–5 days, worsens or rebounds, add non-corticosteroid 
immunosuppressive medication 
o Additional guidance is provided in Table 6 (Section 6.5.2.1.2) 
Additionally, any bempegaldesleukin-related liver function test abnormality that meets the 
following criteria requires discontinuation of bempegaldesleukin: 
• Total bilirubin > 5 × ULN 
• Concurrent AST or ALT > 3 × ULN and total bilirubin > 2 × ULN 


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6.5.1.1.3 
Immune-Related Adverse Events and Cytokine-Mediated Toxicity: 
Monitoring and Management 
Management algorithms for immune-related AEs (irAEs, which are also referred to as 
immune-mediated AEs [imAEs] in this document) are provided in Section 6.5.2.1.2. 
Cytokine-release syndrome (CRS) is a clinical diagnosis presenting usually with a constellation 
of symptoms often characterized by but not limited to, persistent fever, hypotension, dyspnea 
associated with or without tachypnea, headache, tachycardia, and rash caused by the release of 
cytokines. End organ dysfunction with varied manifestation can be seen in CRS as well. Many of 
these symptoms overlap with known AEs seen in bempegaldesleukin and checkpoint inhibitors 
combination therapy (ie, pyrexia and hypotension). These symptoms may be seen in infusion 
reactions as well as other known syndromes, such as tumor lysis syndrome and macrophage 
activation syndrome. Note: 
• For suspected, serious AE of CRS of Grade ≥ 3, the Investigator is required to contact the 
Sponsor. 
• For patients in Arm A receiving bempegaldesleukin:  an algorithm for the management of 
CRS is provided Appendix 6. 
6.5.1.1.4 
Monitoring and Management of Bempegaldesleukin-Induced Eosinophilia 
for Patients in Arm A Receiving Bempegaldesleukin: 
Frequent and significant eosinophilia has been observed in patients receiving 
bempegaldesleukin, primarily starting at Cycle 2 or later, consistent with the known biological 
effect of IL-2 therapy. Clinical data analysis demonstrated that frequency of selected AEs 
(primarily Grade 1 or 2 in severity) such as rash, pruritus, edema, nausea, vomiting, diarrhea, and 
dizziness increased with level of eosinophilia. Isolated cases of hypereosinophilic syndrome and 
other eosinophilic disorders have been reported. 
For patients in Arm A receiving bempegaldesleukin:  absolute eosinophil count should be closely 
monitored per protocol. If a study patient is suspected to have eosinophilic disorder (symptoms 
may involve skin, lungs, digestive tract, heart, blood, or nervous systems) with absolute 
eosinophil count at or above 5000/µL (5 × 109/L) level, bempegaldesleukin treatment may need 
to be withheld, and the patient should be treated as clinically indicated (Table 4). 
Table 4: 
Management of Bempegaldesleukin-Induced Eosinophilia For 
Patients in Arm A Receiving Bempegaldesleukin 
Event 
 
Absolute Eosinophil Value 
Symptomatic?a 
Clinical Management 
≥ 5000/µL (5 × 109/L) 
Yes 
Bempegaldesleukin may need to be withheld; treat 
patient symptoms as clinically indicated. 
a. 
Symptoms may involve skin, lungs, digestive tract, heart, blood, and nervous systems. 


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6.5.1.2 
Bempegaldesleukin Dose Delay and Reduction Criteria 
Dose delays and one dose reduction are permitted for bempegaldesleukin. Bempegaldesleukin 
may be delayed or reduced to 0.003 mg/kg based on observed drug-related toxicities. Medical 
Monitor consultation is required for dose reduction. For patients who have a dose reduction to 
0.003 mg/kg:  if the toxicity requiring dose reduction has resolved, bempegaldesleukin 
0.006 mg/kg may be reinstated after a careful risk assessment. 
Bempegaldesleukin may be delayed or reduced for the following reasons: 
• For infusion reactions, refer to Section 6.5.2.1.1. 
• For irAEs, refer to Section 6.5.2.1.2. 
• Grade ≥ 2 creatinine increase: 
o For patients who must delay study treatment due to Grade ≥ 2 creatinine increase due to a 
non-inflammatory cause, delay retreatment with study drug for approximately 3 to 
5 days. After the dosing delay, the patient may resume study drug when serum creatinine 
has returned to Grade ≤ 1, as assessed within 24 hours prior to redosing (or as soon as 
locally feasible, except where permanent discontinuation of study drug is required [see 
Section 6.5.1.3]).  
• Grade ≥ 3 toxicity at least possibly related to bempegaldesleukin:  bempegaldesleukin must 
be delayed until resolution to Grade 1 or baseline (unless otherwise requiring permanent 
discontinuation per Section 6.5.1.3), patients with the following laboratory values can 
continue study drug: 
o Grade ≥ 3 lymphopenia  
o Grade ≥ 3 asymptomatic amylase or lipase elevation 
• Patient has acute infection (eg, fever, upper or lower respiratory tract infection) requiring 
systemic antibiotic therapy. Patient may resume study treatment once free of signs or 
symptoms for 72 hours after completion of antibiotic therapy. 
• For eosinophilia, refer to Section 6.5.1.1.4. 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, warrants delaying the dose of study medication. 
Bempegaldesleukin dosing may resume at the same bempegaldesleukin dose or at the lower 
bempegaldesleukin dose level when toxicity resolves to Grade ≤ 1 or returns to baseline, except 
for instances where the potential recurrence of the event poses an undue risk for the patient. 
6.5.1.3 
Bempegaldesleukin Discontinuation Criteria 
For toxicities requiring discontinuation of treatment with bempegaldesleukin, pembrolizumab 
alone may continue as a monotherapy if the toxicity is considered by the Investigator to be not 
related to pembrolizumab. 


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For CVA events and suspected TIA events, follow the criteria described below (additional details 
are provided in the CVA management algorithm in Appendix 2). 
Bempegaldesleukin treatment should be permanently discontinued for the following: 
• For infusion reactions, in accordance with the criteria in Section 6.5.2.1.1. 
• For irAEs, in accordance with the criteria in Section 6.5.2.1.2. 
• For any Grade 4 drug-related AE or clinically significant laboratory abnormality, with the 
exception of the following events, which do not require discontinuation: 
o Grade 4 neutropenia ≤ 7 days. 
o Grade 4 lymphopenia or leukopenia ≤ 14 days in duration. 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis and decrease to Grade < 4 or return to baseline 
within 7 days. 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset. 
• Any AE, laboratory abnormality, or intercurrent illness that, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued treatment. 
• Any new CVA event confirmed by imaging (diffusion-weighted imaging [DWI] MRI 
preferred unless otherwise contraindicated) regardless of neurological symptoms 
(eg, cryptogenic CVA) and for a suspected TIA event without clear alternative etiology 
(see Appendix 2). 
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. 
6.5.2 
Pembrolizumab 
6.5.2.1 
Dose Modification (Withhold, Treat, Discontinue) and Toxicity Management for 
Specific Adverse Events  
6.5.2.1.1 
Infusion Reactions  
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion 
reactions are provided in Table 5. 
These guidelines apply to patients receiving bempegaldesleukin in combination with 
pembrolizumab OR either pembrolizumab or bempegaldesleukin treatment as a 


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monotherapy. For toxicities requiring treatment discontinuation, bempegaldesleukin or 
pembrolizumab alone may continue as a monotherapy if the toxicity is considered not related to 
that study drug by the Investigator. 
Table 5: 
Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
Pembrolizumab monotherapy: None 
Bempegaldesleukin alone or in 
combination with pembrolizumab:   
Patient may be premedicated 1.5 hours 
(± 30 minutes) prior to infusion of study 
intervention with: 
• 
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine). 
• 
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic). 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 hours 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the 
original infusion rate (eg, from 100 
mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the patient should be 
premedicated for the next scheduled 
dose. 
Patients who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention. 
Patient may be premedicated 1.5 hours 
(± 30 minutes) prior to infusion of study 
intervention with: 
• 
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine). 
• 
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic). 


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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
Hospitalization may be indicated. 
** In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Patient is permanently discontinued 
from further study drug intervention. 
No subsequent dosing 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National 
Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 


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6.5.2.1.2 
Immune-related AEs Associated with Pembrolizumab  
AEs associated with pembrolizumab exposure may represent an immune-related response. These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications. Based on existing 
clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation.  
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 6. These guidelines apply to patients receiving 
bempegaldesleukin in combination with pembrolizumab OR either treatment as a 
monotherapy. 
For toxicities requiring treatment discontinuation, bempegaldesleukin or pembrolizumab alone 
may continue as a monotherapy if the toxicity is considered not related to that study drug by the 
Investigator. 
For patients in Arm A receiving bempegaldesleukin, elevations of AST or ALT occurring in 
Cycle 1 should be managed according to the guidelines in Section 6.5.1.1.2. For elevations of 
AST or ALT occurring in Cycle 2 or beyond, follow the dose modification and toxicity 
management guidelines in Table 6. 
 


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Table 6: 
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Study 
Treatment 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids. 
2. Study treatment must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤ 10 mg/day within 12 weeks of the last 
treatment. 
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study treatment has been withheld, treatment may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action with Study 
Treatment  
Corticosteroid and/or Other 
Therapies  
Monitoring and Follow-Up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1 - 2 mg/kg prednisone or 
equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
• Monitor patients for signs and 
symptoms of pneumonitis 
• Evaluate patients with suspected 
pneumonitis with radiographic 
imaging and initiate 
corticosteroid treatment 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 


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irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action with Study 
Treatment  
Corticosteroid and/or Other 
Therapies  
Monitoring and Follow-Up  
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1 - 2 mg/kg prednisone or 
equivalent) followed by taper 
• Monitor patients for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus) 
• Patients with ≥Grade 2 diarrhea 
suspecting colitis should consider 
GI consultation and performing 
endoscopy to rule out colitis 
• Patients with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion 
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 
AST or ALT elevation 
or Increased Bilirubinf 
Grade 2 a 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5 - 1 mg/kg prednisone or 
equivalent) followed by taper 
• Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1 - 2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes mellitus 
(T1DM) or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia associated 
with evidence of b-cell 
failure 
Withhold d 
• Initiate insulin replacement therapy 
for patients with T1DM 
• Administer anti-hyperglycemic in 
patients with hyperglycemia 
• Monitor patients for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated 
• Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 


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irAEs 
Toxicity Grade 
(CTCAE v5.0) 
Action with Study 
Treatment  
Corticosteroid and/or Other 
Therapies  
Monitoring and Follow-Up  
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
• Monitor for signs and symptoms 
of thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care 
• Monitor for signs and symptoms 
of thyroid disorders 
Nephritis: 
grading according to 
increased creatinine or 
acute kidney injury 
Grade 2 
Withhold 
• Administer corticosteroids 
(prednisone 1 – 2 mg/kg or 
equivalent) followed by taper 
• Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological toxicities 
Grade 2 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 2, 3, 4 
Permanently 
discontinue 
Exfoliative 
dermatologic conditions 
Suspected SJS, TEN, or 
DRESS 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Confirmed SJS, TEN, or 
DRESS 
Permanently 
discontinue 
All other 
immune-related AEs 
Persistent Grade 2 
Withhold 
• Based on severity of AE administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based on 
the event e  
Recurrent Grade 3 or 
Grade 4  
Permanently 
discontinue 
Abbreviations: AE(s) = adverse event(s); ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for 
Adverse Events; DRESS = drug reaction with eosinophilia and systemic symptoms; GI = gastrointestinal; irAE = immune-related adverse event(s); 
IV = intravenous; SJS = Stevens-Johnson Syndrome; T1DM = type 1 diabetes mellitus; TEN = toxic epidermal necrolysis; ULN = upper limit of normal 


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Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a. 
AST/ALT: > 3.0 - 5.0  ULN if baseline normal; > 3.0 - 5.0  baseline, if baseline abnormal;  
bilirubin:>  1.5 - 3.0  ULN if baseline normal; > 1.5 - 3.0  baseline if baseline abnormal 
b. AST/ALT: > 5.0 to 20.0  ULN, if baseline normal; > 5.0 - 20.0  baseline, if baseline abnormal;  
bilirubin:>  3.0 - 10.0  ULN if baseline normal; > 3.0 - 10.0 x baseline if baseline abnormal 
c. 
AST/ALT: > 20.0  ULN, if baseline normal; > 20.0  baseline, if baseline abnormal;  
bilirubin: >10.0  ULN if baseline normal; > 10.0  baseline if baseline abnormal 
d. The decision to withhold or permanently discontinue study treatment is at the discretion of the investigator or treating physician. If control achieved or 
≤ Grade 2, study treatment may be resumed. 
e. 
Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis, sclerosing cholangitis). 
f. 
For patients in Arm A receiving bempegaldesleukin in Cycle 1, consult the guidelines in Section 6.5.1.1.2. 
 


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6.5.2.1.3 
Elevated Transaminases With Treated HBV or HCV 
Patients who were treated for HBV or HCV, enrolled in the study, and present with elevated 
transaminases according to the criteria below should be evaluated for viral hepatitis 
exacerbation/reactivation. 
• If baseline AST/ALT < 2  ULN and increase of AST/ALT ≥ 5  ULN 
• If baseline AST/ALT ≥ 2  ULN and increase of AST/ALT > 3  baseline level 
• AST/ALT > 500 U/L regardless of baseline 
Viral load testing and additional hepatitis serologies should be included as required. 
6.5.3 
Other Allowed Dose Interruptions 
Bempegaldesleukin and/or pembrolizumab may be interrupted for situations other than 
treatment-related AEs such as medical or surgical events and/or unforeseen circumstances not 
related to study intervention. However, study intervention is to be restarted within 3 weeks 
(21 days) of the originally scheduled dose and within 42 days of the previously administered 
dose, unless otherwise discussed with the Medical Monitor. The reason for study intervention 
interruption is to be documented in the patient's study record. 
6.6 
Discontinuation Criteria 
Study treatment must be permanently discontinued but patients will continue to be monitored in 
the study for any of the following reasons: 
• Patient’s request to stop study treatment. Patients who request to discontinue study treatment 
will remain in the study and must continue to be followed for protocol specified follow-up 
procedures. The only exception to this is when a patient specifically withdraws consent for 
further assessments or contact with him/her or persons previously authorized by patient to 
provide this information. 
• Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion of the 
Investigator, indicates that continued participation in the study is not in the best interest of 
the patient. 
• Any study treatment-related toxicity specified as a reason for permanent discontinuation as 
defined in the study treatment discontinuation criteria specific to bempegaldesleukin in 
Section 6.5.1.3 and in the guidelines for dose modification due to AEs in Section 6.5.2.1. 
• Termination of the study by the Sponsor. 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note:  Under 
specific circumstances, a patient who has been imprisoned may be permitted to continue as a 
patient. Strict conditions apply and Sponsor approval is required.) 


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• Disease progression in the absence of clinical benefit as determined by the Investigator (see 
Section 6.2.5 for information regarding treatment beyond progression). 
• Occurrence of a clinically significant AE found to be unacceptable or nonresolution of a 
clinically significant AE for > 8 weeks. 
• Symptomatic deterioration in the absence of tumor progression per RECIST 1.1. 
• Noncompliance of the patient with protocol-mandated procedures based on the judgment and 
agreement of both the Investigator and Sponsor. 
• Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.5, require Sponsor 
consultation prior to restarting treatment. If treatment will not be restarted, the patient will 
continue to be monitored in the study and the reason for discontinuation of study intervention 
will be recorded in the medical record. 
• The patient has a medical condition or personal circumstance which, in the opinion of the 
Investigator and/or Sponsor, places the patient at unnecessary risk from continued 
administration of study intervention. 
• Patient is lost to follow-up (as defined in Section 6.2.7). 
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs).  
Patients may choose to discontinue the study at any time, for any reason, and without prejudice 
to further treatment. 
In the event of a patient’s withdrawal, the Investigator will make every effort to complete the 
post-treatment assessments specified in the Schedule of Events (Section 1.2). If a patient has not 
progressed following discontinuation of study drug(s), every effort should be made to continue to 
obtain radiographic tumor assessments (until the patient has documented progression as per the 
BICR). 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately and the Investigator must notify the Sponsor within 24 hours of awareness of the 
pregnancy. Refer to Section 10.16 (Pregnancy). 
All patients who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 1.2. The only exception to this requirement is when a patient 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness). 
If study treatment is discontinued prior to the patient’s completion of the study, the reason for the 
discontinuation must be documented in the patient’s medical records and entered on the 
appropriate case report form (CRF) page. 


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6.7 
Prior and Concomitant Medications/Procedures 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter products, herbal supplements, and IV 
medications, and fluids. If changes occur during the study period, documentation of drug dosage, 
frequency, route, and date should also be included on the eCRF. 
All concomitant medications received within 28 days prior to the first dose of study drug and up 
to 30 days after the last dose of study drug (Follow-Up Visit 1) will be documented and 
recorded. In addition: 
• Prior cancer treatments, including previous immunotherapy, chemotherapy, targeted therapy, 
radiation, over-the-counter (OTC) medications, herbs, and dietary supplements will be 
recorded. 
• Any COVID-19 vaccinations administered to patients prior to signing the ICF and during the 
treatment phase should be captured in the eCRF per the eCRF completion guidelines.  
• All concomitant medications administered during SAEs (defined in Section 10.6), AESIs 
(defined in Section 10.12), or Events of Clinical Interest (ECIs; defined in Section 10.14) are 
to be recorded. 
6.7.1 
Premedication 
If a patient reports symptoms (such as nausea and/or vomiting), prophylactic use of anti-emetics 
may be used.  
If a patient experiences a Grade 1 or 2 infusion reaction during any infusions with 
bempegaldesleukin or pembrolizumab, prophylactic premedications may be administered for 
subsequent infusions (see Section 6.5.2.1.1 for further details on management and prevention of 
infusion reactions). 
Please refer to Section 6.7.3.2 for additional recommendations regarding infusion reaction 
prophylaxis. 
For patients in Arm A receiving bempegaldesleukin:  refer to Section 6.2.3.2 for hydration 
guidance. 
6.7.1.1 
Premedications for Flu-Like Symptoms Associated with Bempegaldesleukin 
For patients in Arm A receiving bempegaldesleukin, prophylaxis for flu-like symptoms with 
either acetaminophen or NSAIDs is permitted on study per the Investigator’s discretion. 
Prophylaxis for flu-like symptoms should be initiated on either Day 1 or Day 2 of the dosing 
cycle and may continue through Day 5 or longer as needed. These premedications do not apply 
to patients receiving pembrolizumab monotherapy. 


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6.7.2 
Prohibited and/or Restricted Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
Investigator is to discuss prohibited medication/vaccination with the Medical Monitor. The final 
decision on any supportive therapy or vaccination rests with the Investigator and/or the patient’s 
primary physician. However, the decision to continue the patient on study intervention requires 
the mutual agreement of the Investigator, the Sponsor, and the patient. 
6.7.2.1 
Prohibited Medications 
Patients are prohibited from receiving the following therapies during the screening and treatment 
periods of this study: 
• Immunosuppressive agents or immunotherapy not specified in this protocol. 
• Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.7.3.1) 
defined as a daily dose of > 10 mg prednisone equivalents. 
• Radiation for disease control. 
Note: Palliative radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the Investigator’s discretion. 
• Antineoplastic systemic chemotherapy or biological therapy is prohibited during the study. 
• Investigational agents other than pembrolizumab or bempegaldesleukin. 
• Live or attenuated vaccines 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 severe acute respiratory syndrome coronavirus 2 
 
 
(SARS-CoV-2; coronavirus virus disease 2019 [COVID-19]). 
• Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study. Use of marijuana and its derivatives for treatment of 
symptoms related to cancer or cancer treatment are permitted if obtained by medical 
prescription or if its use (even without a medical prescription) has been legalized locally. 
In addition, prohibited medications listed in the current pembrolizumab prescribing information 
are not allowed. If the Investigator determines that a patient requires any of the aforementioned 
treatments for any reason, all study intervention must be discontinued. 


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6.7.2.2 
Blood Pressure Medications for Patients Receiving Bempegaldesleukin 
For patients in Arm A receiving bempegaldesleukin: 
• Consideration should be given to withholding antihypertensive medications including 
diuretics, as well as other drugs with hypotensive properties (eg, alpha blockers for benign 
prostatic hyperplasia), particularly when therapy involves multiple antihypertensive drugs 
and classes other than thiazide diuretics. If withholding antihypertensive medications, 
withhold no less than 12 hours and no more than 48 hours prior to each dose of 
bempegaldesleukin. 
• Patients who are receiving medications with antihypertensive effects for the treatment of 
coronary artery disease (eg, β-blockers, calcium channel blockers, nitrates, etc.) should be 
able to withhold these drugs prior to initiation of treatment at the Investigator’s discretion. 
• Antihypertensive medications may be reinstituted in between doses of bempegaldesleukin at 
any time as clinically indicated (eg, based on blood pressure monitoring results). 
• For patients receiving β-blockers, consider a step-wise tapering of doses before initiation of 
bempegaldesleukin to avoid reflex tachycardia. If Grade ≥ 2 hypertension is observed in any 
cycle, patients should be monitored more frequently (at least weekly) until a new stable 
antihypertensive regimen is identified. Patients may be monitored more frequently at the 
discretion of the Investigator as clinically warranted. 
6.7.3 
Permitted Concomitant Medications 
6.7.3.1 
Steroids 
Systemic glucocorticoids are permitted only for the following purposes: 
• To modulate symptoms of an AE that is suspected to have an immunologic etiology 
• As needed for the prevention of emesis 
• Premedication for IV contrast allergies 
• Short-term oral or IV use in doses > 10 mg/day prednisone equivalent for chronic obstructive 
pulmonary disease (COPD) exacerbations 
• For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent 
In addition, the following glucocorticoid use is allowed: 
• For topical use or ocular use 
• Intraarticular joint use 
• For inhalation in the management of asthma or chronic obstructive pulmonary disease 
Patients with pre-existing adrenal impairment requiring corticosteroid supplementation may be at 
increased risk for hypotensive episodes during treatment with bempegaldesleukin and may 


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require co-management with an endocrinologist. For these patients, their existing corticosteroid 
dose may be increased to adrenal replacement steroid doses > 10 mg of daily prednisone or 
equivalents for the first 4 days after administration of bempegaldesleukin based on an assessment 
of the degree of adrenal impairment and the extent of existing corticosteroid supplementation.  
A brief (less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or 
for treatment of nonautoimmune conditions (eg, pneumonia, delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted. Use of corticosteroids for the management of 
immune-related AEs as outlined in Section 6.5.2.1.2 is permitted. Short-term use of systemic 
corticosteroids or immunosuppressive medication is permitted if administered for AE treatment.  
6.7.3.2 
Prophylaxis 
Prophylaxis for flu-like symptoms and rash and/or pruritus can be initiated on either Day 1 or 2 
of the dosing cycle and may continue through Day 5 or longer as needed at the discretion of the 
Investigator as follows for: 
• Flu-like symptoms:  prophylactic use of either acetaminophen (paracetamol) or non-steroidal 
anti-inflammatory agents (eg, ibuprofen) is permitted. 
• Rash and/or pruritus:  prophylactic use of antihistamines is permitted. 
As appropriate, additional treatment measures may be provided based on local treatment 
standards and guidelines (see Section 6.5.2.1.1). 
Prophylactic use of antibiotics is also permitted for signs of potential asymptomatic urinary tract 
infection. 
6.7.3.3 
Thromboembolism Prophylaxis and Treatment for Patients Receiving 
Bempegaldesleukin 
Patients in Arm A receiving bempegaldesleukin with a history of a venous or arterial 
thromboembolic event must be receiving a stable regimen of therapeutic anticoagulation 
(preferably LMWH or DOAC). Unless there is a new medical contraindication observed after 
Cycle 1 Day 1, a patient with a history of venous or arterial thromboembolic event must be 
maintained on therapeutic anticoagulation throughout the patient’s time on study treatment (ie, 
through discontinuation of all study drug[s]). 
• 
Use of warfarin is permitted; however, therapeutic dosing should target a specific 
international normalized ratio (INR) stable for at least 4 weeks prior to enrollment. 
Because bempegaldesleukin has the potential to downregulate metabolizing enzymes for 
warfarin for approximately 1 week after administration of each dose of 
bempegaldesleukin, frequent monitoring of INR especially during the first 7 days after 
bempegaldesleukin administration and ongoing consideration of warfarin dose 
adjustments are warranted for all patients receiving bempegaldesleukin throughout the 
patient’s participation in the study. 


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6.7.3.4 
Rescue Medications, Palliative and Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator. Suggested supportive care measures for the management of infusion-related AEs 
and AEs with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 6.5.2.1.1 and Section 6.5.2.1.2. 
Concomitant palliative and supportive care for disease-related symptoms (including 
bisphosphonates and RANK-L inhibitors for osteoporosis) is allowed. 
6.7.4 
Effect of Bempegaldesleukin on the PK of Concomitant Medications 
Clinical drug interaction studies with bempegaldesleukin have not been performed. 
Bempegaldesleukin may have the potential to affect the clearance of co-administered drugs 
based on its ability to modulate cytokines. Bempegaldesleukin causes increases in circulating 
cytokines typical of those associated with an acute inflammatory response to infection or tissue 
injury. The increases in inflammatory cytokines induced by bempegaldesleukin are generally 
moderate, persist for about one week after bempegaldesleukin dosing, and return to baseline 
levels prior to the next dose. Several of these cytokines (IFN-γ, IL-6, IL-10, etc.) have the 
potential to decrease the activity of multiple enzymes and drug transporters, and the suppressive 
effects can be additive (Haas 2005; Zidek 2009). Similar to changes that occur during a typical 
inflammatory response, bempegaldesleukin may lead to downregulation of drug metabolizing 
enzymes, such as cytochrome P450 (CYP) enzymes, hepatic flavin monooxygenases, 
uridine 5'-diphospho–glucuronosyltransferases (UDP-glucuronosyltransferases), 
sulfotransferases, and glutathione S-transferases. Consequently, treatment with 
bempegaldesleukin may lead to temporary decrease in clearance of drugs that are substrates of 
drug metabolizing enzymes, or drug transporters. Investigators should carefully monitor for 
occurrence of adverse effects in patients receiving drugs with narrow therapeutic indices or drugs 
that are sensitive substrates of drug metabolizing enzymes or drug transporters, and adjust the 
dose of these drugs as clinically indicated. 
6.7.4.1 
Interaction of Bempegaldesleukin and Warfarin 
Bempegaldesleukin has the potential to down‑regulate metabolizing enzymes for warfarin for 
approximately 1 week after administration of each dose of bempegaldesleukin. See 
Section 6.7.3.3 for guidelines on monitoring of INR in patients using warfarin. 
6.8 
Adverse Events 
For reporting of AEs, see Section 10.5. 
For reporting of SAEs, see Section 10.7. 






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The Drug Accountability Log may record specifics to study drug (ie, bempegaldesleukin or 
pembrolizumab) dispensation such as: 
• Records of product delivery, inventory, temperature monitoring, destruction, and return as 
per Sponsor’s instructions. 
• Doses 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. 


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8.0 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
Tumor Imaging and Assessment of Disease 
Tumor assessments for all patients will be performed as specified in Section 1.2. 
Tumor response will be evaluated using RECIST 1.1 described in Section 9.1. 
The process for image collection and transmission to the central vendor can be found in the Site 
Imaging Manual. Tumor imaging may be performed by computed tomography (CT) (preferred) 
or magnetic resonance imaging (MRI), but the same imaging technique should be used in a 
patient throughout the trial. CT scan is the more commonly used modality and is preferred for 
the majority of patients. An MRI can be utilized if clinically appropriate. 
Imaging should include the head, neck, chest, and abdomen at all time points specified in 
Section 1.2. Imaging of the pelvis is optional unless clinically indicated. A CT from the vertex of 
the head to the thoracic inlet or a brain CT is strongly preferred. For an individual patient, 
imaging should be consistent at all time points (ie, follow-up scans should image the same areas 
as the baseline area, using the same imaging modality). 
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1 will be 
used to determine patient eligibility. Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, a maximum of 10 target lesions in total and 5 per organ are 
allowed. All scheduled images for all study patients from the sites will be submitted to the 
central imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at an unscheduled time point to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the central 
imaging vendor as well. 
The central imaging vendor will receive radiologic images for a retrospective analysis of patient 
baseline disease and treatment response. In addition, radiologic progression will be based on the 
independent central assessment of progression, rather than site assessment. The central imaging 
vendor will verify progressive disease (PD) following first radiologic evidence of PD assessed 
by the local site investigator. Verification of radiologic progression applies to both treatment 
arms. Expedited verification of radiologic progression as determined by central review 
(following site assessment of progression) will be communicated to the site (see Section 8.1.3). 
8.1.1 
Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days prior to the date of randomization. The 
site study team must review pre-trial images to confirm the patient has measurable disease per 
RECIST 1.1. 


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Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days prior to the date of 
randomization. 
8.1.2 
Tumor Imaging During the Study 
Imaging should be performed every 6 weeks (42 days ± 7 days) from the date of randomization 
or more frequently if clinically indicated. One year after randomization, patients who remain on 
treatment will have imaging performed every 9 weeks (± 14 days). This imaging schedule should 
be maintained regardless of treatment delays or other changes in treatment schedule. 
The scan for confirmation of partial response or complete response may be performed at the 
earliest 4 weeks after the date the response was first documented, or at the next scheduled scan 
(ie, 6 weeks later), whichever is clinically indicated. Imaging should then return to the original 
schedule beginning with the next protocol-specified time point. 
Patients who obtain a confirmation scan at 4 weeks do not need to undergo the next scheduled 
imaging assessment if it is due < 4 weeks later; imaging may resume at the subsequent scheduled 
time point. 
Continue to perform imaging until whichever of the following occurs first: 
• Initial site-assessed disease progression is verified by the central imaging vendor.  
• The start of new anticancer treatment 
• Withdrawal of consent 
• Death 
• The end of the study 
Note:  If the site-assessed disease progression is verified by the central imaging vendor, it is the 
discretion of the Investigator to continue to treat the patient (see Section 6.2.5) and follow the 
regular imaging schedule intervals until progression is confirmed provided the patient meets the 
conditions detailed in Section 8.1.3. 
8.1.3 
Assessment of Disease 
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (eg, discontinuation of study therapy). Scans showing 
site-assessed progressive disease should be submitted to the central imaging vendor immediately. 
The site will be notified if the imaging vendor verifies disease progression using RECIST 1.1. 
Section 6.3.1 provides additional information about the Follow-up Visits. 


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8.2 
Pharmacokinetic and Immunogenicity Measurements 
Pharmacokinetic (PK) and immunogenicity (IMG) assessment data will be collected from study 
patients randomized to Arm A (bempegaldesleukin plus pembrolizumab) depending on the Phase 
of the study as follows: 
• See Table 8 for patients randomized in the Phase 2 portion of the study. 
• See Table 9 for patients randomized in the Phase 3 portion of the study. 
All time points are relative to the start of each study drug administration, unless indicated 
otherwise. All on-treatment time points are intended to align with days on which study drug is 
administered; if dosing occurs on a different day, the PK and IMG 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. All predose samples should be collected within 24 hours 
before the start of any dose infusion. 
Further details of sample collection, processing, and shipment will be provided in the Laboratory 
Manual. 
Serum PK samples will be analyzed for pembrolizumab by a validated ligand binding assay. 
Plasma PK samples will be analyzed for NKTR-214 related molecules with a validated or 
qualified ligand-binding assay. 
Validated methods will be used to detect anti-drug antibodies (ADA) as determined by 
measurements of anti-pembrolizumab, anti-bempegaldesleukin, and anti-IL-2 in the 
immunogenicity samples. Immunogenicity sample testing will be done in tiers as per the 2019 
FDA guidance (FDA 2019). Samples will be first tested with screening 
electrochemiluminescence assays (ECLA). Putative positive samples for anti-pembrolizumab, 
anti-bempegaldesleukin, or anti-IL-2 ADA will then be analyzed in a competition ECLA to 
confirm positivity. Confirmed anti-bempegaldesleukin ADA positive samples will be tested 
further in a PEG immuno-competition assay to determine the antibody specificity of the 
reactivity to the PEG or non-PEG (IL-2, linker) moiety of bempegaldesleukin. Confirmed 
positive samples from anti-pembrolizumab, anti-bempegaldesleukin and anti-IL-2 ADA assays 
will then be tested to obtain a titer. Samples confirmed to be positive for anti-pembrolizumab, 
anti-bempegaldesleukin and anti-IL-2 ADA may also be tested for neutralizing activity for IL-2 
and pembrolizumab using validated cell-based assays. 
Blood samples designated for assessments (eg, immunogenicity, PK) from the same collection 
time point may be used interchangeably for analyses, if required (eg, insufficient volume for 
complete assessment, to follow-up on suspected immunogenicity related AE, etc.). Blood 
samples or plasma isolated from blood samples for assessments (eg, immunogenicity, PK) may 
be assessed by ELISA, seromics, microRNA profiling, metabolomics and/or other relevant 
multiplex-based protein assay methods for immune-related factors that may predict for 
pembrolizumab and/or bempegaldesleukin benefit or AEs; 
 


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Additionally, residual blood samples will be archived and may be used for potential exploratory 
analysis (eg, analysis of ADA immune complexes, exploratory PK) and/or for additional method 
purposes (eg, cross-validation, ADA/PK selectivity, cut point etc.). 
For all PK blood samples, the date and actual time collected must be recorded. For patients 
whose only peripheral access is via a venous access device or peripherally inserted central 
catheter, refer to the Laboratory Manual for the proper technique to ensure undiluted whole 
blood for PK assessments. 
Table 8: 
Phase 2 Portion of the Study: Pharmacokinetic and Immunogenicity 
Sampling (for Arm A [Bempegaldesleukin plus Pembrolizumab]) 
Study Day of Sample Collection 
(1 Cycle = every 3 weeks) 
Event 
Time (relative to start 
of bempegaldesleukin 
infusion) Hour:Min 
Bempegaldesleukin 
Blood Sample 
Pembrolizumab 
Blood Sample 
PKd 
IMG 
PK 
IMG 
Cycle 1 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
EOIb 
00:30b 
X 
 
 
 
Cycle 1 Day 3c 
 
48:00c 
X 
 
 
 
Day 1 of Cycles 2, 5, 8, 11, 17, 
25, and 33 
Predosea 
00:00 
X 
X 
X 
X 
Follow Up Visit 1, 30 (± 7) days 
from last dose of all study drugs 
 
 
X 
X 
X 
X 
Follow Up Visit 2, 
90 (± 7) days from last dose of all 
study drugs 
 
 
X 
X 
X 
X 
Abbreviations:  EOI = end of infusion; IMG = immunogenicity; PK = pharmacokinetic 
a. 
Predose samples should be collected within 24 hours before the start of any dose infusion.  
b.  The end of infusion sample should be taken up to 30 minutes after the end of the bempegaldesleukin infusion. 
End of infusion samples may not be collected from the same IV access as drug was administered. If the end of 
infusion is delayed to beyond the nominal infusion duration, the collection of this sample should also be delayed 
accordingly. 
c.  Time window for Day 3 is −1 day (ie, 24 to 48 hours from the start of bempegaldesleukin infusion).  
d.  The bempegaldesleukin PK blood samples may also be used for assessing inflammatory cytokines and 
chemokines (see Section 8.2 for more details). 
 


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Table 9: 
Phase 3 Portion of the Study: Pharmacokinetic and Immunogenicity 
Sampling (for Arm A [Bempegaldesleukin plus Pembrolizumab]) 
Study Day of Sample Collection 
(1 Cycle = every 3 weeks) 
Event 
Time (relative to start 
of bempegaldesleukin 
infusion) Hour:Min 
Bempegaldesleukin 
Blood Sample 
Pembrolizumab 
Blood Sample 
PKe 
IMG 
PK 
IMG 
Cycle 1 Day 1 
Predosea 
00:00 
X 
X 
X 
X 
EOIb 
00:30b 
X 
 
 
 
Cycle 1 Day 3c 
 
48:00c 
X 
 
 
 
Cycle 1 Day 5d 
 
96:00d 
X 
 
 
 
Day 1 of Cycles 2, 5, 8, 11, 17, 
25, and 33 
Predosea 
00:00 
X 
X 
X 
X 
Follow Up Visit 1, 30 (± 7) days 
from last dose of all study drugs 
 
 
X 
X 
X 
X 
Follow Up Visit 2, 
90 (± 7) days from last dose of all 
study drugs 
 
 
X 
X 
X 
X 
Abbreviations:  EOI = end of infusion; IMG = immunogenicity; PK = pharmacokinetic 
a. 
Predose samples should be collected within 24 hours before the start of any dose infusion.  
b.  The end of infusion sample should be taken up to 30 minutes after the end of the bempegaldesleukin infusion. 
End of infusion samples may not be collected from the same IV access as drug was administered. If the end of 
infusion is delayed to beyond the nominal infusion duration, the collection of this sample should also be delayed 
accordingly.  
c.  Time window for Day 3 is −1 day (ie, 24 to 48 hours from the start of bempegaldesleukin infusion).  
d.  Time window for Day 5 samples is ± 1 day (ie, 72 to 120 hours from the start of bempegaldesleukin infusion).  
e.  The bempegaldesleukin PK blood samples may also be used for assessing inflammatory cytokines and 
chemokines (see Section 8.2 for more details). 
 
 
 
 
 
 
 


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Table 10: 
Tumor Tissue 
 
Study Day of Sample Collection 
(1 Cycle = every 3 weeks) 
Event 
Tumor Tissue 
Collection 
  
 
Screening 
 
Xa 
 
Cycle 1 Day 1 
Predoseb 
 
 
Cycle 3 Day 1 
Predoseb 
 
 
Cycle 5 Day 1 
Predoseb 
 
  
Follow Up Visit 1,  
30 (± 7) days from last dose of study drug 
 
 
 
 
a. 
See Section 8.3.1. 
b. Predose samples should be collected within 24 hours before the start of any dose infusion.  
 
8.3.1 
Tumor Tissue Collection and Assessments 
All patients must have tumor tissue available to be sent to the central laboratory during the 
Screening period: 
• A newly obtained core, incisional, or excisional biopsy of a tumor lesion that was not 
previously irradiated (recurrent lesions in a previously irradiated area can be biopsied if 
progression has been shown in such lesions since irradiation). 
OR 
• An archival tumor tissue sample from a recurrent lesion with no intervening treatment or 
radiation (recurrent lesions in a previously irradiated area can be biopsied if progression has 
been shown in such lesions since irradiation) between time of acquisition and randomization. 
Newly obtained biopsies are preferred to archived tissue. 
Archival tumor tissue should be provided in a formalin-fixed paraffin-embedded (FFPE) block 
(obtained within 12 months of randomization) or as unstained slides (minimum of 8 slides, 
preferably 15-25 slides) obtained within 4 months (if stored in the dark at room temperature up 
to 25°C) or 6 months (if stored in the dark at 2°C–8°C) of randomization. If 8 unstained slides 
are not available, fewer slides may be submitted; please contact the Medical Monitor for written 
approval. Leftover tissue blocks, but not slides, will be returned upon request. 
Biopsy in bone lesions cannot be accepted. Fine needle aspirates/biopsy or other cytology 
specimens are insufficient. Target lesions should not be biopsied unless there are no other lesions 
suitable for biopsy. 
PD-L1 status will be determined by a local laboratory or the central laboratory. The tissue 
sample will be used to ascertain PD-L1 status using the PD-L1 IHC 22C3 PharmDx diagnostic 


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kit. The PD-L1 IHC 22C3 PharmDx assay kit is currently approved to assess PD-L1 status in 
patients with HNSCC for treatment with pembrolizumab. The 22C3 PharmDx evaluations will 
determine CPS, which is the number of PD-L1 staining cells (tumor cells, lymphocytes, 
macrophages) divided by the total number of viable tumor cells, multiplied by 100. The 
specimen will be considered to have positive PD-L1 expression if CPS ≥ 1. Repeat samples may 
be required if adequate tissue is not provided for assessment of PD-L1 status; additional details 
of sample collection, processing, and shipment will be provided in the Laboratory Manual. 
The PD-L1 result will not be masked to the site. 
 
 
 
 
 
8.3.1.1 
Patients with Oropharyngeal Cancer:  Collection of Tumor Tissue for HPV 
Status 
Patients with oropharynx cancer must have assessment of HPV status from tumor tissue prior to 
randomization. HPV stratification in this trial may be performed using local testing of HPV 
status in patients with oropharynx cancer using the specified method. 
Note:  Tumor p16 expression must be evaluated by assessment of IHC analysis with 
CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using 
‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and standard protocol. Positive p16 
expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or 
more of the tumor cells.  
Note: If local p16 testing results are not available, or cannot be assessed by the specified 
method, a tumor tissue sample may be submitted for p16 testing at the designated central 
laboratory. 
8.3.2 
 
 
 
 




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Further details of sample collection and processing will be provided to the site in the Laboratory 
Manual. 
8.4 
Health-Related Quality of Life (HRQoL) 
The evaluation of patient-reported outcomes in oncology clinical trials is becoming increasingly 
important to understand the benefits and risks of treatment from a patient perspective. Patients 
will be asked to complete the EORTC QLQ-C30, EORTC QLQ-H&N35, and EuroQol EQ-5D 
as outlined in Section 1.2 to assess changes from baseline in patient-reported outcomes, which 
will be affected by both disease progression and treatment tolerability. 
Refer to Section 9.2 for additional information. 


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9.0 
ASSESSMENT OF EFFICACY 
9.1 
Assessment of Tumor Response and Progression 
Response and progression will be determined by blinded independent central review (BICR) 
using RECIST 1.1 (Appendix 4). Screening and follow-up images should be acquired as outlined 
in Section 1.2 (Schedule of Events). 
9.2 
Patient-Reported Outcomes 
Section 1.2 provides the schedule for the health-related quality of life (HRQoL) assessments, 
EORTC QLQ-C30, EORTC QLQ-H&N35, and EuroQol EQ-5D. 
If the patient withdraws from the study prematurely, all attempts should be made to obtain a final 
quality of life questionnaire prior to patient discontinuation. Reasons for missing patient-reported 
outcome questionnaires should also be documented so that the appropriate imputation method 
can be employed to correct for missing data in the analysis.  
The questionnaires will be completed by the patients before any clinical assessments are 
performed and treatments administered at any given visit. It is a best practice and strongly 
recommended that patient-reported outcome (PRO) questionnaires are administered to patients 
prior to drug administration, AE event evaluation, and disease status notification. If patients 
refuse to complete all or any part of a questionnaire, this will be documented. Questionnaires 
should be completed in the language most familiar to each patient, and patients should be given 
adequate time and space to complete the questionnaire. 
The EQ-5D should be completed by patients first before completing the EORTC QLQ-C30 and 
EORTC QLQ-H&N35. 
9.2.1 
EQ-5D 
The EuroQol-5D (EQ-5D) is a standardized instrument for use as a measure of health outcome. 
The EQ-5D will provide data for use in economic models and analyses including developing 
health utilities or quality adjusted life-years (QALYs).  
The 5-level version of the EQ-5D (EQ-5D-5L) (EuroQol Group 1990; Herdman 2011) will be 
used to assess treatment effects on perceived health status and to generate utility data for health 
economic evaluations. The EQ-5D-5L is a generic multi-attribute health-state classification 
system by which health is described in 5 dimensions:  mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension is evaluated using 5 response levels:  
no problems, slight problems, moderate problems, severe problems, and extreme problems. 
Responses to these 5 dimensions are converted into 1 of 3,125 unique EQ-5D health state 
descriptions, which range between no problems on all 5 dimensions (11111) to extreme problems 
on all 5 dimensions (55555). Using appropriate country-specific value weighting algorithms, a 
respondent’s self-described health state can be converted into a utility index representing the 


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societal desirability of his or her own health. In addition, the EQ-5D includes a visual analogue 
scale (VAS) allowing a respondent to rate his/her health on a scale ranging from 0-100 with 0 
being the worst health state imaginable and 100 being the best health state imaginable. 
The EQ-5D-5L uses a recall period of today. 
9.2.2 
EORTC QLQ-C30 and EORTC QLQ-H&N35 
The EORTC QLQ-C30 (Aaronson 1993) is the most commonly used quality of life instrument in 
oncology trials. The EORTC QLQ-C30 is composed of multi-item scales and single item 
measures. These include 5 functional scales (physical, role, emotional, cognitive, and social), 
3 symptom scales (fatigue, nausea/vomiting, and pain), a global health status/HRQoL scale, and 
6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 
difficulties). Each of the multi-item scales includes a different set of items – no item occurs in 
more than one scale. 
The EORTC QLQ-H&N35 is in use worldwide as one of the standard instruments for measuring 
quality of life in head and neck cancer patients (Mehanna 2006; Tschiesner 2008) and consists of 
7 multi-item scales measuring pain in the mouth, problems with swallowing, senses, speech, 
social eating, social contact, and sexuality, and 11 single-item scales assessing problems with 
teeth, mouth opening, dry mouth, sticky saliva, coughing, feeling ill, use of analgesics, use of 
nutritional supplements, use of feeding tube, weight gain, and weight loss (Bjordal 1999; 
Bjordal 1994). The EORTC QLQ-C30 and EORTC QLQ-H&N35 are psychometrically and 
clinically validated instruments appropriate for assessing quality of life in patients with head and 
neck cancer. These instruments were used in the EXTREME registration trial (NCT00122460) 
comparing platin-5-fluorouracil alone versus combined with cetuximab as first-line treatment in 
recurrent or metastatic HNSCC, which led to the FDA approval of cetuximab monotherapy in 
patients with recurrent or metastatic HNSCC refractory to cisplatin (Bjordal 2000; Chera 2014). 
They were also used in the Phase 3 trial of patients with locoregionally advanced head and neck 
cancer receiving radiotherapy alone or radiotherapy plus cetuximab (Tschiesner 2008). 
For the global health status/quality of life and function scales, a higher value indicates a better 
level of function; for symptom scales and items, a higher value indicates increased severity of 
symptoms. Prior literature indicates that head and neck pain and the ability to swallow are 
clinically relevant symptom measures in the recurrent or metastatic HNSCC population 
(Bjordal 2000; Chera 2014; Mesia 2010; Machiels 2014). Thus, time to deterioration in the pain 
and swallowing multi-item scales of the EORTC QLQ-H&N35, in addition to time to 
deterioration and mean change from baseline in global health status/quality of life scale of the 
EORTC QLQ-C30, will be evaluated as secondary objectives. 
Both the EORTC QLQ-C30 and EORTC QLQ-H&N35 use a recall period of the past week. 
 


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10.0 
ASSESSMENT OF SAFETY 
10.1 
AE Definition and Assessment 
An AE is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, at any dose, not necessarily related to the treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. An AE can also arise from any use of the drug and from any route of 
administration, formulation, dose, or overdose. This definition includes intercurrent illnesses or 
injuries, and exacerbation of pre-existing conditions. Clinical laboratory, vital sign, or physical 
examination abnormalities will only be reported as AEs if they are deemed clinically significant 
by the Investigator (eg, associated with signs and symptoms, require treatment, or require 
follow-up).  
Adverse events, SAEs, and other reportable safety events will be reported by the patient (or, 
when appropriate, by a caregiver, surrogate, or the patient’s legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 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. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable 
safety events. Open-ended and nonleading verbal questioning of the patient is the preferred 
method to inquire about AE occurrence. 
For all reports of overdose (whether accidental or intentional) with an associated AE, the AE 
term should reflect the clinical symptoms or abnormal test result. An overdose without any 
associated clinical symptoms or abnormal laboratory results is reported using the terminology 
“accidental or intentional overdose without adverse effect.” 
An AE does not include: 
• A medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, or transfusion); an 
AE is the underlying condition that leads to the procedure. 
• Pre-existing diseases or conditions present or detected before start of study drug(s) 
administration that do not worsen or increase in severity or frequency after the administration 
of study drug(s). 
• Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery for a condition that has not worsened on study, social and/or convenience 
admissions to grant families a respite in caring for a patient). 


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• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
• Surgical procedure(s) planned prior to informed consent to treat a pre-existing condition that 
has not worsened. 
10.2 
Monitoring AEs 
All AEs will be assessed by the Investigator and recorded, including but not limited to, the 
following:  the event term, the date of onset and resolution, seriousness, severity, relationship to 
study drug(s), outcome, treatment of the event, and action taken with the study drug(s). AEs will 
be reported starting immediately after the patient has been administered the first dose of study 
drug(s) until 30 days after the last dose of study drug(s). For serious AEs (SAEs), additional 
reporting requirements also apply (see Section 10.7). 
An event occurring after the patient has provided informed consent, but before the first dose of 
study treatment or confirmed screen failure, will be collected as medical history unless the event 
is either new and attributed to protocol-mandated procedures by the Investigator or there is a 
significant change in the rate of occurrence or an increase in the severity of the pre-existing 
condition which is judged to be clinically important and attributed to the protocol-mandated 
procedures by the Investigator. Under the latter 2 circumstances, the event will be considered an 
AE and will be captured as such. 
• Example 1:  Thrombophlebitis associated with a blood draw for assessments required prior to 
dosing per protocol is an event that is related to protocol-mandated procedures. In this 
scenario, the event of “thrombophlebitis” will be captured as an AE, and it will be 
documented as being “unrelated” to study drug(s), as applicable. 
• Example 2:  An ankle sprain following an unexpected fall from a flight of stairs while at 
home, after the patient has provided informed consent, but before the first dose of study 
drug(s), is clearly unrelated to any protocol-mandated procedures and would therefore be 
captured as medical history. 
10.3 
Grading of AEs 
The severity of an event and the seriousness are not to be considered synonymous. The severity 
is grading the intensity of an event. The seriousness of event is based on the patient/event 
outcome or action criteria. All AEs will be assessed for severity using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 
guidelines. If a particular AE is not listed in the NCI-CTCAE, the following criteria will be used: 
• Grade 1 = Mild (event results in mild or transient discomfort, not requiring or needing only 
minimal intervention or treatment; does not limit or interfere with daily activities [eg, 
insomnia, mild headache]). 


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• 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. 
10.4 
Causality Relationship of AEs 
In combination therapy, it is often not possible to distinguish causal association of 
treatment-emergent AEs with specific study drug especially when both drugs contribute to 
activation of the body’s immune mechanism. However, medical judgment is to be used to assess 
AEs based on unique immune activation pathways of each drug, time to onset from therapy drug 
administration, and known safety profiles of checkpoint inhibitors and IL-2 therapy. A general 
guidance on causal association assessment is provided below. In absence of clear evidence on 
causal association, relatedness is suggested to be assigned to both drugs after ruling out 
alternative etiologies based on medical history, concurrent illness, concomitant medications, etc. 
The relationship of each AE to each study drug (bempegaldesleukin or pembrolizumab) as 
applicable will be evaluated by the Investigator using the following definitions: 
• Not related:  An AE that does not follow a reasonable temporal sequence from administration 
of study drug(s), and/or that can be reasonably explained by other factors such as the 
patient’s medical history, pre-existing medical condition, underlying disease, concurrent 
illness, or concomitant medications/therapies. 
• Related:  There is a reasonable possibility that the AE is caused by the study drug(s). A 
plausible temporal sequence exists between the time of administration of the study drug(s) 
and the development of the AE. 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. 
10.5 
AE Reporting and Follow-up 
After initiation of study drug treatment, all AEs (both nonserious and serious AEs) will be 
reported from the time of first study drug(s) administration until 30 days after the last dose of all 
study drug(s) (ie, (Follow-Up Visit 1) and only SAEs until 90 days after the last dose of all study 
drugs (ie, Follow-Up Visit 2). Additionally, AEs related to protocol-mandated procedures 
occurring between the signing of consent and first dose of study drug will be reported (see 
Section 10.2). Progression of the head and neck cancer under study and death related to the 
progression of this cancer will not be reported (see Section 10.9). 


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All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames indicated in Table 11. 
All ongoing AEs will be followed until resolution, the patient is lost to follow-up (as defined in 
Section 6.2.7), patient death, or until the Follow-Up Visit 2. If the AE has not completely 
resolved by the last Follow-Up Visit, the final outcome of these ongoing AEs will be captured as 
“Not Recovered/Not Resolved” or “Recovering/Resolving”, whichever is applicable. 
For specific instructions on identifying and reporting SAEs, see Sections 10.6 and 10.7. 
Table 11: 
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events 
Type of Event 
Reporting Time Period: 
Consent to Randomization/ 
Allocation 
Reporting Time 
Period: 
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Perioda 
Reporting Time Period: 
After the 
Protocol-specified Follow-
up Period 
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor 
NSAE 
Report if: 
- due to protocol-specified 
intervention 
- causes exclusion 
Report all 
Not required 
Per data entry 
guidelines 
SAE including 
Cancerb and 
Overdose 
Report if: 
- due to protocol-specified 
intervention 
- causes exclusion 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 24 hours 
of learning of 
event 
Pregnancy/ 
Lactation 
Exposure 
Report if: 
- patient has been exposed to any 
protocol-specified intervention 
(eg, procedure, washout) 
Exception: A positive pregnancy 
test at the time of initial screening 
is not a reportable event. 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 24 hours 
of learning of 
event 
ECI  
(require 
regulatory 
reporting) 
Report if: 
- due to intervention 
- causes exclusion 
Report 
- potential DILI 
- require regulatory 
reporting 
Not required 
Within 24 hours 
of learning of 
event 
ECI  
(do not require 
regulatory 
reporting) 
Report if: 
- due to intervention 
- causes exclusion 
Report 
- non-DILI ECIs and 
those not requiring 
regulatory reporting 
Not required 
Within 5 calendar 
days of learning 
of event 
AESI (require 
regulatory 
reporting) 
Report if: 
- due to intervention 
- causes exclusion 
Report all 
Not required 
Within 24 hours 
of learning of 
event 
Abbreviations:  AESI = adverse event of special interest; DILI = drug-induced liver injury; ECI = Event of Clinical Interest; 
NSAE = nonserious adverse event; SAE = serious adverse event. 
a. 
Follow-up period includes: 
Follow-Up Visit 1: reported until 30 days after the last dose of all study drug(s) and  
Follow-Up Visit 2: reported only for SAEs until 90 days after the last dose of all study drug(s). 
b. 
A new cancer that is not a condition of the study indication. 
 


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10.6 
Serious AE Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
Note:  Death is an outcome of an AE and not an AE in itself. All events leading to death, 
regardless of relationship to study drugs, that occur during the protocol-specified reporting 
period, must be reported with the exception of deaths attributed to disease progression (refer 
to Section 10.9). 
• Is life threatening, that is, in the opinion of the Investigator, the AE places the patient at 
immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a patient’s participation in a clinical study, except for those due to the 
following: 
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 (eg, elective hospitalization for social reasons or due to long travel 
distances or for prophylactic patient observation), in the absence of an AE. 
Note: “Inpatient hospitalization” means the patient has been admitted to a hospital for 
medical reasons. 
• 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 (eg, a new cancer that is not a condition of the study indication 
or is a serious symptom of study drug overdose). 
An efficacy failure is not considered an SAE. 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. 
10.7 
Serious AE Reporting 
Serious AEs will follow the same monitoring process as referenced in Section 10.2; however, 
events occurring after the patient has provided informed consent, but before the first dose of 
study treatment or confirmed screen failure, will be collected as medical history unless the event 
is either new and attributed to protocol-mandated procedures by the Investigator or there is a 
significant change in the rate of occurrence or an increase in the severity of the pre-existing 
condition which is judged to be clinically important and attributed to the protocol-mandated 
procedures by the Investigator. Any new or clinically significant changes in the patient’s medical 


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and/or cancer history that occur after the first dose of drug and meet the SAE criteria will be 
recorded as SAEs. All SAEs meeting serious criteria, from the time of treatment randomization 
through 90 days after cessation of study treatment or 30 days after cessation of study treatment if 
the patient initiates new anticancer therapy, whichever is earlier, must be reported by the 
Investigator to Nektar Therapeutics Drug Safety immediately (ie, no more than 24 hours after 
learning of the event). 
In addition, all SAEs that occur beyond 90 days after the last dose of all study drug(s) that are 
assessed by the Investigator as related to study drug(s) will also be reported to Nektar 
Therapeutics Drug Safety immediately without undue delay, under no circumstances later than 
24 hours following knowledge of the event. 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 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. 
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 possible to record the SAE information electronically, that is, the eCRF 
database is not functioning, 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 provided in the List of Study Contacts 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. 
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, AESI, or ECIs 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 10.8. 


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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. 
10.8 
Serious AE Follow-up 
All study treatment-related SAEs that have not resolved by the last Follow-Up Visit (Section 6.3) 
will be followed until any of the following occur (whichever comes first): 
• The event resolves. 
• The event has stabilized. 
• The event returns to baseline, if a baseline value is available. 
• It is unlikely that any additional information can be obtained (eg, patient or healthcare 
practitioner refuses to provide additional information; lost to follow-up after demonstration 
of due diligence with follow-up efforts [as defined in Section 6.2.7]). 
• The patient dies or is lost to follow-up (as defined in Section 6.2.7). 
All ongoing SAEs assessed as unrelated to study drug(s) will be followed until resolution or until 
the last Follow-Up Visit (Section 6.3), whichever is earlier. In the case where an unrelated SAE 
has not completely resolved by the last Follow-Up Visit, the final outcome of these unrelated 
ongoing SAEs will be captured as “Not Recovered/Not Resolved” or “Recovering/Resolving”, 
whichever is applicable. 
10.9 
Disease Progression and Death due to Disease Progression– Not Reportable as an 
AE or SAE 
It is anticipated that during this study a proportion of patients will experience disease recurrence 
prior to study discontinuation. In some patients this may result in hospitalization or death. Such 
events leading to hospitalization or death of a study patient are typically considered “serious,” 
requiring submission of an SAE report. However, because disease recurrence is an endpoint for 
this study, reporting the term “disease recurrence” as either an AE or SAE is not necessary. Signs 
and symptoms with no principal clinical manifestation related to disease recurrence, may be 
considered as “disease recurrence” without a requirement to report it as an AE or SAE. 
For all SAEs assessed as clinical manifestations associated with fatal disease progression, the 
following criteria will apply: 
• Seriousness Criteria cannot equal Death 
• Severity cannot equal Grade 5 
• Outcome = Ongoing at time of Death 


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Deaths that are attributed solely to disease recurrence by the Investigator should not be reported 
as SAEs. 
However, if there are separate identifiable clinical manifestations of the disease recurrence that 
the Investigator is unsure that the events are attributed solely to disease recurrence, for example, 
pleural effusion or weight loss, these manifestations are reportable as AEs. Such an event should 
be recorded on the AE CRF and, if the event meets any of the “serious” criteria, it must also be 
reported on the SAE form. 
10.10 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or 
SAEs 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data are 
monitored to safeguard the patients in the study. 
10.11 Immune-Mediated Adverse Events 
Immune-mediated AEs (also referred to as immune-related AEs [irAEs] in this document) are 
AEs consistent with an immune-mediated mechanism or immune-mediated component for which 
non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. 
Immune-mediated AEs can include events with an alternate etiology which were exacerbated by 
the induction of autoimmunity. Investigators should use clinical judgment characterizing an AE 
as immune-mediated, including the requirement for steroid treatment, and are encouraged to rule 
out neoplastic, infectious, metabolic, toxic, or other etiologies to the extent possible, before 
characterizing an event as immune-mediated. Information supporting the assessment of immune-
mediated AEs will be collected on the CRF. 
10.12 Adverse Events of Special Interest for Bempegaldesleukin 
Selected serious and nonserious AEs for bempegaldesleukin are also known as adverse events of 
special interest (AESIs) and must be reported to the Sponsor. 
An AESI for bempegaldesleukin in this study is CVA, which should follow the AE grading 
criteria (see Section 10.3) and the standard seriousness definition (see Section 10.6). All AESIs 
occurring in both arms are required to follow the timeline for SAE reporting (within 24 hours as 
described in Table 11 and Section 10.7) in order to remove potential bias from dissimilar 
reporting between the treatment arms. The purpose of such reporting criteria is to obtain 
adequate information for proper clinical assessment of CVA events. Patients with recurrent and 
metastatic disease are known to have a higher risk for CVA. 
CVA Management Guidelines for the study are provided in Appendix 2. 


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10.13 Potential Drug-Induced Liver Injury for Bempegaldesleukin 
For patients in Arm A receiving bempegaldesleukin, wherever possible, timely confirmation of 
initial liver-related laboratory abnormalities should occur prior to the reporting of a potential 
drug-induced liver injury (DILI) event according to the elevated liver enzyme criteria defined in 
Section 10.14. For patients in Arm A receiving bempegaldesleukin, all occurrences of potential 
DILIs meeting the criteria defined in Section 10.14 must be assessed for causal etiology with 
concomitant medications and/or for individual study drug association and reported as SAEs (see 
Section 10.7 for reporting details). 
10.14 Events of Clinical Interest for Pembrolizumab 
Selected serious and nonserious AEs for pembrolizumab are also known as events of clinical 
interest (ECIs) and must be reported to the Sponsor. 
Events of clinical interest for pembrolizumab in this study include:  
1. 
An overdose of Sponsor's product, as defined in Section 10.15. 
2. 
An elevated AST or ALT laboratory value that is greater than or equal to 3  ULN and an 
elevated total bilirubin laboratory value that is greater than or equal to 2  ULN and, at 
the same time, an alkaline phosphatase laboratory value that is less than 2  ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. 
10.15 Treatment of Overdose 
For this study: 
• For pembrolizumab, an overdose will be defined as any dose of 1000 mg pembrolizumab or 
greater. 
• For bempegaldesleukin, an overdose is defined as the accidental or intentional administration 
of any dose of a product that is considered both excessive and medically important. 
No specific information is available on the treatment of overdose of pembrolizumab or 
bempegaldesleukin. In the event of overdose, the patient should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
Overdoses that meet the regulatory definition of SAE will be reported as an SAE (see 
Section 10.6). All instances of accidental overdose and/or dosing errors should be reported on the 
Dosage Administration Record CRF. 


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10.16 Pregnancy Tests/Pregnancy 
10.16.1 
Pregnancy Tests 
Serum or urine pregnancy tests will be performed on women of childbearing potential (WOCBP) 
according to the Schedule of Events (Section 1.2). Pregnancy testing (urine or serum as required 
by local regulations) should also be conducted 120 days after the last dose of study drug. 
Pregnancy testing requirements for study inclusion are described in Section 5.1. 
Pregnancy testing (urine or serum as required by local regulations) should be conducted prior to 
every cycle (q3w) or more frequently if required by local regulations. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study. 
Urine pregnancy tests should have a highly sensitive pregnancy test. 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 (see 
Appendix 5) for at least 1 year or surgically sterile for at least 3 months before signing the ICF. 
10.16.2 
Pregnancy 
10.16.2.1 Pregnancy and Lactation in Female Patients 
The Sponsor must be notified immediately without undue delay, under no circumstances later 
than 24 hours following knowledge of the initial report and any follow-up reports of a female 
patient becoming pregnant or breastfeeding during the course of the study and for 120 days after 
the last dose of study drug or 30 days after cessation of study drug if the patient initiates a new 
anticancer treatment for female patients. All reports should be submitted via the Pregnancy 
Notification Form. Pregnancy, although reportable, is not considered an AE/SAE unless a female 
patient experiences signs or symptoms of pregnancy complications; however, the contact 
information for pregnancy reporting is the same as for SAE reporting and listed in Section 10.7. 
Female patient(s) who become pregnant will be followed until the outcome of the pregnancy is 
known. Pregnancy follow-up should describe the outcome of the pregnancy, including any 
voluntary or spontaneous termination, details of the birth, and the presence or absence of any 
congenital abnormalities or birth defects in the offspring. Pregnancy outcomes of ectopic 
pregnancy, spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage, and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
If a female patient becomes pregnant, administration of the study drug(s) must be discontinued 
immediately. 


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10.16.2.2 Arm A Only: Pregnancies in Female Partners of Male Patients 
For patients treated with bempegaldesleukin, any pregnancy occurring during the course of the 
study and for 3 months after the last dose of bempegaldesleukin in a female partner of a male 
patient must be reported to the Sponsor. The Sponsor must be notified immediately without 
undue delay, under no circumstances later than 24 hours following knowledge of the initial 
report and any follow-up information. All reports should be submitted via the Pregnancy 
Notification Form. In order for the Sponsor or designee to collect any pregnancy surveillance 
information, the pregnant patient or partner must sign an informed consent form (See 
Section 14.2). 
Pregnancy, although reportable, is not considered an AE/SAE unless a female partner of a male 
patient experiences signs or symptoms of pregnancy complications; however, the contact 
information for pregnancy reporting is the same as for SAE reporting and listed in Section 10.7. 
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 drug 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. Pregnancy outcomes of ectopic 
pregnancy, spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage, and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
10.17 Emergency Medical Support and Patient Card 
Patients enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor. The Emergency Medical 
Support card is based on the need to provide clinical trial patients with a way of identifying 
themselves as participating in a clinical trial, and subsequently to give health-care providers 
access to the information about this participation that may be needed to determine the course of 
the patient’s medical treatment. 
This service is designed to provide information to healthcare providers who are not part of the 
clinical trial. Clinical trial Investigators, who are already aware of the clinical trial protocol and 
treatment, have other means of accessing the necessary medical information for the management 
of emergencies occurring in their patients. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected patient. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he/she will answer 
any questions. Any subsequent action will follow the standard processes established for the 
Investigators. In cases where the Investigator is not available, the Sponsor will provide a 24-hour 


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contact number, whereby healthcare providers are given access to a physician designated by the 
Sponsor who can assist with the medical emergency. 
10.18 Clinical Laboratory Tests 
Clinical laboratory tests will be conducted according to the Schedule of Events (Section 1.2). A 
list of the clinical laboratory analytes to be tested is provided in Appendix 1. 
Clinical laboratory tests will be performed by the central laboratory. For randomization, if the 
central laboratory tests are cancelled, lost, or considered inadequate for analysis, the site may 
forward an identical set of local laboratory samples for eligibility review (with central laboratory 
testing repeated prior to the first dose of study drug). If local laboratory results are determined to 
be acceptable during eligibility review, randomization may proceed. Additional clinical 
laboratory tests may be ordered at the Investigator’s discretion. 
The Investigator will review all laboratory results for clinical significance. Any laboratory result 
deemed clinically significant (ie, is associated with signs and symptoms, requires treatment, or 
requires follow up) will be recorded as an AE as described in Section 10.1. 
10.19 Physical Examinations 
Physical examinations should be conducted according to the Schedule of Events (Section 1.2).  
Full physical examinations evaluate all major organ systems, including the following categories:  
general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, 
extremities, integumentary, and neurologic. Targeted physical examinations are at the discretion 
of the Investigator to identify changes from baseline or evaluate changes based on the patient’s 
clinical symptoms. 
10.20 Vital Signs 
Vital sign measurements will be recorded according to the Schedule of Events (Section 1.2). 
Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure, and 
temperature. It is preferred that the same arm be used for all blood pressure readings, if possible. 
Weight is to be reported at each vital sign visit, height at screening visit only. 
10.21 Electrocardiograms 
All patients will have 12-lead electrocardiogram (ECG) done during Screening as specified in 
the Schedule of Events (Section 1.2). ECG data will be locally assessed. On-treatment ECGs 
should be obtained if clinically indicated. 
10.22 Echocardiograms 
Standard echocardiogram will be performed at screening to assess cardiac function and LVEF 
according to the Schedule of Events (Section 1.2). A MUGA scan can be performed to assess 


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cardiac function and LVEF if a standard echocardiogram cannot be performed. After 
randomization, patients with clinically significant cardiac toxicity should have this assessment 
repeated as indicated. 


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11.0 
STATISTICAL PLAN 
11.1 
General Considerations 
In general, continuous data will be summarized by descriptive statistics, including number of 
patients, mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized by the number and percentage of patients. Unless otherwise specified, data will be 
summarized by treatment arm. 
All efficacy evaluations will be analyzed using the intent-to-treat (ITT) population unless 
otherwise specified, and all safety endpoints will be summarized using the Safety population. In 
general, the following three stratification factors will be used in stratified analysis in comparing 
response rates and survival curves of the two arms (bempegaldesleukin plus pembrolizumab 
versus pembrolizumab), and in Cox proportional hazard analysis unless otherwise specified: 
disease status (metastatic vs recurrent only), PD-L1 tumor expression (CPS ≥ 20 vs CPS 1-19) 
and HPV status (positive vs negative). 
The detailed description of analysis methods will be provided in the statistical analysis plan 
(SAP). 
11.2 
Determination of Sample Size 
The sample size of the study accounts for the following two primary efficacy endpoints: ORR 
and OS. The overall alpha for this study is 0.05, which is split into 0.001 to evaluate ORR and 
0.049 to evaluate OS. All alpha levels are two-sided. At the first interim analysis (Interim 
Analysis 1 [IA1]), ORR will be analyzed at least one month after the last patient of the Phase 2 
portion has been randomized into the study. IA2 will occur when at least 231 OS events have 
been observed. ORR and OS will be analyzed at IA2 for efficacy and OS will be analyzed for 
efficacy at the final analysis (FA). 
In addition, a fallback approach will be used to reallocate the alpha from ORR to OS. If ORR is 
significant in favor of the combination of bempegaldesleukin and pembrolizumab, the alpha of 
0.001 will be passed to OS. OS can then be tested at 0.05 (instead of 0.049) level. The testing 
procedure of ORR and OS is described in Figure 2. A total of approximately 500 patients will be 
randomized into the two treatment arms (bempegaldesleukin plus pembrolizumab versus 
pembrolizumab) in a 1:1 ratio. 


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Figure 2: 
Statistical Testing Procedure 
Abbreviations:  ~ = approximately;  = change; FA = final analysis; GNG = go no go decision; IA = interim 
analysis; IA1 = Interim Analysis 1 (first interim analysis); IA2 = Interim Analysis 2 (second interim analysis); 
mos. = months; ORR = objective response rate; OS = overall survival; p = p-value 
 
11.2.1 
Sample Size Justification for ORR  
It is projected that IA1 will occur approximately 14 months after the first patient’s randomization 
date (10 months of accrual of 200 patients in both arms, one month of ORR follow-up, and 
3 months for data cleaning). IA1 is for ORR futility assessment. 
Given a two-sided family-wise error rate of 0.001, 500 patients in the ITT population will 
provide approximately 96% power to detect a 20% difference in ORR between the 2 treatment 
arms using a Chi-square test at IA2, assuming an ORR of 19% for pembrolizumab 
(Burtness 2019). If the observed ORR difference at IA2 is greater than 13.1%, the result will be 
statistically significant. 
11.2.2 
Sample Size Justification for OS 
The study is powered to detect an improvement in OS for bempegaldesleukin combined with 
pembrolizumab compared with pembrolizumab monotherapy. An initial total of 298 OS events 
are needed to detect a hazard ratio (HR) of 0.7 with 85% power at a 2-sided significance level of 
0.049. Assuming a median OS time for the pembrolizumab arm of 12.3 months (Burtness 2019), 
with a total sample size of 500, it is projected the total study duration is up to 52 months to reach 
393 OS events (after an initial varying staged incremental accrual in the first 5 months to 
35 patients per month, then a 4-month enrollment pause after 200 patients have been randomized 


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and resumed at an initial varying staged incremental accrual in the first 3 months to 35 patients 
per month until 500 patients are randomized). 
One interim analysis of OS is planned for this study at IA2. The interim analysis is projected to 
occur at 32 months from the first patient randomized into the study. The stopping boundaries at 
interim and final analyses will be derived based on the number of deaths using O’Brien and 
Fleming alpha spending function in software EAST 6.5. The detailed alpha spending and 
statistical significance level at each analysis below are for the planned number of events. If the 
actual number of events at the time of the analysis is different from the planned one, the actual 
alpha and statistical significance level will be adjusted using O’Brien and Fleming alpha 
spending function in software EAST 6.5. 
There are two possible testing scenarios at IA2 for OS: 
1. The ORR difference is statistically significant at IA2 at alpha level of 0.001. 
The overall Type I error rate is 0.05 for the primary endpoint OS and OS will be tested at 
alpha level of 0.022 at IA2. If the observed HR is tested statistically significant in favor 
of the combination of treatments, OS benefit will be concluded. Otherwise, OS will be 
tested at alpha level of 0.028 at the final analysis (FA) corresponding to the statistical 
significance level of 0.044 calculated based on the correlation of the interim and final 
combination test statistic. 
2. The ORR difference is not statistically significant at IA2. 
The overall Type I error rate is 0.049 for the primary endpoint OS. OS will be tested at 
alpha level of 0.021 at IA2. If the observed HR is tested statistically significant in favor 
of the combination of treatments, then OS benefit will be concluded. Otherwise, the HR 
will be tested at alpha level of 0.029 at the final analysis corresponding to the statistical 
significance level of 0.043 calculated based on the correlation of the interim and final 
combination test statistic. 
The detailed calculation will be provided in the SAP. 
At IA2, if OS is not statistically significant, then conditional power will be calculated. The 
adaptive method in Liu and Hu (Liu 2016) and Mehta and Pocock (Mehta 2011) will be used to 
determine the number of OS events needed to target approximately 85% to 90% conditional 
power for the final analysis. The final analysis will be triggered when this re-estimated number 
of OS events is reached. 
The minimum and maximum number of OS events for the final analysis are 298 and 393, 
respectively. The minimum event size is calculated to achieve 86% power with alpha = 0.049 
(two-sided) assuming an exponential distribution in each treatment arm and an HR = 0.7 with 
median OS for the pembrolizumab arm of 12.3 months (Burtness 2019). The maximum event 
size is determined to detect the minimum clinically meaningful effect of HR around 0.82. 




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be used to compare the proportion of patients with an objective response between the 2 treatment 
arms.  
The ORR difference between the two treatment arms with its 95% and 99.5% confidence 
intervals (CIs) will be calculated by the CMH test statistic using the normal approximation. The 
ORR and its corresponding 95% exact CI will also be calculated by Clopper-Pearson method for 
each arm. Patients who do not have on-study tumor assessments to evaluate response status will 
be counted as non-responders. 
Overall survival (OS) is defined as the time between the date of randomization and the date of 
death due to any cause. A patient who does not have a date of death will be censored on the last 
date for which the patient was known to be alive. 
As another primary efficacy endpoint, OS will be evaluated at an overall alpha level of 0.049 if 
ORR is not significant and at 0.05 if ORR is significant. The regular stratified log-rank test will 
be used at IA2 to compare overall survival between the two treatment arms. At the final analysis, 
the weighted combination version of the stratified log-rank test with prespecified weights 
(Lehmacher 1999) will be used to compare overall survival between the two treatment arms. A 
stratified Cox proportional hazards model with treatment as the single covariate will be used to 
estimate the hazard ratio and corresponding 95% CI. The weighted combination approaches as 
specified in Brannath et. al. (Brannath 2006) will be performed as an exploratory analysis. The 
Kaplan-Meier method will be used to summarize overall survival per arm, including 
Kaplan-Meier curves, medians with corresponding 95% CIs, etc.  
At the first interim analysis, ORR will be assessed for futility: ORR futility assessment (ie, the 
difference in ORR proportions is ≥ 0% [bempegaldesleukin plus pembrolizumab minus 
pembrolizumab monotherapy]) will serve as a gate to proceed to the Phase 3 portion of the study.  
If the DMC determines that the study should continue based on the prespecified futility 
boundary, Phase 3 of the study will begin following a projected 4-month enrollment pause for 
the first interim analysis readout. At the second interim analysis when 
approximately 500 patients have been randomized and about 231 overall survival events have 
been observed, the following tests will be conducted: 
• ORR will be tested at a statistical significance level of 0.001 at the second interim analysis. 
• If ORR is not significant at the second interim analysis, overall survival will be tested at an 
overall alpha level of 0.049 and at α = 0.021 at the second interim analysis. 
• If ORR is significant at the second interim analysis, the fallback method will be used, and 
overall survival will be tested at an overall alpha level of 0.05 and at α = 0.022 at the second 
interim analysis. 
At the final analysis, the primary analysis of overall survival to claim statistical significance will 
be based on the weighted combination version of the stratified log-rank test with prespecified 


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weights (Lehmacher 1999). Statistical significance level for the final analysis is 0.043 or 0.044 
depending on whether ORR is significant at the second interim analysis. Prespecified weights for 
the primary OS are 𝑤= √231/345 and 1-w for events occurring before and after the second 
interim analysis, respectively. The middle point, 345, of minimum and maximum event sizes is 
chosen to set up the weights. The conventional stratified log-rank test with equal weights for 
every patient will be conducted as a sensitivity analysis. Details will be provided in the SAP. 
11.5.2 
Secondary Analyses  
Progression-free survival (PFS): defined as the time between the date of randomization and the 
first date of documented disease progression using RECIST 1.1 per BICR or death due to any 
cause, whichever comes first. Stratified log-rank test will be used to compare PFS between the 
two treatment arms. PFS will be tested following OS significance and at the same significant 
level as OS. A stratified Cox proportional hazards model with treatment as the single covariate 
will be used to estimate the hazard ratio and corresponding 95% CI for PFS. The Kaplan-Meier 
method will be used to summarize PFS, including Kaplan-Meier curves, medians with 
corresponding 95% CIs, etc. 
The censoring rules for PFS will be detailed in the SAP. 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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11.6 
Safety Analyses 
Overall safety and tolerability of bempegaldesleukin plus pembrolizumab will be measured by 
the incidence of treatment emergent AEs including AEs of special interest, SAEs, deaths, and 
laboratory abnormalities. Safety analyses will be summarized for the Safety population using 
descriptive statistics by treatment arm. 
11.7 
Interim and Final Analyses 
• 
IA1: at least one month after the last patient of the Phase 2 portion has been randomized into 
the study. It is projected that IA1 will occur approximately 14 months after the first patient’s 
randomization date. The analysis is for futility based on ORR. 
• 
IA2: after at least 231 OS events have been observed. The interim analysis is projected to 
occur at 32 months from the first patient randomized into the study. The analysis is for ORR 
for efficacy, for the first OS interim efficacy analysis, and for total number of OS events 
re‑estimation if OS is not significant at IA2. 
• 
FA – OS final: timing will be determined based on the IA2 efficacy results. 
The SAP will further describe the planned interim analyses. 
11.8 
Data Monitoring Committee (DMC) 
An independent, external DMC will be formed, comprised of qualified clinicians and a 
biostatistician all independent from the Sponsor and investigational sites, selected to avoid conflict(s) 
of interest.  
The DMC will evaluate 2 interim analyses. The first interim futility analysis will occur at least 
one month after the last patient of the Phase 2 portion has been randomized into the study. The 
second interim efficacy analysis will be conducted when approximately 500 patients have been 
randomized and about 231 overall survival events have been observed. 
The DMC will assess accumulating safety data and emerging risk/benefit balance at least twice a 
year and on an ad-hoc basis as detailed in the DMC Charter. 
The DMC’s specific activities will be detailed in a mutually agreed upon charter, which will 
define the relevant processes, including meeting proceedings and structure, data assessments, 
documentation and recordkeeping, process for DMC recommendations, and regulatory reporting, 
as applicable. The charter will contain procedures to ensure the minimization of bias, such as 
maintaining confidentiality of any interim data. 
 
 
 
 


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11.9.1 
Pharmacokinetic Analyses 
Plasma concentrations of bempegaldesleukin-related molecules and serum concentrations of 
pembrolizumab will be measured using validated or qualified method(s). 
PK concentrations will be summarized using summary statistics. PK concentrations from this 
study will be combined with data from other studies to conduct population PK analyses. Model 
predicted exposures may be used for exposure-response analyses of selected efficacy and safety 
endpoints. If the analyses are conducted, the results of population PK analyses and 
exposure-response analyses will be reported separately from the Clinical Study Report of this 
study. 
11.9.2 
Immunogenicity Analyses 
Incidence of anti-drug antibodies (ADA) will be determined by measurements of 
anti-bempegaldesleukin, anti-interleukin-2 (anti-IL-2), anti-polyethylene glycol, and 
anti-pembrolizumab antibodies. Validated methods will be used for the ADA measurements. 
Immunogenicity will be reported for ADA positive status and ADA negative status, relative to 
baseline. Presence of neutralizing antibody may be reported, if applicable. Effect of 
immunogenicity on safety/efficacy and PK may be explored. 
11.9.3 
Patient-reported Outcome Analyses 
Patient-reported outcome (PRO) questionnaires, EORTC QLQ-C30 and EORTC QLQ-H&N35, 
will be administered by trained site personnel and completed by patients at baseline and 
throughout the study. It is a best practice and strongly recommended that PROs are administered 
to randomized patients prior to study drug administration, AE evaluation, and disease status 
notification. 
Global health status/quality of life assessment is based on the global health status/quality of life 
scales of the EORTC QLQ-C30 (items 29 and 40); pain is based on the pain multi-item scales of 
the EORTC QLQ-H&N35 (items 31 to 34), and time to deterioration in swallowing (ie, the time 
from baseline to first onset of PRO deterioration with confirmation), is based on the swallowing 
multi-item scales of the EORTC QLQ-H&N35 (items 35 and 38). The deterioration in the global 
health status/quality of life, pain, and swallowing endpoints is defined as a 10 points or greater 
worsening from baseline for each multi-item scale (Bjordal 2000; Osoba 1998; King 1996) and 
confirmed by a second adjacent 10 points or more deterioration from baseline under a 
right-censoring rule. 
Time to PRO deterioration in global health status/quality of life: defined as time from 
baseline to the first onset of PRO deterioration with confirmation at the next visit for the global 
health status/quality of life assessment based on the global health status/quality of life scales of 
the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30). 


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Time to PRO deterioration in pain: defined as time from baseline to the first onset of PRO 
deterioration with confirmation for pain based on the pain multi-item scales of EORTC QLQ 
head and neck cancer specific module (EORTC QLQ-H&N35). 
Time to PRO deterioration in swallowing: defined as time from baseline to the first onset of 
PRO deterioration with confirmation for swallowing based on the swallowing multi-item scales 
of EORTC QLQ-H&N35. 
For the above three time to PRO deterioration endpoints, the stratified log-rank test will be used 
to compare the two treatment arms. A stratified Cox proportional hazards model with treatment 
as the single covariate will be used to estimate the hazard ratio and corresponding 95% CI, and 
the Kaplan-Meier method will be used to summarize these time-to-event endpoints per arm, 
including Kaplan-Meier curves, medians with corresponding 95% CIs, etc. 
Mean change from baseline in global health status/quality of life: defined as mean changes 
from baseline in global health status/quality of life assessment based on the global health 
status/quality of life scales of EORTC QLQ-C30. 
To assess the treatment effects on the PRO score changes from baseline in the global health 
status/quality of life outcome, a constrained longitudinal data analysis (cLDA) model will be 
applied, with the PRO score as the response variable, and treatment by time interaction, and 
stratification factors as covariates. Treatment effect on PRO score change from baseline will be 
primarily evaluated at Week 12. The differences in the least square mean change from baseline 
will be reported at the primary analysis time point. 
Additionally, mean change from baseline in global health status/quality of life will be 
summarized by visit and the graphs for the mean changes across visits will be provided. 
Changes from baseline in HR-QoL assessments: Change from baseline in health-related 
quality-of-life (HR-QoL) assessed by EORTC QLQ-C30 and the EORTC QLQ-H&N35 will be 
summarized by visit and graphs for mean changes by visit will be provided. 
Opioid analgesic use: will be measured based on reported concomitant medications. Opioid 
analgesic use will be summarized descriptively and the mean opioid analgesic use and change from 
baseline will be plotted across visits. 


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12.0 
STUDY OR STUDY SITE TERMINATION 
The Sponsor has the right to suspend or terminate the study or part of the study at any time for 
any reason. 
If an Investigator suspends or terminates their study site, the Investigator will promptly inform 
the Sponsor and the IRB/IEC and provide them with a detailed written explanation. Upon study 
completion, the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency with final 
reports and summaries as required by regulations. 


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13.0 
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. 
13.1 
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 submitted to applicable local 
health authorities, 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. 
13.2 
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 electronic case report forms (eCRFs), study documents, research facilities, and clinical 
laboratory facilities associated with this study at mutually convenient times during and after 
completion of the study. As required by 21 CFR 312 Subpart D (Responsibilities of Sponsors 
and Investigators), ICH GCP, and local regulations, the monitoring visits provide the Sponsor 
with the opportunity to evaluate the progress of the study; verify the accuracy and completeness 
of eCRFs; ensure that all protocol requirements, applicable FDA, ICH GCP, and local 
regulations, and Investigator’s obligations are being fulfilled; and resolve any inconsistencies in 
the study records. This includes inspection of all documents and records that are required to be 
maintained by the Investigator, including but not limited to medical records (office, clinic, or 
hospital) for the patients in this study. The names and identities of all research patients will be 
kept in strict confidence and will not appear on eCRFs or other records provided to or retained 
by the Sponsor. The Investigational New Drug (IND) Application regulations and ICH E6 
guidelines also require the Investigator to allow authorized representatives of the Sponsor, 
IRB/IEC, FDA, and other relevant regulatory authorities direct access to study source records, 
and to inspect and make copies of the same records. The names and identities of the patients 
need not be divulged to the Sponsor; however, the records must nevertheless be available to be 
inspected for review. This can be accomplished by blacking out the patient’s name and replacing 
the name with the patient’s study identification number. If these requirements are in conflict with 
local regulatory restrictions or institutional requirements, the Investigator must inform the 
Sponsor of these restrictions before initiation of the study. 


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13.3 
Direct Access to Source Data/Documents for Audits and Inspections 
Members of the Sponsor or designees may conduct monitoring and auditing activities of a 
clinical site at any time during or after completion of the study. The Investigator will be 
informed of such activities. 
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives, 
may also conduct an inspection or perform an audit of the study. The 
Investigator(s)/institution(s) will permit trial-related audits, IRB/IEC review, and regulatory 
inspection(s) by providing direct access to source data/documents and study records. If informed 
of such an inspection, the Investigator should notify the Sponsor immediately. The Investigator 
will ensure that the inspectors and auditors have access to the clinical supplies, study site 
facilities, and laboratory, and that all data (including original source documentation) and all 
study files are available, if requested. 


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14.0 
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 the current ICH GCP guidelines (ICH E6), as well as with any applicable regulatory 
authority, federal, state and/or local laws and regulations. 
14.1 
IRB/IEC Approval 
Before enrollment of patients into the study, as required by FDA regulations (21 CFR § 56), ICH 
GCP, applicable regulatory authority requirements, and local regulations, the current protocol 
and ICF will be reviewed and approved by an appropriate IRB or IEC. A letter documenting the 
IRB or IEC approval must be received by the Sponsor before the initiation of the study at a 
clinical site. Amendments to the protocol will be subject to the same requirements as the original 
protocol. 
The Investigator, Sponsor, or designee will submit a progress report at least once yearly to the 
IRB or IEC. However, the frequency of these reports will depend on IRB or IEC requirements. 
As soon as possible after completion or termination of the study, the Investigator will submit a 
final report to the IRB or IEC per the IRB or IEC requirements, and in compliance with FDA 
regulations, applicable regulatory authority requirements, and ICH GCPs. 
The Investigator, the Sponsor, or designee shall notify the IRB or IEC of any SAEs, suspected 
unexpected serious adverse reactions (SUSARs), or any other information that may affect the 
safe use of the study drug(s) during the study, per the IRB or IEC local requirements, and in 
compliance with FDA regulations, country and local regulatory authority regulations, and ICH 
GCPs. 
14.2 
Written Informed Consent 
Written documentation of informed consent must be obtained from each patient or (if permitted 
by the local health authority) a patient’s legal representative before entering the study. Patients 
will be informed of the nature of the study, and the ICF must be presented to each patient in the 
language in which the patient is fluent. 
Informed consent will be obtained from and documented for each patient prior to the conduct of 
any protocol-specific procedures. Signed and dated ICFs will be retained by the Investigator with 
the study records. Each patient will be given a copy of the signed and dated ICF. 
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. For the Sponsor or designee to collect any pregnancy 
surveillance information, the pregnant patient or partner must sign an informed consent form for 
disclosure information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 


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15.0 
DATA HANDLING AND RECORD KEEPING 
15.1 
Data Collection Instruments and Source Documents 
15.1.1 
Study Records 
During the study, the Investigator/institution should maintain adequate and accurate source 
documents and trial records that include all pertinent observations on each of the site’s trial 
patients. Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, and 
should be explained if necessary (eg, via an audit trail). The Investigator should ensure the 
accuracy, completeness, legibility, and timeliness of the data reported to the Sponsor in the CRFs 
and in all required reports. The Investigator/institution should, at a minimum, maintain the trial 
documents as specified in Essential Documents for the Conduct of a Clinical Trial (ICH E6 
Section 8) and as required by the applicable regulatory requirement(s). The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
15.1.2 
Data Collection Instruments 
Data collection instruments (DCIs) (eg, eCRFs, electronic clinical outcomes assessments, and/or 
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. 
15.2 
Retention of Essential Documents 
For sites in the US:  All records and documents pertaining to the study including, but not limited 
to, those outlined above will be maintained by the Investigator for a period of at least 2 years 
after FDA approval of the drug or at least 2 years after withdrawal of the IND under which this 
study was conducted, whichever is longer.  
For sites outside the US:  Essential documents should be retained until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the Investigator/institution when these documents no longer need to be retained. 


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To avoid any possible errors, the Investigator will contact the Sponsor before transferring or 
destroying any study records. The Investigator will also promptly notify the Sponsor in the event 
of accidental loss or destruction of any study records. 
15.3 
Confidentiality 
Patient confidentiality will be maintained per local legal and regulatory requirements and 
applicable US federal regulations and ICH GCP guidelines. To comply with GCP guidelines and 
requirements, patient records will be reviewed during monitoring visits and audits conducted by 
the Sponsor, Sponsor's representatives, or health authorities. During these activities, every 
reasonable effort will be made to keep medical information, including patient identifying 
information, as confidential as possible as required by law. 
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 (IRT) system enables de-identification. 
Demographic identifiers that will be collected as part of Study Data include year of birth, age, 
gender, race, and ethnicity. Exact date of birth and patient name/initials are not collected. 
The study site is not to provide any personal data relating to the patient from Study Data that will 
be transferred to Nektar. Only the study site will be able to connect the patient identification 
number with a patient’s personal data. 
15.4 
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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16.0 
PUBLICATION PLAN 
All data are the property of the Sponsor. Any formal presentation or publication of data from this 
study will be considered for joint publication by the Sponsor personnel and Investigator(s). 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the clinical trial agreement governing participation in the study. Study data shared by 
Nektar will not contain patient identifiable information. 
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries. 


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17.0 
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APPENDIX 1: 
CLINICAL LABORATORY TESTS 
Descriptions of the laboratory tests performed in this study are provided in the following 
appendices: 
 
• Appendix 1A: 
Laboratory Tests Performed in This Study 
• Appendix 1B: 
Arm A Only:  Local Clinical Laboratory Tests Obtained Prior to   
 
 
 
Bempegaldesleukin Administration 
 
 


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Appendix 1A: 
Laboratory Tests Performed in This Study 
Clinical Laboratory Tests (Central Laboratory)  
Hematology 
Chemistry 
Serology (screening only) 
• Hemoglobin (Hgb) 
• Hematocrit (HCT) 
• Platelet count 
• White blood cell (WBC) count 
• Absolute neutrophil count 
• Absolute lymphocyte count 
• Monocytes 
• Eosinophils 
• Basophils 
• AST (SGOT) 
• ALT (SGPT) 
• Alkaline phosphatase (ALP) 
• Albumin 
• Creatinine 
• Calculated creatinine clearance 
• Calcium 
• Glucose (non-fasting) 
• Total protein 
• Total bilirubin 
• Direct bilirubin 
• Sodium 
• Potassium 
• Chloride 
• Carbon dioxide (CO2) or 
bicarbonate 
• Blood urea nitrogen (BUN) or 
serum urea 
• Lactate dehydrogenase (LDH) 
• Uric acid 
• Hepatitis B surface antigen 
(HBsAg) 
• Hepatitis C virus antibody 
(anti-HCV) 
• Human immunodeficiency virus 
(HIV) antibody 
Thyroid Function Tests 
Coagulation 
Additional Labs 
• Free or total triiodothyronine (T3) 
• Free thyroxine (T4) 
• Thyroid-stimulating hormone 
(TSH) 
• Activated partial thromboplastin 
time (aPTT) 
• Prothrombin time (PT) 
• International normalized ratio 
(INR) 
• Creatine kinase 
• Lipase 
• Amylase 
• Serum or urine pregnancy 
• For females < 55 years of age: 
Follicle-stimulating hormone 
(FSH) 
Urinalysis 
• Specific gravity 
• pH 
• Glucose 
• Protein 
• Bilirubin 
• Ketones 
• Leukocyte esterase 
• Blood 
For positive protein, white blood cell, or blood: perform a microscopic examination 
including: 
• Red blood cells 
• White blood cells 
• Epithelial cells 
• Bacteria 
• Crystals 
• Casts 
Abbreviations: ALT = alanine transaminase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
transaminase (serum glutamic oxaloacetic transaminase) 
 




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APPENDIX 2: 
CEREBROVASCULAR ACCIDENT ADVERSE EVENT 
MANAGEMENT ALGORITHM FOR PATIENTS IN ARM A 
RECEIVING BEMPEGALDESLEUKIN 
If a new event of CVA including TIA occurs during the study conduct, please assess all 
etiologies of thrombo-embolic causes in these high-risk patients with known hypercoagulable 
state in the advanced cancer setting. 
The table below provides a management algorithm for possible signs/symptoms of CVA for 
patients in Arm A receiving bempegaldesleukin. This general guideline constitutes guidance to 
the Investigator and may be supplemented by clinical judgment of the Investigator and/or 
discussions with the Medical Monitor representing the Sponsor. 
For unexplained neurological symptoms (such as hemiparesis, confusion, dysarthria, or visual 
disturbances) that may be associated with CVA:  
• 
Recommend following the Advanced Cardiac Life Support (ACLS; ACLS 2021) Adult Suspected 
Stroke Algorithm (that includes time-sensitive assessment and rtPA use guidance). 
• 
Perform neurological imaging with DWI MRI as soon as feasible after initial presentation of 
symptoms, preferably within 24 hours, or as indicated following acute intervention. DWI MRI is 
preferred, but if contraindicated, alternative imaging modalities may be used. 
If imaging is consistent with a CVA, proceed to the following: 
1 
For any new CVA events confirmed by imaging (DWI MRI preferred unless contraindicated), 
regardless of neurological symptoms (eg, cryptogenic CVA) and for suspected TIA without 
clear alternative etiology: 
• 
Discontinue bempegaldesleukin. After a careful risk-benefit evaluation of each patient and 
if the CVA/TIA event is not deemed related to the checkpoint inhibitor, pembrolizumab 
may be continued. 
2 
Obtain a neurology consultation 
3 
Perform laboratory assessments (including coagulation studies with D-dimer, complete blood 
count [CBC] with differential, serum blood urea nitrogen [BUN], and creatinine). 
4 
Consider cardiac echocardiogram (trans-esophageal as appropriate) to evaluate for potential 
source of emboli. 
Abbreviations: CVA = cerebrovascular accident; DWI = diffusion-weighted imaging; MRI = magnetic resonance 
imaging; rtPA = recombinant tissue plasminogen activator; TIA = transient ischemic attack. 
Note: The ACLS Adult Suspected Stroke Algorithm is available from: https://acls-algorithms.com/adult-stroke-
algorithm/.  
 
 


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APPENDIX 3: 
PERFORMANCE STATUS CRITERIA 
GRADE 
ECOG PERFORMANCE 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, for example, light housework, 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 
Abbreviation: ECOG = Eastern Cooperative Oncology Group 
Oken 1982 
 


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APPENDIX 4: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) (VERSION 1.1) FOR EVALUATING RESPONSE IN 
SOLID TUMORS 
RECIST version 1.1 (Eisenhauer 2009) will be used in this study for assessment of tumor 
response. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred 
imaging technique in this study. 


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APPENDIX 5: 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
DEFINITIONS 
Women of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 
45 years in the absence of other biological or physiological causes. In addition, females 
under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level 
> 40 mIU/mL to confirm menopause. 
CONTRACEPTION GUIDANCE FOR FEMALE PATIENTS OF CHILDBEARING 
POTENTIAL 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 120 days after the last dose 
of study treatment (Note:  local laws and regulations may require use of alternative and/or 
additional contraception methods). 


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Highly Effective Contraceptive Methods That Are User Dependent  
 Failure rate of < 1% per year when used consistently and correctly.a 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
oral  
• 
intravaginal  
• 
transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• 
oral  
• 
injectable  
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
Hormonal methods of contraception including vaginal ring, injectables, implants and intrauterine hormone-
releasing system (IUS)c 
• 
Intrauterine device (IUD)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.  
• 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the patient. 
• 
It is not necessary to use any other method of contraception when complete abstinence is elected.  
• 
WOCBP patients who choose complete abstinence must continue to have pregnancy tests, as specified in 
Section 1.2.  
• 
Acceptable alternate methods of highly effective contraception must be discussed in the event that the 
WOCBP patients chooses to forego complete abstinence  
NOTES: 
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients participating in 
clinical studies. 
b. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the investigational medicinal product (IMP) and other study medications will not alter 
hormonal exposures such that contraception would be ineffective or result in increased exposures that could 
be potentially hazardous. In this case, alternative methods of contraception should be utilized. 
c. 
Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in 
the absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not 
alter contraception effectiveness. 
 


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 bempegaldesleukin (NKTR-214) and pembrolizumab 
Nektar Therapeutics 
 
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Unacceptable Methods of Contraceptiona 
• 
Male or female condom with or without spermicide. Male and female condoms cannot be used 
simultaneously 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal sponge with spermicide 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mechanism 
of action 
• 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• 
Withdrawal (coitus interruptus) 
• 
Spermicide only 
• 
Lactation amenorrhea method (LAM) 
a. 
Local laws and regulations may require use of alternative and/or additional contraception methods. 
 
CONTRACEPTION GUIDANCE FOR MALE PATIENTS WITH PARTNER(S) OF 
CHILDBEARING POTENTIAL 
For Arm A (bempegaldesleukin plus pembrolizumab):  male patients with female partners of 
childbearing potential are eligible to participate if they agree to the following during the 
treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the Investigator. 
• Male patients are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 3 months after the last dose of bempegaldesleukin. 
• Female partners of males participating in the study to consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 3 months after 
the last dose of bempegaldesleukin in the male patient. 
• Male patients with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the treatment and until 3 months after the last dose of 
bempegaldesleukin.  
• Refrain from donating sperm for the duration of the study treatment and until 3 months 
after the last dose of bempegaldesleukin. 
For Arm B (pembrolizumab monotherapy):  For male patients receiving pembrolizumab 
monotherapy, there are no contraception requirements. 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information is provided in Section 10.16. 


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 bempegaldesleukin (NKTR-214) and pembrolizumab 
Nektar Therapeutics 
 
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APPENDIX 6: 
CYTOKINE-RELEASE SYNDROME (CRS) MANAGEMENT 
MEASURES/ALGORITHM FOR PATIENTS IN ARM A 
RECEIVING BEMPEGALDESLEUKIN 
The following treatment management guideline is provided for general guidance for patients in 
Arm A receiving bempegaldesleukin. Cytokine-release syndrome (CRS) is a diagnosis of 
exclusion. This guideline should not substitute for a more individualized, tailored approach to 
managing a patient experiencing CRS. 
As a general principle, differential diagnoses should be diligently evaluated according to standard medical practice. 
Non-inflammatory etiologies should be considered and appropriately treated. 
For patients with suspected CRS: 
• For Grade 1 or Grade 2 events, implement supportive care, including management of isolated symptoms based 
on institutional practices 
• Consider admitting the patient for monitoring and to provide supportive care, including management of isolated 
symptoms based on institutional practices and protocol management guideline (eg, hydration management 
guidelines in Section 6.2.3.2). 
• For patients with a persistent or worsening clinical condition after initial treatment of CRS, re-evaluate for other 
contributing conditions. It is particularly important to reassess the patient for coexisting infections, cardiac, 
pulmonary, thromboembolic, and other complications. 
Grading Assessment  
per CTCAE Version 5.0 
Treatment Measures Recommended 
CRS 
Grade 3 
• Hypotension managed 
with 1 pressor 
• Hypoxia requiring 
> 40% O2 
• Vasopressin administration should be considered if the hypotensive 
event is refractory to > 3 L of fluid resuscitation. 
• Oxygen therapy (nasal canula, non-invasive positive pressure 
ventilation, etc.) for respiratory symptoms with consideration of 
intubation for a patient with severe respiratory manifestations. 
• Supportive care for renal, hepatic and other organ function 
deteriorations. 
• Steroid therapy should be considered (eg, hydrocortisone 100 mg 
every 8 hours, dexamethasone 10 mg up to 4 times daily, 
1 to 2 mg/kg/day methylprednisone IV or PO equivalent). 
• High-dose steroid (eg, solumedrol 2 mg/kg up to 1 gram daily for 
3 days) may be considered for severe CRS that failed to respond after 
repetitive steroid treatments. 
• For severe CRS cases that require simultaneously aggressive 
management of hypotension, oxygenation and cardiac telemetry, 
consult Intensivist for ICU evaluation. 
CRS 
Grade 4 
• Life-threatening 
consequences 
• Pressor or ventilatory 
support indicated 
Abbreviations: ICU = intensive care unit; O2 = oxygen; PO = by mouth 

SAP_001.pdf: 
Protocol 20-214-36 Statistical Analysis Plan 
        bempegaldesleukin (NKTR-214) and pembrolizumab 
Nektar Therapeutics 
 
Page 1 of 3 
Confidential and Proprietary 
 
06 MAY 2022  
 
Nektar Therapeutics 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2/3, Randomized, Open-label Study to Compare Bempegaldesleukin Combined 
with Pembrolizumab Versus Pembrolizumab Alone in First-Line Treatment of Patients 
with Metastatic or Recurrent Head and Neck Squamous-Cell Carcinoma with PD-L1 
Expressing Tumors (PROPEL-36)  
 
 
 
Protocol Number: 20-214-36, Original 
SAP Version: V2.0 
Date: 06 May 2022 
  
 
 
 
 
 
 
 
 
 
 
 


Protocol 20-214-36 Statistical Analysis Plan 
        bempegaldesleukin (NKTR-214) and pembrolizumab 
Nektar Therapeutics 
 
Page 2 of 3 
Confidential and Proprietary 
 
06 MAY 2022  
 
 
 
PREPARED BY: 


Protocol 20-214-36 Statistical Analysis Plan 
        bempegaldesleukin (NKTR-214) and pembrolizumab 
Nektar Therapeutics 
 
Page 3 of 3 
Confidential and Proprietary 
 
06 MAY 2022  
1.0 
INTRODUCTION 
This document provides an update of the statistical analysis plan for data captured in Nektar 
Therapeutics Protocol 20-214-36 “A Phase2/3, Randomized, Open-label Study to Compare 
Bempegaldesleukin Combined with Pembrolizumab Versus Pembrolizumab Alone in First-Line 
Treatment of Patients with Metastatic or Recurrent Head and Neck Squamous-Cell Carcinoma 
with PD-L1 Expressing Tumors (PROPEL-36)” Original version dated 14 June 2021.   
On March 14, 2022, Nektar Therapeutics reported negative efficacy results in their Phase 3 
melanoma study. On April 14th, 2022, negative topline results from both PIVOT-9 (renal cell 
carcinoma) and PIVOT-10 (urothelial) studies were reported. Based on three negative studies, 
Nektar Therapeutics made the decision to discontinue the bempegaldesleukin in combination 
with nivolumab program. As part of this decision, SFJ Pharmaceuticals, Inc. and Nektar 
Therapeutics, in consultation with the study Independent Data Monitoring Committee, have 
decided to discontinue the PROPEL-36 trial. 
2.0 
ANALYSIS PLAN 
One patient was enrolled and treated in this study. No summary will be produced, instead, 
individual patient level listings with the following data will be provided. 
Patient disposition, demographics and baseline characteristics will be described using listings of 
individual patient data. Patient demographics and baseline characteristics will include age, 
gender, ethnicity, race, geographic region, disease stage, primary tumor location, and disease 
status (metastatic vs recurrent only), PD-L1 tumor expression (CPS ≥ 20 vs CPS 1-19), and HPV 
status (positive or negative), as applicable. 
Prior and concomitant medications and therapies will be described using listings of individual 
patient data.  
Adverse events (AEs) collected in the study will be described using AE listings including AE 
start and end dates, grade, relatedness to study drug, action taken and AE outcome. Adverse 
events will be coded by system organ class (SOC) and preferred term (PT) using MedDRA 
version 24.0. Adverse event severity will be based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade (version 5.0). An AE is 
considered as related to treatment if it is related to any study drug; an AE with a missing 
relationship will be counted as related to study drug. An AE is considered as leading to treatment 
discontinuation if it is leading to discontinuation of any study drug. An AE is considered as 
leading to death if the severity grade is 5 or the outcome is fatal.