Clinical trial NCT04936841
Conditions: Head and Neck Cancer
Sponsor: University of Wisconsin, Madison
Start date: 2021-08-05; Completion date: 2022-10-04
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial will evaluate safety and efficacy of the combination of anti-PD1, NKTR-214, and palliative radiation therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Twenty-four participants will be enrolled to evaluate the efficacy of this combination.

Detailed description:
Following an informed consent process, participants will receive anti-PD-1 therapy with 200 mg of pembrolizumab and NKTR-214 at 0.006 mg/kg. Palliative radiation therapy will then be delivered to tumor sites causing or felt by the treating physician to have a high potential for causing symptoms with either 8 Gy X 3 or 4 Gy X 5 completed 3 to 7 days prior to cycle 2 of anti-PD1 and NKTR-214. Combined anti-PD-1 and NKTR-214 will then be delivered each subsequent cycle.

Efficacy will be measured by overall response rate (ORR), progression free survival (PFS), overall survival (OS), clinical benefit (CB), and duration of response with ORR the primary outcome being compared to historical control data. Toxicity will be evaluated prior to administration of each 21-day cycle, while receiving NKTR-214 followed by every four months after the participant is off trial. Health related quality of life questionnaires will be completed with cycle 1 and 2 and then every 4 cycles thereafter.

Arms: arm 1: Cycle 1 consists of anti-PD-1 therapy (200mg) and NKTR-214 (0.006 mg/kg3 administered intravenously), followed by palliative radiation (8 Gy x 3 or 4 Gy x 5 fractions) combined with anti-PD-1 therapy and NKTR-214 in cycle 2.

In subsequent cycles participants will receive NKTR-214 and anti-PD-1.
Interventions: intervention 1: NKTR-214 intervention 2: anti-PD-1 therapy intervention 3: Palliative Radiation
Intervention descriptions: intervention 1: Bempegaldesleukin (NKTR-214) is an immunotherapeutic protein prodrug specifically designed to activate the patient's immune system for the treatment of cancer by providing a controlled, sustained signal to the interleukin-2 (IL-2) receptor pathway (pharmacological classification: immunostimulatory interleukin cytokine) intervention 2: immunotherapy drug, monoclonal antibody intervention 3: radiation to relieve symptoms

Protocol documents:
Prot_SAP_000.pdf: 
V 04/19/2021 
 
 
 
II
 
Phase II Study of Bempegaldesleukin (NKTR-
214) Together with Palliative Radiation and anti-
PD-1 Checkpoint Blockade in Patients with 
Recurrent or Metastatic Head and Neck 
Squamous Cell Carcinoma (HNSCC)1 
Study Co-Chairs: Zachary Morris, MD, PhD and Paul Harari MD 
Principal Investigators: Adam Burr, MD, PhD and Justine Bruce MD 
IND Sponsor: Zachary Morris, MD, PhD  
IND Number: 155886 
 
 
NCT04936841 


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III 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Council for Harmonization 
guidelines for Good Clinical Practice (GCP) (ICH E6) and the Code of Federal Regulations on 
the Protection of Human Subjects (45 CFR Part 46). National Institutes of Health (NIH)-funded 
investigators and clinical trial site staff who are responsible for the conduct, management, or 
oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP 
Training. 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
Principal Investigator or Clinical Site Investigator: 
Signed:  
 
Date:  
 
Zachary Morris, MD, PhD 
Vice-Chair, Department of Human Oncology 
 
University of Wisconsin School of Medicine and Public Health 


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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ............................................................................................... III 
SIGNATURE PAGE .................................................................................................................. IV 
TABLE OF CONTENTS ............................................................................................................. V 
LIST OF ABBREVIATIONS ....................................................................................................... IX 
PROTOCOL SUMMARY .......................................................................................................... XII 
KEY ROLES AND CONTACT INFORMATION ........................................................................... 1 
1. 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......... 3 
1.1. 
Background Information .......................................................................................... 3 
1.1.1. Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma ............... 3 
1.1.2. Checkpoint Inhibitor Immunotherapy in Metastatic Head and Neck 
Cancer ........................................................................................................ 3 
1.1.3. NKTR-214 in Combination with Anti-PD-1 Following Palliative Radiation .... 3 
1.2. 
Rationale ................................................................................................................ 4 
1.3. 
Potential Risks and Benefits ................................................................................... 5 
1.3.1. Potential Risks ............................................................................................ 5 
1.3.2. Potential Benefits ........................................................................................ 7 
2. 
OBJECTIVES AND OUTCOME MEASURES ..................................................................... 8 
2.1. 
Primary ................................................................................................................... 8 
2.2. 
Secondary .............................................................................................................. 8 
2.3. 
Tertiary/Exploratory .............................................................................................. 10 
3. 
STUDY DESIGN .............................................................................................................. 10 
4. 
STUDY POPULATION ..................................................................................................... 11 
4.1. 
Participant Inclusion Criteria ................................................................................. 11 
4.2. 
Participant Exclusion Criteria ................................................................................ 12 
4.3. 
Strategies for Recruitment and Retention ............................................................. 13 
4.4. 
Treatment Assignment Procedures ....................................................................... 13 
4.5. 
Participant Withdrawal or Discontinuation from Study Procedures/Intervention..... 14 
4.5.1. Reasons for Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention ............................................................................ 14 
4.5.2. Handling of Participant Withdrawals from Study or Participant 
Discontinuation of Study Intervention ........................................................ 14 
4.6. 
Premature Termination or Suspension of Study .................................................... 15 
5. 
STUDY INTERVENTION .................................................................................................. 15 
5.1. 
Pembrolizumab (Standard of Care) ....................................................................... 15 
5.1.1. Acquisition ................................................................................................. 15 
5.1.2. Formulation, Packaging, Labeling, and Administration .............................. 15 
5.2. 
NKTR-214 (Research-related) .............................................................................. 15 
5.2.1. Acquisition ................................................................................................. 15 
5.2.2. Formulation, Packaging, and Labeling....................................................... 16 
5.2.3. Product Storage and Stability .................................................................... 16 
5.2.4. Dosage, Preparation and Administration of Study Product ........................ 16 
5.2.5. Premedication for Flu-like Symptoms ........................................................ 16 


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5.3. 
Accountability Procedures for the Study Product .................................................. 17 
5.4. 
Assessment of Participant Compliance with Study Product Administration ........... 17 
5.5. 
Modification or Delay of Protocol Therapy ............................................................. 17 
5.6. 
Concomitant Medications/Treatments ................................................................... 18 
5.6.1. Allowed Concomitant Medications ............................................................. 18 
5.6.2. Prohibited Concomitant Medications ......................................................... 18 
5.7. 
Administration of Intervention ................................................................................ 18 
5.7.1. Pre-medication, Hydration, and Ancillary Medications ............................... 18 
5.7.2. Supportive Care ........................................................................................ 19 
5.7.3. NKTR-214+anti-PD-1 following palliative RT administration ...................... 19 
5.8. 
Palliative Radiation Therapy (RT)—Standard of Care ........................................... 20 
5.8.1. Selection of an Index Tumor Site ............................................................... 20 
5.8.2. Radiation Dose (SOC) ............................................................................... 21 
5.8.3. Radiotherapy Delivery (SOC) .................................................................... 21 
6. 
STUDY SCHEDULE ......................................................................................................... 24 
6.1. 
Screening (Day -28) .............................................................................................. 24 
6.2. 
Cycle one .............................................................................................................. 25 
6.2.1. Cycle one, day 1 (C1D1) ........................................................................... 25 
6.2.2. Cycle one, day 8 (C1D8) ± 5 days ............................................................. 25 
6.3. 
Palliative Radiation Therapy (to be completed between C2D-7 to C2D-3 or 
C1D15 to C1D19) ................................................................................................. 25 
6.4. 
Cycle two .............................................................................................................. 25 
6.4.1. Cycle two, day 1 (C2D1 or C1D22) ± 5 days ............................................. 25 
6.4.2. Cycle two, day 8 (C2D8) ± 5 days ............................................................. 26 
6.5. 
Cycle three and thereafter .................................................................................... 26 
6.5.1. Cycle three and thereafter, day 1 (C3+D1) ± 7 days .................................. 26 
6.5.2. Cycle three only, day 8 (C3D8) ± 7 days ................................................... 26 
6.6. 
Long term follow-up (Every 4 months +/- 30 days if no progression, every 6 
months +/- 6 months after progression) ................................................................ 27 
6.7. 
Safety Follow-up (30 days after therapy completion +/- 14 days) .......................... 27 
6.8. 
Final Study Visit or Withdrawal Visit ...................................................................... 27 
7. 
STUDY PROCEDURES/EVALUATIONS ......................................................................... 28 
7.1. 
Study Procedures/Evaluations .............................................................................. 28 
7.1.1. Demographics (SOC) ................................................................................ 28 
7.1.2. Medical History (SOC) ............................................................................... 28 
7.1.3. Physical Exam (SOC) ................................................................................ 28 
7.1.4. Vital Signs (SOC) ...................................................................................... 28 
7.1.5. Adverse events (RR/SOC) and concomitant medications (SOC) ............... 28 
7.1.6. Weight (SOC) ............................................................................................ 28 
7.1.7. Diagnostic biopsy (SOC) ........................................................................... 28 
7.1.8. Index tumor biopsy (RR)............................................................................ 28 
7.1.9. Blood draw (RR) ........................................................................................ 28 
7.1.10. ECOG Performance Status (SOC) ............................................................ 29 
7.1.11. Quality of Life Measures (RR) ................................................................... 29 


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7.1.12. Diagnostic Imaging (SOC) ......................................................................... 29 
7.2. 
Laboratory Procedures/Evaluations ...................................................................... 30 
7.2.1. Clinical Laboratory Evaluations ................................................................. 30 
7.2.2. Specimen Preparation, Handling, and Storage .......................................... 30 
8. 
ASSESSMENT OF SAFETY ............................................................................................ 31 
8.1. 
Specification of Safety Parameters ....................................................................... 31 
8.1.1. Unanticipated Problems (UPs) .................................................................. 32 
8.1.2. Adverse Events (AEs) ............................................................................... 32 
8.1.3. Serious Adverse Events (SAEs) ................................................................ 32 
8.1.4. Adverse Event of Special Interest (AESI) .................................................. 33 
8.2. 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 33 
8.2.1. Safety Follow-up Evaluations .................................................................... 33 
8.2.2. Long Term Follow-up Evaluations ............................................................. 33 
8.3. 
Characteristics of an Adverse Event ..................................................................... 33 
8.3.1. Relationship to Study Intervention ............................................................. 33 
8.3.2. Expectedness ............................................................................................ 34 
8.3.3. Severity of Event ....................................................................................... 35 
8.4. 
Reporting Procedures ........................................................................................... 35 
8.4.1. Unanticipated Problem (UP) Reporting ...................................................... 35 
8.4.2. Serious Adverse Event Reporting .............................................................. 35 
8.4.3. Reporting of Safety Events to FDA ............................................................ 40 
9. 
STUDY OVERSIGHT ....................................................................................................... 40 
9.1. 
Monitoring and Reporting Guidelines .................................................................... 41 
9.1.1. Review and Oversight Requirements ........................................................ 41 
10. 
IND APPLICATION MANAGEMENT ................................................................................ 42 
10.1. Initial Submission .................................................................................................. 42 
10.2. Amendments ........................................................................................................ 43 
10.3. Safety Reports ...................................................................................................... 43 
10.4. Annual Reports ..................................................................................................... 43 
11. 
STATISTICAL CONSIDERATIONS .................................................................................. 43 
11.1. Study Hypotheses ................................................................................................. 43 
11.2. Sample Size Considerations ................................................................................. 43 
11.3. Final Analysis Plan ............................................................................................... 44 
11.3.1. Analysis Plans for Primary Objective ......................................................... 44 
11.3.2. Analysis Plans for Secondary Objectives .................................................. 44 
11.3.3. Analysis Plans for Exploratory Objectives ................................................. 44 
11.3.4. Subgroup Analyses ................................................................................... 44 
12. 
CRITERIA FOR DISEASE EVALUATION ........................................................................ 45 
12.1. Measurable Disease ............................................................................................. 45 
12.1.1. Malignant Lymph Nodes ............................................................................ 45 
12.2. Non-measurable Lesions ...................................................................................... 45 
12.3. Target Lesions ...................................................................................................... 45 
12.4. Non-target Lesions ............................................................................................... 46 
12.5. Evaluation of Target Lesions ................................................................................. 46 


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12.6. Evaluation of Non-target Lesions .......................................................................... 46 
12.7. Evaluation of Best Overall Response .................................................................... 47 
12.8. Definitions for Response Evaluation – RECIST 1.1 ............................................... 48 
12.8.1. Objective Response Rate .......................................................................... 48 
12.8.2. Clinical Benefit Rate .................................................................................. 48 
12.8.3. Progression Free Survival ......................................................................... 48 
12.8.4. Overall Survival ......................................................................................... 48 
12.8.5. Duration of Response ................................................................................ 48 
13. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 48 
14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 49 
14.1. Ethical Standard ................................................................................................... 49 
14.2. Institutional Review Board (IRB) ........................................................................... 49 
14.3. Informed Consent Process ................................................................................... 49 
14.4. Exclusion of Children (Special Populations) .......................................................... 49 
14.5. Subject Confidentiality .......................................................................................... 49 
14.5.1. Certificate of Confidentiality ....................................................................... 50 
14.5.2. NIH Data Sharing Policies ......................................................................... 50 
14.6. Future Use of Stored Specimens and Other Identifiable Data ............................... 51 
15. 
DATA HANDLING AND RECORD KEEPING ................................................................... 51 
15.1. Management of Banked Samples ......................................................................... 52 
15.2. Data Management Responsibilities ....................................................................... 52 
15.3. Data Capture Methods .......................................................................................... 53 
15.4. Types of Data ....................................................................................................... 53 
15.5. Schedule and Content of Reports ......................................................................... 53 
15.6. Study Records Retention ...................................................................................... 53 
15.7. Protocol Deviations ............................................................................................... 53 
16. 
PUBLICATION/DATA SHARING ...................................................................................... 54 
17. 
REFERENCES ................................................................................................................. 54 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................... A 
APPENDIX B: CEREBROVASCULAR ACCIDENT ADVERSE EVENT MANAGEMENT 
ALGORITHM FOR THE COMBINATION OF BEMPEGALDESLEUKIN WITH 
CHECKPOINT INHIBITORS.............................................................................................. C 
APPENDIX C: HYDRATION GUIDELINES ................................................................................ D 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
BUN 
Blood Urea Nitrogen 
CB 
Clinical Benefit 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CoC 
Certificate of Confidentiality 
CR 
Complete Response 
CRCO 
Clinical Research Central Office 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
CVA 
Cerebrovascular Accident 
DCR 
Disease Control Rate 
DHHS 
Department of Health and Human Services 
DOAC 
Direct Oral Anticoagulation 
DOT 
Disease Oriented Team 
DSMC 
Data and Safety Monitoring Committee 
EBRT 
External Beam Radiation Therapy 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EQD2 
Equivalent Dose in 2 Gy Fractions 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GTV 
Gross Tumor Volume 
Hgb 
Hemoglobin 
HHS 
Health and Human Services 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 


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HNSCC 
Head and Neck Squamous Cell Carcinoma 
HRQoL 
Patient-reported Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
IFN 
Interferon 
IME 
Important Medical Event 
IMRT 
Intensity Modulated Radiation Therapy 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LMWH  
Low Molecular Weicht Heparin 
MHC 
Major Histocompatibility Complex 
MOS 
months 
MTD 
Maximum Tolerated Dose 
N 
Number (typically refers to participants) 
NKTR-214 
Bempegaldesleukin 
OHRP 
Office for Human Research Protections 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PD-1 
Programmed death one 
Anti-PD1 
Anti-program death one 
PEG 
Polyethylene glycol 
PFS 
Progression-free Survival 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PR 
Partial Response 
PRC 
Pharmaceutical Research Center 
PSR 
Protocol Summary Reports 
PTV 
Planning Target Volume 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SD 
Stable Disease 


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SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
UW 
University of Wisconsin 
UWCCC 
University of Wisconsin Carbone Cancer Center 
WBC 
White Blood Cell  
WOCBP 
Women of Childbearing Potential 


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PROTOCOL SUMMARY 
Title: 
Phase II Study of Bempegaldesleukin (NKTR-214) Together with 
Palliative Radiation and anti-PD-1 Checkpoint Blockade in Patients 
with Recurrent or Metastatic Head and Neck Squamous Cell 
Carcinoma 
Précis: 
This is a Phase II study of NKTR-214 in combination with palliative 
radiation and anti-PD-1 checkpoint blockade in patients with 
recurrent or metastatic head and neck cancer. For all enrolled 
participants, cycle 1 consists of anti-PD-1 therapy and NKTR-214, 
followed by palliative radiation combined with anti-PD-1 therapy and 
NKTR-214 in cycle 2. In subsequent cycles participants will receive 
NKTR-214 and anti-PD-1. Participants who have one or more sites 
in need of palliative radiation therapy who have not received 
previous PD-1 directed therapy are eligible. The phase II study will 
enroll 24 subjects with a primary endpoint of overall response rate. 


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Objectives: 
Primary Objective:  
• 
Evaluate the objective response rate (ORR) to NKTR-214 in 
combination with anti-PD-1 therapy and palliative radiation in 
the efficacy-evaluable population. 
o Outcome measure: ORR will include confirmed 
complete response (CR) + confirmed partial response 
(PR) and will be determined as per RECIST1.1, by 
investigator assessment. 
 
Secondary Objectives:  
• 
Determine the safety, as well as, the progression free 
survival (PFS), overall survival (OS), clinical benefit (CB, 
defined as CR + PR + stable disease at ≥ 6 months (SD)), 
and duration of response with NKTR-214, anti-PD-1, and 
palliative radiation in the efficacy-evaluable population 
• 
Outcome measures:  
o Toxicities ≥ Grade 3 is defined by the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. Toxicities not “unrelated” to treatment, will 
be considered treatment-related.  
o PFS is defined as the time from D1 of treatment until 
the criteria for disease progression is met as defined 
by RECIST1.1 or death as a result of any cause. 
o OS is defined as time from D1 of treatment until death 
as a result of any cause. 
o CB will include confirmed complete response (CR) + 
confirmed partial response (PR) + stable disease at ≥ 
6 months (SD) and will be determined as per 
RECIST1.1.  
o Duration of response is the period measured from the 
time that measurement criteria are met for complete 
or partial response (whichever status is recorded first) 
until the date that recurrent or progressive disease is 
objectively documented. 
 
• 
Determine the impact of NKTR-214, palliative RT, and anti-
PD-1 therapy on patient-reported health-related quality of life 
(HRQoL) 
o Outcome measures: Patient-reported HRQoL will be 
monitored to evaluate participant tolerance of 
treatment using EORTC QLQ-C30, EORTC QLQ-
H&N35, and EQ-5D. These will be administered at 
baseline; 7 days after cycle 1 and cycle 2; then every 
12 weeks to the end of treatment + once more at 30 
days post treatment. HRQoL will be analyzed in pts 
who received ≥ 1 dose of study drug and have ≥ 1 
HRQoL assessment.  
 
 


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Exploratory Objectives: 
• 
Evaluate each subject’s tumor expression of PD-L1 by 
histology (using anti-PD-L1 clone 22c3 – standard in UW 
Surgical Pathology) and determine whether this predicts 
response to NKTR-214, palliative RT, and anti-PD-1 therapy  
• 
Evaluate the immunologic activation induced by NKTR-214, 
palliative RT, and anti-PD-1 using serologic and flow 
cytometry immune assays and T cell receptor sequencing 
• 
Evaluate for histological evidence of antitumor activity based 
on the cellular phenotype of infiltrate 
 
Population: 
24 adult patients of any gender, race or ethnicity, age ≥ 18 with 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
0-2 and a biopsy-proven recurrent/metastatic head and neck 
squamous cell carcinoma who are taking or will be starting anti-PD-1 
therapy and have a need for palliative radiation will be eligible for this 
study. 
  
Phase: 
Phase II 
 
Number of Sites: 
1 
 
Description of 
Intervention: 
Following an informed consent process, the subjects will receive 
anti-PD-1 therapy with 200 mg of pembrolizumab and NKTR-214 at 
0.006 mg/ml. Palliative radiation therapy will then be delivered to 
tumor sites causing or felt by the treating physician to have a high 
potential for causing symptoms with either 8 Gy X 3 or 4 Gy X 5 
completed 3 to 7 days prior to cycle 2 of anti-PD1 and NKTR-214. 
Combined anti-PD-1 and NKTR-214 will then be delivered each 
subsequent cycle. 
 
This trial will evaluate safety and efficacy of the combination of anti-
PD1, NKTR-214, and palliative radiation therapy in patients with 
recurrent or metastatic squamous cell carcinoma of the head and 
neck. Twenty-four participants will be enrolled to evaluate the 
efficacy of this combination. Efficacy will be measured by ORR, PFS, 
OS, CB, and duration of response with ORR the primary outcome 
being compared to historical control data. Toxicity will be evaluated 
prior to administration of each cycle, while receiving NKTR-214 
followed by every four months after the participant is off trial. Health 
related quality of life questionnaires will be completed with cycle 1 
and 2 and then every 4 cycles thereafter. 
Study Duration: 
36 months 
Estimated Mean 
Duration of Subject 
Participation: 
9 months 


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Estimated Time to 
Complete 
Enrollment: 
27 months 
 
 
 
Schematic of Study Design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen patients with biopsy-proven recurrent/metastatic head and neck squamous cell 
carcinoma who are taking or will be starting anti-PD-1 therapy and have a need for 
palliative radiation. Verify eligibility. Obtain informed consent and history, document. 
Cycle 1 (21 days) 
Pembrolizumab and NKTR-214 (Day 1) 
Cycle 2+ 
Pembrolizumab and NTRK-214 
Cycle 2 Day -3 to -7 
Complete palliative radiation therapy 


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KEY ROLES AND CONTACT INFORMATION 
Study co-chairs: 
(with ultimate 
responsibility for 
conduct and oversight 
of the study)  
 
 
 
 
 
 
 
 
 
 
 
 
Zachary Morris, MD, PhD 
IND Sponsor 
UW Carbone Cancer Center, Radiation Oncology 
Vice-Chair, Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
WIMR Room 3131 
1111 Highland Avenue 
Madison, WI 53705 
zmorris@humonc.wisc.edu  
Phone: (608) 263-2603 
 
Paul M. Harari, MD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
K4/438, Bx3684 Clinical Science Center 
600 Highland Avenue 
Madison, WI 53792  
harari@humonc.wisc.edu 
Phone: (608) 263-5009 
 
 
Principal 
Investigators: 
(Primarily responsible 
for patient enrollment 
and care) 
 
 
 
 
 
 
 
 
 
 
 
Adam Burr, MD, PhD 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
0600 Clinical Science Center 
600 Highland Avenue 
Madison, WI 53792  
aburr@humonc.wisc.edu 
Phone: (608) 263-8500 
 
Justine Yang Bruce, MD 
University of Wisconsin Carbone Cancer Center 
WIMR Room 3109 
1111 Highland Avenue 
Madison, WI 53705 
jybruce@medicine.wisc.edu 
Phone: (608) 262-4961 
 
 


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Institution: 
 
 
 
 
University of Wisconsin Carbone Cancer Center (UWCCC) 
600 Highland Avenue 
Madison, WI 53792 
  
Other Key 
Personnel: 
Randy J. Kimple, MD, PhD 
UW Carbone Cancer Center, Radiation Oncology 
Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
rkimple@humonc.wisc.edu  
Phone: (608) 265-9156 
 
Tabassum Kennedy, MD 
UW Carbone Cancer Center, Radiology 
Director, Head and Neck Imaging, Department of Radiology 
University of Wisconsin School of Medicine and Public Health 
tkennedy@uwhealth.org  
Phone: (608) 263-9179 
 
Alexander A. Pieper 
Research Assistant, Department of Human Oncology 
University of Wisconsin School of Medicine and Public Health 
aapieper@wisc.edu 
Phone: (402) 960-1155 
 
Statistician 
Menggang Yu PhD 
Department of Biostatistics & Medical Informatics 
Director, Biostats Shared Resource, UW Carbone Cancer Center 
Director, Biostats Core, UW Head & Neck SPORE 
University of Wisconsin School of Medicine and Public Health 
meyu@biostat.wisc.edu 
Phone: (608) 261-1988 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
1.1. 
Background Information 
1.1.1. Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
Concurrent or induction chemotherapy used with radiation therapy (RT) has the potential to cure 
some patients diagnosed with locoregional head and neck squamous cell carcinoma (HNSCC). 
However, many patients will relapse with locoregional recurrent disease or metastatic spread. 
The median survival for patients with recurrent or metastatic HNSCC is 6-12 months (1). Some 
of these patients are candidates for salvage therapy with intent to cure using surgery or re-
irradiation. Most, however, will ultimately require systemic palliative therapy. 
1.1.2. Checkpoint Inhibitor Immunotherapy in Metastatic Head and Neck Cancer 
Prior to publication of Keynote-048, anti-PD-1 checkpoint inhibition was reserved for patients 
with recurrent or metastatic disease that was refractory to first line platinum agents. Keynote-
048 demonstrated non-inferiority of anti-PD-1 monotherapy to the previous standard of care 
cetuximab, platinum, and 5-FU in the overall study population and demonstrated a 17 % ORR to 
pembrolizumab alone in patients with metastatic or recurrent HNSCC (2). This has resulted in 
approval of anti-PD-1 monotherapy with pembrolizumab for patients with combined positive 
score for PD-L1 of greater than or equal to one. Both nivolumab and pembrolizumab are 
approved following progression on platinum containing chemotherapy. Nivolumab and 
pembrolizumab are checkpoint inhibitors that bind PD-1 surface molecules on immune cells and 
antagonize the interactions of PD-1 with PD-L1. In healthy individuals, this PD-1/PD-L1 
interaction suppresses the immune system, thereby preventing autoimmune disease. HNSCC 
and other tumor types utilize PD-L1 expression as a means to evade immune surveillance and 
turn off an anti-tumor immune response. Nivolumab and pembrolizumab block the PD-1/PD-L1 
interaction in the tumor microenvironment, effectively “taking the breaks off” the immune 
system.  
1.1.3. NKTR-214 in Combination with Anti-PD-1 Following Palliative Radiation 
Preclinical and clinical studies demonstrate a cooperative interaction between radiation and 
anti-PD-1 checkpoint blockade (3). In this context, radiation can function as a method of in situ 
tumor vaccination resulting in enhanced dendritic cell maturation, antigen cross-presentation, 
and diversification of the anti-tumor T cell response. A Phase II clinical trial (MSKCC 15-253) 
delivered combined anti-PD-1 checkpoint blockade together with radiation in patients with 
recurrent/metastatic HNSCC. Early results did not indicate any excess toxicity with this 
combination (11 % incidence of treatment related toxicity ≥ Grade 3). That study demonstrated 
an overall response rate of 22 % and median PFS of 2.4 mos with radiation and anti-PD-1 
therapy in patients with metastatic or recurrent HNSCC. 
Bempegaldesleukin (NKTR‑214), a novel cytokine with enhanced immune system activation, 
has the potential to be an important advancement for the treatment of patients with cancer. 
NKTR‑214 consists of IL2, which has the same amino acid sequence as aldesleukin, 
conjugated at a defined region within the protein to releasable polyethylene glycol (PEG) chains. 
The PEG chains render the molecule inactive. After administration in vivo, the PEG chains are 
slowly hydrolyzed to generate active cytokine conjugates. This affords a superior safety profile 
for NKTR-214 compared to IL2, allowing for outpatient administration and a longer duration of 
action requiring less frequent dosing. The most active IL2 conjugates are 2‑PEG‑IL2 and 


V 04/19/2021 
 
 
 
4
1‑PEG‑IL2. The location of the PEG chains on the active conjugated-IL2 reduces its affinity to 
the IL2 receptor alpha subunit (IL2Ra), responsible for activating undesirable Treg cells to a 
greater extent than affinity to the IL2-receptor beta subunit (IL2Rb) (4, 5). In the tumor, 
NKTR‑214 preferentially activates CD8+ T cells and natural killer (NK) cells over Treg cells and 
provides sustained exposure to active 1‑PEG and 2‑PEG‑IL2 (6). 
Preclinical data from our group and others suggests a synergistic interaction between NKTR-
214 and radiation (7). In this combination, radiation acts as a “spark” by inducing neoantigen 
presentation by tumor cells on MHC-I, increased IFN-γ production, and improved antigen 
presentation (8). NKTR-214 helps to exploit these immunologic changes at the tumor by 
increasing tumor infiltrating lymphocytes (mainly CD4 and CD8 T cells) and NK cells (5). The 
combination has repeatedly been shown to be effective in preclinical syngeneic murine tumor 
models where neither treatment alone is sufficient to decrease tumor burden, but combined 
radiation and NKTR-214 result in decreased tumor burden and ~80 % of the mice become 
disease free.  
In a recent clinical study (PIVOT-02), NKTR-214 demonstrated safety in combination with anti-
PD-1 checkpoint blockade. Grade 3 or 4 treatment-related adverse events (AEs) were observed 
in 5.7 % of patients receiving NKTR-214 dose at or below 0.006 mg/kg plus anti-PD-1 
checkpoint blockade. At a higher NKTR-214 dose 0.009mg/kg with anti-PD-1 blockade, two 
patients experienced dose limiting toxicity in the form of hypotension and metabolic acidosis. 
There were no patient discontinuations due to treatment-related AEs and no treatment-related 
deaths. Based off the PIVOT-02 toxicity results, we have decided to forgo a traditional 3+3 dose 
escalation study exploring the toxicity of NKTR-214 in combination with anti-PD-1 following 
palliative radiation. Instead, we propose to test the safety and efficacy of the MTD dose of the 
PIVOT-02 trial (0.006 mg/kg NKTR-214) in combination with palliative radiation and anti-PD-1 
therapy.  
The PIVOT-02 trial also demonstrated NTKR-214 in combination with anti-PD-1 is effective in 
mounting an anti-tumor immune response. This combination (0.006 mg/kg NKTR-214 + 360 mg 
Nivolumab q3w) has shown efficacy in patients with Stage IV melanoma [ORR 50 %, disease 
control rate (DCR) 71 %], Stage IV renal cell carcinoma (ORR 46 %, DCR 77 %), and Stage IV 
non-small cell lung carcinoma (ORR 75 %, DCR 75 %) (9, 10). 
1.2. 
Rationale 
Based on the available clinical data and preclinical data, we hypothesize that the combination of 
palliative radiation, NKTR-214, and anti-PD-1 checkpoint blockade will improve the ORR 
compared to a 22 % estimated ORR (based on historical data outlined above) for 
pembrolizumab alone or pembrolizumab plus palliative radiotherapy in patients with metastatic 
or recurrent HNSCC. Given the non-redundant and potentially synergistic immunologic effects 
of radiation, NKTR-214, and anti-PD-1 checkpoint blockade, our primary hypothesis is that this 
combination will be effective in generating an anti-tumor immune response against 
recurrent/metastatic HNSCC resulting in ≥ 44 % ORR. We further anticipate a rate of ≤ 25 % 
unexpected grade 3 toxicity with good patient-reported HRQoL and with correlative evidence 
demonstrating a more diversified and activated adaptive anti-tumor immune response. Because 
many side effects related to IL2 based therapies are predictable, transient, and manageable, 
they should not limit the evaluation of overall safety or therapeutic efficacy. 


V 04/19/2021 
 
 
 
5
1.3. 
Potential Risks and Benefits 
1.3.1. Potential Risks 
NKTR-214 
The potential AEs of NKTR-214 have been assessed in recent clinical studies and 
commonly include: fatigue, flu-like symptoms, rash, fever, pruritus, hypotension, 
decreased appetite, arthralgia, and cough. Flu-like symptoms, rash and pruritus are 
assumed to be cytokine mediated and have occurred 3-4 days after treatment. These 
were mild to moderate in severity. Other possible risks include, anemia, periorbital 
edema, cerebrovascular accident, atrial fibrillation and tachycardia, abdominal pain, 
constipation, diarrhea, nausea, weight decrease, myalgia, dizziness, headache, 
syncope, anxiety, dyspnea, dysphonia, and pleural effusion.  
SAEs of cerebrovascular accident (CVA), including one fatal event, have been 
observed in patients who have received NKTR 214 in the triplet combination with 
nivolumab and ipilimumab and in the doublet combination with nivolumab. A 
comprehensive search (data cutoff 21 June 2019) found 3 of 43 patients (7 %) who 
received triplet therapy in Study 16‑214‑02 (PIVOT-02) to have CVA events, all of 
which were considered by the investigator to be related to treatment with 
bempegaldesleukin, nivolumab, and ipilimumab. Additionally, 8 of 478 patients 
(1.7 %) who received doublet therapy (bempegaldesleukin and nivolumab) in Study 
16‑214-02 had CVA events, which were considered by the investigator to be related 
to treatment with bempegaldesleukin and nivolumab in 3 patients, to nivolumab in 1 
patient, and unrelated to treatment in 4 patients. The relationship of these events to 
the triplet and doublet combinations is unclear. Based on these events and a 
comprehensive assessment of CVA across all NKTR-214 clinical studies, CVA has 
been escalated to an adverse event of special interest (AESI) and mitigations have 
been put in place to reduce the risk of CVA. These mitigations include implementation 
of a CVA AESI management algorithm (Appendix B) 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 NKTR-214 
Investigator’s Brochure (IB). 
There is also the risk that previously unidentified AE could occur, as this is an 
investigational agent.  
Anti- PD-1  
The side effects of anti- PD-1 therapy are well described and are similar between 
nivolumab and pembrolizumab. The most common side effects reported in  20 % of 
patients were fatigue, pruritus, diarrhea, decreased appetite, rash, dyspnea, 
constipation, and nausea. Other serious but less common side effects were immune 
related pneumonitis, colitis, hepatitis, endocrinopathies (including hypophysitis thyroid 
disorders and type I diabetes mellitus), nephritis, infusion reactions, and embryonal 
toxicities.  


V 04/19/2021 
 
 
 
6
Palliative radiation therapy    
The side effects related to radiation therapy will vary by the site in need of palliative 
radiation therapy. They are well known but are listed here to distinguish between 
those related to NKTR-214. Within the head and neck region, common side effects 
include: mucositis, difficulty swallowing which may necessitate a feeding tube, dry 
mouth, change in taste and smell, reduced saliva production, hoarseness, radiation 
dermatitis, ear pain/infection, hearing loss, fatigue, weight loss, dehydration requiring 
IV fluids and electrolyte replacement, hair loss, tooth decay, decreased thyroid 
function. Rare and serious side effects include: breathing and swallowing issues that 
require a tracheotomy, nerve damage in the head and neck region, radiation necrosis 
of the jaw, damage to the larynx or nerves, damage to the skin, soft tissues or other 
parts of the head and neck that may require a surgery to correct and damage to the 
spinal cord which may cause permanent weakness. 
Outside of the head and neck, side effects vary by body region. Within the thorax, 
common side effects include esophagitis, dry cough, and fatigue. Esophagitis may 
require gastrostomy tube placement. Rare but significant side effects include 
radiation pneumonitis, radiation fibrosis, and rib fracture. Within the abdominal and 
pelvic regions, common side effects include diarrhea, nausea, and fatigue. Rare but 
significant side effects include ulcer, hemorrhage, obstruction, liver failure, renal 
failure, radiation cystitis, radiation proctitis, and pelvic insufficiency fracture. At 
extremity and skin sites, common side effects include skin reaction and fatigue. 
Significant effects include lymphedema and rarely non-healing wound. 
Other risks from research-related procedures 
• 
Biopsy tissue collection: primary risks include temporary discomfort, bleeding, 
infection, and ulceration 
o There are some risks associated with a tissue biopsy and steps will be 
taken to minimize these. Standard laboratory tests will be done to assess 
bleeding risk before the procedure is done. The sample will be taken from 
an area of reduced risk of complications. Possible side effects of a biopsy 
include bleeding, infection, bruising, pain or discomfort at the biopsy site 
and possible side effects from the local anesthetic (pain or bruising at the 
site where anesthetic is given). The main discomfort associated with this 
test is pain when the bone or tissue is being withdrawn. In order to make 
the procedure more comfortable, subjects may get a local anesthetic such 
as lidocaine to numb the area, at the discretion of the physician 
performing the biopsy. Local anaesthesia is generally very safe, however 
potential risks include blurred vision, dizziness, vomiting, headache, 
muscle twitching, continuing numbness, weakness, tingling, and allergic 
reaction. It is recommended that subjects be observed for at least 2 hours 
after the biopsy.  
• 
CT scans for biopsies: At the time of biopsy, a CT scan may be done to 
determine where the biopsy will be done. After the biopsy, a CT scan may be 
done over the biopsy site to look for any immediate complications. These 
scans will be performed in addition to the scans as part of normal cancer 
care. The scans involve exposure to radiation in the form of x-rays. The level 
of radiation used is kept to a minimum to prevent damage to body cells. 
Under some rare circumstances of prolonged, high-dose exposure, x-rays 


V 04/19/2021 
 
 
 
7
can cause adverse health effects, such as skin reddening (erythema), skin 
tissue injury, hair loss, and cataracts. The amount of radiation from the 
additional scans in this study is not known to be associated with any serious 
health risks. The exposure related to this CT scan equals approximately one 
year of standard environmental background radiation. 
• 
IV fluid bolus is generally very safe, however potential risks include injury to 
peripheral vein, bleeding, bruising, infection at infusion site, and development 
of peripheral or pulmonary edema. 
• 
Blood draws for clinical laboratory testing risks include bruising, swelling at 
the injection site, dizziness and lightheadedness. 
• 
Questionnaire risk loss of confidentiality, which is possible but not likely with 
data security safeguards in place. 
1.3.2. Potential Benefits 
There is no known benefit to subjects’ participation in this study. While there is hope 
that a subject’s cancer will respond to treatment with the combination of NKTR-214 
with palliative radiation, anti-PD-1 checkpoint inhibitor, there is no proof of that at this 
stage. Pembrolizumab was shown to be non-inferior to EXTREME chemotherapy in 
patients with cancer positivity score  1 on Keynote-048. Anti- PD-1 is the standard of 
care for all patients after progression on platinum doublet. Thus, as this therapy adds 
to the standard of care, we expect it to be no less effective. The current ORR with 
anti-PD-1 therapy or anti-PD-1 therapy together with palliative radiation in this patient 
population is 20 % and PFS is approximately 5 months, demonstrating an unmet 
need. This study is likely to yield knowledge about the use of NKTR-214 in treating 
HNSCC when combined with palliative external beam radiation therapy and 
checkpoint inhibitors, which could help future patients. 
 


V 04/19/2021 
 
 
 
8
2. OBJECTIVES AND OUTCOME MEASURES 
2.1. 
Primary 
Objective 
Brief 
Description/Justification 
of Outcome Measure 
Outcome Measured 
By  
Time Frame 
Evaluate ORR in 
patients receiving 
NKTR-214 in 
combination with 
palliative radiation, and 
pembrolizumab. 
Response to anti-PD-1 
therapy can be quite durable 
in patients with metastatic or 
recurrent HNSCC (~ 22 
months); however, low ORR 
(~ 20 %) limits therapeutic 
benefit in this population as 
a whole. Improving ORR 
could result in a dramatic 
impact on survival of 
patients with metastatic or 
recurrent HNSCC.  
ORR will include 
confirmed CR + confirmed 
PR and will be determined 
as per RECIST1.1. 
Progression of any 
radiated tumors will be 
considered in this 
evaluation but response of 
radiated tumor(s) will not 
be considered as 
evidence of response for 
the purpose of this study. 
 
• Pre-treatment 
standard-of-care 
imaging 
• Standard-of-care 
imaging 3 to 6 
months after Cycle 
1 
2.2. 
Secondary 
Objective 
Brief Description/ 
Justification of 
Outcome Measure 
Outcome Measured By  
Time Frame 
Evaluate the safety 
of NKTR-214 in 
combination with 
anti-PD-1 therapy 
and palliative 
radiation. 
Grade 3 or grade 4 adverse 
event except those listed in 
8.3.2 are anticipated to 
occur in < 25 % of patients 
based on the previous rate 
of 11 % with PD-1 inhibition 
and radiation. The safety of 
this combination must be 
established prior to 
evaluation of efficacy. 
Toxicities ≥ Grade 3 will be 
defined by the NCI Common 
Terminology Criteria for 
Adverse Events (CTCAE) v5.  
Toxicities not determined to be 
“unrelated” to treatment, will 
be considered treatment-
related (including those that 
are unlikely, possibly, 
probably, or definitely related). 
• Study screening 
• Cycle 1, day 1, 8 
• Cycle 2, day 1, 8 
• Cycle 3+, day 1 
• Every 4 months 
once off study 
without progression 
for 5 years, Every 6 
months once off 
study with 
progression for 3 
years 


V 04/19/2021 
 
 
 
9
Objective 
Brief Description/ 
Justification of 
Outcome Measure 
Outcome Measured By  
Time Frame 
Determine CB, PFS, 
duration of response, 
and OS after 
treatment with 
NKTR-214, anti- PD-
1, and palliative 
radiation. 
 
PFS, OS, CB, and duration 
of response were chosen as 
efficacy outcomes based on 
prior immunotherapy trials. 
Duration of response is 
particularly important, as 
more durable responses are 
expected with 
immunotherapy. 
• CB will include confirmed 
complete response (CR) + 
confirmed partial response 
(PR) + stable disease at ≥ 6 
months (SD) and will be 
determined as per RECIST1.1.  
• PFS is defined as the time 
from D1 of treatment until the 
criteria for disease progression 
is met as defined by 
RECIST1.1 or death as a 
result of any cause.  
• OS is defined as time from 
D1 of treatment until death as 
a result of any cause. 
• Duration of response is the 
period measured from the time 
that measurement criteria are 
met for complete or partial 
response (whichever status is 
recorded first) until the date 
that recurrent or progressive 
disease is objectively 
documented. 
• D1 of treatment 
• Standard-of-care 
imaging follow-up 
~3 and 6 months 
after Cycle 1 
• Time of disease 
progression 
• Death 
 
Determine the 
impact of NKTR-214, 
palliative RT, and 
anti-PD-1 therapy on 
patient-reported 
health-related quality 
of life (HRQoL) 
In incurable diseases, 
patient reported outcomes 
and quality of life have great 
influence in a patients’ 
choice of therapy.  
• Patient-reported HRQoL will 
be monitored to evaluate 
patient tolerance of treatment 
using EORTC QLQ-C30, 
EORTC QLQ-H&N35, and EQ-
5D.  
• HRQoL will be analyzed in 
subjects who received ≥ 1 
dose of study drug and have 
≥ 1 HRQoL assessment.  
• Cycle 1, Day 1 
pre-treatment 
• Cycle 1, Day 8  
• Cycle 2, Day 8 
• Cycle 3, day 1 and 
every day 1 every 
4 cycles (Q12 
weeks) to 
discontinuation of 
therapy (Sect 5.5) 
30 days post 
treatment 


V 04/19/2021 
 
 
 
10
2.3. 
Tertiary/Exploratory 
Objective 
Brief 
Description/Justification of 
Outcome Measure 
Outcome Measured 
By  
Time Frame 
Evaluate each 
subject’s tumor 
expression of PD-L1 
by histology and 
determine whether 
this predicts 
response to NKTR-
214, palliative RT, 
and anti-PD-1 
therapy. 
PD-L1 expression has been 
shown to predict response to 
immunotherapy regimens. If 
PD-L1 expression correlates 
with outcome, it could be used 
in the future to select patients 
who have greatest benefit from 
this regimen.  
• Expression of PD-L1 
by histology 
• Baseline  
• Cycle 2, Day 8 
 
Evaluate the 
immunologic 
activation induced by 
NKTR-214, palliative 
RT, and anti-PD-1 
using serologic and 
flow cytometry 
immune assays and 
T cell receptor 
sequencing.  
Evaluation of the in vivo 
immune response will help 
better define the mechanism of 
action of this combination 
therapy. 
• Levels of IFN-γ 
expressing and 
CD122+ T cells in 
Peripheral Blood 
Mononuclear Cells 
(PBMC) 
• Diversity and clonality 
of the T cell receptor 
repertoire by deep 
sequencing of PBMC 
• Cycle 1, 2, and 3, 
Day 1 prior to 
treatment infusion 
• Cycle 1, 2, and 3,  
Day 8 
• 30 days post-
treatment  
Evaluate for 
histological evidence 
of antitumor activity 
based on the cellular 
phenotype of 
infiltrate. 
Evaluation of the in vivo 
immune response will help 
better define the mechanism of 
action of this combination 
therapy. 
• Levels of tumor 
infiltrating lymphocytes 
by histology 
• Baseline 
• Cycle 2, Day 8  
 
3. STUDY DESIGN 
This is a Phase II study to characterize the efficacy of NKTR-214 in combination with palliative 
radiation, and anti-PD1 in metastatic head and neck cancer patients. These patients very 
frequently require palliation of local symptoms with radiation in combination with systemic 
therapies and currently have very limited systemic options, making this an ideal population for 
investigation of NKTR-214 combination therapy. The study has been designed as a phase II 
due to the results of PIVOT-02, which demonstrate safety of anti-PD1 and NKTR-214 at the 
doses utilized in this study. The palliative radiation therapy delivered is unlikely to significantly 
increase toxicity. We will conduct efficacy evaluation on 24 participants. Under the null 
hypothesis for ORR ≤ 0.22, based on one-sided one sample proportion test with type I error of 
0.1, the expected power levels to detect alternative ORRs of 0.35, 0.4, and 0.45 are 55 %, 
74 %, 87 % respectively. The null hypothesis will be rejected and superiority concluded if 8 or 
more responses are observed in 24 participants. This design yields a type I error rate of .04 and 
power of 0.8 when the true response rate is 44 %. 
 


V 04/19/2021 
 
 
 
11
4. STUDY POPULATION 
4.1. 
Participant Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Written informed consent and HIPAA authorization for release of personal health 
information. NOTE: HIPAA authorization may be included in the informed consent or 
obtained separately 
2. Qualify for anti-PD-1 therapy based on current guidelines at the time of registration. This 
includes the standard requirement for the participant’s tumor to have been previously 
determined to express PD-L1 with a combined positive score ≥ 1, as determined by an 
FDA-approved test. 
3. Age 18 years and older at the time of consent 
4. ECOG Performance Status of 0-2 within 30 days prior to enrollment 
5. Histologically proven diagnosis of head and neck squamous cell carcinoma that is 
metastatic or recurrent disease that is surgically incurable 
6. Prior cancer treatment other than anti-PD-1 therapy must be completed at least 30 days 
prior to registration and the subject must have recovered from all reversible acute toxic 
effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. Patients may not 
undergo concurrent anti-cancer treatment during treatment with protocol therapies. This 
includes no treatment with growth factors, tyrosine kinase inhibitors, tumor-specific 
antibodies, or cytotoxic chemotherapies such as cisplatin. Patients who have previously 
or are currently taking an anti-PD-1 therapy are eligible for this study if they meet eligibility 
criteria 2. Patients who have previously taken any other immune checkpoint inhibitor are 
eligible as long as they have completed that treatment at least 30 days prior to registration 
and meet all other eligibility criteria. 
7. Subjects with central nervous system (CNS) metastases are eligible if the CNS lesions 
are stable for at least 2 months and if tapered off treatment doses of systemic 
corticosteroids for at least 2 weeks prior to enrollment on the trial. Management with 
maintenance physiologic doses of corticosteroids (equivalent doses of prednisone ≤ 10 
mg daily) is acceptable. 
8. Subjects must have an “index” tumor that: 1) is deemed by the treating radiation 
oncologist to potentially benefit from palliative radiation 2) is amenable to biopsy, 3) is ≥ 
1 cm in longest dimension. 
9. Demonstrate adequate organ function as defined in the table below; all screening labs to 
be obtained within 30 days prior to enrollment 
System 
Laboratory Value 
Hematological 
White blood cell (WBC) 
≥ 3,000/mm3 
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Hemoglobin (Hgb) 
≥ 9 g/dL 
Platelets 
≥ 100,000/mm3 
Renal 
Serum creatinine 
≤ 2.0 mg/dL 
Hepatic 


V 04/19/2021 
 
 
 
12
Total Bilirubin 
≤ 2.0 × ULN (< 3.0 for subjects with 
Gilbert’s Syndrome) 
Aspartate aminotransferase (AST) 
≤ 3 × ULN 
Alanine aminotransferase (ALT) 
≤ 3 × ULN 
 
10. Females of childbearing potential must have a negative serum pregnancy test within 
14 days prior to enrollment and must agree to use effective contraception during active 
treatment and for 5 months after last dose of pembrolizumab and/or NKTR-214. NOTE: 
Females are considered of childbearing potential unless they are surgically sterile (have 
undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are 
naturally postmenopausal for ≥ 12 consecutive months. 
11. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study 
4.2. 
Participant Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Subjects with significant intercurrent illnesses per physician discretion 
2. Subjects with active or acute infections or active peptic ulcers, unless these conditions 
are adequately corrected or controlled, in the opinion of the treating physician 
3. Subjects with a diagnosed auto-immune disease (exceptions: subjects with controlled 
diabetes mellitus type I, thyroid disease, rheumatoid arthritis, vitiligo and alopecia areata 
not requiring treatment with immunosuppressants are eligible) 
• 
Subjects with a history of diabetes mellitus requiring systemic therapy within the 
past 3 months (i.e. either oral hypoglycemic agents or insulin) must have a 
documented Hemoglobin A1c < 8.0 % within 90 days of registration.  
4. Subjects with known genetic conditions causing pre-disposition to RT toxicity (i.e.: Li-
Fraumeni, ATM deficiency, active scleroderma, etc.)  
5. Subjects with a prior diagnosis of CVA or transient ischemic attack (TIA) 
6. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study) 
7. Known additional malignancy that is active and/or progressive requiring treatment; 
exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder 
cancer, or other cancer for which the subject has been disease-free for at least three 
years prior to enrollment 
8. Prolonged Fridericia’s corrected QT interval (QTcF) > 450 ms for men and > 470 ms for 
women at time of enrollment 
9. Subjects with symptoms of ischemic cardiac disease, congestive heart failure, or 
myocardial infarction within 6 months of registration and/or uncontrolled cardiac rhythm 
disturbance  
10. Subjects with a pulmonary embolism, deep vein thrombosis, or prior clinically significant 
venous or non-CVA/TIA arterial thromboembolic event (e.g., internal jugular vein 
thrombosis) within 3 months prior to enrollment 
• 
Patients with a history of a venous or arterial thromboembolic event must be 
asymptomatic prior to enrollment and must be receiving a stable regimen of 


V 04/19/2021 
 
 
 
13
therapeutic anticoagulation (low molecular weight heparin [LMWH] or direct oral 
anticoagulation [DOAC]). Use of coumadin is permitted; however, therapeutic 
dosing should target a specific international normalized ratio (INR) stable for at 
least 4 weeks prior to enrollment. NKTR-214 has the potential to down-regulate 
metabolizing enzymes for coumadin for approximately 1 week after 
administration of each dose of NKTR-214. Due to the possibility of drug-drug 
interactions between coumadin and NKTR-214, frequent monitoring of INR and 
ongoing consideration of dose adjustments are warranted throughout the 
patient’s participation on study. 
11. Subjects with significant psychiatric disabilities or seizure disorders if considered unsafe 
in the opinion of the treating physician 
12. Subjects with symptomatic pleural effusions or ascites 
13. Subjects with organ allografts 
14. Subjects who require, or are likely to require, systemic treatment doses of 
corticosteroids, or other immunosuppressive drugs, or have used them within 2 weeks of 
registration (clarification: subjects receiving physiologic maintenance or replacement 
doses of systemic steroids or inhaled steroids are eligible) 
15. Subjects with known human immunodeficiency virus (HIV) infection, active or chronic 
hepatitis B or hepatitis C infection, or with clinical evidence of hepatitis 
16. Subjects with known hypersensitivity to IL2 or those who experienced significant 
immune-related AEs requiring treatment with steroids or other immunosuppressant 
therapy during prior treatment with ipilimumab, or anti- PD-1/PD-L1 checkpoint blockade 
therapy 
17. Subjects who cannot provide independent, legal, informed consent 
4.3. 
Strategies for Recruitment and Retention 
The methods used for recruitment of subjects in the study will be devoid of any procedures that 
may be construed as coercive. The recruitment process will not involve any restrictions on 
socio-demographic factors, including gender or ethnic characteristics, of the subject population. 
However, the composition of the study participant population will depend on patient sources 
available to the clinical site. 
The trial will be managed by physicians at the University of Wisconsin Hospital and Clinics and 
will be conducted at the University of Wisconsin Hospital and Clinics. 24 eligible subjects will be 
recruited from the treating physicians’ own clinical practice, through clinic contacts, and referring 
physicians. 
4.4. 
Treatment Assignment Procedures 
Patients who agree to participate in the clinical trial and have been deemed eligible to do so 
based upon inclusion/exclusion criteria will be enrolled after they provide written informed 
consent. The study coordinator will assign a case number and register the patient in the 
UWCCC OnCore database prior to study therapy. The following information will be recorded for 
the purpose of registration. 
• 
Protocol number 
• 
Subject’s name 
• 
Subject’s medical record number 
• 
Subject’s demographic data such as: 


V 04/19/2021 
 
 
 
14
o Birth date 
o Race 
o Ethnicity 
o Gender 
o Insurance type 
• 
Date of consent 
4.5. 
Participant Withdrawal or Discontinuation from Study Procedures/Intervention 
4.5.1. Reasons for Participant Withdrawal or Discontinuation from Study 
Procedures/Intervention 
Subjects are free to withdraw from participation in the study at any time upon request. 
Treatment may continue as specified in the above treatment modality sections or until one of the 
following criteria applies: 
• 
disease progression;  
• 
intercurrent illness that prevents further administration of treatment;  
• 
unacceptable adverse event(s) (as determined by the subject or treating physician) 
• 
subject decides to withdraw consent for participation in the study;  
• 
subject refuses further treatment (without withdrawing consent for study participation);  
• 
general or specific changes in the subject's condition render the subject unacceptable 
for further treatment in the judgment of the treating physician;  
• 
new data related to the experimental agent which would suggest that continuing 
treatment on protocol would impose unwarranted potential risks beyond what was 
known at the time of treatment initiation;  
• 
delay of any protocol therapy for > 15 weeks 
• 
a female subject becomes pregnant; 
 
Subjects will be removed from protocol therapy and the site investigator notified when any of the 
criteria listed above apply. The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF). 
4.5.2. Handling of Participant Withdrawals from Study or Participant 
Discontinuation of Study Intervention 
Subjects will be removed from protocol therapy and the site investigator notified when any of the 
criteria listed above apply. The reason for discontinuation of protocol therapy will be 
documented on the eCRF. 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts 
should be made to complete the final study assessments. The study team will attempt to contact 
the subject by telephone or through a clinic visit to determine the reason for the study 
withdrawal. If the reason for withdrawal is an adverse event, it will be recorded on the eCRF. 
The study team will make all efforts to undertake protocol-specified safety follow-up procedures 
to capture AEs, serious adverse events (SAEs), and unanticipated problems (UPs).  


V 04/19/2021 
 
 
 
15
If a subject leaves the study prior to administration of NKTR-214, they will be replaced by an 
additional subject.  
4.6. 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the UWCCC DSMC and regulatory 
authorities. The principal investigator will also promptly inform the  institutional review board 
(IRB) and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient adherence to protocol requirements  
• 
Poor enrollment (< 1 patient in any 18 month period) 
• 
Request to discontinue the study from a regulatory authority 
• 
Company business decision 
• 
Data that are not sufficiently complete and/or evaluable 
5. STUDY INTERVENTION 
5.1. 
Pembrolizumab (Standard of Care) 
5.1.1. Acquisition  
Pembrolizumab is kept on formulary and would be administered as part of the standard of care 
for participants enrolled on this study. 
5.1.2. Formulation, Packaging, Labeling, and Administration 
Commercial supplies will be utilized. Formulation and labeling will be per package inserts. UW 
Health standard operating procedures will be followed for administration. 
5.2. 
NKTR-214 (Research-related) 
The study will utilize the UWCCC’s Pharmaceutical Research Center (PRC). The PRC ensures 
that drug research protocols proceed optimally through UWCCC’s established medication use 
system and in accordance with all federal, state, institutional and sponsor regulations governing 
clinical research.  
5.2.1. Acquisition 
NKTR-214 will be provided by Nektar Therapeutic’s designated manufacturer and an estimated 
3-4 month supply will be delivered directly to the institution based on anticipated rates of 
accrual. 
 


V 04/19/2021 
 
 
 
16
5.2.2. Formulation, Packaging, and Labeling 
NKTR-214 drug product is packaged as a sterile, single-use, lyophilized powder in 5 mL glass 
vials to be reconstituted and diluted for IV injection. Each vial of NKTR-214 drug product has a 
label claim of 1.0 mg rhIL2.  
5.2.3. Product Storage and Stability 
The product will be stored at -20 ºC +/- 5 ºC. Vials will be protected from light prior to 
reconstitution. After reconstitution, the solution does not need to be protected from light. The 
solution may be held at room temperature for up to 6 hours prior to infusion. 
5.2.4. Dosage, Preparation and Administration of Study Product 
NKTR-214 will be reconstituted in 1.1 mL water for injection by the PRC. The reason for 
reconstitution in 1.1 mL is a 0.1 mg overflow (total of 1.1 mg per vial) to ensure the full 1 mg of 
medication can be withdrawn for injection. The product should not be shaken to reconstitute but 
can be gently inverted. It should subsequently be diluted into 5 % dextrose or 0.9 % sodium 
chloride, USP. The final concentration for infusion should be 0.0024 mg/mL to 0.0675 mg/mL.  
PRC will document release of NKTR-214 to research nurse/staff or physician. Each subject will 
receive NKTR-214 through a freely-running peripheral IV catheter in the D5W or NS as noted 
above. Dosage will be 0.006 mg/kg and can be decreased to 0.003 mg/kg for some participants 
according to rules in section 5.5 of this protocol. AN IN-LINE FILTER INCLUDING IN-LINE 
FILTER EXTENSION SETS MUST NOT BE USED DUE TO DRUG LOSSES ON THE FILTER 
MEMBRANE. If a filter must be used, only 15 μm pore size drip-chamber filters are acceptable. 
NKTR-214 infusion must be promptly followed by a flush of diluent to clear the line. Care must 
be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. NKTR-214 infusions prepared in 0.9 % NaCl 
solution or 5 % Dextrose solutions are compatible with polyvinyl chloride or polyolefin containers 
and infusion sets, as well as closed-system transfer devices (CSTDs) when following specific 
instructions to ensure prepared dose accuracy. Please refer to the Pharmacy Manual/current 
Investigators Brochure for requirements regarding preparation and  
administration.  
 
5.2.5.  Premedication for Flu-like Symptoms 
 
These recommendations have been developed to reduce the risk of flu-like symptoms 
during the first week of each treatment cycle. Investigator may modify these 
recommendations based on the needs of individual patient.  
• 
Administer acetaminophen (eg, 650 mg every 6 hours) or NSAIDs (eg, ibuprofen 400 mg 
every 6 hours) a minimum of 30 minutes prior to treatment on Day 1 of each cycle. 
 
• 
Administer acetaminophen or NSAIDs q6h on Day 2 to 5 of each cycle.  
 


V 04/19/2021 
 
 
 
17
• 
Instruct patients on the signs and symptoms (fever over 100.4 °F or 38 °C, chills and 
sweats, muscle aches or join paint, fatigue and weakness), how to treat with 
acetaminophen or NSAIDs, and when to call their treating oncologist or present for 
medical care. 
 
5.3. 
Accountability Procedures for the Study Product 
A 3-4 month supply of NKTR-214 will be delivered from Nektar Therapeutics to the UWCCC 
Pharmaceutical Research Center (PRC) at the beginning of the study and will be replenished 3-
4 times annually in an amount sufficient to meet the demands of anticipated study accrual. 
UWCCC PRC will maintain careful inventory of the study drug, per standard operating 
procedures. Any unused NKTR-214 remaining at the end of this study will be destroyed by the 
UWCCC PRC. 
5.4. 
Assessment of Participant Compliance with Study Product Administration 
All therapeutic medications will be administered at UW facilities via intravenous route and 
delivery will be documented in the UWHC electronic medical record system by research nurses 
or treating physicians. External beam radiation therapy delivery will be confirmed via the record 
and verify system. 
 
5.5. 
Modification or Delay of Protocol Therapy 
Participants experiencing Grade 4 toxicity with a probable or definite attribution to NKTR-214 
will discontinue this treatment indefinitely. Participants experiencing Grade 4 toxicity with an 
unrelated, unlikely, or possible attribution to NKTR-214 will delay further therapy with this agent 
until this toxicity resolves to baseline or < Grade 2, or is deemed irreversible. 
Participants with toxicities ≤ Grade 3 will remain eligible to continue or to resume NKTR-214, but 
may be required to take a treatment break according to the following rules:  
Participants experiencing Grade 3 toxicity with an unrelated, unlikely, or possible 
attribution to NKTR-214 or Grade 2-3 toxicity with a probable or definite attribution to 
NKTR-214 will delay further therapy with this agent until this toxicity resolves to baseline 
or < Grade 2, or is deemed irreversible. In participants who experience such a toxicity, if 
this toxicity resolves to baseline or < Grade 2 prior to the participant’s next scheduled 
dose of NKTR-214 then no delay of therapy is required.  Participants with any Grade 1 
toxicity or Grade 2 toxicity with a unrelated, unlikely, or possible attribution to NKTR-214 
will continue that therapy.  
Participants who experience a treatment delay due to a Grade 3 toxicity with a possible, 
probable, or definite attribution to NKTR-214 or who experience a Grade 4 toxicity with a 
possible attribution to NKTR-214 will undergo a dose reduction to 0.003 mg/kg if resuming 
NKTR-214 dosing.  
For all participants, protocol treatment may be delayed ≤ 1 week from the expected day of the 
next treatment for any reason. If protocol treatment is delayed > 1 week, subjects will proceed 
with protocol therapy once they are determined by the treating physician to be appropriate for 
further protocol therapy. Any dosing interruption will not impact the time interval or dose of 
subsequent treatment cycles for participants that remain on study. Missed doses of drug will not 


V 04/19/2021 
 
 
 
18
be made up. Patients requiring systemic corticosteroids during a treatment break must be 
tapered off treatment doses of these prior to resuming protocol therapy. Patients delayed for > 
15 weeks will be discontinued from protocol therapy. 
Anti-PD-1 therapy and radiation therapy will be delivered and/or held per standard-of-care 
practice for all patients in this study, per the determination of the treating physician. Any patient 
for whom anti-PD-1 therapy is discontinued will also discontinue treatment with NKTR-214. Any 
patient for whom anti-PD-1 therapy is held will also have NKTR-214 held at least until the 
patient is determined by the treating physician to be eligible for anti-PD-1 therapy again, per 
standard-of-care practice. In that setting the above rules for discontinuing or holding NKTR-214 
will still apply and a patient becoming eligible to resume anti-PD-1 therapy after a hold may 
resume NKTR-214 only if they also meet the above criteria for resuming NKTR-214. If NKTR-
214 is held or discontinued, a patient may continue on anti-PD-1 therapy on this study if this is 
deemed to be within the standard-of-care for anti-PD-1 therapy administration, per the treating 
physician.  
 
 
5.6. 
Concomitant Medications/Treatments 
5.6.1. Allowed Concomitant Medications 
All treatments the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care 
provided they are not growth factors, steroids, or myelosuppressive anti-neoplastic drugs. 
5.6.2. Prohibited Concomitant Medications 
Treatment with systemic treatment doses of corticosteroids will result in discontinuation of 
protocol therapy with NKTR-214 + anti-PD-1 (clarification: physiologic maintenance or 
replacement doses of systemic steroids and topical steroids are acceptable). If the use of 
systemic treatment doses of corticosteroids or other immunosuppressive drugs is considered 
unlikely or not related to NKTR-214 + anti-PD-1, the NKTR-214 + anti-PD-1 treatment may be 
resumed two weeks following discontinuation of systemic steroids with the subsequent cycle at 
the discretion of the responsible physician. 
No other cancer chemotherapy, growth factors, or therapeutic doses of corticosteroids can be 
used unless required to manage immune-related toxicity. Management with maintenance 
physiologic doses of corticosteroids is acceptable (prednisone equivalent dose ≤ 10 mg daily). 
5.7. 
Administration of Intervention 
5.7.1. Pre-medication, Hydration, and Ancillary Medications 
Hydration Guidelines - Adequate hydration mitigates the development of hypotension 
associated with NKTR-214 administration. Hydration and renal function must be assessed 
within 72 hours, or as soon as locally feasible, prior to NKTR-214 study drug administration (see 
Appendix C for the list of analytes that require collection and evaluation prior to NKTR-214 study 
drug administration). For participants who must delay study treatment due to creatinine 
increase, see additional information regarding criteria to delay (Sections 6.4), resume (Section 
6.4), or permanently discontinue study treatment (Section 5.5). Underlying reasons for 
decreased oral intake (e.g., nausea) should be addressed and treatment (e.g., IV hydration) 


V 04/19/2021 
 
 
 
19
should be provided. The Investigator may modify these recommendations based on the needs 
of the individual participant. Participants will also be provided a handout with hydration 
guidance.  
Participants should be administered 1 liter of IV fluid on the day of each dosing of NKTR-214. In 
addition, consider administering 1 liter of normal saline IV when the Participants return for clinic 
visits (e.g., if the participant returns for PK draws on Days 3 and 5 of Cycle 1), anytime based 
on the participant’s need, or as clinically indicated. Participants are to be instructed that for the 
next 3 days after administration of NKTR-214, they should 1) drink at least 2 liters per day of 
self‑administered oral hydration and 2) avoid activity which may contribute to dehydration 
(including, but not limited to, strenuous activity, long hot showers, and saunas) for 3 days 
following treatment with NKTR-214.  
Allergic reaction guidelines - Any subject showing allergic symptoms with NKTR-214+anti-PD-1 
should receive diphenhydramine, acetaminophen, and an H2 blocker (e.g. ranitidine 150 mg 
PO) as premedication before all subsequent doses.  
In the case of common symptoms related to NKTR-214+anti-PD-1: appropriate antibiotics, 
blood products, antiemetics, fluids, electrolytes, and general supportive care are to be used as 
necessary. 
In the case of a severe allergic reaction (anaphylactic precautions should be taken): treatment 
can include: 
• 
Dexamethasone 10 mg IV 
• 
Diphenhydramine 50 mg IV 
• 
Epinephrine 3-5 mL IV [1:10,000]; 0.5 mL SC [1:1000]  
• 
Equipment for assisted ventilation 
• 
A free flowing IV line must be established at all times.  
5.7.2. Supportive Care 
Treatment of any immune-related toxicities will be guided by the NCCN guidelines on this 
subject. Treatment of any radiation-related toxicities will be guided by the treating radiation 
oncologist. Any necessary supportive care is permitted, except as noted above. 
5.7.3. NKTR-214+anti-PD-1 following palliative RT administration 
Drug 
Dose1 
Route 
Schedule2 
Palliative 
RT 
8 Gy x 3 
fractions or 
4 Gy x 5 
fractions 
External beam radiation 
(EBRT) with MV 
photons, MV electrons, 
or protons  
Completed 3-7 days before 
the second dose of anti-PD-
1. Delivered in person by 
UWCCC Radiation 
Therapists under the 
direction of the treating 
physician. Approximately 30 
minute duration of each 
treatment fraction. 
NKTR-214 
0.006 mg/kg3 
IV  
Q3W. Administered in 
person by UWCCC staff 


V 04/19/2021 
 
 
 
20
under the direction of the 
treating physician, 
immediately prior to anti-PD-
1 infusion. Approximately 1 
hour infusion. 
Anti-PD-1 
200 mg 
pembrolizumab  
IV  
Pembrolizumab Q3W, 
administered in person by 
UWCCC staff under the 
direction of the treating 
physician, immediately 
following NKTR-214 
infusion. Approximately 1 
hour infusion. 
1 Based on subject’s actual body weight.  
2 A window of ± 7 days may be applied to all treatment visits and ± 7 days for all clinic 
visits to accommodate observed holidays, inclement weather, scheduling conflicts 
etc. Date and time of each drug administration should be clearly documented in 
subject’s and eCRFs. 
3 Dose of NKTR-214 may be reduced to 0.003 mg/kg according to rules defined in 
section 5.5 of this protocol. 
5.8. 
Palliative Radiation Therapy (RT)—Standard of Care 
All procedures in Section 6.9 are considered standard of care and are described in detail to 
assure consistent treatment among study participants. In the study, subjects must be 
determined by the treating physician to have a need for palliative RT based on current or 
potential symptoms at a tumor site(s). These subjects will receive a course of palliative RT 
targeting any sites deemed to merit palliative RT treatment and will complete this RT on days -7 
to -3 relative to the second doses of anti-PD-1 and NKTR-214. 
Palliative radiation therapy on this study may be directed to tumor(s) at any location in the body, 
except those located in the brain/brainstem or in the spinal cord. Targets adjacent to but not 
directly involving these exception sites may be targeted. No limit is placed on the maximum size 
of a tumor that can be radiated, given the palliative intent of this treatment.  Patients can have 
received previous radiation to the target site(s). 
Following radiation therapy, acute and late AEs related to the RT will be assessed at all 
scheduled follow-ups where AEs are evaluated.  
5.8.1. Selection of an Index Tumor Site  
From the tumor site(s) receiving palliative RT, a targeted (index) tumor will be selected at the 
discretion of the attending physician based on need for palliative radiation, ease of being able to 
obtain post-treatment biopsies from that site, and size at least 1 cm in longest dimension. 
Whenever possible, the targeted region should not have received RT prior to enrollment in this 
study. Palliative RT may be delivered to other sites of disease if deemed necessary and safe.  


V 04/19/2021 
 
 
 
21
5.8.2. Radiation Dose (SOC) 
The treating physician will use his/her discretion to decide between a dose and fractionation 
schedule of 8 Gy x 3 or 4 Gy x 5. Radiation can be delivered either daily or every other day and 
is generally provided on weekdays only. The treating physician will also use his/her discretion if 
multiple sites of disease will be treated with RT. If multiple sites of disease are being treated, 
these treatments should conclude between days -7 to -3 relative to the second doses of 
anti-PD-1 and NKTR-214.  
5.8.3. Radiotherapy Delivery (SOC) 
RT delivery will follow standard practice for palliative RT treatment and will utilize megavoltage 
(MV) photons or electrons. Any number or arrangement of beams may be used at the discretion 
of the treating physician to achieve target coverage and conformality.  
Treatment Simulation, Subject Positioning and Set-up 
Subject will be positioned in a comfortable position. Any immobilization apparatus may be used 
at the discretion of the treating physician as long as it does not interfere with the proper 
functioning of any necessary treatment planning or image-guidance systems. A CT simulation 
will be performed for all patients to facilitate treatment planning, consistent with standard 
practice approaches for the planning of palliative RT. The planning CT scan may be done with 
intravenous contrast if this is beneficial for target or normal tissue segmentation. CT scan 
thickness will be ≤ 0.3 cm. Planning CT scan will be acquired with the subject in the same 
position and using the same immobilization device as for treatment. At a minimum, all tissues 
within 5 cm of the target volume will be included in the CT scan. For spinal lesions treated with 8 
Gy x 3, a pre-treatment MRI is required to assess the extent of disease and position of the cord. 
This must be fused with the planning CT scan. 
Treatment positioning and simulation techniques will follow standard approaches for palliative 
radiation. Examples are detailed below for specific body sites.  
 
Head and neck 
Immobilization will be performed using a thermoplastic head mask. A head and shoulder 
masks should be used if treatment includes cervical nodes to help immobilize the shoulders. 
Head only masks can be used if lesion does not extend to the neck. Patients will be planned 
in the supine position with their arms at their sides, ensuring the shoulders are situated as 
far inferior as possible to avoid entry and exit through the shoulders. Additional 
immobilization devices such as a bite block are permitted.  
 
Thoracic 
The patient will typically be positioned supine and a vac lock mold or a wingboard with arms 
overhead may be used for immobilization. Body fix is not required unless an 8Gy X 3 plan is 
utilized to a target site located within 1 cm of the spinal canal. The CT will include the entire 
volume of both lungs. Both 4D-CT and use of respiratory gating are permissible but not 
required.  
 
Abdomen and pelvis  


V 04/19/2021 
 
 
 
22
The patient will typically be simulated supine with arms on chest or overhead. Immobilization 
with vac lock body fix can be utilized and a 4DCT or respiratory gating are permissible but 
not required. If the tumor is adjacent to the bladder, bladder filling instructions will be 
provided to the patient, and the patient should be treated with the same bladder filling as 
simulation.  
Tumor Localization and Target and Normal Tissue Volumes  
CT will be the primary image platform for treatment planning. Treatment planning and dosimetry 
will be performed to confirm adequate target coverage. Tumor localization will be performed by 
the treating physician. This can be done clinically by visual demarcation for electron treatment 
and can be aided by placing a wire or other marker at the time of CT simulation. The Gross 
Tumor Volume (GTV) will be defined by the treating physician using a combination of clinical 
assessment, available diagnostic imaging, and the planning CT scan. The GTV should 
encompass the entirety of the tumor volume. This volume will be expanded to generate a 
clinical target volume (CTV). The CTV will typically be an expansion of the GTV by 3-5 mm, 
however in certain instances, the treating physician may elect a 0 mm expansion of GTV to CTV 
in some or all directions due to proximity of adjacent critical structures or anatomic barriers to 
microscopic spread of disease. The CTV will be confined by an external skin contour. The CTV 
may include any contiguous areas that the treating physician deems likely to harbor microscopic 
disease. The CTV will be expanded to define a planning target volume (PTV) that accounts for 
potential variations in positioning and set-up, as well as isodose convergence at depth in the 
case of electron therapy. PTV will be 2-3 mm in the neck, 5 mm in the lung with 4DCT per 
institutional standards, customized if respiratory gating is used (based on calculated uncertainty 
from 5 repeat scans), and 2-10 mm in the abdomen and pelvis depending on location (i.e. spine 
may be 2-3 mm, while a soft tissue lesion will require larger margins). 
Organs at risk that are visible in the planning CT scan will be contoured. Any organs at risk will 
be contoured and considered as solid structures. Structures not deemed to be at risk due to 
their distance from the target area need not be contoured. If the targeted lesion is within 10 cm 
of the following organs it is anticipated they will be contoured: spinal cord, kidneys, bowel, 
stomach, liver, heart, lungs, esophagus, bladder, rectum, brain, eyes, lenses, cochlea, 
brainstem, larynx, oral cavity, gonads, genitalia. Contouring of these organs at risk should be 
done following the region-specific contouring atlas guidelines of the NRG, found here: 
https://www.nrgoncology.org/ciro-contouring-atlases-templates-and-tools.  
Radiation Treatment Planning and Dosimetry 
3D-conformal RT planning will be utilized to determine target coverage and to evaluate the dose 
delivered to other organs at risk. For all patients, image artifacts on the CT simulation scan such 
as streaks near metal, dental implants, fillings, surgical shunts, clips or other high or low density 
objects should be overridden with appropriate Hounsfield Units. Intensity modulated radiation 
therapy (IMRT) planning and delivery may be utilized, if deemed necessary by the treating 
physician for the purpose of achieving target coverage, conformality, or other dosimetric 
parameters. The treating physician will use his or her discretion to determine the appropriate 
dose, fractionation, and treatment planning/delivery approach for any treatment site, working 
within the parameters set forth in this protocol. Dose conformality should be maximized, when 
feasible. The point of maximum dose should be placed within the GTV when practical.  
The goal for target coverage will be for 95% of the PTV to receive 95% of the prescription dose. 
This is consistent with standard practice for a palliative radiotherapy plan. Also consistent with a 
palliative plan, it is understood that in some cases this will not be possible due to normal tissue 


V 04/19/2021 
 
 
 
23
constraints. In those cases, lower coverage is acceptable for the purpose of achieving normal 
tissue constraints and there is not minimal acceptable dose coverage for this reason. The 
maximum acceptable dose to 0.03 cc in any treatment plan is 150% of the prescription dose 
within the GTV and 115% of the prescription dose outside of the GTV. 
We will use the collapsed-cone superposition-convolution calculation algorithm in the 
RayStation for treatment planning software for treatments using Tomotherapy or Varian linear 
accelerators with photon plans. For electron plans, we will use Monte Carlo calculations in 
Raystation. For ViewRay we will use Monte Carlo algorithm for treatment planning. The grid size 
is <=3 mm for all plans. 
Treatment planning will be carried out respecting all normal tissue constraints. Dose constraints 
for three- and five-fraction radiotherapy treatments will be those specified in table 3 of the report 
of the AAPM Task Group 101 on stereotactic body radiation therapy: 
https://aapm.onlinelibrary.wiley.com/doi/full/10.1118/1.3438081. Each of these constraints will 
take priority over GTV, CTV, and PTV coverage because of the palliative nature of the standard 
of care radiotherapy being used in this study. 
For patients who have received prior radiotherapy to a target site, an EQD2 composite plan will 
be generated to account for the hypofractionated approach utilized in this study. All attempts will 
be made to limit the dose to 0.03 cc to the spinal cord to < 60 Gy in the composite; however, a 
dose of 65 Gy will be the absolute limit in this circumstance. The brainstem will be constrained 
to 70 Gy in the composite. Mandible will be constrained to a maximum dose of 105Gy in the 
composite. The uninvolved larynx will be limited to an EQD2 composite mean dose of 35 Gy. 20 
Gy in 5 fractions will be used for any tumor sites that have previously been treated to an EQD2 
of ≥ 60 Gy. 
Every radiotherapy treatment plan will be approved by the attending physician and a quality 
assurance check will be performed, per standard of care, by a medical physicist. All 8 Gy X 3 
radiotherapy treatment plans will be reviewed, per standard practice, at the weekly UW 
Radiation Oncology Chart Rounds. 
Treatment Verification 
After the subject is setup on the treatment table, standard imaging approaches (orthogonal x-
rays, CT, MRI, and/or light field clinical set-up) will be used to align the subject with the 
treatment machine geometry based on the treatment plan. After initial alignment, shifts or 
rotations will be made as necessary using couch motion to achieve precise replication of the 
planned positioning. After initial localization is performed, all effort should be made to initiate the 
treatment delivery as quickly as possible. If reproducible positioning is not achieved treatment 
re-planning will be allowed as deemed necessary by the treating physician.  
Sequencing of Radiation with Other Treatments 
Following RT, subjects will receive cycle two of anti-PD-1 + NKTR-214. A minimum of 3 days 
should separate completion of RT from the second NKTR-214 dose and second anti-PD-1 dose. 
A maximum of 7 days should separate completion of RT from the second NKTR-214 dose and 
second anti-PD-1 dose. 
Radiotherapy dose modifications, interruptions, or discontinuation 
Because radiation therapy is delivered as a standard-of-care on this study the dose will not be 
modified once that treatment has commenced. If radiotherapy is interrupted for any reason 
including participant missing an appointment or a treatment machine being temporarily out-of-


V 04/19/2021 
 
 
 
24
service, that treatment can be resumed after interruption so long as radiotherapy is completed 
greater than 3 days prior to cycle 2 of NKTR-214 and anti-PD-1. Notably, as specified in section 
5.5, delivery of NKTR-214 and anti-PD-1 therapy can be delayed by ≤ 1 week if needed for any 
reason and this includes for allowing time to complete radiotherapy. Radiotherapy will not be 
interrupted electively by the treating physician. The treating physician may discontinue a course 
of radiotherapy for a participant for any Grade 3 or greater toxicity that develops after initiating 
radiation or for any situation in which the treating physician determines that standard-of-care 
practice or patient safety would deem it necessary to discontinue radiation therapy. Any 
participant receiving at least one fraction of radiotherapy and subsequently discontinuing 
radiotherapy will remain eligible to proceed on study and receive planned cycles of NKTR-214 
and anti-PD-1 therapy. Any participant deciding to discontinue radiotherapy prior to receiving 
any radiotherapy will be discontinued from the study. 
Additional Radiation Treatments 
For subjects who meet criteria for continuing on trial after completion of cycle 3 of NKTR-
214+anti-PD-1 injections, additional courses of palliative RT may be delivered if deemed 
clinically necessary for palliative purposes by the treating radiation oncologist. Whenever 
possible, a dose of 8 Gy x 3 or 4 Gy x 5 will be used for these additional course(s) of palliative 
RT. RT in these courses may target any tumor sites that become currently or imminently 
symptomatic. 
 
6. STUDY SCHEDULE 
Cycle = 21 days 
6.1. 
Screening (Day -28) 
Screening/Baseline Visit (Day -28 to -1)  
• 
Obtain demographics, medical and smoking history (SOC) 
• 
Confirm diagnosis and staging (SOC) 
• 
Confirm histologically proven recurrence (SOC) 
• 
Perform physical exam (SOC) 
• 
Collect vital signs, ECOG Performance status (SOC) 
• 
Obtain and review concomitant medications (SOC) 
• 
Obtain EKG and confirm no QT prolongation [Research Related (RR)] 
• 
Review trial awareness, obtain, and document informed consent (one copy to be 
provided to subject) (RR) 
• 
Collect laboratory assessments (SOC): 
o Complete blood count with diff (CBC w/diff) 
o Comprehensive Metabolic Profile (CMP) 
o Amylase and lipase 
o PT/INR and PTT 
o Thyroid function (TSH, T4) 
o Pregnancy test (serum or urine) for women of child bearing potential (WOCBP) 


V 04/19/2021 
 
 
 
25
• 
Perform disease assessments (SOC) 
o CT of neck 
o PET scan and/or CT of Chest ± CT of Abdomen/Pelvis 
• 
Confirm eligibility based on inclusion/exclusion criteria (RR) 
• 
Collect health-related quality of life (HRQoL) questionnaires (RR) 
• 
Specimen Collection 
o Archival tumor tissue (SOC) 
 
Unstained fixed formalin, paraffin embedded (FFPE) slides (if available) 
6.2. 
Cycle one 
6.2.1. Cycle one, day 1 (C1D1) 
• 
Perform physical exam (SOC) 
• 
Collect vital signs and ECOG performance status (SOC) 
• 
Perform Laboratory Assessments (SOC) 
o CBC w/diff (if within 7 days of screening labs, no need to repeat) 
o CMP (if within 7 days of screening labs, no need to repeat) 
o Amylase and Lipase (if within 7 days of screening labs, no need to repeat) 
• 
Collect blood for serum and PMBC prior to infusion of anti-PD-1 or NKTR-214 (RR) 
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1) and review concomitant 
medications (SOC) 
• 
Administer anti-PD-1 (SOC) 
• 
Administer NKTR-214 (RR) 
6.2.2. Cycle one, day 8 (C1D8) ± 5 days 
• 
Collect HRQoL questionnaires (RR) 
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1) and review concomitant 
medications (SOC) 
• 
Collect blood for serum and PMBC (RR) 
6.3. 
Palliative Radiation Therapy (to be completed between C2D-7 to C2D-3 or 
C1D15 to C1D19) 
• 
Administer palliative RT to index tumor (SOC) 
6.4. 
Cycle two 
6.4.1. Cycle two, day 1 (C2D1 or C1D22) ± 5 days 
• 
Perform physical exam (SOC) 
• 
Collect vital signs and ECOG performance status (SOC) 
• 
Collect blood for serum and PBMC prior to infusion of anti-PD-1 or NKTR-214  (RR) 
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1 and RT) and review concomitant 
medications (SOC) 


V 04/19/2021 
 
 
 
26
• 
Perform Laboratory Assessments (SOC) 
o CBC w/diff 
o CMP 
o Amylase and Lipase 
o TSH and T4 
• 
Administer anti-PD-1 (SOC) 
• 
Administer NKTR-214 (RR) 
6.4.2. Cycle two, day 8 (C2D8) ± 5 days 
• 
Collect HR-QoL questionnaires (RR) 
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1 and RT) and concomitant 
medications (SOC) 
• 
Collect biopsy of index tumor (RR) 
• 
Collect blood for serum and PBMC (RR) 
6.5. 
 Cycle three and thereafter 
6.5.1. Cycle three and thereafter, day 1 (C3+D1) ± 7 days 
• 
Collect HRQoL questionnaires (RR) (Q4 cycles) 
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1 and RT) and concomitant 
medications (SOC) 
• 
Perform physical exam (SOC) 
• 
Collect vital signs and ECOG performance status (SOC) 
• 
Perform Laboratory Assessments (SOC) 
o CBC w/diff  
o CMP  
o Amylase and Lipase 
o TSH, T4 (prior to even cycles) 
• 
Perform imaging assessment (SOC) 
o CT neck (Q4 cycles) 
o CT chest, abdomen, and/or pelvis of all known sites of disease OR PET/CT (Q4 
cycles) 
• 
Collect blood for serum and PMBC prior to infusion of anti-PD-1 or NKTR-214 (cycle 
three only, RR) 
• 
Administer anti-PD-1 (SOC) 
• 
Administer NKTR-214 
6.5.2. Cycle three only, day 8 (C3D8) ± 7 days 
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1 and RT) and review concomitant 
medications (SOC) 
• 
Collect blood for serum and PBMC (RR) 


V 04/19/2021 
 
 
 
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6.6. 
Long term follow-up (Every 4 months +/- 30 days if no progression, every 6 
months +/- 6 months after progression) 
If the subject discontinues therapy for reasons other than progression, the participant will be 
followed per SOC, typically every 3-6 months for a total of 5 years follow-up. If the subject 
develops progression, they will enter SOC follow-up every 3-6 months for a total of 3 years.  
• 
CT neck (SOC) 
• 
CT chest, abdomen, and/or pelvis of all know sites of disease OR PET/CT (SOC) 
• 
Documentation of survival status and subsequent therapy (SOC) 
• 
Document AE > grade 3 with attribution of possibly, probably and definitely related to 
study treatment (RR for NKTR-214, SOC for anti-PD-1 and RT) 
6.7. 
Safety Follow-up (30 days after therapy completion +/- 14 days) 
This visit will be performed per standard of care, 30 days after the last dose of study therapy. 
This can be due to disease progression or due to other reasons for discontinuation as noted 
above.  
• 
Document AEs (RR for NKTR-214, SOC for anti-PD-1 and RT) and concomitant 
medications (SOC) 
• 
Collect HR-QoL questionnaire at 30 days after study discontinuation (RR) 
• 
Perform physical exam (SOC) 
• 
Collect vital signs and ECOG performance status (SOC) 
• 
Collect blood for serum and PBMC (RR) 
• 
Perform Laboratory Assessments (SOC) 
o CBC w/diff  
o CMP  
o TSH and free T4 
6.8. 
Final Study Visit or Withdrawal Visit 
If the participant decides they no longer wish to participate in study follow-up, that visit will 
constitute the final study visit. Otherwise, the final study visit will occur at the completion of long-
term follow-up, as noted above. 
• 
Record AEs as reported by participant or observed by investigator (RR for NKTR-214, 
SOC for anti-PD-1 and RT) 
• 
Collect HRQoL questionnaire (RR) 
• 
Perform physical examination (SOC) 
 


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7. STUDY PROCEDURES/EVALUATIONS 
7.1. 
Study Procedures/Evaluations 
7.1.1. Demographics (SOC) 
Birth date, gender, race, and ethnicity will be collected at screening (recorded for the study from 
medical records maintained as part of standard clinical care). 
7.1.2. Medical History (SOC) 
A thorough review of the subject’s medical history, taking into account all recent and pertinent 
medical conditions including prior cancer treatment, will be performed at screening. This will be 
recorded for the study from medical records maintained as part of standard clinical care. 
7.1.3. Physical Exam (SOC) 
A physical exam will be completed at the time of screening, C1D1, and D1 of each subsequent 
cycle, safety follow-up, withdrawal visit, and final visit. This will be recorded for the study from 
medical records maintained as part of standard clinical care 
7.1.4. Vital Signs (SOC) 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) will be recorded at 
screening, C1D1, and D1 of each subsequent cycle, and safety follow-up. This will be recorded 
for the study from medical records maintained as part of standard clinical care. 
7.1.5. Adverse events (RR/SOC) and concomitant medications (SOC) 
AEs will be recorded at screening and each clinic and research visit, and at the safety follow-up. 
All of these recordings will be performed as part of the standard of care. AEs will be assessed 
as described in Section 9. Concomitant medications will also be assessed at this time point. 
7.1.6. Weight (SOC) 
Weight will be recorded at screening, C1D1, and D1 of each subsequent cycle. This will be 
recorded for the study from medical records maintained as part of standard clinical care. 
7.1.7. Diagnostic biopsy (SOC) 
An SOC biopsy is required to prove metastatic or recurrent disease. When available in excess 
of what is required for Surgical Pathology diagnosis, archival FFPE tissue (up to 20 slides of 
5um tissue) will be provided to the biological correlates study team.  
7.1.8. Index tumor biopsy (RR)  
A research-related biopsy will be performed by core needle, punch, or incisional technique at 
the discretion of the surgeon/interventional radiologist on day 8 (+/- 5 days) of cycle 2.  
7.1.9. Blood draw (RR) 
Blood will be collected (10 mL each in separate tubes for PBMC and serum) and sent on ice 
immediately to the UW H&N SPORE Pathology Core facility or the Morris lab for processing and 
storage prior to treatment infusion on Day 1 of C1, C2, and C3, at Day 8 of C1, C2, and C3, and 
at the safety follow-up.  


V 04/19/2021 
 
 
 
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7.1.10. ECOG Performance Status (SOC) 
Determination of the subject’s performance scale based on the ECOG rating scale (Appendix D) 
will be made at the time of screening, C1D1, D1 of each subsequent cycle, and safety follow-up. 
This will be recorded for the study from medical records maintained as part of standard clinical 
care.  KPS scores will be converted to ECOG ratings using a conversion table (Appendix E). 
7.1.11. Quality of Life Measures (RR) 
Quality of life (HRQoL) surveys will be collected at screening/baseline, C1D8, C2C8, C3+D1 
(every 4 cycles), at safety follow-up, and at long-term follow-up or withdrawal. The surveys are 
anticipated to take ~ 10 minutes to complete. 
• 
EORTC QLQ-C30 
• 
EORTC QLQ-H&N35 
• 
EQ-5D 
The completion of HRQoL surveys is a research procedure. 
Validated health outcome surveys will be used to assess subject perception of mental and 
physical health, HRQoL, and cancer-related H&N functioning (11). 
Each subject will serve as his or her own control with complete HRQoL evaluation prior to and 
following treatment. Current phase III NRG trials evaluating quality of life have not defined a 
minimally important difference using the above selected quality of life metrics, and further work 
is needed for this to be robustly defined. However, the EORTC QLC-C30 has been shown to be 
robust across trials and will allow for comparison of QOL to prior studies. This will take into 
account various baseline dysfunctions that may be present due to metastatic head and neck 
cancer. 
Perception of general health and HRQoL will be evaluated using the European Organization for 
Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and 
EQ-5D (12) (13, 14). The EORTC QLQ-C30 was chosen for its sensitivity to cancer-related 
quality of life and symptomatology, such as nausea/vomiting, fatigue and pain, and because it 
was identified previously as being well-developed, reliable, valid, and responsive (15). The EQ-
5D was chosen due to its wide use in assessing generic health status. It assesses five 
dimensions of health status: mobility, self-care, usual abilities, pain/discomfort, and 
anxiety/depression (16).  
Specific cancer-related H&N functioning will be assessed with the EORTC QOL Questionnaire 
H&N35 (EORTC QLQ-H&N35) (17, 18). This validated instrument incorporates items related to 
swallowing, eating, dry mouth, and saliva production and is sensitive to cancer site and stage 
(17). The EORTC QLQ-C30 and QLQ-H&N35 will be administered together and will yield a 
global health status score.  
7.1.12. Diagnostic Imaging (SOC) 
Diagnostic imaging will be performed at screening, prior to cycle 3, and then every four cycles. 
Imaging studies can be obtained at any time if clinically indicated by the treating physician. 
Imaging studies shall consist of a CT neck to evaluate locoregional disease status and a 
PET/CT or CT of the chest, abdomen, and pelvis to evaluate known systemic disease status.  
Imaging studies are standard clinical care procedures being done within routine care guidelines. 


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30
7.2. 
Laboratory Procedures/Evaluations  
Laboratory testing will be completed by CLIA-certified labs.  
7.2.1. Clinical Laboratory Evaluations 
Complete Blood Count with Differential (SOC) 
Blood will be drawn for CBC with differential at screening, and prior to treatment infusion on 
C1D1, D1 of each subsequent cycle, and at safety follow-up. This is part of the standard of care 
for anti-PD-1 therapy.  
The CBC will include red blood cell count, hemoglobin, hematocrit, WBC count with differential 
including % neutrophils, lymphocytes, monocytes, eosinophils and basophils, absolute 
neutrophil count, and platelet count. 
Serum Chemistries (SOC) 
Blood will be drawn for serum chemistries at screening, C1D1, D1 of each subsequent cycle, 
and at safety follow-up. This is part of the standard of care for anti-PD-1 therapy. 
The serum chemistries will include sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, total bilirubin, calcium, protein, albumin, 
phosphorus, amylase, and lipase. 
Pregnancy Test (SOC) 
A urine pregnancy test will be completed within 7 days of registration and within 7 days C1D1. 
Women who are postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, 
bilateral oophorectomy, or hysterectomy) are not considered to be of childbearing potential.  
Pregnancy testing is being done as part of standard clinical care. 
Thyroid Function Tests (SOC) 
Blood will be drawn for serum analysis of TSH and free T4 at screening, prior to even cycles, 
and at safety follow-up. This is a standard clinical procedure performed within routine guidelines 
for participants receiving anti- PD-1 therapy.  
Electrocardiogram (EKG) (RR) 
A standard 12-lead EKG will be obtained at screening to evaluate for QT prolongation. 
 
7.2.2. Specimen Preparation, Handling, and Storage 
Index tumor biopsy will be obtained day 8 (+/-5) of cycle 2. Blood will be drawn for PBMC and 
serum prior to treatment infusion on Day 1 of Cycle 1, 2, and 3, on Day 8 of Cycle 1, 2, and 3,  
and at the safety follow-up after treatment discontinuation. 
Source and Timing of Biospecimen Collections 
Standard biopsy is required to prove metastatic or recurrent disease and archival tissue will be 
obtained from that biopsy whenever possible.  


V 04/19/2021 
 
 
 
31
Whole blood specimens (10 mL each for PBMC and Serum, in separate tubes) will be collected 
and sent on ice immediately to the UW H&N SPORE Pathology Core facility or the Morris lab for 
processing and storage. 
Index tumor biopsies (research biopsy) will be performed by core needle, punch, or incisional 
technique at the discretion of the surgeon/interventional radiologist. Tissue from these biopsy 
specimens will be used, in order of availability, for formalin-fixed paraffin embedded histology 
and flash frozen in an Eppendorf tube. Surplus tissue should be flash frozen.  
Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples that were collected for study-
specific correlative research. The UW H&N SPORE Pathology Core facility and/or the Morris lab 
will manage the banked samples.  
Confidentiality of Biospecimens 
Samples will be identified by a subject’s study number assigned at the time of registration to the 
trial. Any material issued to collaborating researchers will be anonymized and only identified by 
the subject’s study number and specimen description. 
 
8. ASSESSMENT OF SAFETY 
8.1. 
Specification of Safety Parameters 
The Investigator should elicit information regarding the occurrence of AEs through open-ended 
questioning of the subject, physical examination, and review of laboratory results. AE data 
collection and reporting, which are required as part of every clinical trial, are done to ensure the 
safety of participants enrolled in the studies as well as those who will enroll in future studies 
using similar agents. AEs are reported in a routine manner at scheduled times during a trial. 
Additionally, certain AEs must be reported in an expedited manner to allow for optimal 
monitoring of participant safety and care. The first step is to identify the event using the NCI 
CTCAE version 5.0. The CTCAE document provides descriptive terminology for adverse event 
reporting. A grading (severity) scale is provided for each AE term. 
All AEs, whether serious or not, will be described in the source documents and the AE page of 
the eCRF. All new events, as well as those that worsen in intensity or frequency relative to 
baseline, that occur after administration of study drug through the period of protocol-specified 
follow-up must be captured. 
Specific anticipated AEs are described in section 2.3. 
Information to be reported in the description of each AE includes but is not limited to: 
• 
Medical diagnosis of the event. (If a medical diagnosis cannot be determined, a 
description of each sign or symptom characterizing the event should be recorded.)  
• 
The date of onset of the event  
• 
The date of resolution of the event 
• 
Whether the event is serious or not 
• 
Action taken 


V 04/19/2021 
 
 
 
32
• 
Outcome 
• 
Relatedness to the study drug and expectedness (see below) 
• 
Subject’s condition is intermittent or continuing 
• 
The grade of the event based on the CTCAE v5.0 
8.1.1. Unanticipated Problems (UPs) 
The Office for Human Research Protections (OHRP) considers UPs involving risks to subjects 
or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
subject population being studied; 
• 
related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.1.2. Adverse Events (AEs) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• 
Unintended or unfavorable sign or symptom 
• 
A disease temporally associated with participation in the protocol 
• 
An intercurrent illness or injury that impairs the well-being of the subject 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests.  
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator.  
8.1.3. Serious Adverse Events (SAEs) 
A serious adverse event is defined as any adverse event that meets one or more of the 
following criteria: 
• 
Results in death; OR 
• 
Is life-threatening; OR 
• 
Requires hospitalization or prolongs existing hospitalization; OR 
• 
Results in significant or persistent disability or incapacity; OR 
• 
Results in a congenital anomaly/birth  


V 04/19/2021 
 
 
 
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Planned hospitalizations for disease-related surgery, routine procedures, non–disease-related 
procedures, and grade 3 toxicities listed in section 2.6.1.2 are not considered SAEs. 
8.1.4. Adverse Event of Special Interest (AESI) 
Based on the results of prior studies, CVA has been defined as an AESI. Any CVA 
will be reported as an AESI. 
8.2. 
Time Period and Frequency for Event Assessment and Follow-Up 
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization. 
• 
UP will be recorded in the data collection system throughout the study.  
• 
AEs with start dates occurring any time after informed consent until 30 days after end of 
treatment.  
• 
SAEs with start dates occurring any time after informed consent until 90 days after end 
of treatment or until a new anti-cancer therapy begins. 
• 
After 90 days post completion of therapy, only SAEs with the attribution of possibly, 
probably or definitely will be recorded. 
8.2.1. Safety Follow-up Evaluations 
A safety follow-up visit should occur when subjects permanently stop study treatment for 
whatever reason (toxicity, progression, or at discretion of site investigator) and should be 
performed 30 days (±7 days) after the last dose of treatment. Subjects who have an ongoing 
≥ grade 2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to 
≤ Grade 1 or baseline, is deemed clinically insignificant, and/or until a new anti-cancer treatment 
starts, whichever is earlier. 
8.2.2. Long Term Follow-up Evaluations 
All subjects will be followed until documented disease progression. Subjects who discontinue 
treatment for any reason without documented disease progression will be followed for disease 
progression every 4 months for 5 years.  
Once disease progression is documented, subjects will enter a survival follow up period every 4 
months for 3 years from the time of documented progression. Follow up may be accomplished 
via clinic visit, phone call, or other avenues as appropriate. 
8.3. 
Characteristics of an Adverse Event 
Each event will be recorded on an appropriate case report form that includes assessment of the 
characteristics defined below. These characteristics, along with the frequency of an event’s 
occurrence, will be considered in determining if the event is a UP. 
8.3.1. Relationship to Study Intervention 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  


V 04/19/2021 
 
 
 
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Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
8.3.2. Expectedness  
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, package insert, or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.  
The Study PI and/or study-appointed, clinically/medically responsible individual will determine 
whether an AE is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the intervention.  
There are expected significant toxicities and AEs associated with SOC EBRT. These toxicities 
include Grade 3 radiation mucositis and Grade 3 radiation dermatitis.  
IL2 based therapies have been utilized for over 2 decades. Many of the side effects are 
predictable, transient, and well controlled clinically. The list below delineates some of the 
toxicities and AEs that are expected for NKTR-214:  
a) Grade 3 pain, requiring intravenous narcotics, provided that the narcotics are 
controlling the pain, and that IV narcotics for pain are not required > 96 hours after 
completion of NKTR-214 during any cycle;  
b) Grade 3 nausea, vomiting, or diarrhea that resolves within 96 hours after 
completion of NKTR-214 during any cycle;  
c) Grade 3 fever (i.e.: T > 40° C) lasting < 6 hours and controllable with 
antipyretics;  
d) Grade 3 transient hypotension that resolves with hydration;  
e) Grade 3 systemic skin toxicity (rash, erythema) that does not require 
management with steroids and improves with non-steroidal treatment (e.g., IV 
diphenhydramine) within 24 hours;  
f) Grade 3 metabolic/laboratory toxicity of hyponatremia, hyperglycemia, or 
hypophosphatemia, in the absence of CNS symptoms and/or sequelae, that 
improve with or without treatment within 48 hours;  


V 04/19/2021 
 
 
 
35
g) Grade 3 hematologic toxicity (or grade 4 lymphopenia – a known transient 
marker of immune activation by IL2) which improves to at least Grade 2 or pre-
therapy baseline values before the subsequent NKTR-214 treatment cycle;  
h) Grade 3 infusion reactions lasting less than 24 h, readily controlled with 
supportive (non-steroidal) treatments (i.e., Benadryl or subcutaneous 
epinephrine);  
i) Grade 3 fatigue or decrease of ECOG performance status to an ECOG 
performance status of 3 that resolves to pre-treatment, baseline values in < 1 
week;  
j) Grade 3 infection that resolves in < 1 week either with or without antibiotic 
therapy;  
8.3.3. Severity of Event 
AEs will be documented and recorded at each visit using NCI CTCAE v5.0.  
8.4. 
Reporting Procedures 
8.4.1. Unanticipated Problem (UP) Reporting  
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of 
an UP report form. OHRP recommends that investigators include the following information when 
reporting an adverse event, or any other incident, experience, or outcome as an UP to the IRB: 
• 
appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB project number; 
• 
a detailed description of the adverse event, incident, experience, or outcome;  
• 
an explanation of the basis for determining that the adverse event, incident, experience, 
or outcome represents an UP;  
• 
a description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:  
• 
UP that are SAE will be reported to the IRB per Table 1 timeline.  
• 
Any other UP will be reported to the IRB per Table 2 timeline.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and OHRP within one month of the IRB’s receipt of the report of the problem from the 
investigator. 
8.4.2. Serious Adverse Event Reporting  
Depending on the nature, severity, and attribution of the serious adverse event an SAE report 
will be phoned in, submitted in writing, or both according to Table 1 below. All SAEs must also 
be reported to the UWCCC DSMC. All SAEs must also be reported to the UW IRB (if 
applicable), and any sponsor/funding agency not already included in the list. 


V 04/19/2021 
 
 
 
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Determine the reporting timeline for the SAE in question by using the following table.  
 
Table 1: 
FDA Reporting Requirements.  
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1,2 FDA Reporting Requirements for Serious Adverse Events 
(21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the UWCCC DSMC, Nektar Therapeutics, and the IRB 
(if applicable) and any other parties outlined in the protocol ANY SAE, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event (the subject was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe). 
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. * 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SAE that meet the above criteria MUST be immediately reported to the UWCCC DSMC and Nektar 
within the timeframes detailed in the table below: 
 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 Timeframes 
Resulting in 
hospitalization ≥ 
24 hours 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hours 
Not required 
 
*Planned hospitalizations for disease-related surgery, routine procedures (such as G-tube 
placement), non–disease-related procedures, and grade 3 toxicities listed in section 2.6.1.2 will 
be exempt from SAE reporting as they are not dose limiting toxicities.  
 
Expedited AE reporting timelines are defined as: 


V 04/19/2021 
 
 
 
37
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
Serious adverse events that occur more than 90 days post completion of therapy, only SAEs with the 
attribution of possibly, probably or definitely will require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
Serious Adverse Event – Reported Within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as described in the protocol) 
must also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via 
an email to saenotify@uwcarbone.wisc.edu within one business day.  The OnCore SAE 
Details Report must be submitted along with other report materials as appropriate (NCI 
AdEERS form or FDA Medwatch Form #3500 and/or any other documentation available 
at that time of initial reporting). The DSMC Chair will review the information and 
determine if immediate action is required. Within 10 working days, all available 
subsequent SAE documentation must be submitted electronically along with a 24 hour 
follow-up SAE Details Report and a completed UWCCC SAE Routing Form to 
saenotify@uwcarbone.wisc.edu. All information is entered and tracked in the UWCCC 
database. 
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB, the sponsor, and the funding agency and provides documentation of 
these notifications to the DSMC. 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-
investigator, the PI reviews the event to determine whether the SAE requires reporting to 
the FDA and other participating investigators.   
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are 
reported to the FDA as well as to all participating investigators. 
 
See Section [II] for detailed instructions on SAE reporting. 
a) Serious Adverse Event – Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the protocol) 
must also be reported to the Data and Safety Monitoring Committee (DSMC) Chair via 
an email to saenotify@uwcarbone.wisc.edu.  The OnCore SAE Details Report must 
be submitted along with other report materials as appropriate (NCI AdEERS form or FDA 
Medwatch Form #3500 and/or any other documentation available at the time of initial 
reporting). The DSMC Chair will review the information and determine if further action is 
required. All information is entered and tracked in the UWCCC database. 


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The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB, the sponsor, and the funding agency and provides documentation of 
these notifications to the DSMC. 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-
investigator, the PI reviews the event to determine whether the SAE requires reporting to 
the FDA and other participating investigators.   
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are 
reported to the FDA as well as to all participating investigators. 
 
See Section [II] for detailed instructions on SAE reporting. 
 
c) Sponsor-Investigator Responsibilities for SAE Review 
In the event the UWCCC Principal Investigator is acting as the Sponsor-Investigator (i.e., 
the PI holds the IND), the PI assumes responsibilities of the study sponsor in 
accordance with FDA 21 CFR 312.32.  In this capacity, the UWCCC PI reviews all 
reports of serious adverse events occurring on the study at the UWCCC and 
participating external sites and makes a determination of 1) suspectedness (i.e., 
whether there is a reasonable possibility that the drug caused the AE); and 2) 
unexpectedness (the event is not listed in the Investigator’s Brochure or is not listed at 
the specificity or severity that has been observed) in the context of this study.  SAE with 
suspected causality to study drug and deemed unexpected are reported as IND Safety 
Reports by the UWCCC PI to the FDA, all participating investigators on the study, and 
the external global sponsor (if applicable) within 15 calendar days. All fatal or life-
threatening SAE that are unexpected and have suspected causality to the study drug will 
be reported by the UWCCC PI to the FDA, all participating investigators on the study, 
and the external global sponsor (if applicable) within 7 calendar days. 
 
Report to the UWCCC and Nektar 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow for 
DOTs on the UWCCC website (http://kb.wisc.edu/uwccc) for specific instructions on how and 
what to report to the UWCCC for [24] hour initial and follow-up reports. A follow-up report is 
required to be submitted within 10 days of the initial [24] hour report. 
 
For this protocol, the following entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. Study Chairs: Zachary Morris, MD, PhD and Paul Harari, MD  
c. UWCCC PIs: Justine Yang Bruce, MD and Adam Burr, MD, PhD 
d. UWCCC PM: Diana Trask 
e. Nektar Therapeutics (Pharmacovigilance@nektar.com) 
f. Any other appropriate parties listed on the SAE Routing Form (for follow-up reports only) 


V 04/19/2021 
 
 
 
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Report to the IRB 
Consult the UW-IRB website for reporting guidelines.  
Reported within 10 Calendar Days 
SAE requiring reporting within 10 calendar days (as described above) must also be reported to 
the DSMC Chair via an email to saenotify@uwcarbone.wisc.edu. SAEs will also be reported to 
Nektar in the same timeframe. The SAE Details Report must be submitted along with other 
report materials as appropriate. The UWCCC DSMC Chair will review the information and 
determine if further action is required. All information is entered and tracked in the UWCCC 
database. 
The Principal Investigator notifies all investigators involved with the study at the UWCCC, the 
IRB, Nektar, and provides documentation of these notifications to the DSMC.  
For this protocol, the following entities are required to be notified: 
a. saenotify@uwcarbone.wisc.edu 
b. Study Chairs: Zachary Morris, MD, PhD and Paul Harari, MD  
c. UWCCC PIs: Justine Yang Bruce, MD and Adam Burr, MD, PhD 
d. UWCCC PM: Diana Trask 
e. Nektar Therapeutics (Pharmacovigilance@nektar.com) 
f. Any other appropriate parties listed on the SAE Routing Form (for follow-up reports only) 
Report to the IRB 
Consult the UW-IRB website for reporting guidelines.  
 
 
 
Table 2.  Other Reportable Events Timeframe 
Event 
Definition 
Reporting  
Breach of 
confidentiality 
The exposure of any study information or 
communications directly related to a study subject 
to anyone not named as study staff or the release 
of a study subject’s identifiable information to study 
staff who were not specified to receive such 
information in the protocol or IRB application.  
Within 14 business days 
of knowledge of event 
Protocol 
deviation 
A deviation is an incident involving a departure 
from the IRB-approved protocol in the actual 
conduct of the study. Deviations may result from 
the action of the participant, investigator, or staff. 
See details below 


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Event 
Definition 
Reporting  
Major 
deviations 
Deviations are considered major when the 
unapproved change(s) in previously approved 
research activities, implemented without IRB 
approval, may potentially adversely affect subjects’ 
rights, safety, welfare, or willingness to continue 
participation, or affect the scientific design of the 
study and/or the integrity of the resultant data. 
Within 14 business days 
of knowledge of event  
Minor 
deviations  
Deviations are considered minor when the 
unapproved change(s) in previously approved 
research activities, implemented without IRB 
approval, do not adversely affect subjects or the 
integrity of the study data. 
Cumulative minor 
deviations are reported 
at the time of continuing 
review.  
Protocol 
violation 
An incident involving an intentional deviation from 
the IRB-approved protocol that was not 
implemented in response to an emergency 
situation and that may impact a subject’s rights, 
safety, and/or welfare, makes a substantial 
alteration to risks to subjects, or affects the 
scientific design of the study and/or the integrity of 
the resultant data. Violations may also be repeated 
deviations (major or minor) of the same nature. 
Violations can represent serious or continuing non-
compliance with the federal regulations and 
guidelines for ethical conduct of human subject 
research. 
Within 14 business days 
of knowledge of event  
Protocol 
Exceptions 
A protocol exception is an IRB-approved deviation 
for a single subject or a small group of subjects but 
is not a permanent revision to the research 
protocol. 
Protocol exceptions 
must be approved by 
local IRB prior to 
implementation. 
 
Report to the IRB: 
Consult the UW-IRB website for reporting guidelines. 
 
8.4.3. Reporting of Safety Events to FDA 
As the University of Wisconsin will hold the IND for this study, they will assume responsibility for 
reporting all events in accordance with FDA 21 CFR 312.32. 
 
9. STUDY OVERSIGHT 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the regular 
review and monitoring of all ongoing clinical research in the UWCCC.  A summary of DSMC 
activities are as follows: 


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• 
Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity. 
• 
Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as defined 
in the protocol, for all clinical trials conducted at the UWCCC, and studies conducted 
at external sites for which the UWCCC acts as an oversight body. 
• 
Reviews all reports generated through the UWCCC DSMS elements (Internal Audits, 
Quality Assurance Reviews, Response Reviews, Compliance Reviews, and Protocol 
Summary Reports). 
• 
Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, any 
requirements for corrective action related to data or safety issues. 
• 
Notifies the CRC of DSMC decisions and any correspondence from the DSMC to the 
protocol Principal Investigator. 
• 
Works in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and unanticipated 
problems reported by the UWCCC research staff.  
• 
Ensures that notification of SAEs requiring expedited reporting is provided to external 
sites participating in multi-institutional clinical trials coordinated by the UWCCC. 
` 
 
9.1. 
Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study sponsorship and 
risk level of the protocol as determined by the PRMC. All protocols (including Intervention Trials, 
Non-Intervention Trials, Behavioral and Nutritional Studies, and trials conducted under a 
Training Grant) are evaluated by the PRMC at the time of committee review. UWCCC 
monitoring requirements for trials without an acceptable external DSMC are as follows: 
 
Protocols subject to intermediate monitoring generally include UW Institutional Phase I/II and 
Phase II Trials. These protocols undergo review of subject safety at regularly scheduled DOT 
meetings where the results of each subject’s treatment are discussed and the discussion is 
documented in the DOT meeting minutes. The discussion includes the number of subjects 
enrolled, significant toxicities, dose adjustments, and responses observed. Protocol Summary 
Reports are submitted on a quarterly basis by the study team for review by the DSMC.  
 
9.1.1. Review and Oversight Requirements 
 
• 
Study Progress Review  
o Protocol Summary Reports (PSR) are required to be submitted to the UWCCC 
DSMC quarterly. The PSR provides a cumulative report of SAEs, as well as 
instances of noncompliance, protocol deviations, and UPs, toxicities and responses 
that have occurred on the protocol in the timeframe specified. PSRs for those 
protocols scheduled for review are reviewed at each DSMC meeting.  
o Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study suspension or 
closure. This information is evaluated by the DSMC in conjunction with other reports 
of quality assurance activities (e.g., reports from Internal Audits, Quality Assurance 
Reviews, etc.) occurring since the prior review of the protocol by the DSMC. 
 


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In the event that there is significant risk warranting study suspension or closure the UWCCC 
DSMC will notify the PI of the findings and ensure the appropriate action is taken for the 
protocol (e.g., suspension or closure). The DSMC ensures that the PI reports any temporary or 
permanent suspension of a clinical trial to the appropriate agencies. Any UWCCC DSMC 
findings and requirements for follow-up action are submitted to the UWCCC CRC. 
Study Monitoring 
Per UWCCC policy, the Clinical Research Central Office (CRCO) monitoring team monitors 
clinical trials by conducting a Quality Assurance Review (QAR) within 6 months of when the 
first subject is accrued to the study.  Aspects of study conduct reviewed during a QAR 
include, but are not limited to, documentation of the informed consent process, subject 
eligibility, subject registration documentation, overall adherence to the protocol by the study 
team, and regulatory documentation.  
 
Internal Audits are completed by the CRCO monitoring team on an approximately annual 
basis. Aspects of study conduct reviewed during an internal audit include, but are not limited 
to, documentation of the informed consent process, subject eligibility, response and toxicity 
(if applicable), investigational drug accountability records, regulatory files, and overall 
adherence to the protocol.  
 
The CRCO monitoring team provides written reports to the PI, UWCCC DSMC, and IRB 
following the reviews described above.   
 
10. IND APPLICATION MANAGEMENT 
In compliance with FDA regulations, the sponsor-investigator manages the IND through its 
lifecycle, including the initial application, submission of amendments, new information, safety 
and annual reports. 
 
The sponsor-investigator may seek guidance on the FDA IND submission process with the 
ICTR IND/IDE Consultation Service (I3CS). 
10.1. Initial Submission 
The sponsor-investigator and/or study team members (as applicable) prepare and submit 
the initial application to the FDA, and maintain copies of all communications and 
correspondence between the FDA and sponsor-investigator. The FDA acknowledgment 
letter lists the assigned IND number and a statement that the IND will become active if the 
sponsor-investigator does not hear back from the FDA within 30 days of the date of receipt.  
• 
The date of the acknowledgement letter is used as the IND activation date if further 
correspondence from the FDA is not received.  
• 
If further communication is required, and all issues have been resolved, the FDA will 
send a letter stating that the clinical investigation may begin, including the IND 
activation date. 
The sponsor-investigator maintains all FDA documentation, specifically the IND activation 
date, in the regulatory files. 


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10.2. Amendments 
When necessary, the sponsor-investigator and/or study team members (as applicable) 
prepare and submit protocol amendments. Once submitted to the FDA, the FDA will not 
respond unless requested.  
10.3. Safety Reports 
The sponsor-investigator and/or study team members (as applicable) prepare and submit 
any serious, unexpected and related adverse events to the FDA, and all participating 
investigators, in an IND safety report.  
 
Adverse Events that are: 
Notify: 
• 
Serious 
• 
Suspected/Related 
• 
Unexpected 
FDA and all participating institutions as soon 
as possible, but no later than 15 calendar days 
after learning of the event 
• 
 Serious 
o Life-threatening or 
Fatal 
• 
Suspected/Related 
• 
Unexpected 
FDA and all participating institutions within 7 
calendar days after learning of the event 
 
10.4. Annual Reports 
Within 60 days of the anniversary date that the IND application went into effect, the sponsor-
investigator and/or study team members (as applicable) prepare and submit the annual 
report. Once submitted to the FDA, the FDA will not respond unless requested.   
 
11. STATISTICAL CONSIDERATIONS 
11.1. Study Hypotheses 
We hypothesize that the combination of radiation, NKTR-214, and anti-PD-1 checkpoint 
blockade will improve efficacy compared to the pembrolizumab arm of Keynote 048. Given the 
non-redundant immune modulatory roles of radiation, NKTR-214, and anti-PD-1 checkpoint 
blockade, our secondary hypotheses are that this combination will be effective in generating an 
anti-tumor immune response against recurrent/metastatic head and neck squamous cell 
carcinoma resulting in an ORR ≥ 44 % with good patient reported quality of life and with 
correlative evidence demonstrating a more diversified and activated adaptive anti-tumor 
immune response. 
11.2. Sample Size Considerations 
This study will enroll 24 participants to test the hypothesis that the combination of NKTR-214 
with palliative radiation and anti-PD-1 therapy results in an ORR ≥ 44 %. Under the null 
hypothesis for ORR ≤ 0.22, based on one-sided one sample proportion test with type I error of 
0.1, the expected power levels to detect alternative ORRs of 0.35, 0.4, and 0.45 are 55 %, 
74 %, 87 % respectively. The null hypothesis will be rejected and superiority concluded if 8 or 
more responses are observed in 24 participants. This design yields a type I error rate of .04 and 
power of .8 when the true response rate is 44 %. 


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11.3. Final Analysis Plan 
Any subject who receives at least one dose of NKTR-214 on this protocol will be evaluable for 
ORR. All subjects with measurable disease who have received at least one cycle of treatment 
and have their disease re-evaluated will be evaluable for assessment of objective response.  
11.3.1. Analysis Plans for Primary Objective 
ORR will include confirmed complete response (CR) + confirmed partial response (PR) and will 
be assessed based on RECIST 1.1 criteria. ORR will be reported with the 95 % confidence 
interval (CI). Progression of any radiated tumors will be considered in this evaluation but 
response of radiated tumor(s) will not be considered as evidence of response for the purpose of 
this study unless all tumor sites are radiated. 
11.3.2. Analysis Plans for Secondary Objectives 
Treatment-related AE will be reported in tabular format, and AE rates, including the proportion of 
participants experiencing Grade 3+ treatment-related toxicities, will be reported with the 
95 % CI.  
PFS will be analyzed using the Kaplan-Meier method, and median PFS will be computed with 
the associated 95 % CI. Subjects who have not progressed and are still alive will be right-
censored at the date of the last disease evaluation. Kaplan-Meier curves will be plotted. 
OS will be analyzed using the Kaplan-Meier method, and median OS will be computed with the 
associated 95 % CI. Subjects who have not died will be right-censored at the date of the last 
follow-up, and Kaplan-Meier curves will be plotted.  
Clinical benefit rate (defined as CR + PR + SD at ≥ 6 months) will be reported via waterfall plot, 
and the 95 % CI for the clinical benefit rate will be computed.  
Duration of response, duration of overall complete response and time to progression will be 
evaluated using the Kaplan-Meier method. Medians will be computed with the associated 
95 % CI, and Kaplan-Meier curves will be plotted. 
Patient-reported health-related quality of life will be evaluated using summary statistics and 
generalized linear mixed-effects models for measurements over time. 
11.3.3. Analysis Plans for Exploratory Objectives 
For the exploratory objectives, descriptive statistics will be used to summarize the levels of anti-
tumor response, IFN-γ expressing T cells in peripheral blood, T cell receptor repertoire diversity 
and clonality, and tumor infiltrating lymphocytes and expression of PD-L1 as determined by 
immunohistochemistry. 
11.3.4. Subgroup Analyses 
Subgroup analyses for ORR will be performed on the basis of high versus low tumor mutation 
burden, high versus low PD-L1 expression on cycle 1 index tumor biopsy, HPV/EBV status, 
metastatic versus locally recurrent disease, and tobacco smoking history. 
 


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12. CRITERIA FOR DISEASE EVALUATION 
The following sections describe the recommended method to track disease response per the 
RECIST1.1 (see Eisenhauer EA et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Can, 2009.45:p.228-247). Progression of any radiated 
tumors will be considered in this evaluation but response of radiated tumor(s) will not be 
considered as evidence of response for the purpose of this study. 
Refer to the RECIST1.1 publication for complete details on these criteria. 
12.1. Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm 
using standard clinical measurements, such as calipers or single use measuring paper by 
clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
12.1.1. Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. 
12.2. Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are preferred for selection 
as target lesions. 
12.3. Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion that can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 


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measurable dimension of the disease. Target lesions will not include radiated tumor sites for this 
study unless all tumor sites have been radiated. 
12.4. Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 
12.5. Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (Eur J Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
Partial 
Response (PR) 
At least a 30 % decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive 
Disease (PD) 
At least a 20 % increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20 %, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered 
progressions). 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study 
12.6. Evaluation of Non-target Lesions 
Complete 
Response (CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological 
in size (< 10 mm short axis) 
 
Note: If tumor markers are initially above the upper normal 
limit, they must normalize for a subject to be considered in 
complete clinical response. 
Non-CR/ Non-
PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive 
Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal 


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progression should not normally trump target lesion status. It 
must be representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
12.7. Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 


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12.8. Definitions for Response Evaluation – RECIST 1.1 
12.8.1. Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
12.8.2. Clinical Benefit Rate 
The Clinical Benefit rate is the proportion of all subjects with stable disease (SD) at ≥ 6 months 
from cycle 1 day 1, or partial response (PR), or complete response (CR) according to RECIST 
1.1, from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 
12.8.3. Progression Free Survival 
A measurement from study treatment day 1until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation. 
12.8.4. Overall Survival 
Overall survival is defined by the date of study treatment day 1 to date of death from any cause. 
12.8.5. Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
13. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in compliance 
with ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of participants. Study staff will permit authorized representatives of regulatory 
agencies to examine (and when required by applicable law, to copy) research records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety, progress, and 
data validity.  
Source documents will include all records within the HealthLink Electronic Medical Records 
system such as hospital records, clinical and office charts, laboratory notes, memoranda, 
pharmacy dispensing records, copies or transcriptions certified after verification as being 
accurate and complete, photographs or digital photo files, x-rays, and subject files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. In addition, protocol specific forms will be designed which require treating physician 
signature to serve as source documents. This may include forms such as toxicity forms with 
grading and attribution and tumor measurement forms. 
 


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14. ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1. Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6.  
14.2. Institutional Review Board (IRB) 
The final study protocol and the final version of the informed consent form must be approved in 
writing by the University of Wisconsin Health Sciences IRB.  
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB as local regulations 
require.  
Progress reports and notifications of AEs will be provided to the IRB according to local 
regulations and guidelines. 
14.3. Informed Consent Process 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. A consent form describing in detail the study procedures and risks will be given to the 
participant. Consent forms will be IRB-approved, and the participant is required to read and 
review the document or have the document read to him or her.  
The investigator or designee will explain the research study to the participant and answer any 
questions that may arise. The participant will sign the informed consent document prior to any 
research-only assessments or procedures. Participants will be given the opportunity to discuss 
the study with their surrogates or think about it prior to agreeing to participate. They may 
withdraw consent at any time throughout the course of the study. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their clinical care will not 
be adversely affected if they decline to participate in this study. 
The consent process will be documented in the clinical or research record.  
14.4. Exclusion of Children (Special Populations) 
Adults of any gender or racial/ethnic group may participate. Since children do not make up a 
significant portion of the subjects with recurrent metastatic head and neck squamous cell 
carcinoma, children are excluded from this study. 
14.5. Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the study 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to any study information relating to participants. 


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The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the study sponsor. 
The study shall be conducted in full compliance with (i) all applicable laws, regulations, and 
guidance of Regulatory Authorities relating to human clinical research of the type described in 
the Protocol, including the United States Federal Food, Drug and Cosmetic Act (“FDC Act”) and 
the relevant provisions of Title 21 of the United States Code of Federal Regulations;  (ii) 
generally accepted standards of Good Clinical Practice (“GCP”), including ICH E6 Good Clinical 
Practice: Consolidated Guidance (April 1996) as adopted by the FDA; and (iii) all applicable 
laws relating to the collection, use, storage and disclosure of individually-identifiable patient 
medical information, records and data, including but not limited to the Health Insurance 
Portability and Accountability Act of 1996 as amended by the Health Information Technology for 
Economic and Clinical Health Act of 2009 and similar state, local and foreign laws (collectively 
“Privacy and Security Regulations”). 
Regulatory Authorities will have access to any and all of the following as may be required by 
applicable law and regulations or guidances of Regulatory Authorities: (i) the Principal 
Investigator, any other Investigator, or other personnel involved with the Study; (ii) Study 
facilities; and (iii) books, accounts, Study Drug records, patient records, case report forms, 
source data (as that term is defined and used in ICH E6 Good Clinical Practice: Consolidated 
Guidance (April 1996)), and other records, documents, materials and sources of information 
related to the Study (“Records”).  
AEs will be reported to Regulatory Authorities promptly in compliance with applicable law. In 
addition, any Serious Adverse Event ("SAE") will be reported to Nektar within 24 hours from the 
time it is determined by study personnel that such an event or reaction has occurred, or 
immediately if the event or reaction is fatal or life-threatening. 
14.5.1. Certificate of Confidentiality  
To further protect the privacy of study participants, the Secretary of Health and Human Services 
(HHS), has issued a Certificate of Confidentiality (CoC) to all researchers engaged in 
biomedical, behavioral, clinical, or other human subjects research funded wholly or in part by 
the federal government. Recipients of NIH funding for human subjects research are required to 
protect identifiable research information from forced disclosure per the terms of the NIH Policy 
(https://humansubjects.nih.gov/coc/index). As set forth in 45 CFR Part 75.303(a) and NIHGPS 
Chapter 8.3, recipients conducting NIH-supported research covered by this Policy are required 
to establish and maintain effective internal controls (e.g., policies and procedures) that provide 
reasonable assurance that the award is managed in compliance with Federal statutes, 
regulations, and the terms and conditions of award. It is the NIH policy that investigators and 
others who have access to research records will not disclose identifying information except 
when the participant consents or in certain instances when federal, state, or local law or 
regulation requires disclosure. NIH expects investigators to inform research participants of the 
protections and the limits to protections provided by a Certificate issued by this Policy. 
14.5.2. NIH Data Sharing Policies  
For this study, the correlative objectives are funded in part, through the NIH. As described in 
section 17, it is NIH policy that the results and accomplishments of the activities that it funds 
should be made available to the public (see https://grants.nih.gov/policy/sharing.htm). PIs and 
funding recipient institutions will ensure that all mechanisms used to share data include proper 


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plans and safeguards to protect the rights and privacy of individuals who participate in NIH-
sponsored research. This will apply to the results of the correlative outcomes analysis. 
14.6. Future Use of Stored Specimens and Other Identifiable Data 
Subject consent will be obtained to bank any leftover samples that were collected for study-
specific correlative research. The UW H&N SPORE Pathology Core facility and/or the Morris lab 
will manage the banked samples. All patient health information with the sole exception of 
sample date will be removed.  The sample date will be available to the study team only to 
facilitate database structure. Any samples provided to collaborators; however, will be stripped of 
all PHI, including the date. Instead, samples will be coded with research sample ID and time 
point description.  
 
15. DATA HANDLING AND RECORD KEEPING 
This study will report clinical data using the UWCCC OnCore data management system and 
RedCap utilizing study specific case report forms. Key study personnel are trained on the use of 
case report forms and will comply with protocol specific instructions for data collection.  
 
Subject demographics, subject-specific study treatment calendars, AEs and other information 
will be maintained UW Department of Human Oncology REDCap database.  
 
Participant data will be collected using protocol specific eCRFs. The eCRFs will be approved by 
the study’s Principal Investigator and the study biostatistician prior to release for use. The Study 
Coordinator or designee will be responsible for registering the subject into the data 
management system at time of study entry, completing eCRFs based on the subject specific 
calendar, and updating the subject record until subject death or end of required study 
participation.  
To protect the confidentiality of subjects in this study the blood and tissue samples will be 
coded, using a limited data set.  The only PHI will be the sample date, restricted to the study 
team members. The coded samples may be labeled with any subset of the following: sample 
number, subject ID number, date of biopsy/blood draw, biopsy location (if applicable), and study 
number. The key will be saved in computer files that are protected via passwords and access 
rights. The research data will also be saved in secure computer files and in the OnCore 
database, all of which are only accessible via username, password, and access rights. When 
not in use paper files will be stored in the research offices that are locked when not occupied, or 
in locked closets or cabinets associated with the Morris lab. Research samples will be stored in 
the Morris lab, or a collaborating laboratory at the University of Wisconsin - Madison.  
Identifiers and information to be collected for this study  
Name 
Medical record number 
Date of birth 


V 04/19/2021 
 
 
 
52
Gender, Race and Ethnicity 
Address, telephone & fax numbers 
E-mail address 
Health Insurance Information 
Tumor characteristics & genetic information 
Medical history including dates of treatments and procedures 
Information generated from participation in the study 
15.1. Management of Banked Samples 
The table below outlines the data to be maintained for samples banked for future research. 
Information listed will be available to lab staff for use in selecting samples for potential future 
research projects. All future research projects using coded samples would be IRB approved 
before use of the samples.  
 
Data to be maintained with samples banked for future research  
Study number & study subject ID number (eg: UW20###_1) 
Lab sample ID number 
Diagnosis 
Stage of disease 
Therapeutic response 
Types and timing of treatments received 
Time points/sequence of sample collection  
Biopsy locations 
Results of lab analysis completed for the study 
 
If the results of the study are published, participants’ identity will remain confidential. 
15.2. Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed 


V 04/19/2021 
 
 
 
53
by the study team and data entry staff, who will ensure that they are accurate and complete. 
UPs and AEs must be reviewed by the investigator or designee.  
UWCCC Radiotherapy will serve as the Clinical Research Office for this trial.  
15.3. Data Capture Methods 
Data will be collected through the web-based clinical research platform REDCap which is 
HIPAA compliant. UWCCC personnel will coordinate and manage data for quality control 
assurance and integrity. All data will be collected and entered into the appropropriate database 
by study site personnel. We will utilize REDCap for Biospecimen-related data, REDCap for 
clinical data. Registration and demographic information from OnCore. The data available to the 
correlative research labs will be coded in REDCap, and a limited data set, with only the sample 
date as a subject identifier will be available to the correlative research team.  Any collaborative 
researchers will be provided coded research only—stripped of all PHI. 
15.4. Types of Data 
Subject demographics, subject medical history, subject specific study treatment calendars, AEs, 
laboratory/pathology reports obtained during the course of treatment and afterwards, e.g., blood 
tests, biopsy results), findings from physical exams, and imaging scan reports/outcomes will be 
maintained within EPIC Healthlink, with research specific data being recorded in REDCap, and 
OnCore. There is potential for HNC-related genomic studies to be performed on future banked 
samples. 
15.5. Schedule and Content of Reports 
The UWCCC Protocol Review and Monitoring Committee (PRMC) determines the level of risk, 
thus the appropriate timelines for review of study documents, conduct and accrual. Protocol 
Safety Reports are run, reviewed and signed off by the study PI per the determined schedule. 
PSRs are then sent for review to the DSMC. Protocol Safety Reports include information such 
as accrual, AEs, SAEs, and UPs. Annual review by the UW Health Sciences IRB will review 
accrual, reportable events, and study progress.  
15.6. Study Records Retention 
Shadow research charts with original consent forms and documents specifically created for this 
study will be maintained in the Department of Human Oncology until the study is terminated. 
The records will then be sent to Wisconsin State Records Archiving facility for long-term storage 
(10 years) and re-archived as needed. Study records will be maintained for at least three years 
from the date that the grant federal financial report (FFR) is submitted to the NIH. 
15.7. Protocol Deviations 
Except in the case of a medical emergency, no protocol deviation is authorized. Changes to the 
protocol will be established by amendments by the Principal Investigator approved by the UW 
HS IRB. Protocol deviations may affect the conduct of the study from legal and ethical points of 
view and may influence the statistical analysis and pertinence of the study. Medical 
emergencies have to be handled in the subjects’ best interest. The investigator has to contact 
the IND Sponsor to clarify if a subject may continue in the study when a protocol violation out of 
medical reasons has occurred. Protocol deviations that are not identifiable from the eCRF have 
to be recorded in a protocol deviation form. Protocol deviations will be evaluated at the data 
review meeting before database lock and will be described in the statistical analysis plan.  


V 04/19/2021 
 
 
 
54
All deviations must be addressed in study source documents and reported to the UW HS IRB 
per their policies using Table 1 as a guideline. The Principal Investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. 
 
16. PUBLICATION/DATA SHARING  
The NIH funds a portion of the correlative research on biospecimens from this study. Therefore, 
data resulting from the correlative research will be subject to the NIH Public Access Policy, 
which ensures that the public has access to the published results of NIH funded research. It 
requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to 
the digital archive PubMed Central upon acceptance for publication. 
The clinical trial will be registered on ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. 
At least thirty (30) days prior to any public dissemination of the results of the study, results will 
be provided to Nektar for review.  The materials to be disseminated shall be forwarded to the 
Nektar Medical Contact. During the Review Period, Nektar may provide written suggestions or 
comments to Sponsor which Sponsor may incorporate in its own discretion.  In the event that 
Nektar identifies any Confidential Information during its review, the PIs agree to remove the 
Nektar Confidential Information if requested by Nektar in writing prior to public dissemination. If 
during the Review Period, Nektar notifies the PIs that Nektar desires patent applications to be 
filed on any Nektar Inventions disclosed or contained in the disclosures, PIs will defer 
publication or other public disclosure for a period, not to exceed an additional sixty (60) days, 
sufficient to permit Nektar or  any Nektar Nominee to file any desired patent applications.  
Unless otherwise required by the journal in which a publication is to appear, or the forum in 
which a poster or presentation is to be made, PIs will comply with recognized ethical standards 
concerning publications and authorship, including the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals established by the International Committee of Medical Journal 
Editors.  The support of Nektar will be acknowledged in any publication or presentation related 
to the Study, unless Nektar notifies Sponsor in writing in advance that Nektar declines to be so 
acknowledged.  
In the event either the PIs or Nektar desire to issue any press release or other publicity 
materials relating to the study, then a draft of the proposed release or other materials shall be 
submitted to the other party at least ten (10) business days in advance of public disclosure for 
the other party’s review and comment.  The submission to the other party shall state the 
proposed date on which the submitting party plans to make the public release.   
17. REFERENCES 
1. 
Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, 
Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, 
Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab 
for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 
2016;375(19):1856-67. doi: 10.1056/NEJMoa1602252. PubMed PMID: 27718784; PMCID: 
PMC5564292. 


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2. 
Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G, Jr., Psyrri A, 
Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, 
Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, 
Cheng JD, Jin F, Rischin D, Investigators K-. Pembrolizumab alone or with chemotherapy 
versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the 
head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 
2019;394(10212):1915-28. doi: 10.1016/S0140-6736(19)32591-7. PubMed PMID: 31679945. 
3. 
Gong J, Le TQ, Massarelli E, Hendifar AE, Tuli R. Radiation therapy and PD-1/PD-L1 
blockade: the clinical development of an evolving anticancer combination. J Immunother 
Cancer. 2018;6(1):46. doi: 10.1186/s40425-018-0361-7. PubMed PMID: 29866197; PMCID: 
PMC5987486. 
4. 
Doberstein SK. Bempegaldesleukin (NKTR-214): a CD-122-biased IL2 receptor agonist 
for cancer immunotherapy. Expert Opin Biol Ther. 2019;19(12):1223-8. doi: 
10.1080/14712598.2019.1685489. PubMed PMID: 31652082. 
5. 
Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, Sheng D, Liu X, 
Sims PW, VanderVeen LA, Ali CF, Chang TK, Konakova M, Pena RL, Kanhere RS, Kirksey YM, 
Ji C, Wang Y, Huang J, Sweeney TD, Kantak SS, Doberstein SK. NKTR-214, an Engineered 
Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in 
Mouse Tumor Models. Clin Cancer Res. 2016;22(3):680-90. doi: 10.1158/1078-0432.CCR-15-
1631. PubMed PMID: 26832745. 
6. 
Sharma M, Khong H, Fa'ak F, Bentebibel SE, Janssen LME, Chesson BC, Creasy CA, 
Forget MA, Kahn LMS, Pazdrak B, Karki B, Hailemichael Y, Singh M, Vianden C, Vennam S, 
Bharadwaj U, Tweardy DJ, Haymaker C, Bernatchez C, Huang S, Rajapakshe K, Coarfa C, 
Hurwitz ME, Sznol M, Hwu P, Hoch U, Addepalli M, Charych DH, Zalevsky J, Diab A, Overwijk 
WW. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-
mediated cancer therapy. Nat Commun. 2020;11(1):661. doi: 10.1038/s41467-020-14471-1. 
PubMed PMID: 32005826; PMCID: PMC6994577. 
7. 
Walker JM, Rolig AS, Charych DH, Hoch U, Kasiewicz MJ, Rose DC, McNamara MJ, 
Hilgart-Martiszus IF, Redmond WL. NKTR-214 immunotherapy synergizes with radiotherapy to 
stimulate systemic CD8(+) T cell responses capable of curing multi-focal cancer. J Immunother 
Cancer. 2020;8(1). doi: 10.1136/jitc-2019-000464. PubMed PMID: 32457127; PMCID: 
PMC7252958. 
8. 
Patel SA, Minn AJ. Combination Cancer Therapy with Immune Checkpoint Blockade: 
Mechanisms and Strategies. Immunity. 2018;48(3):417-33. Epub 2018/03/22. doi: 
10.1016/j.immuni.2018.03.007. PubMed PMID: 29562193; PMCID: PMC6948191. 
9. 
Diab A TN, et al. , editor. Pivot-02: Preliminary safety, efficacy and biomarker results 
from Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with 
locally advanced/metastatic solid tumors. Society of Immunotherapy for Cancer meeting; 2017 
2017; Washington, DC. 
10. 
Diab A HM, et al. , editor. NKTR-214 (CD-122-biased agonist) plus Nivolumab in 
patients with advanced solid tumors: Preliminary Phase I,II results of PIVOT-02. . ASCO; 2018; 
Chicago, IL. 
11. 
Connor NP, Cohen SB, Kammer RE, Sullivan PA, Brewer KA, Hong TS, Chappell RJ, 
Harari PM. Impact of conventional radiotherapy on health-related quality of life and critical 


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functions of the head and neck. Int J Radiat Oncol Biol Phys. 2006;65(4):1051-62. Epub 
2006/05/10. doi: 10.1016/j.ijrobp.2006.01.054. PubMed PMID: 16682129. 
12. 
Hammerlid E, Silander E, Hornestam L, Sullivan M. Health-related quality of life three 
years after diagnosis of head and neck cancer--a longitudinal study. Head Neck. 
2001;23(2):113-25. Epub 2001/04/17. doi: 10.1002/1097-0347(200102)23:2<113::aid-
hed1006>3.0.co;2-w. PubMed PMID: 11303628. 
13. 
Hjermstad MJ, Fossa SD, Bjordal K, Kaasa S. Test/retest study of the European 
Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire. J Clin 
Oncol. 1995;13(5):1249-54. Epub 1995/05/01. doi: 10.1200/JCO.1995.13.5.1249. PubMed 
PMID: 7738629. 
14. 
Kemmler G, Holzner B, Kopp M, Dunser M, Margreiter R, Greil R, Sperner-Unterweger 
B. Comparison of two quality-of-life instruments for cancer patients: the functional assessment 
of cancer therapy-general and the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-C30. J Clin Oncol. 1999;17(9):2932-40. Epub 1999/11/24. 
doi: 10.1200/JCO.1999.17.9.2932. PubMed PMID: 10561373. 
15. 
Ringash J, Bezjak A. A structured review of quality of life instruments for head and neck 
cancer patients. Head Neck. 2001;23(3):201-13. Epub 2001/06/29. doi: 10.1002/1097-
0347(200103)23:3<201::aid-hed1019>3.0.co;2-m. PubMed PMID: 11428450. 
16. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. 
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual 
Life Res. 2011;20(10):1727-36. Epub 2011/04/12. doi: 10.1007/s11136-011-9903-x. PubMed 
PMID: 21479777; PMCID: PMC3220807. 
17. 
Bjordal K, Hammerlid E, Ahlner-Elmqvist M, de Graeff A, Boysen M, Evensen JF, 
Biorklund A, de Leeuw JR, Fayers PM, Jannert M, Westin T, Kaasa S. Quality of life in head 
and neck cancer patients: validation of the European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire-H&N35. J Clin Oncol. 1999;17(3):1008-19. Epub 
1999/03/10. doi: 10.1200/JCO.1999.17.3.1008. PubMed PMID: 10071296. 
18. 
Sherman AC, Simonton S, Adams DC, Vural E, Owens B, Hanna E. Assessing quality of 
life in patients with head and neck cancer: cross-validation of the European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Head and Neck module (QLQ-
H&N35). Arch Otolaryngol Head Neck Surg. 2000;126(4):459-67. Epub 2000/04/20. doi: 
10.1001/archotol.126.4.459. PubMed PMID: 10772298. 
 
 
 


V 04/19/2021 
 
 
 
A
APPENDIX A: SCHEDULE OF EVENTS  
Cycle = 21 days 
Screen 
Cycle 11,2 
Radiation 
C1D15 – 
C1D19 
Cycle 22 
(C1D22) 
Cycle 3+ 2 
Safety 
follow 
up2 
Long-term 
Follow up5 
-28 
days1 
Day 
1 
Day 
8 
 
Day 
1 
Day 
8 
Day 1 
Day 83 
30 days 
post Tx2,4 
 
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
Medical history, smoking history, trial awareness7 
X 
 
 
 
 
 
 
 
 
 
Diagnosis and Staging6 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
X 
 
X 
 
X 
 
Weight 
X 
X 
 
 
X 
 
X 
 
 
 
Vital signs, ECOG Performance status8 
X 
X 
 
 
X 
 
X 
 
X 
 
Health-related quality of life questionnaire 
X 
 
X 
 
 
X 
Q4 cycles 
 
X 
X 
AEs & concomitant medications 
X 
X 
X 
 
X 
X 
X 
 
X 
X5 
LABORATORY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
Complete Blood Cell Count with diff (CBC) 
X 
X1 
 
 
X 
 
X 
 
X 
 
Comprehensive Metabolic Profile (CMP)9 
X 
X1 
 
 
X 
 
X 
 
X 
 
Amylase and Lipase 
X 
X1 
 
 
X 
 
X 
 
 
 
PT/INR and PTT 
X 
 
 
 
 
 
 
 
 
 
Thyroid Function (TSH, T4)10 
X 
 
 
 
 
 
 
 
X 
 
Electrocardiogram (EKG) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (serum or urine) WOCBP11 
X 
 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT11 
 
 
 
 
 
 
 
 
 
 
CT of neck 
X 
 
 
 
 
 
Q4 cycles12 
 
 
X 
PET Scan and/or CT Chest +/-CT Abdomen/Pelvis 12 
X 
 
 
 
 
 
Q4 cycles12 
 
 
X 
TREATMENT EXPOSURE 
 
 
 
 
 
 
 
 
 
 
Anti-PD-1 (pembrolizumab13)  
 
X 
 
 
X 
 
X 
 
 
 
Palliative radiation to index tumor 
 
 
 
X 
 
 
 
 
 
 
NKTR-214  
 
X 
 
 
X 
 
X 
 
 
 
CORRELATIVE STUDIES (SPECIMEN COLLECTION) 
 
 
 
 
 
 
 
 
 
 
Archival tumor tissue14 
X 
 
 
 
 
 
 
 
 
 
Biopsy of index tumor15 
 
 
 
 
 
X 
 
 
 
 
BANKING SAMPLES (SPECIMEN COLLECTION) 
 
 
 
 
 
 
 
 
 
 
PBMC16 
 
X 
X 
 
X 
X 
X3 
X3 
X 
 
Unstained Slides and Biopsy Specimens17 
X 
 
 
 
 
X 
 
 
 
 
Serum16 
 
X 
X 
 
X 
X 
X3 
X3 
X 
 
FOLLOW-UP 
 
 
 
 
 
 
 
 
 
 
Survival status, subsequent therapy 
 
 
 
 
 
 
 
 
 
X 
1If screening (baseline) labs were performed within 7 days of D1 of treatment, these do not need to be repeated.  


V 04/19/2021 
 
 
 
B
2A window of 5 days will be applied to all treatment study visits for cycle 1 and 2, a window of 7 days will be applied to all treatment study visits 
for cycle 3 and thereafter, and for the safety follow-up visit and tumor imaging, a 14-day window will apply. 
3These events apply only to cycle 3. 
4A safety follow-up visit will occur 30 days (±14 days) after the last dose of treatment. [SAEs will be collected for 90 days after the end of 
treatment, and Q4 mos for 12 mos after treatment for SAEs thought to be at least possibly related to study therapy, See Section 9.] 
5Subjects without documented disease progression will be followed for disease progression every 4 months +/- 30 days for 5 years. Once 
disease progression is documented, subjects will enter a survival follow up period every 6 months +/- 6 months for 3 years from the time of 
documented progression.  
6Diagnosis and staging to include pathology report and AJCC 8th Ed staging. Standard biopsy to prove metastatic or recurrent disease should be 
available prior to registration 
7Medical history to include smoking history and trial awareness question. 
8Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status 
9CMP to include sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, 
alkaline phosphatase 
10Prior to even cycles of drug. 
11For WOCBP: urine or serum βhCG, within 7 days prior to study registration. If a urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
12Tumor response assessment will be performed using standard-of-care imaging of all known sites of disease every 4th cycle starting with 
cycle 3; tumor imaging to be done at treatment discontinuation at discretion of investigator. 
13Per standard of care, Pembrolizumab infusions will be given every 3 weeks and NKTR-214 administered on the same day each cycle.  
14Fixed paraffin-embedded and/or frozen blocks/slides will be requested from the standard biopsy taken to prove metastatic or recurrent disease. 
15Biopsy of the index tumor will be obtained by core, punch, or incisional biopsy on day 8 (+/- 5) of cycle 2.  
16Serial blood samples for PBMC and serum will be collected prior to anti-PD-1 or NKTR-214 on Day 1 of Cycle 1, 2, and 3, on Day 8 of Cycle 1, 
2, and 3, and at safety follow-up. 
17Submission of unstained slides/blocks/frozen specimens for banking (if available). 
 
 
 


V 04/19/2021 
 
 
 
C
APPENDIX B: CEREBROVASCULAR ACCIDENT ADVERSE EVENT MANAGEMENT ALGORITHM FOR THE 
COMBINATION OF BEMPEGALDESLEUKIN WITH CHECKPOINT INHIBITORS 
The table below provides a management algorithm for possible signs of CVA and follow-up of CVA for patients treated with the 
combination of NKTR-214 with any checkpoint inhibitor.  This general guideline constitutes guidance to the Investigator and may be 
supplemented by discussions with the Medical Monitor representing the Sponsor. 
 


V 04/19/2021 
 
 
 
D
APPENDIX C: HYDRATION GUIDELINES 
Adequate hydration mitigates the development of hypotension.  Hydration and renal function should be assessed within 24 hours prior to study drug 
administration as specified in individual protocols, or as soon as locally feasible.  Unless otherwise stipulated in the protocol, patients should be given 
at least one liter of IV fluids at each dosing of bempegaldesleukin (Day 1).  For the next 3 days (Days 2- 4) after bempegaldesleukin administration, 
instruct patients to drink at least 2 liters per day of self-administered oral hydration.  Advise patients to restrain from activity that may contribute to 
dehydration (including, but not limited to, strenuous activity, long hot showers, and saunas) for Days 1 to 4 following each bempegaldesleukin 
administration.  Following bempegaldesleukin administration, patients should be contacted to ensure compliance with hydration guidelines as 
specified in the individual protocols.  Per clinical judgment, IV fluids may be administered at any time in any cycle.  The Investigator may decide to 
forego administering IV fluids to a patient if this is deemed in the best interest of the patient (e.g., evidence of fluid overload). 
 
 
 
APPENDIX D:  ECOG RATING SCALE  
 
ECOG 
RATING 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
0 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, e.g., light house work, office work 
1 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 
50% of waking hours 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 
50% of waking hours 
2 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
3 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 
 


V 04/19/2021 
 
 
 
E
 
 
APPENDIX E:  ECOG AND KPS CONVERSION TABLE 
 
The table below is derived from data available on the ESMO Oncology PRO website:  http://oncologypro.esmo.org/Guidelines-Practice/Practice-
Tools/Performance-Scales 
 
Karnofsky Grade 
ECOG Grade 
100 
0 
90 
1 
80 
1 
70 
2 
60 
2 
50 
3 
40 
3 
30 
4 
20 
4 
10 
4 
0 
5