Clinical trial NCT03162224
Conditions: Head and Neck Cancer Human Papilloma Virus
Keywords: Head and Neck Squamous Cell Carcinoma Oropharyngeal Cancer HPV Human Papilloma Virus Cancer Immunotherapy Check point inhibitors PD-L1 inhibitor Recurrent or Metastatic Cancer Durvalumab MEDI0457 Antineoplastic agents Neoplasms
Sponsor: MedImmune LLC
Start date: 2017-06-26; Completion date: 2021-03-19
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1b/2a, open-label, multi-center study to evaluate the safety and tolerability, anti-tumor activity, and immunogenicity of MEDI0457 (also known as INO 3112) a HPV Deoxyribonucleic Acid (DNA) vaccine in combination with durvalumab (also known as MEDI4736) which is a human monoclonal antibody directed against Programmed Death Ligand 1 (PD-L1), which blocks the interaction of PD-L1 with PD-1 and Cluster of differentiation 80 (CD80).

An initial three to 12 participants (Safety Analysis Run-in participants) will be enrolled and assessed for safety before additional participants are enrolled.

The initial safety analysis run-in participants along with an approximate total of 50 participants with human papilloma virus associated recurrent or metastatic head and neck squamous cell cancer (HNSCC) will be enrolled in this study and evaluated also for anti-tumor efficacy to MEDI0457 in combination with durvalumab.

Detailed description:

Arms: arm 1: Participants with recurrent or metastatic disease and were non-refractory to neoadjuvant/adjuvant platinum based chemotherapy, will receive MEDI0457 7 mg intramuscularly followed by electroporation on Day 1 of Weeks 1, 3, 7, 12, and then every 8 weeks (Q8W) and durvalumab 1500 mg intravenously on Day 1 of Week 4 and then every 4 weeks (Q4W) until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurs first. arm 2: Participants with R/M disease and were refractory to neoadjuvant/adjuvant platinum based chemotherapy, will receive MEDI0457 7 mg intramuscularly followed by electroporation on Day 1 of Weeks 1, 3, 7, 12, and then Q8W and durvalumab 1500 mg intravenously on Day 1 of Week 4 and then Q4W until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurs first. arm 3: Participants with R/M disease and were treated with 1 or more lines of platinum based chemotherapy, will receive MEDI0457 7 mg intramuscularly followed by electroporation on Day 1 of Weeks 1, 3, 7, 12, and then Q8W and durvalumab 1500 mg intravenously on Day 1 of Week 4 and then Q4W until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurs first.
Interventions: intervention 1: MEDI0457 intervention 2: CELLECTRA®5P device intervention 3: Durvalumab
Intervention descriptions: intervention 1: MEDI0457 7 mg will be administered intramuscularly followed by electroporation (EP) using CELLECTRA®5P device. intervention 2: MEDI0457 7 mg will be administered intramuscularly followed by EP using CELLECTRA®5P device. intervention 3: Durvalumab will be administered intravenously at a dose of 1500 mg every 4 weeks.

Protocol documents:
Prot_002.pdf: 
 
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Clinical Study Protocol  
Drug Substance 
MEDI0457 (INO-3112) 
Durvalumab (MEDI4736) 
Study Code 
D8860C00005 
Version 
8.0 
Date 
17 March 2021 
A Phase 1b/2a, Multi-Center Open-Label Study to Evaluate the Safety and 
Efficacy of Combination Treatment with MEDI0457 (INO-3112) and 
Durvalumab (MEDI4736) in Patients with Recurrent / Metastatic Human 
Papilloma Virus Associated Head and Neck Squamous Cancer 
Sponsor:  MedImmune, LLC/Ltd, a wholly owned subsidiary of AstraZeneca PLC. 
MedImmune Sponsor Medical Monitor: 
Primary Medical Monitor 
Name: 
 
Job Position: 
 
 
Company Name: MedImmune, LLC/Ltd 
Address: One MedImmune Way, 
Gaithersburg, MD 20878, United States of America. 
Telephone Number: 
 
E-mail:  
 
PPD
PPD
PPD
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Clinical Study Protocol 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
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VERSION HISTORY 
Version 8.0, 17 March 2021 
The following changes were incorporated into Version 8.0 of the Clinical Study Protocol: 
• 
Section 4 (Table 3): Addition of COVID-19 vaccine footnote “p”. Aligned 
footnote “d” with Section 7.2.  
• 
Section 4.4: Addition of an option to allow Investigators to remove patients from 
the Continued Treatment Period after 2 years of treatment. Update to remove 
collection of non-serious AEs from the Continued Treatment Period. 
• 
Section 5.5.2: Addition of COVID-19 vaccine guidance.  
 
Version 7.0, 01 September 2020 
The following changes were incorporated into Version 7.0 of the Clinical Study Protocol: 
• 
Title Page: Secondary Medical Monitor information removed. 
• 
Synopsis: Updated estimated date of last patient completed. 
• 
Section 4: Discontinuation of tests for HPV-16/HPV-18 E6/E7 antibody, 
HPV-16/HPV-18 E6/E7 ELISPOT and flow cytometry-based assay, as well as 
Tumor cell and tumor cell HPV DNA or RNA. Edit to vital signs footnote for 
clarification in Table 3. 
• 
Section 4.4: Addition of Continued Treatment Period 
• 
Section 5.8.1.1: Clarification that tumor biopsies collected as part of clinical care 
can be submitted for further analysis unless AZ determines to end sample 
collection/analysis. 
• 
Appendix H: Removed the link to the Durvalumab Dosing Modification and 
Toxicity Management Guidelines (https://tmg.azirae.com), as the web portal has 
been decommissioned. 
• 
Other minor formatting edits were made throughout the document. 


Clinical Study Protocol 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
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Version 6.0, 27 January 2020 
The following changes were incorporated into Version 6.0 of the Clinical Study Protocol: 
• 
Title Page: Primary and Secondary Medical Monitors and contact information 
updated. 
• 
Section 6.12.1: Addition of a reference to the latest Durvalumab Investigator’s 
Brochure. Text detailing dose modifications for durvalumab infusion-related 
reactions was removed and a reference to Appendix H was added. 
• 
Section 11: Updated references to Durvalumab and MEDI0457 Investigator’s 
Brochures. 
• 
Appendix H: Durvalumab Treatment Modification and Toxicity Management 
Guidelines tables in Appendix H removed and are to be maintained as a stand-
alone document within the Site Master File and are available through the 
following link: https://tmg.azirae.com.  
• 
Other minor edits were made throughout the document for clarification. 
 
Version 5.0, 12 July 2017 
The following changes were incorporated into Version 5.0 of the Clinical Study Protocol: 
• 
 
 
 
• 
Clarification between the Safety Analysis Run-in patients and the Safety Analysis 
patients. 
• 
Update with Durvalumab Investigator Brochure details to reflect the more recent 
version for the Introduction and Adverse events of special interest sections. 
• 
Changes to the collection of screening biopsies. 
• 
Changes made to Inclusion criterion #9. 
• 
The reason for the screen failures will be recorded. 
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Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
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• 
Details of the Safety Data Monitoring Committee have been revised / clarified 
based on the discussions during the preparation of the Safety Data Monitoring 
Committee Charter. 
• 
Corrections and clarifications made to the footnotes of Tables 3 and 4. 
• 
Visit Windows: modifications of the visit windows for the treatment period 
(Table 3). 
• 
Pregnancy tests:  The frequency of pregnancy testing has been reduced to once 
every 4 weeks.  The removal of the wording that a pregnancy test must be 
performed before every tumor biopsy or study drug administration since the 
frequency of pregnancy testing has been reduced to every 4 weeks. 
• 
Addition of new creatine phosphokinase sampling times during the treatment 
period (at Weeks 7, 8 and 12 and then every 8 weeks) and at the Follow-up visit. 
• 
Inclusion of white blood cell count and absolute eospinophil count to hematology 
assessments (Table 5). 
• 
 
 
• 
Replacement of the fluorescence activated cell sorting assay with the flow 
cytometry-based assay. 
• 
Removal of the method of measurement of serum HPV-specific antibody levels 
with a multiplexed serology assay. 
• 
Amendment of TS Biorepository to MedImmune Biorepository. 
• 
Inclusion of the independent central review of all scans used in the assessment of 
tumors by RECIST version 1.1 and/or irRECIST. 
• 
Clarification of administration site reactions as adverse events of special interest. 
• 
Removal of the dose-limiting toxicity criterion: Any Grade 2 pneumonitis that 
does not resolve to ≤ Grade 1 within 3 days of the initiation of maximal 
supportive care is a dose-limiting toxicity. 
• 
Correction made for study drug accountability.  Study drug accountability will be 
captured using Interactive Voice and Web Response. 
• 
Removal of the duplicate Safety Design table from the Safety Analysis run-in 
section. 
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Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
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• 
The definition of the Response-evaluable Population has reworded for 
clarification. 
• 
The definition of the Pharmacokinetic Analysis Set has been updated to reflect 
the definition provided in the Statistical Analysis Plan. 
• 
Clarifications made to the reporting of serious adverse events if the Web based 
Data Capture system is not available. 
• 
Removal of the follow-up and documentation of pregnancy outcome for the 
partners of the male patients. 
• 
Update made to the study timetable. 
• 
Addition of abbreviations due to the introduction of new text. 
• 
Removal of the signature pages from the protocol. 
• 
Other minor edits were made throughout the document for clarification. 
 
Version 4.4, 09 December 2016 
Initial creation 
 
 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and / or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 
 
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PROTOCOL SYNOPSIS 
 
A Phase 1b/2a, Multi-Center Open-Label Study to Evaluate the Safety and 
Efficacy of Combination Treatment with MEDI0457 (INO-3112) and 
Durvalumab (MEDI4736) in Patients with Recurrent / Metastatic Human 
Papilloma Virus Associated Head and Neck Squamous Cancer 
 
Study site(s) and number of patients planned 
This will be a multi-center study with the participation of sites in the United States of 
America.  Approximately eight centers will participate in the study.  Approximately 
50 patients will be enrolled to obtain 40 evaluable patients. 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q4 2016 
1 
Estimated date of last patient completed 
Q1 2021 
1 
Study design 
This is a Phase 1b/2a, open-label, multi-center study to evaluate the safety and tolerability, 
anti-tumor activity, and immunogenicity of MEDI0457 (also known as INO-3112) in 
combination with durvalumab (also known as MEDI4736).  Approximately 50 patients with 
human papilloma virus associated recurrent / metastatic head and neck squamous cell cancer 
will be enrolled in this study.  Approximately three to 12 patients (Safety Analysis Run-in 
patients) will be enrolled and assessed for safety before additional patients are enrolled at a 
recommended dose and schedule for the combination.  Because this study is the first time 
MEDI0457 has been combined with durvalumab, the study will start with enrollment of a 
minimum of three patients who will receive four doses of MEDI0457 (Limited Schedule) in 
combination with durvalumab.  Only if the safety analysis of the initial patients who complete 
the 7-week dose-limiting toxicity evaluation period, is deemed acceptable (i.e., none of the 
initial patients experience a dose-limiting toxicity), the vaccination schedule will switch from 
the limited four doses (Limited Schedule) to the Indefinite Schedule (also known as the 
Planned Dosing Schedule, i.e. vaccinations will continue until disease progression).  This 
Indefinite Schedule will be implemented for all subsequent patients following the Safety 
Analysis Run-in. Otherwise, if a third of the initial patients experience a dose-limiting 
toxicity, a minimum of three additional patients (i.e., a minimum total of six patients for the 
Safety Analysis Run-in) will be enrolled and the initial minimum six patients in the Safety 
Analysis Run-in cohort will be limited to a total of four doses of MEDI0457 (Limited 
Schedule) before considering a switch to the Indefinite Schedule, provided the safety data 
was supportive and if only no more than a third of these patients experience a dose-limiting 
toxicity during their 7-week dose-limiting toxicity evaluation period.  If at any time during the 


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Study Code D8860C00005 
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enrollment of these patients, more than a third of the patients experience dose-limiting 
toxicity, then this regimen has exceeded the maximum tolerated dose and the regimen will be 
modified.  The choice of modifications in the Revised Dosing Schedule during the Safety 
Analysis Run-in include the following: (1) decrease the dose of durvalumab to 750 mg every 
four weeks or decrease the total number of durvalumab doses, (2) increase the interval 
between MEDI0457 doses from every 8 weeks to intervals such as 12 or 16 weeks following 
the Week 12 dose or decrease the total number of MEDI0547 doses administered from a total 
of three to either one or two during the dose-limiting toxicity period.  At least a minimum of 
three patients with no dose-limiting toxicity and up to approximately six patients with no more 
than a third with a dose-limiting toxicity must be evaluated using either the Planned Dosing 
Schedule or Revised Dosing Schedule before study enrollment will continue with a 
recommended dose and schedule for the combination.  In the Planned Dosing Schedule both 
MEDI0457 and durvalumab treatment will continue until confirmed disease progression, 
unacceptable toxicity or withdrawal of consent.  Either treatment may be stopped by the 
Investigator while the other treatment continues.  See flowchart and Design for Safety 
Analysis Run-in table below. 


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Study Code D8860C00005 
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Design for Safety Analysis Run-in 
Rules 
• A minimum of three patients will be enrolled and if none of the initial patients 
experience a dose-limiting toxicity, then the vaccination schedule will switch 
from the limited four doses (Limited Schedule) to the Indefinite Schedule 
(also known as the Planned Dosing Schedule, i.e. vaccinations will continue 
until disease progression).  The Indefinite Schedule will be implemented for 
all subsequent patients following the Safety Analysis Run-in. 
• If a third of the initial patients experience a dose-limiting toxicity, then a 
minimum of three additional patients (i.e., a minimum total of six patients) 
will be enrolled into the Safety Analysis Run-in.  These patients will be given 
the Limited Schedule (four doses) of MEDI0457 before considering a switch 
to the Indefinite Schedule provided the safety data was supportive and if no 
more than a third of these patients experience a dose-limiting toxicity during 
their 7-week dose-limiting toxicity evaluation period. 
• 
If at any time during the enrollment of these patients, more than a third of 
the  patients experience a dose-limiting toxicity, then this regimen has 
exceeded the maximum tolerated dose and the regimen will be modified: 
Revised Dosing Schedule (per Safety Data Monitoring Committee). 
• 
At least a minimum of three patients with no dose-limiting toxicity and up to 
approximately six patients with no more than a third with a dose-limiting 
toxicity must be evaluated using either the Planned Dosing Schedule or 
Revised Dosing Schedule before study enrollment will continue with a 
recommended dose and schedule for the combination. 


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Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
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Overall Study Design Flow Chart  
 
 
 
 
 
 
 
 
 
 
 
a 
Planned Dosing Schedule: Minimum time between Week 3 MEDI0457 dose and the Week 4 first durvalumab dose, and the Week 7 MEDI0457 dose and the 
Week 8 durvalumab dose is 7 days.  Starting at Week 12, the administration of MEDI0457 and durvalumab treatments can be given on the same day.  Safety Analysis 
run-in patients will initially receive a total of four doses of MEDI0457 (Limited Schedule) as per schedule above.  Based on the rules shown in the Design for Safety 
Analysis Run-in table, the Limited Schedule (four doses) will be switched to the Indefinite Schedule (also known as the Planned Schedule). 
b 
A Revised Dosing Schedule will be evaluated in up to six patients if two or more patients during the Safety Analysis Run-in period experience a dose-limiting 
toxicity.  
c 
All patients should consent to pre-treatment biopsy of the tumor if it can be done safely (as judged by the Investigator) during screening, otherwise archival tissue 
within 3 years prior to study entry in all patients will be allowed except for a minimum 10 of the first 20 patients who will be required to provide a paired biopsy (a 
fresh biopsy at screening and at Week 10).  After 10 paired biopsies have been obtained then Week 10 on-treatment biopsy will be made optional but will be 
encouraged.   
Tumor Core Biopsy at screening & 
Week 10c 
Planned Dosing Schedule: durvalumab at Weeks 4, 8 
and 12 and then every 4 weeks until disease progression, 
unacceptable toxicitya,b or withdrawal of consent 
Planned Dosing Schedule: MEDI0457 Vaccine: Weeks 1, 
3, 7 and 12 and then every 8 weeks, until disease 
progression, unacceptable toxicitya,b or withdrawal of 
consent 
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Objectives 
Primary Objectives: 
Outcome Measures: 
To determine the safety profile of MEDI0457 
in combination with durvalumab in patients 
with recurrent / metastatic head and neck 
cancer.  
Adverse events / serious adverse events 
 
Collection of hematology, serum chemistry, 
urinalysis, creatine phosphokinase, thyroid function 
testing and pregnancy test 
 
Electrocardiograms.  The following parameters will 
be recorded for each electrocardiogram: date and time 
of electrocardiogram, heart rate (beats/min), PR 
interval (ms), QRS interval (ms), RR interval (ms), 
QT interval (ms), QTcB interval (ms), QTcF interval 
(ms), sinus rhythm (yes / no), and overall evaluation 
(normal / abnormal) 
 
Vital signs  
 
Physical examinations 
 
Concomitant medications 
 
World Health Organization / Eastern Cooperative 
Oncology Group performance status 
To evaluate the anti-tumor activity of 
MEDI0457 in combination with durvalumab in 
patients with confirmed HPV-16 or HPV-18 
associated recurrent / metastatic head and neck 
cancer.  
Objective response rate by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 
(Response-evaluable Population) 
 
Secondary Objectives: 
Outcome Measures: 
To evaluate the pharmacokinetics and 
anti-drug antibodies for durvalumab. 
Serum concentrations of durvalumab  
 
Anti-drug antibodies for durvalumab  


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To evaluate the anti-tumor activity of 
MEDI0457 in combination with durvalumab.  
Objective response rate by RECIST version 1.1 
(As-treated population) and immune-related RECIST 
 
Disease control rate at 16 weeks by RECIST 
version 1.1 
 
Overall survival 
 
Progression free survival as assessed by RECIST 
version 1.1  
 
Exploratory Objectives: 
Outcome Measures: 
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Target patient population 
Male or female patients 18 years of age or older with recurrent or metastatic human papilloma 
virus associated squamous cell carcinoma of the head and neck with persistent or progressive 
disease after treatment with a platinum based chemotherapy and lacking a curative treatment 
option.  Patients who are platinum ineligible may be enrolled if they have received and failed 
an approved treatment and lack a treatment option with curative potential. 
Eligible patients must have at least one "measurable target lesion" according to RECIST 
version 1.1 and one additional lesion that can be safely (as judged by the Investigator) 
biopsied at screening.  Patients are required to provide their consent to have a screening 
biopsy; otherwise, archival tissue within 3 years prior to study entry in all patients will be 
allowed except for a minimum 10 of the first 20 patients who will be required to provide a 
paired biopsy (a fresh biopsy at screening and at Week 10). 
Duration of treatment 
Safety Analysis Run-in patients will initially receive a total of four initial doses of MEDI0457 
as per schedule and will start durvalumab treatment at Week 4 and then every 4 weeks.  Based 
on the rules shown in the Design for Safety Analysis Run-in table, the Limited Schedule 
(four doses) will be switched to the Indefinite Schedule (also known as the Planned 
Schedule).  For the remaining patients, both MEDI0457 and durvalumab treatment will 
continue until confirmed disease progression, unacceptable toxicity or withdrawal of consent.  
Either treatment may be stopped by the Investigator while the other treatment continues. 
Investigational product, dosage and mode of administration 
All patients will receive combination treatment with MEDI0457 (also known as INO-3112) 
and durvalumab (also known as MEDI4736) as per the following Planned Dosing Schedule. 
 
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Study Code D8860C00005 
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Statistical methods 
Sample size: 
 
 
 
 
 
 
Statistical analyses: The safety evaluation will be based on the treated population, which 
includes all patients who receive any investigational product (defined as one dose of either 
study drug).  Demographic and baseline characteristics will be summarized with means, 
medians, standard deviations, ranges or percentages.  Safety will be summarized by the 
percentage of patients with adverse events, with grading according to Common Terminology 
Criteria for Adverse Event version 4.03 and attribution.  The co-primary efficacy analysis of 
objective response rate via RECIST version 1.1 will be based on the Response-evaluable 
Population.  Secondary analyses of objective response rate, disease control rate, 
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progression free survival and overall survival will be performed on both the As-treated and 
Response-evaluable populations.  Immune responses will be analyzed in patients with 
available data by calculating the geometric mean and median antibody and T-cell levels and 
fold-increases along with associated 95% confidence intervals.  Additional details will be 
provided in the Statistical Analysis Plan.  
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 6 
TABLE OF CONTENTS ....................................................................................... 16 
1. 
INTRODUCTION ................................................................................................. 27 
1.1 
Background and rationale for conducting this study ............................................. 27 
1.1.1 
Summary of clinical experience ............................................................................. 27 
1.1.1.1 
MEDI0457 with electroporation ............................................................................ 27 
1.1.1.2 
Durvalumab (investigational name MEDI4736) ................................................... 28 
1.2 
Rationale for study design, doses and control groups ............................................ 30 
1.2.1 
Rationale for the study ........................................................................................... 30 
1.2.2 
Rationale for endpoints .......................................................................................... 32 
1.2.3 
Rationale for doses selected ................................................................................... 32 
1.2.4 
Rationale for study population ............................................................................... 32 
1.3 
Benefit / risk and ethical assessment...................................................................... 33 
1.3.1 
Potential benefits - MEDI0457 .............................................................................. 33 
1.3.2 
Potential benefits - Durvalumab ............................................................................ 33 
1.3.3 
Potential benefits - DNA immunotherapy delivery with electroporation .............. 36 
1.3.4 
Possible risks - MEDI0457 with electroporation ................................................... 36 
1.3.5 
Possible risks - Durvalumab .................................................................................. 37 
1.3.6 
Possible risks and mitigations - MEDI0457 with electroporation + 
Durvalumab ............................................................................................................ 38 
1.4 
Study design ........................................................................................................... 38 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ....................................................... 42 
2.1 
Hypothesis .............................................................................................................. 42 
2.2 
Primary objectives ................................................................................................. 42 
2.3 
Secondary objectives ............................................................................................. 43 
2.4 
Exploratory objectives ........................................................................................... 44 
3. 
PATIENT SELECTION, ENROLLMENT, REGISTRATION, PATIENT 
INSTRUCTIONS, DISCONTINUATION AND WITHDRAWAL ..................... 44 
3.1 
Inclusion criteria .................................................................................................... 44 
3.2 
Exclusion criteria ................................................................................................... 47 
3.3 
Patient enrollment and registration ........................................................................ 50 


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3.4 
Procedures for handling incorrectly enrolled patients ........................................... 50 
3.5 
Methods for assigning treatment groups ................................................................ 51 
3.6 
Methods for ensuring blinding ............................................................................... 51 
3.7 
Methods for unblinding .......................................................................................... 51 
3.8 
Patient instructions ................................................................................................. 51 
3.9 
Discontinuation of investigational product ............................................................ 53 
3.9.1 
Procedures for discontinuation of a patient from investigational product ............. 54 
3.10 
Criteria for withdrawal ........................................................................................... 54 
3.10.1 
Screen failures ........................................................................................................ 55 
3.10.2 
Withdrawal of the informed consent ...................................................................... 55 
3.11 
Safety analysis run-in patients ............................................................................... 56 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 59 
4.1 
Enrollment / screening period ................................................................................ 66 
4.2 
Treatment period .................................................................................................... 66 
4.3 
Follow-up period .................................................................................................... 66 
4.4 
Continued Treatment Period .................................................................................. 66 
5. 
STUDY ASSESSMENTS ..................................................................................... 67 
5.1 
Demographics ........................................................................................................ 67 
5.2 
Medical history ...................................................................................................... 67 
5.3 
Efficacy assessments .............................................................................................. 67 
5.4 
Safety assessments ................................................................................................. 70 
5.4.1 
Laboratory safety assessments ............................................................................... 70 
5.4.2 
Pregnancy testing ................................................................................................... 74 
5.4.3 
Physical examination ............................................................................................. 74 
5.4.4 
WHO / ECOG performance status ......................................................................... 74 
5.4.5 
Post-treatment reaction assessment ........................................................................ 74 
5.4.6 
Vital signs .............................................................................................................. 75 
5.4.7 
Weight and height .................................................................................................. 75 
5.4.8 
Electrocardiogram .................................................................................................. 76 
5.4.9 
Other safety assessments ........................................................................................ 76 
5.4.9.1 
Management of anxiety and pain due to electroporation procedure ...................... 76 
5.4.9.2 
Monitoring of durvalumab administration ............................................................. 77 
5.4.9.3 
Management of infusion reactions due to durvalumab .......................................... 78 
5.4.9.4 
Assessment of clinical adverse events ................................................................... 78 
5.5 
Other assessments .................................................................................................. 78 
5.5.1 
Downloading of electroporation data from CELLECTRA®5P device .................. 78 
5.5.2 
Coronavirus disease of 2019 vaccine ..................................................................... 79 


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5.6 
Pharmacokinetics ................................................................................................... 79 
5.6.1 
Collection of samples ............................................................................................. 79 
5.6.2 
Determination of drug concentration ..................................................................... 79 
5.6.3 
Storage and destruction of pharmacokinetic / anti-drug antibody samples ........... 79 
5.6.4 
Collection of samples to measure for the presence of anti-drug antibody ............. 80 
5.7 
Pharmacogenetics .................................................................................................. 80 
5.8 
Biomarker analysis ................................................................................................. 80 
 
 
5.8.3 
Storage, reuse and destruction of biological samples ............................................ 83 
5.8.4 
Labeling and shipment of biological samples ........................................................ 84 
5.8.5 
Chain of custody of biological samples ................................................................. 84 
5.8.6 
Withdrawal of informed consent for donated biological samples ......................... 84 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 85 
6.1 
Definition of adverse events .................................................................................. 85 
6.2 
Definitions of serious adverse events..................................................................... 86 
6.3 
Definition of adverse reactions .............................................................................. 87 
6.4 
Definition of suspected adverse reactions .............................................................. 87 
6.5 
Definition of unexpected events / reactions ........................................................... 87 
6.6 
Definition of life-threatening events / reactions .................................................... 88 
6.7 
Recording of adverse events .................................................................................. 88 
6.7.1 
Time period for collection of adverse events ......................................................... 88 
6.7.2 
Methods and timing of the collection and recording of adverse events................. 88 
6.7.3 
Follow-up of unresolved adverse events ................................................................ 89 
6.7.4 
Variables ................................................................................................................ 89 
6.7.5 
Severity codes for adverse events .......................................................................... 90 
6.7.6 
Causal relationship of investigational product to adverse events .......................... 91 
6.7.7 
Relationship to protocol procedures ...................................................................... 92 
6.7.8 
Adverse events based on signs and symptoms....................................................... 92 
6.7.9 
Adverse events based on examinations and tests ................................................... 92 
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6.7.10 
Abnormal laboratory value .................................................................................... 93 
6.7.11 
New cancers ........................................................................................................... 93 
6.7.12 
Disease progression ............................................................................................... 94 
6.7.13 
Deaths .................................................................................................................... 94 
6.8 
Reporting of serious adverse events....................................................................... 94 
6.9 
Reporting of serious and unexpected suspected adverse reactions ........................ 95 
6.10 
Overdose ................................................................................................................ 96 
6.11 
Pregnancy ............................................................................................................... 96 
6.11.1 
Maternal exposure .................................................................................................. 96 
6.11.2 
Paternal exposure ................................................................................................... 97 
6.12 
Management of investigational product related toxicities ..................................... 97 
6.12.1 
Dose modifications ................................................................................................ 97 
6.12.2 
Toxicity management ............................................................................................. 98 
6.12.2.1 Dose-limiting toxicity ............................................................................................ 99 
6.12.2.2 Events requiring expedited reporting within 24 hours ......................................... 100 
6.12.2.3 Events requiring reporting within 72 hours ......................................................... 102 
6.12.3 
Stopping rules ...................................................................................................... 102 
6.12.4 
Adverse events of special interest ........................................................................ 103 
6.12.5 
Unanticipated (serious) adverse device effect ..................................................... 105 
6.13 
Study governance and oversight .......................................................................... 105 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................. 106 
7.1 
Identity of investigational product(s) ................................................................... 106 
7.1.1 
MEDI0457 ........................................................................................................... 106 
7.1.2 
Durvalumab .......................................................................................................... 106 
7.2 
Dose and treatment regimens ............................................................................... 108 
7.3 
Labeling ............................................................................................................... 109 
7.4 
Storage ................................................................................................................. 110 
7.4.1 
Storage - MEDI0457 ............................................................................................ 111 
7.4.2 
Storage - Durvalumab .......................................................................................... 111 
7.5 
Preparation and dispensing .................................................................................. 111 
7.5.1 
Preparation and dispensing - MEDI0457 ............................................................. 111 
7.5.2 
Preparation and dispensing - Durvalumab ........................................................... 111 
7.6 
Investigational product inspection ....................................................................... 112 
7.7 
Compliance .......................................................................................................... 112 
7.8 
Accountability ...................................................................................................... 113 
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7.8.1 
Accountability - investigational products ............................................................ 113 
7.8.2 
Accountability - investigational device................................................................ 113 
7.9 
Return and destruction of investigational products and investigational 
device ................................................................................................................... 113 
7.11 
Post study access to study treatment .................................................................... 114 
8. 
STATISTICAL ANALYSES .............................................................................. 114 
8.1 
Statistical considerations ...................................................................................... 114 
8.2 
Sample size estimate ............................................................................................ 115 
8.3 
Definitions of analysis sets .................................................................................. 117 
8.3.1 
Efficacy analysis set ............................................................................................. 117 
8.3.2 
Safety analysis set ................................................................................................ 118 
8.3.3 
Pharmacokinetics analysis set .............................................................................. 118 
8.4 
Outcome measures for analyses ........................................................................... 119 
8.4.1 
Primary endpoints ................................................................................................ 119 
8.4.1.1 
Adverse events ..................................................................................................... 119 
8.4.1.2 
Safety assessments ............................................................................................... 119 
8.4.1.3 
Investigator RECIST version 1.1-based assessments .......................................... 119 
8.4.2 
Secondary efficacy endpoints .............................................................................. 120 
8.4.2.1 
Pharmacokinetics and antibodies for durvalumab ............................................... 121 
 
 
 
8.5 
Methods for statistical analyses ........................................................................... 121 
8.5.1 
Analysis of the primary variable(s) ...................................................................... 122 
8.5.1.1 
Safety ................................................................................................................... 122 
8.5.2 
Analysis of the secondary variable(s) .................................................................. 122 
8.5.2.1 
Pharmacokinetic analysis ..................................................................................... 122 
8.5.2.2 
Anti-drug antibody analysis ................................................................................. 122 
8.5.2.3 
Anti-tumor analysis – objective response rate, disease control rate at 16 
weeks, progression free survival and overall survival ......................................... 122 
8.5.3 
Exploratory analysis ............................................................................................. 122 
 
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8.5.4 
Subgroup analysis ................................................................................................ 123 
9. 
STUDY AND DATA MANAGEMENT ............................................................. 124 
9.1 
Training of study site personnel ........................................................................... 124 
9.2 
Monitoring of the study ....................................................................................... 124 
9.2.1 
Source data ........................................................................................................... 125 
9.2.2 
Study agreements ................................................................................................. 125 
9.2.3 
Archiving of study documents ............................................................................. 125 
9.2.4 
Deviation from the clinical study protocol .......................................................... 125 
9.3 
Study timetable and end of study ......................................................................... 126 
9.4 
Data management ................................................................................................. 126 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 127 
10.1 
Ethical conduct of the study ................................................................................. 127 
10.2 
Patient data protection .......................................................................................... 127 
10.3 
Ethics and regulatory review................................................................................ 127 
10.4 
Informed consent ................................................................................................. 128 
10.5 
Changes to the protocol and informed consent form ........................................... 128 
10.6 
Audits and inspections ......................................................................................... 129 
11. 
LIST OF REFERENCES ..................................................................................... 130 
 
LIST OF TABLES 
Table 1 
Effective Methods of Contraception ......................................................... 53 
Table 2 
Study Plan - Screen Procedures ................................................................ 59 
Table 3 
Study Plan - Study Administration Procedures ........................................ 61 
Table 4 
Study Plan - Follow-up Visit Procedures ................................................. 65 
Table 5 
Laboratory Safety Variables - Hematology .............................................. 71 
Table 6 
Laboratory Safety Variables - Serum Chemistry ..................................... 72 
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Table 7 
Laboratory Safety Variables - Urinalysis ................................................. 73 
 
Table 9 
A Summary of Efficacy Endpoints with Corresponding Methods 
of Assessment and Populations .............................................................. 118 
 
LIST OF FIGURES 
Figure 1 
Overall Study Design Flow Chart ............................................................ 41 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information ................................................................ 135 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ............................................................................... 137 
Appendix C 
Pharmacogenetics Research ................................................................... 139 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .......................................................................... 142 
Appendix E 
CELLECTRA®5P Error Reporting Form .............................................. 148 
Appendix F 
Guidelines for Evaluation of Objective Tumor Response using 
RECIST version 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors) ......................................................................................... 149 
Appendix G 
Guidelines for Evaluation of Progression Free Survival using 
Immune-related RECIST Criteria ........................................................... 156 
Appendix H 
Durvalumab Dose Modification for Toxicity Management ................... 157 
Appendix I 
Administration Site Reaction Grading and Management ....................... 158 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
AChE 
Acetylcholinesterase 
ADA 
Anti-Drug Antibody 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALK 
Anaplastic Lymphoma Kinase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
Anti PCP 
Anti-Pneumocystis Pneumonia 
Anti-PD-1 
Anti-Programmed Cell Death Protein 1 
Anti-PD-L1 
Anti-Programmed Death Ligand 1 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
β-HCG 
Beta-Human Chorionic Gonadotropin 
COVID-19 
Coronavirus disease of 2019 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CRF 
Case Report Form (electronic) 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DCR 
Disease Control Rate 
DCR-16w 
Disease Control Rate at 16 weeks 
DCR-24w 
Disease Control Rate at 24 weeks 
DILI 
Drug Induced Liver Injury 
DLT 
Dose-Limiting Toxicity 
EC 
Ethics Committee, synonymous to Institutional Review Board 
(IRB) and Independent Ethics Committee (IEC) 


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Abbreviation or special 
term 
Explanation 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
ELISPOT 
Enzyme-Linked Immunosorbent Spot 
EOS 
End of Study 
EOT 
End of Treatment 
EP 
Electroporation 
FDA 
Food and Drug Administration 
FDG 
Fludeoxyglucose 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
HBcAb 
Hepatitis Virus B Core Antibody 
HBsAg 
Hepatitis Virus B Surface Antigen 
HIV 
Human Immunodeficiency Virus 
HL 
Hy’s Law 
HPV 
Human Papilloma Virus 
HPV-16 
Human Papilloma Virus Type 16 
HPV-18 
Human Papilloma Virus Type 18 
HR 
Heart Rate 
IATA 
Airline Transportation Association 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
IgG 
Immunoglobulin G 
IgG1 
Immunoglobulin G1 
ILD 
Interstitial Lung Disease 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
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Abbreviation or special 
term 
Explanation 
International Co-ordinating 
Investigator 
If a study is conducted in several countries the International Co-
ordinating Investigator is the Investigator co-ordinating the 
investigators and / or activities internationally.  
IP 
Investigational Product  
irAE 
Immune-Related Adverse Event 
irRECIST 
Immune-Related Response Evaluation Criteria in Solid Tumors 
IV 
Intravenous(ly) 
IVIG 
Intravenous Immunoglobulin 
LD 
Longest Diameter 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone 
LIMS 
Laboratory Information Management System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death Ligand 1 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PHL 
Potential Hy’s Law 
PO 
Oral(ly); by mouth 
PR 
Partial Response 
PR interval 
Interval on the electrocardiogram, from the start of the P wave to 
the start of the R wave 
PRA 
PRA Health Sciences 
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Abbreviation or special 
term 
Explanation 
Q4W 
Every 4 weeks 
QRS interval 
Interval on the electrocardiogram from the start of the Q wave to 
the end of the of the S wave 
QT interval 
Interval on the electrocardiogram, from the beginning of the QRS 
complex to the end of the T wave 
QTcB interval 
QT interval corrected for heart rate based on the Bazett formula 
QTcF interval 
QT interval corrected for heart rate based on the Fridericia 
formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous Cell Carcinoma of the Head and Neck 
SD 
Stable Disease 
SDMC 
Safety Data Monitoring Committee 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBL 
Total Bilirubin 
TNF 
Tumor Necrosis Factor 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBDC 
Web Based Data Capture 
WHO 
World Health Organization 
 
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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
Head and neck cancer accounts for about 3% of all cancers in the United States.  In 2016, an 
estimated 61,760 people (45,330 men and 16,430 women) will develop head and neck cancer.  
It is estimated that 13,190 deaths (9,800 men and 3,390 women) will occur in 2016 from this 
disease. 
There has been a remarkable shift in the epidemiology of head and neck cancer over the past 
30 years.  While exposure to chemical mutagens such as tobacco and alcohol remains the most 
common risk factor for squamous cell cancers of the aerodigestive tract, a rapidly expanding 
subset of head and neck cancers are acquired through human papilloma virus (HPV) infection.  
The oropharynx is uniquely susceptible to HPV, and now up to 70% of oropharyngeal cancers 
in the United States are HPV-related.  The HPV viral oncoproteins, E6 and E7, are 
predominantly responsible for oncogenesis.  E6 promotes degradation of p53, indirectly 
activates telomerase, and disrupts the function of the cellular phosphatase tumor suppressor 
PTPN13.  E7 inactivates retinoblastoma protein and activates Mi2beta.  Together, these 
oncogenic alterations result in the expression of p16, drive rapid cellular proliferation, 
suppress or down regulate key tumor suppressor proteins, and lead to cellular immortality.  In 
addition, E6/E7 expression is required to maintain a malignant transformed phenotype 
(Scheffner et al 1990, Jabbar et al 2009).  
While the currently available prophylactic HPV vaccines are highly effective in preventing 
infection by HPV types 16 and 18, these have no therapeutic effect, and therefore are of no 
value for patients already diagnosed with human papilloma virus type 16 (HPV-16) or human 
papilloma virus type 18 (HPV-18) positive head and neck cancer.   
1.1.1 
Summary of clinical experience 
1.1.1.1 
MEDI0457 with electroporation 
MEDI0457, also known as INO-3112, is a combination of plasmids contained in the drug 
products called VGX-3100 and INO-9012. 
 
 
 
 
 
 
 
 
 
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1.1.1.2 
Durvalumab (investigational name MEDI4736) 
Durvalumab is a human monoclonal antibody of immunoglobulin G1 (IgG1) kappa subclass 
that inhibits binding of programmed death ligand 1 (PD-L1).  The proposed mechanism of 
action for durvalumab is interference of the interaction of PD-L1, expressed on cancer cells 
and a subset of leukocytes, with the programmed cell death protein 1 (PD-1) molecules on 
antigen-presenting cells and T-cells.  By binding to PD-L1 on tumor cells, the mechanism of 
action of durvalumab includes stimulation of the patient’s anti-tumor immune response. 
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1.2 
Rationale for study design, doses and control groups 
1.2.1 
Rationale for the study 
Although HPV associated head and neck cancers are generally associated with better 
prognosis than non-HPV cancer, approximately 20-25% of patients treated with curative 
intent for locoregional disease will have disease progression within 3 years (Ang et al 2010).  
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In addition, ~8-10% of patients will present with de novo incurable metastatic disease.  
Emerging data from anti-programmed cell death protein 1 (anti-PD-1) / anti-programmed 
death ligand 1 (anti-PD-L1) therapy in head and neck cancer as well as in other solid tumors 
are very promising with a subset of patients showing tumor regression and delayed 
progression and improvement in survival (Ferris et al 2016, Bauml et al 2016).  However, a 
majority of patients do not respond to these novel treatments and thus are in need of additional 
therapies, including rational immunotherapy combinations.   
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1.2.2 
Rationale for endpoints 
In this first study of MEDI0457 and durvalumab in combination, safety and efficacy will be 
the primary endpoints.  The secondary endpoints of immunogenicity, disease control rate 
(DCR), progression free survival (PFS) and overall survival (OS) will be used for deciding if 
further studies are warranted.  In this study, there will be a Safety Analysis Run-in period 
because MEDI0457 and durvalumab have never been administered together.  The Safety 
Analysis Run-in period patients will be included in the efficacy analysis. 
 
 
1.2.3 
Rationale for doses selected 
 
 
 
 
 
 
 
 
 
Durvalumab (also known as MEDI4736) has an acceptable safety profile.  As of the data 
cut-off date of 12 July 2016, 5,225 patients have been exposed to one or more doses of 
durvalumab in AstraZeneca or MedImmune sponsored studies, either as monotherapy or in 
combination, including 2,878 patients in open-label trials, and 2,347 patients as an estimate 
based on the randomization scheme in studies where the treatment arm is blinded.  
Additionally, > 1,700 patients have been exposed to one or more doses of durvalumab in 
externally-sponsored / investigator-initiated clinical trials. The data are not completely 
validated as all studies are ongoing and the databases have not been locked and fully cleaned.  
Please refer to the Durvalumab Investigator’s Brochure for detailed data from ongoing studies.  
The 20 mg/kg (or its equivalent 1500 mg fixed dose) of durvalumab every 4 weeks has been 
tested in multiple studies and has been well tolerated. 
1.2.4 
Rationale for study population 
The incidence of HPV associated head and neck cancers is rising and is expected to continue 
on this trajectory until at least 2030 (Zandberg et al 2013).  The oropharynx is uniquely 
susceptible to HPV with ~70% of patients with cancer in this site are positive for oncogenic 
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HPV.  A large majority (> 90%) of the cancers are positive for HPV-16 and / or HPV-18.  The 
combination of HPV vaccine with anti-PD-L1 antibody is expected to enhance HPV-specific 
T-lymphocyte responses, resulting in improved outcome for these patients. 
1.3 
Benefit / risk and ethical assessment 
1.3.1 
Potential benefits - MEDI0457 
The safety profile of MEDI0457 (INO-3112) with EP has been generally acceptable, although 
this is based on a limited number of patients who received MEDI0457 with EP.  In addition to 
the safety, other benefits that already have been observed include (1) a generation of robust 
antigen-specific immune responses; (2) clinical benefits in patients with high grade cervical 
intraepithelial neoplasia, including viral clearance and improvement in pathological grade in 
the lesion area including viral clearance and improvement in pathological grade in the lesion 
area (Trimble et al 2015). 
We expect to observe both immune response to MEDI0457 and clinical benefits in most 
patients in this study. 
1.3.2 
Potential benefits - Durvalumab  
The majority of the safety and efficacy data currently available for durvalumab are based on 
the first-time-in-human, single agent study (CD-ON-MEDI4736-1108) in patients with 
advanced solid tumors.  Safety data are described in the current Durvalumab Investigator’s 
Brochure.  Efficacy data are available for three monotherapy studies 
(CD-ON-MEDI4736-1108, D4190C00007 and D4191C00003 [ATLANTIC] and two 
combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006).  Clinical activity 
has been observed across the five studies (Durvalumab Investigator’s Brochure). 
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For further details, please refer to the Durvalumab Investigator’s Brochure. 
1.3.3 
Potential benefits - DNA immunotherapy delivery with electroporation 
DNA vaccines developed by Inovio have been delivered without EP (1 study) or with the 
Inovio EP devices (23 studies).  Inovio EP devices have also been used to deliver DNA 
vaccines developed outside of Inovio in three different studies and two studies have evaluated 
the tolerability of Inovio EP devices with normal saline.  None of these studies have shown 
any safety concern related to the use of an EP device.  Electroporation indeed significantly 
enhances DNA transfer to host cells, resulting in robust immune responses (Sardesai and 
Weiner 2011). 
1.3.4 
Possible risks - MEDI0457 with electroporation 
DNA based vaccines in general are less risky based on their safety information compared to 
other forms of vaccines that utilize viral and bacterial vectors.  
In two companion papers by Sheets et al (Sheets et al 2006a, Sheets et al 2006b), potential 
toxicities (both intrinsic and immunotoxicities) and biodistribution profiles were compared for 
21 different plasmid DNA constructs, in nine separate Good Laboratory Practice 
(GLP)-compliant studies.  Despite differing plasmid DNA backbones, promoters, and 
sequence inserts, toxicity and biodistribution profiles were similar for all plasmid DNA 
constructs.  With respect to the toxicity assessments, the authors reported that toxicity was 
localized to the site of the injection for all 21 plasmid DNA constructs.  Similarly, all plasmid 
DNA constructs evaluated showed evidence that they were localized to the injection site and 
surrounding tissue in all studies.   
Further, four separate GLP toxicology and biodistribution studies have been performed for 
eight additional plasmid DNA vaccine candidates developed by Inovio with identical 
backbones delivered by EP yielding similar toxicity and biodistribution profiles.  
Intramuscular (IM) co-administration of interleukin-12 plasmid was evaluated in nonclinical 
studies to support the studies of IM interleukin-12 plasmid in humans.  INO-9012 has been 
used in combinations with other DNA vaccines, including VGX-3100 (i.e., MEDI0457), in 
several ongoing studies (HPV-004 Study, HPV-005 Study, HPV-006 Study, PCa-001 Study 
and TRT-001 Study).  There was no safety issue reported from these studies (for further 
details refer to MEDI0457 Investigator’s Brochure). 
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Interleukin-12 may cause autoimmune events.  This is at least partially associated with its 
Th1-promoting activity, which could favor Th1-mediated immunopathology and, in particular, 
the induction of Th1-mediated autoimmune diseases.  With our clinical experience in the 
HPV-005 Study, we have not observed any AEs that suggest autoimmune activity or 
autoimmune disorder in patients who have received a DNA vaccine treatment that contains 
INO-9012 (human interleukin-12 DNA plasmid).  This may reflect the use of IL-12 as a local 
adjuvant in relatively low concentrations as opposed to the administration of systemic doses.  
The study team will continue to vigilantly monitor patients for any possible risk of 
autoimmune AEs during the trial. 
The EP procedure with CELLECTRA®5P could cause patient discomfort, such as transient 
injection site edema, swelling, or pain.  Adverse events of administration site reactions are of 
special interest to the Sponsor.  These are defined, for the purpose of this protocol, as all AEs 
occurring as a result of the administration of the study treatment.  Guidelines for the grading 
and management of administration site reactions are outlined in Appendix I.  In order to 
regularly monitor possible muscle damage, creatine phosphokinase (CPK) testing is scheduled 
during the study treatment.  
Although safety data are generally acceptable for clinical testing, MEDI0457 is an 
investigational agent, and the full safety profile is unknown.  Additionally, it is unknown 
about the possible risk due to the proposed changes in MEDI0457 administration regimen in 
this study and its combination in this study with other investigational agent durvalumab.  This 
study will provide additional information on the safety profiles of these study treatments alone 
and in combination. 
1.3.5 
Possible risks - Durvalumab  
Clinically significant risks of interest include immune-mediated reactions and their associated 
signs and symptoms, risks due to immunogenicity, and other potential risks. 
Immune-mediated reactions / immune-related AEs (irAEs) that are important risks include: 
dermatitis / rash / pruritus, ALT / AST increases / hepatitis / hepatotoxicity, endocrinopathy 
(i.e., events of hypophysitis / hypopituitarism, adrenal insufficiency, type 1 diabetes, 
hypothyroidism and hyperthyroidism), neuropathy / neuromuscular toxicity (i.e., events of 
encephalitis, peripheral motor and sensory neuropathies, Guillain-Barré, and myasthenia 
gravis), nephritis and increases in serum creatinine, pancreatitis (or laboratory tests suggestive 
of pancreatitis - increased serum lipase / increased serum amylase), myocarditis / pericarditis / 
uveitis, pneumonitis / interstitial lung disease and diarrhea / colitis.  Hypersensitivity and 
serious allergic reaction events include infusion-related reactions, anaphylaxis / serious 
allergic reactions, and immune complex disease.  These events are managed based on 
established administration and toxicity management guidelines for this entire class of 
therapeutics (see Appendix H, Postow 2015). 
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1.3.6 
Possible risks and mitigations - MEDI0457 with electroporation + Durvalumab 
Risks observed (administration site reactions) and anticipated (CPK elevations and 
autoimmune AEs [immunogenicity]) with the administration of MEDI0457 with EP are 
described in Section 1.3.4.  Mitigations in place to reduce the adverse effects of MEDI0457 
with EP administration include: rotation of injection sites, patients are educated to promptly 
report potential skin reactions and obtain visual assessment; protocol guidelines are in place 
for management and reporting of injection / administration site reactions; administration of 
MEDI0457 with EP will not occur in an extremity that contains a metal prosthesis or skin 
which is obscured with tattoos or having in the ipsilateral extremity of the chest an electronic 
defibrillator / pacemaker device; monitoring of possible muscle damage by measurement of 
CPK testing; clinical manifestation and laboratory monitoring for immunogenicity; and 
persistent CTCAE Grade 3 injection site reactions that persist for > 5 days will be considered 
a dose-limiting toxicity (DLT). 
Clinically significant risks associated with immune oncology drugs (immune-mediated 
reactions and their associated signs / symptoms, and risks due to immunogenicity) have been 
briefly discussed in Section 1.3.5.  It is reasonable to assume there is possible risk for additive 
or synergistic toxicity with this combination.  Mitigations in place to detect and reduce the 
adverse effects of potential immune-mediated reactions include: eligibility criteria excluding 
certain autoimmune conditions present at baseline, baseline laboratory tests and monitoring 
per protocol; patients educated and instructed to notify the sites for any signs / symptoms that 
may represent an immune-mediated reaction; protocol guidelines for dose delay / withdrawal 
physical examinations at each site visit; and enlisting investigators familiar with the latest 
immune oncology toxicity management guidelines (Appendix H, Postow 2015).  
Risks commonly associated with the administration of any foreign protein include: immune 
complex disease, infusion reactions (durvalumab), and anaphylaxis and serious allergic 
reactions.  Mitigations to monitor, detect, and treat these potential adverse effects are: 
monitoring for the induction of anti-drug antibodies with signs / symptoms of immune 
complex disease; and monitoring of patients during and after administration of both 
investigational products (IPs) to detect and treat anaphylaxis / infusion reactions.  
Management criteria are in the protocol and in the appended immune oncology toxicity 
management guidelines (Appendix H, Postow 2015).  
1.4 
Study design  
This is a Phase 1b/2a, open-label, multi-center study to evaluate the safety and tolerability, 
anti-tumor activity, and immunogenicity of MEDI0457 (also known as INO-3112) in 
combination with durvalumab (also known as MEDI4736).  Approximately 50 patients with 
HPV associated recurrent / metastatic SCCHN will be enrolled in this study.  Approximately 
three to 12 patients (Safety Analysis Run-in patients) will be enrolled and assessed for safety 
before additional patients are enrolled at a recommended dose and schedule for the 
combination.  Because this study is the first time MEDI0457 has been combined with 
durvalumab, the study will start with enrollment of a minimum of three patients who will 
receive four doses of MEDI0457 (Limited Schedule) in combination with durvalumab.  Only 


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if the safety analysis of the initial patients who complete the 7-week DLT evaluation period, is 
deemed acceptable (i.e., none of initial patients experience a DLT), the vaccination schedule 
will switch from the limited four doses (Limited Schedule) to the Indefinite Schedule (also 
known as the Planned Dosing Schedule, i.e. vaccinations will continue until disease 
progression).  The Indefinite Schedule will be implemented for all subsequent patients 
following the Safety Analysis Run-in.  Otherwise, if a third of the initial patients experience a 
DLT, a minimum of three additional patients (i.e., a minimum total of six patients for the 
Safety Analysis Run-in) will be enrolled and the initial minimum six patients in the Safety 
Analysis Run-in cohort will be limited to a total of four doses of MEDI0457 
(Limited Schedule) before considering a switch to the Indefinite Schedule, provided the 
safety data was supportive and if only no more than a third of these patients experience a DLT 
during their 7-week DLT evaluation period.  If at any time during the enrollment of these 
patients, more than a third of the patients experience a DLT, then this regimen has exceeded 
the MTD and the regimen will be modified.  The choice of modifications in the Revised 
Dosing Schedule during the Safety Analysis Run-in include the following: (1) decrease the 
dose of durvalumab to 750 mg Q4W or decrease the total number of durvalumab doses (2) 
increase the interval between MEDI0457 doses from every 8 weeks to intervals such as 12 or 
16 weeks following the Week 12 dose or decrease the total number of MEDI0457 doses 
administered from a total of three to either one or two during the DLT period. 
 
 
 If the choice includes decreasing the number of vaccines doses 
administered during the DLT 
 
  At least a minimum of 
three patients with no DLT and up to approximately six patients with no more than a third 
with a DLT must be evaluated using either the Planned Dosing Schedule or Revised Dosing 
Schedule before study enrollment will continue with a recommended dose and schedule for 
the combination.  All dose and schedule decisions will be made after careful review of all 
available data by the SDMC which includes all enrolling investigators and the Sponsor 
Medical Monitor or designee.  In the Planned Dosing Schedule (after the Safety Analysis is 
complete) both MEDI0457 and durvalumab treatment will continue until confirmed disease 
progression, unacceptable toxicity or withdrawal of consent.  Either treatment may be stopped 
by the Investigator while the other treatment continues (refer to Figure 1). 
 
 
 
 The choice of modifications 
include any of the following: (1) decrease the dose of durvalumab to 750 mg Q4W or decrease 
the total number of durvalumab doses, (2) increase the interval between MEDI0457 doses 
from every 8 weeks to intervals such as every 12 or 16 weeks following the Week 12 dose or 
decrease the total number of MEDI0547 doses administered from a total of three to either one 
or two during the DLT period. 
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Figure 1 
Overall Study Design Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Planned Dosing Schedule: Minimum time between Week 3 MEDI0457 dose and the Week 4 first durvalumab dose, and the Week 7 MEDI0457 dose and the Week 8 
durvalumab dose is 7 days.  Starting at Week 12, the administration of MEDI0457 and durvalumab treatments can be given on the same day.  Safety Analysis Run-in 
patients will initially receive a total of four doses of MEDI0457 (Limited Schedule) as per schedule above.  Based on the rules shown in the Design for Safety Analysis 
Run-in table, the Limited Schedule (four doses) will be switched to the Indefinite Schedule (also known as the Planned Schedule). 
b 
A Revised Dosing Schedule will be evaluated in up to six patients if two or more patients during the Safety Analysis Run-in period experience a DLT.   
c 
All patients should consent to pre-treatment biopsy of the tumor if it can be done safely (as judged by the Investigator) during screening, otherwise archival tissue within 
3 years prior to study entry in all patients will be allowed except for a minimum 10 of the first 20 patients who will be required to provide a paired biopsy (a fresh biopsy 
at screening and at Week 10).  After 10 paired biopsies have been obtained then Week 10 on-treatment biopsy will be made optional but will be encouraged. 
 
 
Tumor Core Biopsy at screening & 
Week 10c 
Planned Dosing Schedule: durvalumab at Weeks 4, 8 
and 12 and then every 4 weeks until disease progression, 
unacceptable toxicitya,b or withdrawal of consent 
Planned Dosing Schedule: MEDI0457 Vaccine: Weeks 1, 
3, 7 and 12 and then every 8 weeks, until disease 
progression, unacceptable toxicitya,b or withdrawal of 
consent 
E 
N 
R 
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2. 
HYPOTHESIS AND STUDY OBJECTIVES 
2.1 
Hypothesis 
Primary Hypothesis: MEDI0457 treatment in combination with durvalumab will be safe in 
patients with recurrent / metastatic HPV associated head and neck cancer. 
Secondary Hypothesis: MEDI0457 treatment in combination with durvalumab will be 
immunogenic in patients with recurrent / metastatic head and neck cancer associated with 
HPV-16 and / or HPV-18. 
2.2 
Primary objectives 
Primary Objectives: 
Outcome Measures: 
To determine the safety profile of MEDI0457 
in combination with durvalumab in patients 
with recurrent / metastatic head and neck 
cancer.  
Adverse events / SAEs 
 
Collection of hematology, serum chemistry, 
urinalysis, CPK, thyroid function testing and 
pregnancy test 
 
Electrocardiograms (ECGs).  The following 
parameters will be recorded for each ECG: date and 
time of ECG, heart rate (HR) (beats/min), PR interval 
(ms), QRS interval (ms), RR interval (ms), QT 
interval (ms), QTcB interval (ms), QTcF interval 
(ms), sinus rhythm (yes / no), and overall evaluation 
(normal / abnormal) 
 
Vital signs  
 
Physical examinations 
 
Concomitant medications 
 
World Health Organization (WHO) / ECOG 
performance status 
To evaluate the anti-tumor activity of 
MEDI0457 in combination with durvalumab in 
patients with confirmed HPV-16 or HPV-18 
associated recurrent / metastatic head and neck 
cancer 
Objective response rate by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 
(Response-evaluable Population) 


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2.3 
Secondary objectives 
Secondary Objectives: 
Outcome Measures: 
To evaluate the pharmacokinetics and 
anti-drug antibodies (ADAs) for durvalumab. 
Serum concentrations of durvalumab  
 
Anti-drug antibodies for durvalumab 
To evaluate the anti-tumor activity of 
MEDI0457 in combination with durvalumab.  
Objective response rate by RECIST version 1.1 
(As-treated Population) and immune-related RECIST 
(irRECIST) 
 
Disease control rate at 16 weeks by RECIST 
version 1.1 
Overall survival  
Progression free survival as assessed by RECIST 
version 1.1  
 
 


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2.4 
Exploratory objectives 
Exploratory Objectives: 
Outcome Measures: 
3. 
PATIENT SELECTION, ENROLLMENT, REGISTRATION, 
PATIENT INSTRUCTIONS, DISCONTINUATION AND 
WITHDRAWAL  
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
For inclusion in the study patients should fulfill the following criteria: 
1. 
Written informed consent in accordance with institutional guidelines.  If required by 
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local law, candidates must also authorize the release and use of protected health 
information. 
2. 
Male and female patients age 18 years or older, and be able and willing to comply 
with all study procedures. 
3. 
Patient weight of > 30 kg.  Patients who weigh< 30 kg can be enrolled but will need 
to receive durvalumab at 20 mg/kg at every 4 weeks and if their weight increases to 
≥ 30 kg they can be switched to durvalumab at 1500 mg every 4 weeks.  Only 
patients who weigh ≥ 30 kg can be included in the Safety Analysis Run-in period. 
4. 
Histologically or cytologically confirmed diagnosis of SCCHN associated with 
HPV by a p16 immunohistochemistry (IHC) assay or HPV-16 or HPV-18 positive 
by nucleic acid testing.   
5. 
Recurrent or metastatic disease that has been treated with at least one 
platinum-containing regimen and lacking a curative treatment option.  Patients who 
are platinum ineligible may be enrolled if they have received and failed an approved 
treatment and lack a treatment option with curative potential. 
6. 
Has measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) with a 
minimum size of 10 mm by computed tomography (CT) scan, except lymph nodes 
which must have minimum short axis size of 15 mm (CT scan slice thickness no 
greater than 5 mm in both cases).  Indicator lesions must not have been previously 
treated with surgery, radiation therapy, or radiofrequency ablation unless there is 
documented RECIST version 1.1 progression in the lesion after such therapy.  
7. 
Has at least two SCCHN tumor lesions, one for biopsy and one for RECIST 
tracking.  All patients should consent to pre-treatment biopsy of the tumor if it can 
be done safely (as judged by the Investigator) during screening, otherwise archival 
tissue within 3 years prior to study entry in all patients will be allowed except for a 
minimum 10 of the first 20 patients who will be required to provide a paired biopsy 
(a fresh biopsy at screening and at Week 10).  After 10 paired biopsies have been 
obtained then Week 10 on-treatment biopsy will be made optional but will be 
encouraged.  Fresh tumor biopsies should be preferentially obtained from tumor 
tissues that are safely accessible as determined by the Investigator and achieved via 
non-significant risk procedures (refer to Section 5.8.1.1).  Tumor lesions used for 
biopsy should not be lesions used as RECIST target lesions.  Sites are encouraged 
to confirm adequacy of tumor material at the time of the procedure.  
8. 
World Health Organization / ECOG performance status of 0 or 1.  


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9. 
Adequate organ and bone marrow function within 28 days of starting study 
treatment.  Criteria “a” to “c” cannot be met in patients with ongoing or recent 
(within 14 days of screening test) transfusions or require ongoing growth factor 
support: 
a) 
Hemoglobin ≥ 8 g/dL NOTE: Subjects requiring ongoing transfusions or 
growth factor support to maintain hemoglobin ≥ 8 g/dL are not eligible.  
b) 
Absolute neutrophil count ≥ 1,000/mm3. 
c) 
Platelet count ≥ 100,000/mm3. 
d) 
Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) except 
patients with documented Gilbert's syndrome (> 3 × ULN).  
e) 
Alanine aminotransferase and AST ≤ 3 × ULN. 
f) 
Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min 
(measured or calculated according to the method of Cockcroft and Gault). 
10. 
Adequate venous access for repeated blood sampling according to study schedule.   
11. 
Evidence of post-menopausal status or negative serum pregnancy test for females of 
childbearing potential who are sexually active with a non-sterilized male partner.  
For women of childbearing potential, a negative result for serum pregnancy test 
(test must have a sensitivity of at least 25 mIU/mL) must be available at the 
screening visit (Table 2) and a urine beta-human chorionic gonadotropin (β-HCG) 
pregnancy test during the treatment period (Table 3).  Women will be considered 
post-menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause.  The following age-specific requirements apply: women 
older than 50 years of age (i.e., ≥ 50 years) would be considered post-menopausal if 
they have been amenorrheic for 12 months or more following cessation of 
exogenous hormonal treatments and if they have luteinizing hormone (LH) and 
follicle-stimulating hormone (FSH) levels in the post-menopausal range for the 
institution.  Women younger than 50 years of age (i.e., ≤ 50 years) would be 
considered post-menopausal if they have been amenorrheic for 12 months or more 
following cessation of all exogenous hormonal treatments, had radiation-induced 
oophorectomy with last menses > 1 year ago, had chemotherapy-induced 
menopause with > 1 year interval since last menses, or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
12. 
Female patients of childbearing potential who are sexually active with a 
non-sterilized male partner must use at least one highly effective method of 
contraception (Table 1) from the time of screening and must agree to continue using 
such precautions for 90 days after the last dose of IP.  Not all methods of 


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contraception are highly effective.  Female patients must refrain from egg cell 
donation and breastfeeding while on study and for 90 days after the last dose of IP.   
13. 
Non-sterilized male patients who are sexually active with a female partner of 
childbearing potential must use a condom with spermicide from screening to 
90 days after the final dose of IP.  Not engaging in sexual activity for the duration 
of the study and drug washout period is an acceptable practice; however, periodic or 
occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.  It is strongly recommended for the female 
partners of a male patient to also use at least one highly effective method of 
contraception throughout this period, as described in Table 1.  In addition, male 
patients should refrain from fathering a child or donating sperm during the study 
and for 90 days after the last dose of IP. 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Patients with nasopharyngeal cancer as the primary site will not be included in the 
study. 
2. 
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment; receipt of any investigational or approved anticancer therapy 
(chemotherapy, targeted therapy, biologic therapy, monoclonal antibodies, etc) 
within 21 days or 5 half-lives, whichever is shorter prior to the first dose of IP.  In 
addition, local treatment (e.g. by local surgery or radiotherapy) of isolated lesions 
for palliative intent is acceptable beyond the DLT evaluation period with prior 
consultation and in agreement with the Medical Monitor. 
3. 
Major surgical procedure or significant traumatic injury within 28 days before the 
first dose of study drug or anticipation of the need for major surgery during the 
course of study treatment. 
4. 
Any unresolved toxicity National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE version 4.03) Grade 2 or greater from previous 
anticancer therapy with the exception of alopecia, and the laboratory values defined 
in the inclusion criterion 9.  Hearing loss of Grade 3 or lower and peripheral 
neuropathy of Grade 2 or lower is allowed. 
5. 
Current or prior use of immunosuppressive medication within 14 days prior to first 
study dose, with the exception of intranasal and inhaled corticosteroids or systemic 
corticosteroids at doses not to exceed 10 mg/day of prednisone or equivalent.  
Steroids as premedication for hypersensitivity reactions due to radiographic contrast 
agents are allowed. 


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6. 
Patients requiring therapeutic anticoagulation and irreversible platelet inhibitors 
(e.g., clopidogrel, prasugrel, ticagrelor etc) are excluded.  NOTE: Low dose aspirin 
for cardiac prophylaxis will be permitted.  
7. 
No prior exposure to immune-mediated therapy defined as prior exposure to T-cell 
and natural killer cell directed therapy (e.g., anti-PD-1, anti-PD-L1, anti-CD137, 
and anti-CTLA4, etc).  
8. 
History of allogeneic organ transplantation.  Active or prior documented 
autoimmune or inflammatory disorders (including inflammatory bowel disease 
[e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], 
systemic lupus erythematosus, sarcoidosis, or Wegener syndrome [granulomatosis 
with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).  
The following are exceptions to this criterion: 
− 
Patients with vitiligo or alopecia. 
− 
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement.  
− 
Any chronic skin condition that does not require systemic therapy. 
− 
Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician. 
− 
Patients with celiac disease controlled by diet alone. 
9. 
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, uncontrolled hypertension, interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness / social 
situations that would limit compliance with study requirement, substantially 
increase risk of incurring AEs or compromise the ability of the patient to give 
written informed consent. 
10. 
Patients with spinal cord compression, or a history of leptomeningeal 
carcinomatosis.  At the time of Day 1 of the study, patients with central nervous 
system metastases must have been treated and must be asymptomatic and meet the 
following: 
(a) 
No concurrent treatment, inclusive of but not limited to surgery, radiation, and / or 
corticosteroids.  Note: patients are allowed on systemic steroids at doses not to 
exceed the equivalent of 10 mg/day prednisone but not if these are being 
administered to manage central nervous system metastases.  
(b) 
Neurologic stability (lack of signs or symptoms greater than baseline prior to 
radiotherapy) until the time of dosing of MEDI0457. 


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(c) 
For radiation treatment: 
− 
At least 14 days between last day of stereotactic radiosurgery or gamma-knife 
treatment and Day 1 of protocol treatment.  
− 
At least 28 days between last day of whole brain radiation therapy and Day 1 of 
protocol treatment.  
− 
At least 14 days since last dose of corticosteroids and Day 1 of protocol 
treatment.  
11. 
Patients with cardiovascular (CV) disease conditions including New York Heart 
Association Class 3 or 4 congestive heart failure, unstable angina pectoris or 
clinically important cardiac arrhythmias, a recent (< 3 months) CV event including 
myocardial infarction, unstable angina pectoris, stroke. 
12. 
Mean QT interval corrected for heart rate (QTc) > or = 470 ms calculated from the 
triplicate ECGs using Frederichia's Correction by manual read. 
13. 
History of active primary immunodeficiency. 
14. 
Active tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and tuberculosis testing in line with local 
practice) or Mycobacterium avium intracellulare infection. 
15. 
Presence of acute or chronic hepatitis B or active hepatitis C or immunodeficiency 
virus (HIV) infection.  Patients with a past or resolved hepatitis B virus infection 
(defined as the presence of hepatitis B core antibody [HBcAb] and absence of 
hepatitis B surface antigen [HBsAg]) are eligible provided the hepatitis virus DNA 
test is negative.  Patients positive for hepatitis C antibody are eligible only if 
polymerase chain reaction (PCR) is negative for hepatitis C virus RNA.  Testing for 
HIV is only required if clinically indicated and is not mandatory for this study.  
16. 
History of another primary malignancy except for: 
− 
Malignancy treated with curative intent and with no known active disease 
≥ 2 years before the first dose of IP and of low potential risk for recurrence. 
− 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
− 
Adequately treated carcinoma in situ without evidence of disease. 
17. 
Receipt of live, attenuated vaccine within 30 days prior to the first dose of 
MEDI0457.  Note: Patients, if enrolled, should not receive live vaccine during the 
study and up to 30 days after the last dose of IP. 


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18. 
Pregnant or breastfeeding female patients.  
19. 
Known allergy or hypersensitivity to study treatment or any of the study drug 
excipients.  
20. 
Any medical condition that, in the opinion of the Investigator, would interfere with 
evaluation of the study treatment or interpretation of patient safety or study results.  
21. 
Fewer than two acceptable sites exist for IM injection and EP between the deltoid 
and lateral quadriceps muscles.  Note: A site for injection / EP is not acceptable if 
there are tattoos or scars within 2 cm of the proposed injection / EP site or if there is 
implanted metal within the same limb.  Any device implanted in the chest (e.g., 
cardiac pacemaker or defibrillator excludes the use of the deltoid muscle on the 
same side of the body). 
22. 
Patients who are unable to provide informed consent, are incarcerated or unable to 
follow protocol requirements. 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient enrollment and registration 
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening. 
The investigator(s) will: 
1. 
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed. 
2. 
Assign potential patient a unique enrollment number, beginning with ‘E#’. 
3. 
Determine patient eligibility.  See Section 3. 
If a patient withdraws from participation in the study, then his / her enrollment code cannot be 
reused. 
Study personnel will screen patients and assign unique patient identification number.  
Information regarding patient’s screening number and screen date must be documented on a 
screening log.  
3.4 
Procedures for handling incorrectly enrolled patients 
Patients who fail to meet the eligibility criteria should not under any circumstances be 
enrolled or receive study medication.  There can be no exceptions to this rule.   
Where a patient does not meet all the eligibility criteria but is incorrectly started on-treatment, 
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discussion should occur between the MedImmune Study Physician and the Investigator 
regarding whether to continue or discontinue the patient from treatment.  The MedImmune 
Study Physician must ensure all decisions are appropriately documented. 
3.5 
Methods for assigning treatment groups 
Not applicable for this study.  All patients will receive combination treatment with MEDI0457 
and durvalumab. 
3.6 
Methods for ensuring blinding 
Not applicable for this study.  The study is an open-label study. 
3.7 
Methods for unblinding  
Not applicable for this study.  The study is an open-label study. 
3.8 
Patient instructions 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. 
Patients will be offered medications to manage anxiety and pain due to the EP procedure by 
the Investigator (see Section 5.4.9.1). 
The following medications are considered exclusionary during the study.  The Sponsor must 
be notified if a patient receives any of these during the study. 
1. 
Any concurrent chemotherapy, IP, biologic, radiotherapy (except palliative 
radiotherapy after consultation with the Medical Monitor) or hormonal therapy for 
cancer treatment.  Concurrent use of hormones for noncancer related conditions 
(e.g., insulin for diabetes and hormone replacement therapy) is acceptable.  
Concurrent use of adjuvant hormonal therapy for a history of breast and prostate 
cancer is allowed if the cancer for which the subject is being enrolled on this study 
has been histologically proven NOT to be breast or prostate cancer (Refer to 
Exclusion Criterion 16). 
2. 
MEDI0457 or durvalumab cannot be administered when the subject is taking 
immunosuppressive medications, including corticosteroids with the exception of 
intranasal and inhaled corticosteroids or systemic corticosteroids at doses not to 
exceed 10 mg/day of prednisone or equivalent.  Treatment with corticosteroids to 
prevent or treat hypersensitivity reactions to radiographic contrast agents is allowed.  
A temporary period of steroids will be allowed for different indications after 
discussion with the Medical Monitor (e.g., chronic obstructive pulmonary disease, 
radiation, nausea, etc).  Use of immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies is acceptable.  
Immunosuppressive medications also include drugs like methotrexate, azathioprine 
and tumor necrosis factor-alpha blockers. 


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3. 
Use of anticoagulants and irreversible platelet inhibitors (e.g. clopidogrel, prasugrel, 
ticagrelor etc) are not allowed.  Low dose aspirin for cardiac prophylaxis is allowed. 
4. 
Females of childbearing potential (defined as those who are not surgically sterile 
[i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy] or 
post-menopausal)  who are sexually active with a non-sterilized male partner must 
use at least one highly effective method of contraception (Table 1) from the time of 
screening and must agree to continue using such precautions from 90 days after the 
last dose of IP; cessation of birth control after this point should be discussed with a 
responsible physician.   
Women will be considered post-menopausal if they have been amenorrheic for 
12 months without an alternative medical cause.  The following age-specific 
requirements apply:  
− 
Women < 50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have LH and FSH levels in the 
post-menopausal range for the institution or underwent surgical sterilization 
(bilateral oophorectomy or hysterectomy). 
− 
Women ≥ 50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses 
> 1 year ago, had chemotherapy-induced menopause with last menses > 1 year 
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
A highly effective method of contraception is defined as one that results in a low 
failure rate (i.e., less than 1% per year) when used consistently and correctly.  
Highly effective methods of contraception presented in Table 1 include copper T 
intrauterine device, levonorgestrel-releasing intrauterine system (e.g., Mirena®), 
implants, hormone shot or injection, combined pill and patch.   


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Table 1 
Effective Methods of Contraception  
Barrier Methods  
Intrauterine Methods 
Hormonal Methods 
Male condom plus 
spermicidea,b,c 
Cap plus spermicidea,b,c 
Diaphragm plus 
spermicidea,b,c 
e.g., Copper T intrauterine 
devicee 
Progesterone T intrauterine 
deviced 
Levonorgesterel-releasing 
intrauterine system (e.g., 
Mirena®d,e 
e.g., Implantse 
Hormone shot or injectione 
Combined pille 
Minipillb 
Patche 
a 
Female partners of male patients should use an effective method of birth control 
b 
Not highly effective (failure rate of = 1% per year) 
c 
A male condom plus cap, diaphragm, or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods 
d 
Also considered a hormonal method 
e 
Highly effective (failure rate of < 1% per year) 
 
3.9 
Discontinuation of investigational product 
An individual patient will not receive any further IP if any of the following occur: 
1. 
Initiation of subsequent anticancer therapy including another investigational agent 
2. 
Confirmed PD: the initial assessment of PD by RECIST version 1.1 (baseline PD 
assessment) will be confirmed by a repeat evaluation at the next tumor assessment 
time point, but no sooner than 4 weeks later.  If any tumor assessment time point 
(beyond the first PD assessment) shows ≥ 20% increase in the overall tumor burden 
(the sum of diameters of target lesions and new lesions), when compared to the 
baseline PD assessment (the sum of diameters of target lesions and new lesions), the 
patient would be deemed as having confirmed PD and must be discontinued.  
Patients will need to sign an additional informed consent form (ICF) to continue 
treatment beyond the initial (unconfirmed) PD assessment. 
3. 
An AE that, in the opinion of the Investigator or the Sponsor, contraindicates 
further dosing. 
4. 
Patient experienced a DLT as defined in Section 6.12.2.1.  
5. 
Withdrawal of consent from further treatment with investigational product or lost to 
follow-up.  
6. 
Patient is determined to have met one or more of the exclusion criteria or failed to 
meet all of the inclusion criteria for study participation and continuing to receive 
investigational product might constitute a safety risk. 


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7. 
Pregnancy or intent to become pregnant. 
8. 
Non-compliance with the study protocol that, in the opinion of the Investigator or 
Sponsor, warrants withdrawal from treatment with IP (e.g., refusal to adhere to 
scheduled visits). 
9. 
The treating Physician determines it is not in the best interest of the patient to 
continue on-treatment. 
3.9.1 
Procedures for discontinuation of a patient from investigational product  
At any time, patients are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A patient that decides 
to discontinue investigational therapy will always be asked about the reason(s) and the 
presence of any AEs.  If possible, they will be seen and assessed by an investigator(s).  
Adverse events will be followed up (see Section 6) and all study drugs should be returned. 
If a patient is withdrawn from study, see Section 3.10. 
3.10 
Criteria for withdrawal  
A patient will be considered to have completed the study when he / she completes all protocol 
specified scheduled study assessments.  The Follow-up visit will be the last study visit.  
If a patient discontinues or is withdrawn at any time after initiation of study treatment, the 
Investigator should make every effort to have the patient complete all assessments designated 
for the Follow-up visit.  The Investigator will make every effort to have all scheduled 
assessment blood samples collected as indicated in Table 3.  Any AEs present at the time of 
discontinuation / withdrawal should be followed in accordance with the safety requirements 
outlined in Section 6. 
All patients will be followed for survival and subsequent anticancer therapy until the end of 
the study.  Patients refusing to return to the site should be contacted by phone to assess for 
survival and subsequent anticancer therapy unless consent is withdrawn every 3 months for 
the first year and every 6 months thereafter until the end of study.  Patients who leave the 
study because of a serious or significant safety issues should be followed closely until the AEs 
are fully and permanently resolved or stabilized (if complete resolution is not anticipated), 
with the follow-up data recorded in the Case Report Form (CRF) (see Section 6.7.3 for further 
details regarding the follow-up of unresolved AEs).  Any AEs that are unresolved at the 
patient’s last visit in the study are followed up by the Investigator for as long as medically 
indicated, with follow-up data recording in the CRF.6.7.3). 
If a patient discontinues from treatment for reasons other than disease progression, and 
therefore continues to have tumor assessments, drug or procedure-related SAEs must be 
captured until the patient is considered to have confirmed PD and will have no further tumor 
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Investigator should discuss the reason for any discontinuation of study treatment with the 
Sponsor’s Medical Monitor prior to any action or within 24 hours when information becomes 
available.  
The primary reason for the patient discontinuing study treatments or withdrawal from the 
study should be among the following standard categories:  
• 
Death. 
• 
Withdrawal of Consent: The patient desired to withdraw from further participation 
in the study in the absence of an Investigator-determined medical need to withdraw.  
If the patient gave a reason for withdrawal, it should be recorded on CRF.  This 
reason does not allow for further data collection and should not be selected if 
follow-up data collection of this patient is anticipated by the patient. 
• 
Protocol Deviation: The patient’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
non-compliance, failure to return for defined number of visits).  The violation 
should be discussed with the Sponsor’s Medical Monitor prior to discontinuation of 
study treatments or study withdrawal. 
• 
Lost to Follow-up: The patient fails to attend study visits and study personnel are 
unable to contact the patient after repeated attempts including letter sent by certified 
mail or equivalent. 
• 
Physician Decision: The patient was terminated for a reason other than those listed 
above by the physician caring for the patient. 
• 
Other: The patient was terminated for a reason other than those listed above, such as 
termination of study by the Sponsor. 
3.10.1 
Screen failures  
Screening failures are patients who do not fulfill the eligibility criteria for the study, and 
therefore must not be enrolled into the study.  The reason for the screen failure will be 
recorded. 
3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment. 
A patient who withdraws consent should always be asked about the reason(s) and the presence 
of any AE.  The Investigator should follow-up AEs outside of the clinical study.  
If a patient withdraws from participation in the study, then his / her enrollment code cannot be 
reused.   


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3.11 
Safety analysis run-in patients 
Approximately three to 12 patients will be enrolled and assessed for safety before additional 
patients are enrolled at a recommended dose and schedule for the combination.  Because this 
study is the first time MEDI0457 has been combined with durvalumab, the study will start 
with enrollment of a minimum of three patients who will receive four doses of MEDI0457 
(Limited Schedule) in combination with durvalumab.  Only if the safety analysis of the initial 
patients, who complete the 7-week DLT evaluation period, is deemed acceptable (i.e., none of 
the initial patients experience a DLT), the vaccination schedule will switch from the limited 
four doses (Limited Schedule) to the Indefinite Schedule (also known as the Planned 
Dosing Schedule, i.e. vaccinations will continue until disease progression).  This Indefinite 
Schedule will be implemented for all subsequent patients following the Safety Analysis 
Run-in.  Otherwise, if a third of the initial patients experience a DLT, a minimum of three 
additional patients (i.e., a minimum total of six patients for the Safety Analysis Run-in) will 
be enrolled and the initial minimum six patients in the Safety Analysis Run-in cohort will be 
limited to a total of four doses of MEDI0457 (Limited Schedule) before considering a switch 
to the Indefinite Schedule, provided the safety data was supportive and if only no more than a 
third of these patients experienced a DLT during their 7-week DLT evaluation period.  If at 
any time during the enrollment of these patients, more than a third of the patients experience a 
DLT, then this regimen has exceeded the MTD and the regimen will be modified.  The choice 
of modifications in the Revised Dosing Schedule during the Safety Analysis Run-in include 
the following: (1) decrease the dose of durvalumab to 750 mg Q4W or decrease the total 
number of durvalumab doses (2) increase the interval between MEDI0457 doses from every 
8 weeks to intervals such as 12 or 16 weeks following the Week 12 dose or decrease the total 
number of MEDI0547 doses administered from a total of three to either one or two during the 
DLT period. 
 
 If the choice includes decreasing the number of 
vaccines doses administered during the DLT 
 
.  At least a 
minimum of three patients with no DLT and up to approximately six patients with no more 
than a third with a DLT must be evaluated using either the Planned Dosing Schedule or 
Revised Dosing Schedule before study enrollment will continue with a recommended dose 
and schedule for the combination.  
In order to adequately monitor the safety of patients in Study D8860C00005, there will be two 
levels of ongoing monitoring of safety data for this study. 
• 
 
 
 
 
 
  
 
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• 
 
 
 
 
An analysis of the following data will be performed: 
• 
Adverse events 
• 
Safety laboratory tests (ECG data, hematology, chemistry and urinalysis) 
• 
Vital signs 
• 
Physical examinations 
 
 
 
 
 
 
 
 
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• 
  
• 
 
• 
 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF.  All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
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4. 
STUDY PLAN AND TIMING OF PROCEDURES  
Table 2 
Study Plan - Screen Procedures 
Tests 
Screen (Days -28 to -1) 
Informed consent 
X 
Demographics  
X 
Medical history 
X 
History of prior cancer treatment 
X 
Inclusion / exclusion criteria 
X 
Complete physical examination 
X 
WHO / ECOG performance status 
X 
Adverse event assessment  
X 
Concomitant medications 
X 
History of procedures 
X 
Disease statusa  
X 
Vital signsb  
X 
12-lead ECGc 
X 
Laboratory assessmentsd 
 
p16 IHCe 
X 
Hematology 
X 
Serum chemistry 
X 
Urinalysis 
X 
Creatine phosphokinase 
X 
Thyroid function testing (T3, T4, and TSH)f 
X 
Coagulation (APTT and either INR or prothrombin time) 
X 
Pregnancy testg 
X 
Hepatitis B, hepatitis C and HIV serologyh 
X 
Luteinizing hormone and follicle-stimulating hormonei 
X 
Other laboratory assessments and assaysj  
 
HPV-16/HPV-18 E6/E7 antibody 
X 
Tumor cell and tumor cell HPV DNA or RNA 
X 
HPV-16/HPV-18 E6/E7 ELISPOT and flow 
cytometry-based assay 
X 
Tumor biopsyk 
X  
a 
Magnetic resonance imaging scan of the brain will be performed at screening and also at each assessment if there are abnormalities at 
baseline.  
b 
Vital signs at the screening visit include temperature, respiratory rate, pulse oximetry, blood pressure, HR, weight and height. 
c 
12-lead ECGs will be performed in triplicate (all three ECG assessments within a 5 minute time period) 
d 
Samples will be analyzed at local laboratories. 
e 
Historical tissue samples may be used; there is no need for additional samples / test for histological HPV assessment (p16) to be 
collected just for this protocol. 
f 
Free triiodothyronine (T3) and free thyroxine (T4) will only be measured if thyroid stimulating hormone (TSH) is abnormal.  They 
should also be measured if there is clinical suspicion of an AE related to the endocrine system.  
g 
Serum pregnancy test will be performed for women of childbearing potential. 
h 
Hepatitis B and C testing is mandatory, while HIV serology is only required if clinically indicated. 
i 
Only for women of child bearing potential who may be post-menopausal.  
j 
Samples will be analyzed at central laboratories. 
k 
At least three core samples are required if samples are collected are via a core needle of 18 gauge or larger or are collected as an 
excisional tumor biopsy sample.  When a smaller gauge needle is used, the number of required cores rises to four.  Note: a new 
baseline biopsy is required for all patients.  All patients should consent to pre-treatment biopsy of tumor if it can be done safely (as 
judged by the Investigator) during screening, otherwise archival tissue up to 3 years to study entry in all patients will be allowed except 
for a minimum 10 of the first 20 patients who will be required to provide a paired biopsy (a fresh biopsy at screening and at Week 10). 
 
Abbreviations are on the next page. 
 


Clinical Study Protocol 
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Study Code D8860C00005 
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Abbreviations: 
AE=adverse event; APTT=activated partial thromboplastin time; CPK=creatine phosphokinase; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; ELISPOT=enzyme-linked immunospot; HIV=human immunodeficiency virus; HPV=human papilloma virus; 
IHC=immunohistochemistry; INR=International Normalized Ratio; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; 
WHO=World Health Organization 


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Table 3 
Study Plan - Study Administration Procedures 
Tests  
 
Administration Visits 
 
 
Weeko 
Week 
1 
3 
4 
7 
8  
10 
12 
Every 4 Weeks 
Every 8 Weeks  
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Study Procedures 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
Physical examinationa 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
WHO / ECOG performance status 
Xn 
 
 
 
X 
 
 
 
X 
Adverse events assessment  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications / concomitant procedures p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease statusb,l 
 
 
 
 
X 
 
 
 
X 
Vital signs, pre-dose and post-dosec,d 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
X 
X 
 
 
X 
 
X 
Laboratory Proceduresm 
Hematology 
Xn 
 
 
X 
X 
 
X 
Xk 
Xk 
Serum chemistry 
Xn 
 
 
X 
X 
 
X 
Xk 
Xk 
Creatine phosphokinase 
Xn 
 
 
X 
X 
 
X 
 
X 
Thyroid function testing (T3, T4, and TSH)f 
Xn 
 
X 
 
X 
 
X 
Xk 
Xk 
Pregnancy test 
Xn 
 
X 
 
X 
 
X 
X 
X 
Study Treatment Procedures 
Durvalumab administrationh,l  
 
 
X 
 
X 
 
X 
X 
 
Download EP data 
X 
X 
 
X 
 
 
X 
 
X 
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Table 3 
Study Plan - Study Administration Procedures 
Tests  
 
Administration Visits 
 
 
Weeko 
Week 
1 
3 
4 
7 
8  
10 
12 
Every 4 Weeks 
Every 8 Weeks  
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Tumor biopsyj 
 
 
 
 
 
X 
 
 
 
 


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a 
Targeted physical examination will be performed at all visits except at the Follow-up visit for which a complete physical examination will be performed. 
b 
Patients discontinued from treatment for reasons other than PD will continue disease assessments until confirmed PD or start of subsequent anticancer therapy.  Magnetic 
resonance imaging scan of the brain will be performed at screening and also at each assessment if there are abnormalities at baseline.  The preferred method of disease assessment 
is CT with contrast except for brain metastasis where a magnetic resonance imaging (MRI) with contrast is preferred.  The same method is preferred for all subsequent tumor 
assessments for the same patient. 
c 
Temperature, respiratory rate, pulse oximetry, blood pressure, HR and weight. 
d 
Vital signs will be measured within 30 minutes prior to the start of durvalumab administration, every 30 minutes (± 5 minutes) during durvalumab administration, at the end of 
durvalumab infusion (± 5 minutes), followed by a 1 hour (± 15 minutes) collection, and period of observation except for Week 10.  A 1 hour observation period is required after 
the first infusion of durvalumab is administered. 
e 
Electrocardiograms are to be collected in triplicate (all three ECG assessments within a 5 minute time period) within 30 minutes before dosing of MEDI0457 and 30-60 minutes 
after dosing at Weeks 1, 3, 7 and 12 and thereafter single ECGs at pre-dose at subsequent dosing visits.  Triplicate (all three ECG assessments within a 5 minute time period) 
ECGs will be performed within 30 minutes before dosing of MEDI4736 at Week 4 and 30-60 minutes after dosing of MEDI4736 at Weeks 4 and 12.  An ECG assessment can 
also be performed if clinically indicated and according to the Investigator. 
f 
Free T3 and free T4 will only be measured if TSH is abnormal.  They should also be measured if there is clinical suspicion of an AE related to the endocrine system. 
j 
Core tumor biopsies will be collected.  At least three core samples are required if samples are collected are via a core needle of 18 gauge or larger or are collected as an excisional 
tumor biopsy sample.  When a smaller gauge needle is used, the number of required cores rises to four.  Either fresh tissue or formalin-fixed paraffin-embedded samples may be 
used.  Archival tissue within 3 years prior to study entry in all patients will be allowed except for a minimum 10 of the first 20 patients who will be required to provide a paired 
biopsy (a fresh biopsy at screening and at Week 10).  After 10 paired biopsies have been obtained then Week 10 on-treatment biopsy will be made optional but will be 
encouraged.   
k 
Serum chemistry and hematology will be performed on Day 1, Week 7, Week 8 and Week 12, then every 4 weeks for the first 12 months and every 3 months thereafter until 
study discharge.  Thyroid function testing will be performed on Day 1, Week 4, Week 8 and Week 12, then every 4 weeks for the first 12 months and every 3 months thereafter 
until study discharge.  Urinalysis will only be performed if clinically indicated. 
l 
After scan and durvalumab administration are completed in Week 8.  Disease status assessments should continue to be performed at every 8 weeks ± 5 days for 1 year if CR / PR 
/ SD are achieved and then every 12 weeks ± 7 days until end of treatment (EOT).  
m 
Additional baseline blood samples will be also collected in a 10 mL red top tube in order to have serum samples collected at baseline for future analysis which includes but is not 
limited to an autoimmune work-up (refer to the Laboratory Manual for the processing of this sample). 
n 
If physical examination, ECOG, weight or safety laboratory tests (hematology, chemistry, creatine phosphokinase, thyroid function testing and pregnancy tests) are performed 
within 3 days prior to Day 1, they do not need to be repeated.  Patients with a negative serum pregnancy test within 3 days prior to Day 1, do not require a Week 1 Day 1 
pregnancy test to be performed. 
o 
All visit windows will be ±3 days with the following exceptions: tumor biopsy assessments will have the visit window of ±7 days; disease status assessments every 8 weeks 
(± 5 days) (relative to the date of the first MEDI0457 administration) for 1 year.  After the first year on treatment, if CR / PR / SD are achieved then disease status assessments 
can be performed every 12 weeks (± 7 days) until the EOT.  Disease status assessments will be performed once at the end of treatment if PD is observed, otherwise at end of 
treatment and then at Day 90 ± 7 days, every 3 months after Day 90 up to Month 12 ± 7 days then every 6 months after Month 12 ± 14 days until the death of the patient, 
withdrawal of consent or loss to follow-up.  
p 
Administration of the COVID-19 vaccine and MEDI0457 should be separated by 14 days. 
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Abbreviations are on the next page. 
 
Abbreviations: 
 AZ=AstraZeneca; COVID-19 = coronavirus disease of 2019; CR=complete response; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group;
 EP=electroporation; EOT=end of treatment; =human immunodeficiency virus;
IHC=immunohistochemistry; MRI=magnetic resonance imaging; PD=progressive disease; PR=partial response; SD=stable disease; T3=triiodothyronine; T4=thyroxine; TSH=thyroid 
stimulating hormone; WHO=World Health Organization  
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Study Code D8860C00005 
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Table 4 
Study Plan - Follow-up Visit Procedures 
Tests 
Follow-up visit 28 days after last dose (±7 days) 
Complete physical examination 
X 
WHO / ECOG performance status 
X 
Adverse event assessment 
X 
Concomitant medications 
X 
Vital signs 
X 
12-lead ECGa 
X 
Disease assessmentb,f 
X 
Laboratory assessmentsc 
 
Hematology 
X 
Serum chemistry 
X 
Creatine phosphokinase 
X 
Thyroid function test (free T3, free T4 and TSH)d 
X 
Other laboratory assessments and assayse 
 
HPV-16/HPV-18 E6/E7 antibody 
Collected if the Follow Up Visit occurs, but not 
collected if AZ decides to stop collection 
HPV-16/HPV-18 E6/E7 ELISPOT and flow 
cytometry-based assay 
Collected if the Follow Up Visit occurs, but not 
collected if AZ decides to stop collection 
Tumor cell and tumor cell HPV DNA or RNA 
Collected if the Follow Up Visit occurs, but not 
collected if AZ decides to stop collection 
Collection of survival data and subsequent 
anticancer therapy 
X 
a 
Electrocardiograms will be performed in triplicate (all three ECG assessments within a 5 minute time period). 
b 
Disease assessment to be performed once at EOT if PD, otherwise at EOT and then at Day 90 ± 3 days, every 3 months 
after Day 90 up to Month 12 ± 7 days then every 6 months after Month 12 ± 14 days until the end of study (EOS). 
c 
Samples will be analyzed at local laboratories. 
d 
Free T3 and free T4 will only be measured if TSH is abnormal.  They should also be measured if there is clinical 
suspicion of an AE related to the endocrine system.  
e 
Samples will be analyzed at central laboratories. 
f 
All patients will be followed for survival and subsequent anticancer therapy until the end of the study.  Patients refusing 
to return to the site should be contacted by phone to assess for survival and subsequent anticancer therapy unless 
consent is withdrawn every 3 months for the first year and every 6 months thereafter until the EOS. 
 
Abbreviations: 
AE=adverse event; AZ=AstraZeneca; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
ELISPOT=enzyme-linked immunospot; EOS=end of study; EOT=end of treatment; HPV=human papilloma virus; 
PD=progressive disease; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone, WHO=World Health 
Organization  
 
 


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4.1 
Enrollment / screening period 
Procedures will be performed according to Table 2.  
At screening, consenting patients are assessed to ensure that they meet eligibility criteria.  
Patients who do not meet these criteria must not be enrolled in the study. 
All patients will be required to provide consent to supply a sample of their blood and urine as 
well as a fresh tumor biopsy sample (at least three or four core samples, refer to 
Section 5.8.1.1 for further details) for entry into this study.  This consent is included in the 
main patient ICF. 
4.2 
Treatment period 
Descriptions of the procedures for this period are included in Table 3. 
4.3 
Follow-up period 
Descriptions of the procedures for this period are included in Table 4. 
4.4 
Continued Treatment Period  
The data cut-off for the primary endpoint will be in Q1 2021. Data analysis will be performed, 
and a Clinical Study Report will be written based on this data cut-off. 
Any patients still receiving IP at the time of this data cut-off will be able to continue to receive 
MEDI0457 or durvalumab or both within the current study through a Continued Treatment 
Period.  Patients are eligible for the Continued Treatment Period if the Investigator determines 
the patient is deriving clinical benefit from treatment and the patient has not fulfilled 
discontinuation criteria.  Investigators also have the option to remove patients from the 
Continued Treatment Period after 2 years of treatment with MEDI0457 and durvalumab.  
Patients are often removed from immunotherapy treatment after 2 years because the necessity 
for further treatment is not clear, and disease control with immunotherapy can last for a year 
or more after the end of treatment.  If Investigators decide to keep patients on treatment, these 
patients may continue until 30 April 2023, when the MEDI0457 drug supply expires and the 
study will end. 
During the Continued Treatment Period, assessments will revert to the standard of care for 
each individual site. Data will not be entered into the clinical study database after the data 
cut-off date.  Patients will continue to be monitored for all SAEs, overdoses, and pregnancies 
up to 28 days after the last dose of IP.  Paper-based reporting will be used for any SAE, 
overdose, or pregnancy identified after the data cut-off. All reported events will be entered in 
to the AstraZeneca global safety database. 
The Interactive Voice and Web Response System will be closed following the data cut-off, 
and sites will manually order IP. The IP dispensation and reconciliation will be handled by the 
study site at each patient’s visit. Drug accountability information must still be collected until 
all patients have completed treatment.  


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After the data cut-off for the Clinical Study Report, individual study sites will be closed once 
their final patient completes the 28-day follow-up visit. The Continued Treatment Period will 
remain available to patients until the last patient discontinues treatment and has his or her 
28-day safety follow-up visit. The Last Subject Last Visit in the Continued Treatment Period 
is defined as the date of the last patient’s final visit. 
5. 
STUDY ASSESSMENTS 
The RAVE Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The Investigator will ensure that data are recorded on the electronic CRFs as 
specified in the study protocol and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 
Investigator will sign the completed electronic CRFs.  A copy of the completed electronic 
CRFs will be archived at the study site. 
5.1 
Demographics 
The demographics (date of birth, sex and race) details for each patient will be collected at the 
screening visit. 
5.2 
Medical history 
The Investigator should document all relevant and clinically significant medical conditions 
and illnesses that the patient has experienced at time of screening as medical history.  Medical 
history should include treatment detailed information on all therapy directed against recurrent 
/ metastatic HPV associated SCCHN e.g., past surgical and / or radiation regimens.  Any prior 
chemotherapy or immunotherapies, adjuvants, etc should be recorded on the CRFs. 
Illnesses first occurring or detected after the signing of ICF or during the study and / or 
worsening of an existing illness in severity, frequency or nature after the signing of ICF are to 
be documented as AEs on the CRF. 
5.3 
Efficacy assessments 
RECIST version 1.1 will be used to assess patient response to treatment by determining ORR, 
DCR-16w and PFS.  Objective response rate will also be assessed using irRECIST.  The 
RECIST version 1.1 guidelines for measurable, non-measurable, target and non-target lesions 
are presented in Appendix F.  Overall survival will also be evaluated. 
The methods of assessment of tumor burden used at baseline are CT and / or or magnetic 
resonance imaging (MRI) scans, preferably with IV contrast imaging, of the neck (including 
the base of skull) through chest and abdomen.  Any other areas of disease involvement should 
be additionally imaged based on the signs and symptoms of individual patients.  At the 


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discretion of the Sponsor, an independent central review of all scans used in the assessment of 
tumors by RECIST version 1.1 and/or irRECIST may be conducted.  Guidelines for imaging 
collection and storage will be provided in a separate document.  The management of the 
patients will be based solely upon the results of assessment conducted by the investigator 
based on RECIST version 1.1 per protocol. 
The baseline assessment should be performed no more than 28 days before the start of 
MEDI0457 treatment and ideally as close as possible and not later than the start of the IP.  
Efficacy for all patients will be assessed by disease status assessments every 8 weeks 
(± 5 days) (relative to the date of the first MEDI0457 administration; Table 3) for 1 year.  
After the first year on treatment, if CR / partial response (PR) / SD are achieved then disease 
status assessments can be performed every 12 weeks (± 7 days) until the end of treatment.  
Disease status assessments will be performed once at the end of treatment if PD is observed, 
otherwise at end of treatment and then at Day 90 ± 7 days, every 3 months after Day 90 up to 
Month 12 ± 7 days then every 6 months after Month 12 ± 14 days until the death of the 
patient, withdrawal of consent or loss to follow-up.  Disease assessment will also stop if 
patient is started on subsequent anticancer therapy.  If an unscheduled assessment is 
performed, and the patient has not progressed, every attempt should be made to perform the 
subsequent assessments at their scheduled visits (± 14 days).   
For patients who discontinue therapy due to toxicity in the absence of confirmed objective 
progression, disease status assessments should be continued until confirmed PD or start of 
subsequent anticancer therapy.  
Patients who discontinued from treatment for reasons other than PD will continue disease 
assessments until confirmed PD or start of subsequent anticancer therapy. 
Progression would be considered confirmed if the following criterion is met: 
• 
Confirmed PD: the initial assessment of PD by RECIST version 1.1 (baseline PD 
assessment) will be confirmed by a repeat evaluation at the next tumor assessment 
time point, but no sooner than 4 weeks later.  If any tumor assessment time point 
(beyond the first PD assessment) shows ≥ 20% increase in the overall tumor burden 
(the sum of diameters of target lesions and new lesions), when compared to the 
baseline PD assessment (the sum of diameters of target lesions and new lesions), the 
patient would be deemed as having confirmed PD and must be discontinued from 
treatment.  Patients will need to sign an additional ICF to continue treatment beyond 
the initial (unconfirmed) PD assessment. 
In the absence of clinically significant deterioration, the Investigator should continue study 
treatment until progression is confirmed. 
If progression is not confirmed, the patient should continue on study treatment and 
on-treatment assessments. 


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If a patient discontinues treatment prior to progression, the patient should still continue to be 
followed until confirmed objective disease progression or until subsequent anticancer 
treatment. 
If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to non-target lesion or the appearance of a new lesion, it is advisable to continue 
treatment until the next scheduled assessment or sooner if clinically indicated and reassess the 
patient’s status.  If repeat scans confirm progression, then the date of the initial scan should be 
declared as the date of progression. 
Tumor assessments should include the following evaluations: physical examination (with 
photograph and measurement of skin lesions as applicable) and CT or MRI scan of the neck, 
chest, abdomen, and pelvis (pelvic scan is optional unless known pelvic disease is present at 
baseline).  Magnetic resonance imaging scan of the brain will be performed at screening and 
also at each assessment if the patient is found to have abnormalities at baseline scan.  The 
preferred method of disease assessment is CT with contrast except for brain metastasis where 
an MRI with contrast is preferred.  If CT with contrast is contraindicated, CT without contrast 
is preferred over MRI.  A CT with contrast may be substituted for an MRI with contrast if an 
MRI is contraindicated.  The same method is preferred for all subsequent tumor assessments 
for the same patient.  Note: if a patient receives a combined positron emission tomography 
(PET) / diagnostic quality CT scan at screening, a CT scan without PET later in the study is 
acceptable. 
The response to immunotherapy may differ from the typical responses observed with 
cytotoxic chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013): 
• 
Response to immunotherapy may be delayed. 
• 
Response to immunotherapy may occur after PD by conventional criteria. 
• 
The appearance of new lesions may not represent PD with immunotherapy. 
• 
Stable disease while on immunotherapy may be durable and represent clinical 
benefit. 
Progression free survival measures progression by growth of the primary tumor, nodal spread 
metastases, death from the cancer, or death from other causes.  Progression free survival will 
be assessed by the periodic tumor assessment using imaging per the institutional guidelines at 
the schedules according to Table 3.  
All study evaluations for disease response must be based on RECIST version 1.1. 


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Immune-related RECIST (Appendix G) 
Based on the above-described unique response to immunotherapy and based on guidelines 
from regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of 
anti-cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating 
anticancer compounds, the study will implement the following in addition to standard 
RECIST version 1.1: 
• 
RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the 
absence of clinically significant deterioration.  Treatment with MEDI0457 and 
durvalumab would continue between the initial assessment of progression and 
confirmation for progression.  
5.4 
Safety assessments 
5.4.1 
Laboratory safety assessments  
At screening, blood samples will be collected for hematology and serum chemistry.  Blood 
samples will also be taken for LH and FSH (for select patients), CPK, thyroid function testing 
(if thyroid stimulating hormone [TSH] is abnormal then free triiodothyronine [T3] and free 
thyroxine [T4] will be required to be measured, if TSH is normal then free T3 and free T4 are 
not required to measured), coagulation tests (activated partial thromboplastin time [APTT] 
and either International Normalized Ratio [INR] or prothrombin time), hepatitis B and 
hepatitis C testing.  Testing for HIV is only required if clinically indicated and is not 
mandatory for this study.  A urine sample will also be obtained to determine eligibility (see 
Table 2).  
A serum pregnancy test will be performed for women of childbearing potential at the 
screening visit. A urine pregnancy test will be performed during the treatment period. 
A local laboratory will be used for the collection of blood and urine samples (see Laboratory 
Manual for further details).   
Blood and urine samples will be collected during the IP administration period for 
determination of hematology, serum chemistry, CPK, thyroid function testing (TSH, free T3 
and free T4), coagulation tests (prothrombin time, APTT and INR).  A urine pregnancy test 
will be taken at the times indicated in Table 3.  Urinalysis will be taken if clinically indicated 
as deemed by the Investigator (Table 3). 
Additional baseline blood samples will be also collected in a 10 mL red top tube in order to 
have serum samples collected at baseline for future analysis which includes but is not limited 
to an autoimmune work-up (Table 3) (refer to the Laboratory Manual for the processing of 
this sample). 


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Blood samples will also be taken at the Follow-up visit (28 days after the last dose [± 7 days]) 
for determination of hematology, serum chemistry, CPK and thyroid function testing (TSH, 
free T3 and free T4), at the times indicated in Table 4. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate CRF. 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at the 
Investigator’s site as source data for laboratory variables.  For information on how AEs based 
on laboratory tests should be recorded and reported, see Section 6.7.  Note: In case a patient 
shows an AST or ALT ≥ 3 x ULN or TBL ≥ 2 x ULN please refer to Appendix D for further 
instructions. 
The hematology, serum chemistry and urinalysis will be performed at a local laboratory at or 
near to the Investigator site (see Table 5, Table 6 and Table 7, respectively).  Sample tubes 
and sample sizes may vary depending on laboratory method used and routine practice at the 
site. 
The following laboratory variables will be measured: 
Hematology 
Table 5 
Laboratory Safety Variables - Hematology 
Hematology (whole blood) 
 
Hemoglobin 
 
White blood cell count 
 
Absolute eosinophil count 
 
Absolute lymphocyte count 
 
Absolute neutrophil count 
 
Platelet count 
 
 


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Serum Chemistry 
Table 6 
Laboratory Safety Variables - Serum Chemistry 
Clinical Chemistry (serum) 
Albumin 
Glucose 
ALP 
Lactate dehydrogenase 
ALTa 
Lipaseb 
AST 
Magnesiumc 
Amylaseb 
Potassium 
Bicarbonatec 
Sodium 
Calcium 
TBLa 
Chloridec 
Total protein 
CPK 
Urea or blood urea nitrogen, depending on local practice 
Creatinine 
Gamma glutamyltransferase 
a 
Tests for ALT, AST, ALP and TBL must be conducted and assessed concurrently.  If TBL is ≥ 2 × ULN (and evidence 
of Gilbert’s syndrome) then fractionate into direct and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed.  For sites where only one of these parameters is 
routinely measured then either lipase or amylase is acceptable. 
c 
Bicarbonate (where available), chloride, gamma glutamyltransferase, magnesium, testing are to be performed at 
screening, on Day 0, and if clinically indicated. 
 
Abbreviations: 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; 
TBL=total bilirubin; ULN=upper limit of normal 
 
Luteinizing Hormone and Follicle-Stimulating Hormone 
Levels of LH and FSH will be measured at screening only in select patients.  
Creatine Phosphokinase 
Levels of CPK will be measured at screening, during the study treatment period and at the 
Follow-up visit. 
Thyroid Hormone Function 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of 
an AE related to the endocrine system. 
Coagulation Tests 
Coagulation parameters (APTT and either prothrombin time or INR) are to be assessed at 
baseline and as clinically indicated. 


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Serology 
Antibodies to, hepatitis B and hepatitis C will be measured.  Antibodies to HIV will only be 
measured if clinically indicated. 
Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction (PCR) 
is negative for hepatitis C virus RNA. 
Patients with a positive HBsAg test at screening are not eligible for the study. 
Patients who are HBsAg and HBcAb negative, but are positive for hepatitis virus B surface 
antibody may be included in the study provided that all other eligibility criteria are satisfied.   
A hepatitis virus B DNA test will be performed if the patient is HBsAg negative but HBcAb 
positive (regardless of hepatitis virus B surface antibody status).   
• 
If the hepatitis virus DNA test is positive, the patient will be excluded.   
• 
If the hepatitis virus DNA test is negative, the patient may be included in the study.   
Prophylactic antiviral therapy, in addition to the monitoring described above, may be initiated 
at the discretion of the Investigator.  
If the patient becomes hepatitis virus DNA positive during the study, the Investigator will 
manage the clinical situation as per the standard of care of that institution and the Medical 
Monitor will be notified.   
Urinalysis 
Urinalysis must be done at baseline (screening) and then as clinically indicated.  A urine 
pregnancy test will be performed for women of childbearing potential during the treatment 
period at the frequency shown in Table 3. 
Table 7 
Laboratory Safety Variables - Urinalysis 
Urinalysis (dipstick) 
 
Bilirubin 
pH 
Blood 
Protein 
Glucose 
Specific gravity 
Ketones 
Color and appearance 
 


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5.4.2 
Pregnancy testing 
For women of reproductive potential, a negative result for serum pregnancy test (test must 
have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and a urine 
β-HCG pregnancy test is required to be performed during the treatment period at the 
frequency shown in Table 3.  If at any point, the β-HCG (pregnancy) test is positive, 
indicating that the patient is pregnant, no additional IP will be administered, but the patient 
will be followed for the duration of the study and beyond to determine the outcome of the 
pregnancy (with the patient’s consent). 
5.4.3 
Physical examination 
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, CV, abdomen, skin (for signs of injection site 
reactions due to MEDI0457 or EP), head and neck (including ears, eyes, nose and throat), 
lymph nodes, thyroid, abdomen, musculoskeletal (including spine and extremities) and 
neurological systems at screening and Follow-up visits.  A targeted physical examination to 
document changes in any medical condition since the last visit will be performed at all other 
visits. 
5.4.4 
WHO / ECOG performance status 
A WHO / ECOG performance status will be conducted at screening, during IP administration 
and at follow-up.  A WHO / ECOG performance status will be performed at other visits as 
determined by Investigator or directed per patient complaints. 
WHO / ECOG performance status (Oken et al 1982) will be assessed based on the following: 
0=Fully active; able to carry out all pre-disease performance without restrictions. 
1=Restricted in physically strenuous activity but ambulatory and able to carry out light work 
or work of a sedentary nature, e.g., light housework, office work. 
2=Ambulatory and capable of self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4=Completely disabled.  Unable to carry out any self-care and totally confined to bed or chair. 
5=Dead 
Any significant changes from baseline or screening must be reported as an AE. 
5.4.5 
Post-treatment reaction assessment 
The Investigator will assess local and systemic reactions post-treatment (within 30-60 minutes 
after study treatment) and at post-treatment visits.  Any reported MEDI0457 local 


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post-treatment reactions and systemic post-treatment reactions will be graded per NCI 
CTCAE version 4.03 and all must be recorded on the CRFs. 
5.4.6 
Vital signs 
Vital signs including temperature, respiration rate, pulse oximetry, blood pressure, HR and 
weight will be measured at all the study visits. 
On infusion days, patients receiving durvalumab treatment will be monitored during and after 
infusion of IP as present in the bulleted list below.  
Supine blood pressure will be measured using a semi-automatic blood pressure recording 
device with an appropriate cuff size, after the patient has rested for at least 5 minutes.  Blood 
pressure and pulse will be collected from patients receiving durvalumab before, during and 
after each infusion at the following times (based on a 60 minute infusion): 
• 
Prior to the beginning of the infusion (measured once from approximately 
30 minutes before up to 0 minutes [i.e., the start of the infusion]). 
• 
Approximately every 30 minutes (± 5 minutes) after start of the infusion (half way 
through the infusion). 
• 
At the end of the infusion (approximately 60 minutes ± 5 minutes). 
• 
A 1 hour (± 15 minutes) observation period is required after each infusion of 
durvalumab is administered if clinically significant infusion reactions are observed 
during or after the first dose and at Investigator discretion. 
If no clinically significant infusion reactions are observed during or after the first dose, the 
length of subsequent infusion observation periods can occur at the Investigator’s discretion 
(suggested 30 minutes after each durvalumab infusion).  If the infusion duration exceeds 
60 minutes, then blood pressure and pulse measurements should follow the principles as 
described above or be obtained more frequently if clinically indicated.  The date and time of 
collection and measurement will be recorded on the appropriate CRF.  Additional monitoring 
with assessment of vital signs is at the discretion of the Investigator per standard clinical 
practice or as clinically indicated. 
Situations in which vital signs results should be reported as AEs are described in 
Section 6.7.9. 
5.4.7 
Weight and height 
Height (cm) will be collected at the screening visit only.  Weight (kg) will be collected at the 
screening visit, each additional visit from Week 1 to the Follow-up visit. 


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5.4.8 
Electrocardiogram 
An ECG will be performed at screening within 28 days of Day 0 for all patients to determine 
patient eligibility and as clinically indicated throughout the study.  Three 12-lead ECG 
recordings are required in triplicate (all three ECG assessments within a 5 minute time period) 
at the screening visit. 
The following parameters will be recorded for each ECG: date and time of ECG, HR 
(beats/min), PR interval (ms), RR interval (ms), QRS interval (ms), QT interval (ms), QTcF 
interval (for Fridericia’s) (ms), QTcB interval (ms), sinus rhythm (yes / no), and overall 
evaluation (normal / abnormal). 
Abnormal ECGs should be interpreted as clinically significant or not clinically significant. 
In case of clinically significant ECG abnormalities, including a QTcF value > 470 ms, 
two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to 
confirm the finding.   
Electrocardiograms should be obtained after the patient has been in a supine position for 
5 minutes and recorded while the patient remains in that position.  Electrocardiograms will be 
performed in triplicate.  Electrocardiograms will be read and collected locally and held in 
digital format by core laboratory.  
Electrocardiograms are to be collected in triplicate (all three ECG assessments within a 
5 minute time period) within 30 minutes before dosing of MEDI0457 and 30-60 minutes after 
dosing at Weeks 1, 3, 7 and 12 and thereafter single ECGs at pre-dose at subsequent dosing 
visits.  Triplicate (all three ECG assessments within a 5 minute time period) ECGs will be 
performed within 30 minutes before dosing of MEDI4736 at Week 4 and 30-60 minutes after 
dosing of MEDI4736 at Weeks 4 and 12.  An ECG assessment can also be performed if 
clinically indicated and according to the Investigator. 
5.4.9 
Other safety assessments 
5.4.9.1 
Management of anxiety and pain due to electroporation procedure 
Patients will be offered topical anesthetic (e.g., EMLA [lidocaine + prilocaine]), to prevent 
significant discomfort from the study treatment procedure.  If EMLA (lidocaine 2.5% and 
prilocaine 2.5%) is used, an approximately 1.5 cm diameter amount will be applied with 
occlusion to the site of injection ~30 minutes prior to study treatment.  
Patients may be offered a mild sedative (e.g., 0.5-1 mg lorazepam) for anxiety related to the 
EP procedure.  Mild sedatives may be administered approximately 1 hour prior to EP.  
Patients who receive a mild sedative must not be allowed to operate a motor vehicle for 
3-4 hours after receiving medication and must have arranged transportation to depart the study 
site. 
Patients will be offered an analgesic (e.g., ibuprofen, ketorolac) after study treatment.  Note: 
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definition of severe pain (Grade 3) and therefore will not be offered to the patients unless 
clinically indicated. 
Patients who are allergic to or have contraindications to ibuprofen, ketorolac or lorazepam 
will be offered a suitable alternative. 
Medications administered to manage anxiety and pain due to the EP procedure will be 
captured as concomitant medications on the CRF. 
5.4.9.2 
Monitoring of durvalumab administration  
 
  
Note: Per Inclusion criterion 3, patients who weigh < 30 kg will receive durvalumab at 
20 mg/kg at every 4 weeks and if their weight increases to ≥ 30 kg they can be switched to 
durvalumab at 1500 mg every 4 weeks.  If in the course of the study after the Safety Analysis 
Run-in the dose is reduced to 750 mg of durvalumab, then patients who weigh ≤ 30 kg will 
receive durvalumab at 10 mg/kg at every 4 weeks and if their weight increases to ≥ 30 kg they 
can be switched to durvalumab at 750 mg every 4 weeks. 
The following steps apply specifically to durvalumab.  Each dose of durvalumab should be 
administered using the following guidelines: 
• 
Investigational product must be administered at room temperature by controlled 
infusion into a peripheral vein or central line.  Prior to the start of the infusion, 
ensure that the bag contents are at room temperature to avoid an infusion reaction 
due to the administration of the solution at low temperatures. 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of IP.  Fully functional resuscitation 
facilities should be available.  Investigational product must not be administered via 
IV push or bolus but as a slow IV infusion.  The entire content of each IV bag will 
be infused. 
• 
Lines used for infusion during dose administration will need to be equipped with 
0.22- or 0.2-μm in-line filters. 
• 
Some IP may remain in the IV line after the infusion has completed.  A volume of 
IV solution equal to the priming volume of the infusion set should be used to flush 
the lines.  A separate flush bag may be used to clear the line or remaining IP.  The 
infusion rate should not be changed.  The infusion should be completed according 
to the institutional policy to ensure that the full dose of the IP is administered.  It 
will be documented if the line was not flushed. 
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5.4.9.3 
Management of infusion reactions due to durvalumab  
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the study protocol. 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion.  For patients with a ≤ Grade 2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial rate.  If the patient 
tolerates subsequent infusions without reaction, the infusion rate may be increased again back 
to the initial infusion rate.  Acetaminophen and / or an antihistamine (e.g., diphenhydramine) 
or equivalent medications per institutional standard may be administered at the discretion of 
the Investigator.  If the infusion-related reaction is ≥ Grade 3 or higher in severity, study drug 
will be discontinued. 
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary. 
Note: Any infusion-related reaction is considered as an AESI.  As soon an AE is entered into 
the Medidata RAVE system by the site and an AESI is selected, then the site must inform 
MedImmune within 24 hours post-infusion.  In addition, all infusion-related reactions should 
be reported to MedImmune within 24 hours post-infusion.  If in the opinion of the 
Investigator, the infusion-related reaction is considered to be an SAE, then the infusion-related 
reaction should be reported as an SAE. 
5.4.9.4 
Assessment of clinical adverse events 
Patients will be questioned by the Investigator regarding the occurrence of any possible AEs, 
concomitant medications and new onset chronic disease during their clinic visits.  Patients will 
be reminded to contact study personnel and immediately report any event that may happen for 
the duration of the study.  These events will be recorded on the patient’s CRF. 
5.5 
Other assessments 
5.5.1 
Downloading of electroporation data from CELLECTRA®5P device 
Within 48 hours following each treatment with MEDI0457, data should be downloaded from 
the EP device and the data file that is created should be sent to the Sponsor or designee by 
e-mail to 
.  Instructions on how to download the data are 
provided separately.  Training will be provided.  Appendix E provides the CELLECTRA®5P 
device error reporting form. 
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5.5.2 
Coronavirus disease of 2019 vaccine 
Patients enrolled in the study can receive coronavirus disease of 2019 (COVID-19) vaccines, 
at the discretion of the Investigator, following a benefit/risk evaluation for the individual 
patient and in accordance with local rules and regulations and vaccination guidelines.  
Investigators should consider the potential impact of relevant labelling information (i.e. 
“Indications,” “Contraindications,” “Warnings and Precautions,” “Adverse Reactions”). 
Except for the specific type of vaccine (e.g., live, attenuated virus vaccines) prohibited in the 
study (Section 3.2 Exclusion criteria), any type of COVID-19 vaccinations are acceptable.  
Alternative vaccines available in the investigator’s area would need to be discussed, in the 
interest of the patient, as part of normal patient counselling and good clinical practice. 
Administration of MEDI0457 and the COVID-19 vaccine should be separated by 14 days.  
Ensure the COVID-19 vaccination details (including brand name and manufacturer) are 
captured in the electronic CRF or patient chart as concomitant medication.  
5.6 
Pharmacokinetics 
5.6.1 
Collection of samples 
Blood samples for determination of durvalumab levels in serum will be taken at the visits 
presented in the study plan (Table 3). 
Pre-dose sampling (samples collected up to 60 minutes prior to durvalumab start of 
administration) for both ADA and pharmacokinetic sampling schemes of durvalumab. 
Samples will be collected, labeled stored and shipped as detailed in the Laboratory Manual.  
A central laboratory will be used for the collection of blood for pharmacokinetic analysis (see 
Laboratory Manual for further details). 
5.6.2 
Determination of drug concentration 
Blood samples for determination of durvalumab concentration in serum will be obtained 
according to the assessment schedules (see Table 3).   
Samples for determination of durvalumab concentration in serum will be analyzed by a 
designated third party on behalf of MedImmune, using an appropriate bioanalytical method.  
Full details of the analytical method used will be described in a separate Bioanalytical Report. 
5.6.3 
Storage and destruction of pharmacokinetic / anti-drug antibody samples 
Pharmacokinetic and ADA samples will be disposed of 5 to 10 years after durvalumab is 
approved for marketing. 
Pharmacokinetic and ADA samples may be disposed of or destroyed and anonymized by 
pooling.  Additional analyses may be conducted on the anonymized, pooled pharmacokinetic 


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samples to further evaluate and validate the analytical method.  Results from such analyses 
may be reported separately from the Clinical Study Report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Validation Report. 
 
 
5.6.4 
Collection of samples to measure for the presence of anti-drug antibody 
The presence of ADA will be assessed in serum samples taken according to the assessment 
schedules (see Table 3).   
Samples will be measured for the presence of ADA using validated assays.  Tiered analysis 
will be performed to include screening, confirmatory, and titer assay components, and positive 
negative cut points previously statistically determined from drug-naïve validation samples will 
be employed.  Samples will be collected and stored for potential neutralizing ADA analysis in 
the future.  
5.7 
Pharmacogenetics 
Refer to Appendix C for full details. 
5.8 
Biomarker analysis  
 
 
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5.8.3 
Storage, reuse and destruction of biological samples 
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed.  
 
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5.8.4 
Labeling and shipment of biological samples 
The Principal Investigator ensures that samples are labeled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with MedImmune and appropriate 
labeling, shipment and containment provisions are approved. 
5.8.5 
Chain of custody of biological samples  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
MedImmune keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers. 
Samples retained for further use are registered in the MedImmune Biorepository during the 
entire life cycle. 
5.8.6 
Withdrawal of informed consent for donated biological samples  
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of / destroyed, and the action documented.  If samples are already analyzed, 
MedImmune is not obliged to destroy the results of this research. 
The Principal Investigator: 
• 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to MedImmune. 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of / destroyed, and the action documented. 
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• 
Ensures the laboratory(ies) holding the samples is / are informed about the 
withdrawn consent immediately and that samples are disposed of / destroyed, the 
action documented and the signed document returned to the study site. 
• 
Ensures that the patient and MedImmune are informed about the sample disposal. 
MedImmune ensures the central laboratory(ies) holding the samples is / are informed about 
the withdrawn consent immediately and that samples are disposed of / destroyed and the 
action documented and returned to the study site. 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
6.1 
Definition of adverse events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related (Guidance for Industry and Investigators). 
In this study, such changes will be monitored, classified, and summarized, and as Clinical or 
Laboratory AEs, respectively.  Medical condition / diseases present before starting the 
investigational drug will be considered AEs only if they worsen after starting study treatment. 
An unexpected AE is one not identified in the Investigator’s Brochures (MEDI0457 
Investigator’s Brochure and Durvalumab Investigator’s Brochure) or otherwise not expected 
from the characteristics of the clinical material. 
Adverse events include the following: 
• 
Pre- or post-treatment complications that occur as a result of protocol-mandated 
procedure during or after the first screening visit (before the administration of study 
drug). 
• 
Any pre-existing condition that increases in severity, or changes in nature during or 
as a consequence of the study drug phase of a human clinical trial, will also be 
considered an AE. 
• 
Complications and termination of pregnancy; see Section 6.11 for additional 
information. 
• 
All AEs that occur from the study screening visits onwards and throughout the 
duration of the study, including the follow-up off-study treatment period should be 
recorded as an AE. 


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Adverse events do not include the following: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed; the condition that leads to the procedure is an AE. 
• 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visits that do not worsen. 
• 
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and / or convenience admissions). 
• 
Overdose without clinical sequelae. 
• 
Any medical condition or clinically significant laboratory abnormality with an onset 
date before the consent form is signed and not related to a protocol associated 
procedure is not an AE.  It is considered to be pre-existing and should be 
documented on the medical history CRF. 
• 
Uncomplicated pregnancy (documented on a pregnancy CRF). 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
(documented on a pregnancy CRF). 
The term AE is used to include both serious and non-serious AEs. 
6.2 
Definitions of serious adverse events 
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: death, a life-threatening 
AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly / birth defect.  Important medical events that may not results in death, 
be life-threatening, or require hospitalization may be considered serious when based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (Guidance for 
Industry and Investigators). 
Clarification of Serious Adverse Events 
• 
Death is an outcome of an AE, and not an AE in itself.  Note: death due to disease 
progression is not considered to be an SAE (see Section 6.7.13 for further details). 


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• 
The patient may not have been on IP at the occurrence of the event.  Administration 
may have been given as treatment cycles or interrupted temporarily before the onset 
of the SAE, but may have contributed to the event. 
• 
“Life-threatening” means that the patient was at immediate risk of death from the 
event as it occurred.  This does not include an event that might have led to death if 
it had occurred with greater severity. 
• 
Complications that occur during hospitalizations are AEs.  If a complication 
prolongs the hospitalization, it is an SAE. 
• 
Inpatient hospitalization means the patient has been formally admitted to a hospital 
for medical reasons, for any length of time.  This may or may not be overnight.  It 
does not include presentation and care within an emergency department. 
The Investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and / or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and / or SAE and not the individual signs / symptoms. 
Serious adverse events that are ongoing should be followed until resolution.  The reporting 
period for SAEs is described in Section 6.8. 
For further guidance on the definition of an SAE, see Appendix A to the Clinical Study 
Protocol. 
6.3 
Definition of adverse reactions 
An adverse reaction means any AE caused by a drug.  Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the event 
(Guidance for Industry and Investigators). 
6.4 
Definition of suspected adverse reactions 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  For the purposes of Investigational New Drug (IND) safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the AE.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by a drug (Guidance for Industry 
and Investigators). 
6.5 
Definition of unexpected events / reactions 
An AE or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in the 
Investigator’s Brochure or is not listed as the specificity or severity that has been observed; or 
if an Investigator’s Brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended.  For example, under this definition, hepatic necrosis would be 


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unexpected (by virtue of greater severity) if the Investigator’s Brochure referred only to 
elevated hepatic enzymes or hepatitis.  Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the Investigator Brochure 
listed only cerebral vascular accidents.  ‘‘Unexpected’’ as used in this definition, also refers to 
AEs or suspected adverse reactions that are mentioned in the Investigator’s Brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the particular drug under 
investigation (Guidance for Industry and Investigators). 
6.6 
Definition of life-threatening events / reactions 
An AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the view of either 
the Investigator or Sponsor, its occurrence places the patient or subject at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death (Guidance for Industry and Investigators). 
6.7 
Recording of adverse events 
6.7.1 
Time period for collection of adverse events 
Adverse events and SAEs will be collected from time of signature of informed consent, 
through 90 days after the last dose of the last study treatment.  Note: AEs / SAEs that occur 
post-signature but prior to IP administration are non-treatment-emergent AEs / SAEs.  When a 
patient is defined as a screen failure, AE data will not be collected in the CRF.  The site will 
document AE data and keep the data in their files at the site. 
6.7.2 
Methods and timing of the collection and recording of adverse events 
After study treatment: Patients will be directly observed by study personnel for 30-60 minutes 
after each administration of MEDI0457 IM+EP for immediate reactions.  Injection sites will 
also be assessed at the subsequent study visit. 
The occurrence and severity of any AE during this period will be recorded on the appropriate 
CRF.  Patients will be given an oral thermometer and instructed to take and record their 
temperature daily (at the same time each day). 
Throughout the study: Patients will also be questioned by the Investigator regarding the 
occurrence of any possible AEs, concomitant medications and new onset chronic disease 
during their clinic visits.  Patients will be reminded to contact study personnel and 
immediately report any event that may happen for the duration of the study.  If events occur, 
these events will be recorded on the patient’s CRF.  
On study treatment visits, the assessments will be performed prior to administration.  Study 
patients will be queried at each clinic visit regarding the occurrence of any AEs, including 
SAEs that may have occurred since the last visit.  They will be reminded to contact study 
personnel and immediately report any such event that happens during the course of the study.  
These events will be recorded on the CRFs. 


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6.7.3 
Follow-up of unresolved adverse events 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient.  Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation or study completion. 
Any AEs that are unresolved at the patient’s last visit in the study are followed up by the 
Investigator for as long as medically indicated, with follow-up data recording in the CRF.  
MedImmune retains the right to request additional information for any patient with ongoing 
AE(s) / SAE(s) at the end of the study, if judged necessary. 
6.7.4 
Variables  
The following variables will be collected for each AE: 
• 
Adverse event (verbatim) 
• 
The date and time when the AE started and stopped 
• 
Each CTCAE grade for a repeated AE 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to IP 
• 
Administration of treatment for the AE 
• 
Whether the AE caused the patient’s withdrawal from the study (yes or no) 
• 
Outcome 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
Seriousness criteria fulfilled 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 


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• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) and other medication(s) 
• 
Description of AE 
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all 
events with an assigned CTCAE grading.  For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used.   
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2. 
6.7.5 
Severity codes for adverse events 
Study personnel will grade laboratory AEs and clinical AEs (based on discussions with study 
participants) with respect to the following levels of severity as defined in NCI CTCAE version 
4.03. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the Investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below: 
• 
Grade 1 (mild): An event that is usually transient and may require only minimal 
treatment or therapeutic intervention.  The event does not generally interfere with 
usual activities of daily living (ADL). 
• 
Grade 2 (moderate): An event that is usually alleviated with additional specific 
therapeutic intervention.  The event interferes with usual ADL, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 
• 
Grade 3 (severe): An event that requires intensive therapeutic intervention.  The 
event interrupts usual ADL, or significantly affects the clinical status of the patient. 
• 
Grade 4 (life-threatening): An event, and / or its immediate sequelae, that is 
associated with an imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the patient to perform ADL (eating, ambulation, 
toileting, etc). 
• 
Grade 5 (fatal): Death (loss of life) as a result of an event. 


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6.7.6 
Causal relationship of investigational product to adverse events 
A causally related AE is one judged to have a possible, probable or definite relationship to the 
administration of the IP and / or the investigational device.  An AE may also be assessed as 
not related to the IP and / or the investigational device.  Because the Investigator is 
knowledgeable about the patient (e.g., medical history, concomitant medications), administers 
the IP, and monitors the patient’s response to the IP, the Investigator is responsible for 
reporting AEs and judging the relationship between the administration of the IP and EP and a 
subsequent AE.  The Investigator is aware of the patient’s clinical state and thus may be 
sensitive to distinctions between events due to the underlying disease process versus events 
that may be product related and may have observed the event.  The Sponsor will assess the 
overall safety of the IP delivered by EP and determine whether to report expeditiously to the 
regulatory agencies. 
Investigators should use their knowledge of the Study Patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or not an 
AE is considered to be related to the IP and / or the investigational device indicating "yes" or 
"no" accordingly.  Causality should be assessed by the Investigator as “yes, related” or “no, 
unrelated” by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event. 
• 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and / or EP. 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable). 
• 
Known association of the event with the IP, EP or with similar treatments. 
• 
Known association of the event with the disease under study. 
• 
Presence of risk factors in the Study Patient or use of concomitant medications 
known to increase the occurrence of the event. 
The Investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form.  This includes non-treatment-emergent SAEs (i.e., SAEs 
that occur prior to the administration of IP) as well as treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (e.g., blood collection, washout of an existing medication).  The following guidelines 
should be used by investigators to assess the relationship of SAEs to the protocol: 


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Protocol related: The event occurred due to a procedure / intervention that was described in 
the protocol for which there is no alternative etiology present in the patient’s medical record. 
Not protocol related: The event is related to an etiology other than the procedure / intervention 
that was described in the protocol (the alternative etiology must be documented in the study 
patient’s medical record). 
6.7.7 
Relationship to protocol procedures 
The Investigator is also required to provide an assessment of the relationship of SAEs to 
protocol procedures on the SAE Report Form.  This includes both non-treatment-emergent 
(i.e., SAEs that occur prior to the administration of IP) and treatment-emergent SAEs.  A 
protocol-related SAE may occur as a result of a procedure or intervention required during the 
study (e.g., blood collection).  The following guidelines should be used by investigators to 
assess the relationship of SAEs to the protocol: 
• 
Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record. 
• 
Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol.  The alternative etiology must be 
documented in the study patient’s medical record. 
6.7.8 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit / you 
were last asked?” or revealed by observation will be collected and recorded in the CRF.  
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
6.7.9 
Adverse events based on examinations and tests 
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
Clinical Study Report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfill any of the SAE 
criteria or are the reason for discontinuation of treatment with the IP. 
If deterioration in a laboratory value / vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
/ vital sign will be considered as additional information.  Wherever possible the reporting 
Investigator uses the clinical, rather than the laboratory term (e.g., anemia versus low 
hemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s). 


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Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE / SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
6.7.10 
Abnormal laboratory value 
Laboratory abnormalities are only to be reported as AEs, if the Investigator feels they are 
clinically significant.  At the time of entry, the site physician will grade the laboratory 
abnormality that they feel is an AE.  Other laboratory abnormalities will not be graded.  In 
addition, laboratory or other abnormal assessments (e.g., ECG, x-rays, vital signs) that are 
associated with signs and / or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE (or SAE) as described in Sections 6.1 and 6.2.  If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the 
laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency from the 
baseline condition and meets one of the following criteria will be recorded as an AE: 
• 
Requires therapeutic intervention or diagnostic tests 
• 
Leads to discontinuation of study treatment 
• 
Has accompanying or inducing symptoms or signs 
• 
Is judged by the Investigator as clinically significant 
Grade is an essential element of these criteria.  Each CTCAE grading term in the current 
version is a unique representation of a specific event used for medical documentation and 
scientific analysis and is a single Medical Dictionary for Regulatory Activities (MedDRA) 
Lowest Level Term.  Note: the most current version of MedDRA will be used. 
Investigators are asked to take the CTCAE grading criteria into account when assessing if a 
laboratory abnormality qualifies as a laboratory AE.  Their clinical judgment ultimately 
determines whether the abnormality in question is “clinically significant” or “not clinically 
significant” and the severity of the event.  CTCAE grading can be used as a reference when 
making this determination.  It is the responsibility of the investigators to ensure all AEs are 
accurately reported and graded. 
6.7.11 
New cancers 
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study. 


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6.7.12 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied.  It may be an increase in the severity of the 
disease under study and / or increases in the symptoms of the disease.  The development of 
new, or progression of existing metastasis to the primary cancer under study should be 
considered as disease progression and not an AE.  Events, which are unequivocally due to 
disease progression, should not be reported as an AE during the study. 
6.7.13 
Deaths 
All deaths that occur during the study, or within the protocol-defined follow-up period after 
the administration of the last dose of study treatment, must be reported as follows: 
• 
Death clearly resulting from disease progression should be reported to the Study 
Physician at the next monitoring visit and should be documented in the CRF.  It 
should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the Study Physician as an SAE 
within 24 hours.  The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign main and contributory 
causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE.  A 
post-mortem examination may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to 
MedImmune Drug Safety or its representative within the usual timeframes. 
6.8 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate MedImmune representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it. 
PRA works with the Investigator to ensure that all the necessary information is provided to the 
MedImmune Patient Safety Data Entry Site within 1 calendar day of initial receipt for fatal 
and life-threatening events and within 5 calendar days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
MedImmune representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 


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Once the investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated e-mail alert is sent to the designated MedImmune representative. 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports an SAE to the appropriate MedImmune representative by telephone.  The Principal 
Investigator must use the back-up paper SAE Report recognizing that the same reporting time 
frames still apply. 
The MedImmune representative will advise the investigator / study site personnel how to 
proceed.  
6.9 
Reporting of serious and unexpected suspected adverse reactions 
The Sponsor must report in an IND safety report any suspected adverse reaction to study 
treatment (i.e., including active comparators) that is both serious and unexpected.  Before 
submitting an IND safety report, the Sponsor needs to ensure that the event meets all three of 
the definitions (Guidance for Industry and Investigators): 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 
If the AE does not meet all three of the definitions, it should not be submitted as an IND 
safety report. 
The timeframe for submitting an IND safety report, any serious unexpected suspected adverse 
reaction which is not fatal or life-threatening to the Food and Drug Administration (FDA) is 
no later than 15 calendar days after the Sponsor determines that the suspected adverse 
reaction or other information qualifies for reporting. 
Unexpected fatal or life-threatening suspected adverse reactions shall be reported by the 
Sponsor to FDA is no later than 7 calendar days after the Sponsor’s initial receipt of the 
information (in accordance with 21 CFR 312.32(c)(2)). 
The day of initial receipt for cases that are interpretable as single cases and the day the 
Sponsor determines that multiple cases qualify for expedited reporting are considered day 
zero.  
If FDA requests any additional data or information, the Sponsor shall submit it to FDA as 
soon as possible, but no later than 15 calendar days after receiving the request (in 
accordance with 21 CFR 312.32(c)(1)(v)).  


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6.10 
Overdose 
An overdose is defined as a patient receiving a dose of IP(s) in excess of that specified in the 
Investigator’s Brochures (MEDI0457 Investigator’s Brochure and Durvalumab Investigator’s 
Brochure), unless otherwise specified in this protocol. 
Any overdose of a study patient with IP, with or without associated AEs / SAEs, is required to 
be reported within 24 hours of knowledge of the event to the Sponsor designee.  If the 
overdose results in an AE, the AE must also be recorded as an AE (see Section 6.7).  
Overdose does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be recorded and 
reported as an SAE (see Section 6.8).  There is currently no specific treatment in the event of 
an overdose of either MEDI0457 or durvalumab (see MEDI0457 Investigator’s Brochure and 
Durvalumab Investigator’s Brochure).  
The Investigator will use clinical judgment to treat any overdose. 
• 
An overdose with associated AEs is recorded as the AE diagnosis / symptoms on 
the relevant AE modules in the CRF and on the Overdose CRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose CRF 
module. 
If an overdose on a MedImmune study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate MedImmune representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
PRA works with the Investigator to ensure that all relevant information is provided to the 
MedImmune Patient Safety Data Entry Site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 6.8.  
For other overdoses, reporting must occur within 30 days. 
6.11 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to MedImmune. 
6.11.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study the IP should be discontinued 
immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities / birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 


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birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the PRA within 1 day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
PRA works with the Investigator to ensure that all relevant information is provided to the 
MedImmune Patient Safety Data Entry Site within 1 or 5 calendar days for SAEs (see 
Section 6.8) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy. 
6.11.2 
Paternal exposure  
Male patients must refrain from fathering a child or donating sperm during the study since the 
potential for chromosomal aberrations in male gametes, and possible teratogenic effects 
thereof, has not yet been thoroughly investigated.  Male patients who are sexually active must 
use a barrier (condom with spermicide) method of contraception from the first dose until 
90 days after the last dose of IP. 
Pregnancy of the patients’ partners is not considered to be an AE.   
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
must inform PRA within 1 day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
PRA will work with the Investigator to ensure that all relevant information is provided to the 
MedImmune Patient Safety Data Entry Site within 1 or 5 days for SAEs, see Section 6.8 and 
within 30 days for all other pregnancies. 
6.12 
Management of investigational product related toxicities 
6.12.1 
Dose modifications 
Either treatment may be stopped by the Investigator while the other treatment continues. 
MEDI0457 and durvalumab dose should not be modified.  
Durvalumab: For AEs that are considered at least partly due to administration of durvalumab 
the following dose adjustment guidance may be applied: 
• 
Treat each of the toxicities with maximum supportive care (including holding 
durvalumab). 


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• 
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of durvalumab along with appropriate continuing 
supportive care.  If medically appropriate, dose modifications are permitted for 
durvalumab. 
• 
All dose modifications should be documented with clear medical reasoning and 
documentation of the approach taken. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (Appendix H, Postow 2015). 
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (Appendix H, Postow 2015).  All toxicities will be 
graded according to NCI CTCAE version 4.03. 
Based on the mechanism of action of durvalumab leading to T-cell activation and 
proliferation, there is the possibility of observing irAEs during the conduct of this study.  
Potential irAEs include immune-mediated dermatitis, hepatitis / hepatotoxicity, 
endocrinopathy (hypothyroidism, hyperthyroidism, hypophysitis, and adrenal insufficiency), 
neuropathy / neuromuscular toxicity, nephritis, pancreatitis (elevated lipase / amylase), 
pneumonitis, and colitis.  Patients should be monitored for signs and symptoms of irAEs.  In 
the absence of an alternate etiology (e.g., infection or PD) signs or symptoms of dermatitis, 
hepatitis / hepatotoxicity, endocrinopathy (hypothyroidism, hyperthyroidism, hypophysitis, 
and adrenal insufficiency), neuropathy / neuromuscular toxicity, nephritis, pancreatitis 
(elevated lipase / amylase), pneumonitis, and colitis should be considered to be immune-
related.  Refer to the latest Durvalumab Investigator’s Brochure for more information. 
Dose modifications will not be required for AEs that are clearly not attributable to durvalumab 
(such as an accident) or for laboratory abnormalities that are not deemed to be clinically 
significant.  Administration may continue despite concurrent vitiligo of any AE grade. 
Acetaminophen and / or an antihistamine (e.g., diphenhydramine) or equivalent medications 
per institutional standard may be administered prior to infusion at the discretion of the 
Investigator for primary prophylaxis against infusion-related reactions. For more information 
on dose modification for immune-related reactions please refer to Appendix H.  
As with any antibody, allergic reactions to dose administration are possible.  Appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis.  The study 
site must have immediate access to emergency resuscitation teams and equipment in addition 
to the ability to admit patients to an intensive care unit if necessary. 
6.12.2 
Toxicity management 
The Sponsor’s Medical Monitor or a designee will be responsible for the overall safety 
monitoring of the study. 


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6.12.2.1 Dose-limiting toxicity 
Grading of DLTs will be according to the NCI CTCAE version 4.03. 
For the Safety Analysis Run-in patients, the DLT period will be 4 weeks after their first 
durvalumab dose. 
A DLT will be defined as any Grade 3 or higher treatment-related toxicity that occurs during 
the DLT evaluation period (i.e., 4 weeks after the first dose of durvalumab is administered for 
patients in the Safety Analysis Run-in), including the following treatment-related toxicities: 
(a) 
Any Grade 4 irAE is a DLT. 
(b) 
Any ≥ Grade 3 colitis is a DLT. 
(c) 
Any ≥ Grade 3 non-infectious pneumonitis irrespective of duration is a DLT. 
(d) 
Any ≥ Grade 3 neurotoxicity (to include but not limited to limbic encephalitis, 
autonomic neuropathy, including peripheral neuromotor syndromes such as 
myasthenia gravis and Guillain-Barré) irrespective of duration is a DLT. 
(e) 
Any ≥ Grade 3 cardiotoxicity (to include but not limited to arrhythmias, myocarditis 
with cardiomyopathy, ventricular dysfunction) irrespective of duration is a DLT. 
(f) 
Any ≥ Grade 3 ocular toxicity (including but not limited to iritis, uveitis, significant 
vision changes) irrespective of duration is a DLT. 
(g) 
Any ≥ Grade 3 irAE, excluding colitis or pneumonitis or neurotoxicity or 
cardiotoxicity and ocular toxicity as mentioned above, that does not downgrade to 
Grade 2 within 3 days after onset of the event despite optimal medical management 
including systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline 
within 14 days. 
(h) 
Alanine aminotransferase or ALT elevation > 8 × ULN or TBL > 5 × ULN. 
(i) 
Any ≥ Grade 3 non-irAE, except for the exclusions listed below. 
− 
Grade 3 or greater injection site reaction that is persistent beyond 5 days or 
does not downgrade to ≤ Grade 1 in 14 days. 
− 
Grade 3 or greater fever, not associated with above listed events (a to f), 
assessed by Principal Investigator as related to study treatment. 
− 
Grade 3 or greater systemic symptoms, not associated with above listed events 
(a to e), assessed by Principal Investigator as related to study treatment. 
− 
Any Grade 3 or greater anaphylaxis related to study treatment.  


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The DLT definition excludes the following conditions: 
• 
Grade 3 fatigue lasting ≤ 7 days. 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and / or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and / or hormone 
replacement therapy and the patient is asymptomatic. 
• 
Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc). 
• 
Concurrent vitiligo or alopecia of any AE grade. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least one grade within 3 days.  Grade 3 or Grade 4 febrile 
neutropenia will be a DLT regardless of duration or reversibility. 
• 
Grade 3 or 4 lymphopenia. 
• 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
that requires medical intervention, and improves by at least one grade within 3 days. 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days. 
Immune-related AEs are defined as AEs of immune nature (i.e., inflammatory) in the absence 
of a clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory testing 
will be conducted to confirm significant laboratory findings prior to designation as a DLT. 
6.12.2.2 Events requiring expedited reporting within 24 hours 
Overdose 
An overdose is defined as a patient receiving a dose of IP in excess of that specified in the 
Investigator’s Brochures (MEDI0457 Investigator’s Brochure and Durvalumab Investigator’s 
Brochure), unless otherwise specified in this protocol. 
Any overdose of a study patient with IP, with or without associated AEs / SAEs, is required to 
be reported within 24 hours of knowledge of the event to the Sponsor designee.  If the 
overdose results in an AE, the AE must also be recorded as an AE (see Section 6.7).  
Overdose does not automatically make an AE serious, but if the consequences of the overdose 
are serious, for example death or hospitalization, the event is serious and must be recorded and 


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reported as an SAE (see Section 6.8).  There is currently no specific treatment in the event of 
an overdose of MEDI0457 or durvalumab.  
The Investigator will use clinical judgment to treat any overdose. 
Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 6.12.4) in a study patient, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor or designee unless a definitive 
underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is 
unrelated to IP has been confirmed. 
If the definitive underlying diagnosis for the abnormality has been established and is unrelated 
to IP, the decision to continue administration of the study patient will be based on the clinical 
judgment of the investigator. 
If no definitive underlying diagnosis for the abnormality is established, administration of IP to 
the study patient must be interrupted immediately.  Follow-up investigations and inquiries 
must be initiated by the investigational site without delay.  Each reported event of hepatic 
function abnormality will be followed by the Investigator and evaluated by the Sponsor. 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law (HL). 
Pregnancy 
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the Sponsor or designee within 1 day, i.e., immediately, but no later than 
24 hours of when he or she becomes aware of it.   


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The designated Sponsor representative will work with the Investigator to ensure that all 
relevant information is provided to Sponsor or its designee within 1 to 5 calendar days for 
SAEs and within 30 days for all other pregnancies.  The same timelines apply when outcome 
information is available. 
6.12.2.3 Events requiring reporting within 72 hours 
The following events must be reported to Sponsor within 72 hours of the occurrence of the 
event to discuss whether further administration should continue for the participant. 
• 
Grade 3 or greater injection site reaction.  
• 
Grade 3 or greater fever, not associated with above listed events (a to f) in 
Section 6.12.2.1, assessed by Principal Investigator as related to study treatment. 
• 
Grade 3 or greater systemic symptoms, not associated with above listed events 
(a to e) in Section 6.12.2.1, assessed by Principal Investigator as related to study 
treatment. 
6.12.3 
Stopping rules 
The Sponsor reserves the right to temporarily pause or terminate the study at any time.  The 
reasons for temporarily pausing or terminating the study may include but are not limited to the 
following: 
• 
If at any time during the study one-third or more patients experience any DLT 
assessed as related to study treatment, further enrollment and study treatments may 
be halted until a thorough investigation has been conducted by the Sponsor.  
• 
If a death occurs within 8 weeks of a dose of MEDI0457 or durvalumab and it is 
assessed as related to study treatment, further enrollment and study treatments may 
be halted depending upon further discussions between the Sponsor and / or 
investigator.  
• 
In the event of any unexpected Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatments may be halted until a thorough 
investigation has been conducted by the Sponsor and / or investigator. 
• 
The study may be halted for any report of Grade 3 anaphylaxis from study treatment 
with MEDI0457 or durvalumab in two or more patients. 
• 
Non-compliance that might significantly jeopardize the validity or integrity of the 
study. 
• 
Sponsor decision to terminate development. 
• 
Sponsor decision to terminate the study based on a planned futility analysis. 


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6.12.4 
Adverse events of special interest 
An AESI is of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and rapid communication by the Investigator to the Sponsor.  An 
AESI may be serious or non-serious.  The rapid reporting of AESIs allows ongoing 
surveillance of these events in order to characterize and understand them in association with 
the use of this IP.  
Adverse events of special interest for MEDI0457 and durvalumab include but are not limited 
to events with a potential inflammatory or immune-mediated mechanism and which may 
require more frequent monitoring and / or interventions such as steroids, immunosuppressants 
and / or hormone replacement therapy.  These AESIs are being closely monitored in clinical 
studies with durvalumab monotherapy and combination therapy.  An irAE is defined as an AE 
that is associated with drug exposure and is consistent with an immune-mediated mechanism 
of action and where there is no clear alternate etiology.  Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis.  
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the irAE.  If the Investigator has any questions in regards to an AE 
being an irAE, the Investigator should promptly contact the Study Physician.  Identified risks 
(listed / expected reactions) for durvalumab include:  diarrhea, ALT increase, AST increase, 
pneumonitis, and colitis / enterocolitis.  
Adverse events of special interest observed with MEDI0457 and durvalumab include: 
• 
Diarrhea / colitis 
• 
Pneumonitis  
• 
ALT / AST increases / hepatitis / hepatotoxicity 
• 
Neuropathy / neuromuscular toxicity (i.e., events of encephalitis, peripheral motor 
and sensory neuropathies, Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e., events of hypophysitis, hypopituitarism, adrenal insufficiency, 
type 1 diabetes, hypothyroidism and hyperthyroidism) 
• 
Dermatitis / rash / pruritus 
• 
Nephritis  
• 
Pancreatitis (or laboratory tests suggestive of pancreatitis - increased serum lipase, 
increased serum amylase) 
• 
Myocarditis / pericarditis 
• 
Uveitis 


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• 
Infusion-related reactions / hypersensitivity / anaphylactic reactions  
• 
Administration site reactions (any administration site reaction other than pain, and if 
the event is pain it must be Grade 3 or greater pain) 
 
Further information on these risks (e.g., presenting symptoms) can be found in the current 
version of the MEDI0457 Investigator’s Brochure or the Durvalumab Investigator’s Brochure.  
For more specific guidelines for their evaluation and treatment refer to Appendix H. 
Adverse events of special interest are required to be reported within 24 hours of knowledge 
of the event on the electronic CRF, even if the event is considered to be non-serious.  
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 x ULN together with TBL ≥ 2 x ULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of HL.   
Colitis:  
Diarrhea, colitis, and enterocolitis are irAEs that have been reported with durvalumab.  In rare 
cases, colon perforation may occur that requires surgery (colectomy) or can lead to a fatal 
outcome if not properly managed.  Diarrhea / colitis in patients receiving durvalumab should 
be managed as per the guidelines for the management of diarrhea and enterocolitis (refer to 
Appendix H). 
Pneumonitis:  
Adverse events of pneumonitis are also of interest for the Sponsor.  Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry.  Pulmonary 
consultation is highly recommended.  For guidelines for management of patients with 
pneumonitis refer to Appendix H. 
Hypersensitivity Reactions:  
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (Brahmer et al 2012).  As with the administration of any 
foreign protein and / or other biologic agents, reactions following the infusion of monoclonal 
antibodies can be caused by various mechanisms, including acute anaphylactic 
(immunoglobulin E-mediated) and anaphylactoid reactions against the monoclonal antibodies, 
and serum sickness.  Acute allergic reactions may occur, may be severe, and may result in 
death.  Acute allergic reactions may include hypotension, dyspnea, cyanosis, respiratory 
failure, urticaria, pruritus, angioedema, hypotonia, urticaria, arthralgia, bronchospasm, 


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wheeze, cough, dizziness, fatigue, headache, hypertension, myalgia, vomiting and 
unresponsiveness.  For guidelines for management of patients with hypersensitivity reactions 
(including anaphylactic reactions) refer to Appendix H.  
Infusion-Related Reactions:  
Adverse events of infusion reactions (also termed infusion-related reactions) are of special 
interest to the Sponsor and are defined, for the purpose of this protocol, as all AEs occurring 
from the start of the study treatment infusion up to 48 hours after the infusion start time.  For 
all infusion reactions, the electronic CRF should be completed as instructed in Section 6.7, 
and all SAEs should be reported to MedImmune Patient Safety as described in Section 6.8.  
For guidelines for management of patients with infusion-related reactions refer to 
Appendix H. 
Administration Site Reactions:  
Adverse events of administration site reactions are of special interest to the Sponsor.  These 
are defined, for the purpose of this protocol, as all AEs occurring as a result of the 
administration of the study treatment (vaccine and / or EP).  Guidelines for the grading and 
management of administration site reactions are outlined in Appendix I.  
6.12.5 
Unanticipated (serious) adverse device effect 
Unanticipated adverse device effect means any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in 
the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of patients.  
Per the definition above, an unanticipated adverse device effect is a type of SAE that requires 
expedited reporting on the part of the Sponsor.  As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
Investigator within 24 hours.  Sponsor will assess each device related SAE to determine if 
anticipated based on prior identification within the investigational plan. 
6.13 
Study governance and oversight 
The safety of all MedImmune clinical studies is closely monitored on an ongoing basis by 
MedImmune representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance this could involve amendments to the study protocol and letters to 
investigators. 


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7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
7.1.1 
MEDI0457 
7.1.2 
Durvalumab  
Durvalumab (also known as MEDI4736) is a human IgG1 kappa monoclonal antibody 
directed against human PD-L1.  Durvalumab selectively binds human PD-L1 with high 
affinity and blocks its ability to bind to PD-1 and CD80.  The fragment crystallizable domain 
of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy chain that 
reduces binding to the complement component C1q and the Fcγ receptors responsible for 
mediating antibody dependent cell mediated cytotoxicity (Oganesyan et al 2008). 
Durvalumab will be supplied by MedImmune or its designee as a 500 mg vial solution for 
infusion after dilution.  The solution contains 50 mg/mL durvalumab, 26 mM histidine / 
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histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) polysorbate 
80; it has a pH of 6.0.  The nominal fill volume is 10 mL.  Durvalumab must be used within 
the individually assigned expiry date on the label. 
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7.2 
Dose and treatment regimens 
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7.3 
Labeling 
This study is open-labeled.  Therefore the patient, the investigator’s site personnel and the 
Sponsor or its designee are not blinded to study treatment.  Each vial of IP will be labeled with 
a single panel label.  
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.  The labels will fulfill Good Manufacturing Practice Annex 13 requirements for 
labeling.  Label text will be translated into local language. 
 
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Example labels for the CELLECTRA®5P Device (Pulse Generator, Applicator and Array) are 
shown below. 
 
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the vial and kit specifies the appropriate storage. 
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The study Sponsor will be responsible for assuring that the quality of the IP is adequate for the 
duration of the study.  
7.4.1 
Storage - MEDI0457 
Vials must be stored at -25°C to -15°C (-13°F to 5°F) inside a -20°C freezer at all times upon 
receipt at the clinical site.  A freezer temperature log must be monitored daily and maintained 
at the site. 
7.4.2 
Storage - Durvalumab  
Vials will be shipped under refrigerated condition.  A temperature monitor will track the 
temperature throughout the shipment and will indicate any excursion during the shipment.  
Vials must be stored at 2°C to 8°C (36°F to 46°F) upon receipt in a secure area with restricted 
access.  A refrigerator temperature log must be monitored daily and maintained at the site.  
Vials should not be frozen. 
7.5 
Preparation and dispensing 
It is the responsibility of the Investigator to ensure that IP is dispensed to study participants.  It 
must be dispensed only from official study sites by authorized personnel according to local 
regulations and must be recorded appropriately on the IP accountability record. 
7.5.1 
Preparation and dispensing - MEDI0457 
 
 
  
 
7.5.2 
Preparation and dispensing - Durvalumab  
The dose of durvalumab for administration must be prepared by the investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
Durvalumab will be administered using an IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose, with a final durvalumab concentration ranging from 1 to 20 mg/mL, and delivered 
through an IV administration set with a 0.2- or 0.22-μm in-line filter.   
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For the 1500 mg dose add 30 mL (750 mg dose add 15 mL) of durvalumab to the IV bag such 
that final concentration is within 1 mg/mL to 20 mg/mL.  Mix the bag by gentle inversion to 
ensure homogeneity of the dose in the bag.  Infusion solutions must be allowed to equilibrate 
to room temperature prior to commencement of administration. 
Durvalumab will be administered at room temperature by controlled infusion into a peripheral 
or central vein.  Following preparation of durvalumab, the entire contents of the IV bag should 
be administered as an IV infusion over approximately 60 minutes (±5 minutes), using a 0.2 or 
0.22-μm in-line filter.  Less than 55 minutes is considered a deviation. 
The IV line will be flushed with a volume of IV bag diluent equal to the priming volume of 
the infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed. 
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. 
In the event that either preparation time or infusion time exceeds the time limits, a new dose 
must be prepared from new vials.  Durvalumab does not contain preservatives, and any unused 
portion must be discarded.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. 
7.6 
Investigational product inspection 
Each vial selected for dose preparation should be inspected. 
During the inspection, if the solution is not clear or any turbidity, discoloration, or particulates 
are observed, notify your site monitor and store the vial(s) in QUARANTINE at refrigerated 
temperature of the IP under the appropriate storage conditions for drug accountability and 
potential future inspection. 
If there are any defects noted with the IP, the Investigator and site monitor should be notified 
immediately.   
7.7 
Compliance 
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the CRF. 
Treatment compliance will be assured by site reconciliation of the medication dispensed and 
returned. 


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7.8 
Accountability 
7.8.1 
Accountability - investigational products 
The study drug provided for this study will be used only as directed in the study protocol.  
Study drug accountability will be captured in the Interactive Voice and Web Response 
System. 
It is the responsibility of the Investigator to ensure that a current record of IP disposition is 
maintained at each study site where IP is inventoried and disposed.  Records or logs must 
comply with applicable regulations and guidelines, and should include: 
• 
Amount received and placed in storage area 
• 
Amount currently in storage area 
• 
Label ID number or batch number and use date or expiry date 
• 
Dates and initials of person responsible for each IP inventory entry / movement 
• 
Amount dispensed to each patient, including unique patient identifiers 
• 
Amount transferred to another area / site for dispensing or storage 
• 
Amount returned to Sponsor or its designee 
• 
Amount destroyed at study site, if applicable 
7.8.2 
Accountability - investigational device 
Each clinical site is responsible for maintaining investigational device accountability.  This 
includes recording the CELLECTRA®5P serial number, IM applicator serial number, and IM 
array lot number used for injection / EP of each patient.  Site personnel will be required to 
download EP data and provide to MedImmune after each treatment. 
7.9 
Return and destruction of investigational products and 
investigational device 
Upon completion or termination of the study, all unused and / or partially used IP must be 
returned to MedImmune, if not authorized by MedImmune or local regulations to be destroyed 
at the site. 
If the IP is to be destroyed on site, it is the investigator’s responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted by 
MedImmune, procedures for proper disposal have been established according to applicable 
regulation and guidelines and institutional procedures, and appropriate records of the disposal 
have been documented.  The unused IP can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor.  


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The Study Monitor will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery, destruction and return should be 
signed. 
7.11 
Post study access to study treatment 
There are no plans to provide MEDI0457 or durvalumab (MEDI0457) after the completion of 
the study. 
8. 
STATISTICAL ANALYSES 
8.1 
Statistical considerations 
Statistical analyses will be performed by PRA.  
A comprehensive Statistical Analysis Plan (SAP) will be developed.  
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8.2 
Sample size estimate  
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8.3 
Definitions of analysis sets 
The analysis of data will be based on different subsets according to the purpose of the 
analysis, i.e., efficacy, safety and pharmacokinetic, respectively.  Patients in the Safety 
Analysis Run-in period will be included in the analysis sets as applicable (i.e., meet the 
analysis set definitions). 
8.3.1 
Efficacy analysis set 
Response-evaluable Population: The co-primary endpoint of ORR by RECIST version 1.1 
will be based on the Response-evaluable Population.  This population will include all patients 
with confirmed HPV-16 or HPV-18 associated disease who have received one dose of both 
study drugs, have a baseline scan with measurable disease at baseline and either (i) at least one 
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on treatment scan or (ii) patients who discontinue due to disease progression or (iii) death 
without an on-treatment scan.   
Secondary efficacy analyses will be based on both the Response-evaluable and the As-treated 
populations.  The As-treated Population will include all patients who receive any IP (defined 
as at least one dose of either study drug).  
Table 9 provides a summary of the efficacy endpoints with their corresponding methods of 
assessment and populations. 
Table 9 
A Summary of Efficacy Endpoints with Corresponding Methods of 
Assessment and Populations 
Type of efficacy 
endpoint 
Endpoint 
Method 
Population(s) 
Co-primary 
ORR 
RECIST version 1.1 
Response-evaluable 
 
 
 
 
Secondary 
ORR 
RECIST version 1.1  
As-treated  
 
ORR 
irRECIST 
Response-evaluable 
and As-treated  
 
DCR-16w 
RECIST version 1.1 
Response-evaluable 
and As-treated 
 
PFS 
RECIST version 1.1 
Response-evaluable 
and As-treated 
 
OS 
Kaplan-Meier 
Response-evaluable 
and As-treated 
Abbreviations 
DCR-16w=disease control rate at 16 weeks, irRECIST=Immune-Related Response Evaluation Criteria in Solid Tumors, 
ORR=objective response rate, OS=overall survival, PFS=progression free survival, RECIST= Response Evaluation Criteria in 
Solid Tumors 
 
8.3.2 
Safety analysis set 
The safety evaluation will be based on the As-treated Population and the Safety Analysis Set 
will include all patients who receive any IP (defined as at least one dose of either study drug).  
8.3.3 
Pharmacokinetics analysis set 
The Pharmacokinetic Analysis Set will include all patients who receive at least one dose of 
durvalumab and have at least one evaluable post-dose serum concentration measurement of 
durvalumab. 


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8.4 
Outcome measures for analyses 
8.4.1 
Primary endpoints 
The co-primary endpoints are the assessment of safety (including AEs, SAEs, laboratory 
evaluations, vital signs, ECG, performance status assessments, physical examinations and 
concomitant medications) and ORR by RECIST version 1.1. 
8.4.1.1 
Adverse events 
Adverse event data will be summarized by the percentage of patients with AEs.  Adverse 
events (both in terms of MedDRA preferred terms and CTCAE grade) will be listed 
individually by patient.   
Any AE occurring before treatment with IP will be included in the data listings but will not be 
included in the summary tables of AEs.  Any AE occurring within 90 days of discontinuation 
of IP may be included in the AE summaries, but the majority of those summaries will omit 
those AEs observed after a patient has received further therapy for cancer.  Further details will 
be provided in the SAP.  Any events in this period that occur after a patient has received 
further therapy for cancer (following discontinuation of IP) will be flagged in the data listings. 
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced.  These events will not be included in AE summaries. 
8.4.1.2 
Safety assessments 
For the change from baseline summaries for vital signs, laboratory data, ECGs, performance 
status, and physical examination, the baseline value will be the latest result obtained prior to 
the start of study treatment.  Concomitant medication data will be listed only. 
8.4.1.3 
Investigator RECIST version 1.1-based assessments 
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations.  This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy.  
At each visit, patients will be assigned a RECIST version 1.1 visit response of CR, PR, SD, or 
PD depending on the status of their disease compared with baseline and previous assessments 
by the Investigator.  Note: at the discretion of the Sponsor, an independent central review of 
all scans used in the assessment of tumors by RECIST version 1.1 and/or irRECIST may be 
conducted (refer to Section 5.3 for further details).  Baseline will be assessed within the 
28 days prior to enrollment.  If a patient has had a tumor assessment that cannot be evaluated, 
then the patient will be assigned a visit response of not evaluable (unless there is evidence of 
progression in which case the response will be assigned as PD). 
Please refer to Appendix F for the definitions of CR, PR, SD, and PD. 


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Objective Response Rate (ORR) 
Objective response rate is defined as the number (%) of patients with at least one visit 
response of CR or PR via RECIST 1.1 and will be based on the Response-evaluable 
Population for the co-primary endpoint.   
8.4.2 
Secondary efficacy endpoints 
Objective Response Rate (ORR) 
Objective response rate will be assessed as a secondary endpoint in the As-treated Population 
using RECIST version 1.1.  Objective response rate will be also assessed in the 
Response-evaluable and As-treated populations using irRECIST (Appendix G). 
Progression Free Survival (PFS) 
Progression free survival measures progression by growth of the primary tumor, nodal spread 
metastases, death from the cancer, or death from other causes.  Progression free survival will be 
assessed by the periodic tumor assessment using imaging per the institutional guidelines at the 
schedules according to Table 3. 
All study evaluations for disease response must be based on RECIST version 1.1 (Appendix F). 
Progression free survival will be defined as the time from the date of start of IP treatment until 
the documentation of disease progression according to RECIST version 1.1 or death due to 
any cause, whichever occurs first.  Patients who have not progressed or died at the time of the 
analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST version 1.1 assessment.  However, if the patient progresses or dies after two or more 
missed visits, the patient will be censored at the time of the latest evaluable RECIST 
version 1.1 assessment prior to two missed visits.   
The PFS time will always be derived based on scan / assessment / death dates and not visit 
dates. 
RECIST version 1.1 assessment / scans contributing towards a particular visit may be 
performed on different dates.  The following rule will be applied: 
For investigator assessments, the date of progression will be determined based on the earliest 
of the RECIST version 1.1 assessment / scan dates of the component that indicates 
progression. 
When censoring a patient for PFS, the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment. 
Note: For target lesions, only the latest scan date is recorded out of all scans performed at that 
assessment for the target lesions, and similarly for non-target lesions, only the latest scan date 
is recorded out of all scans performed at that assessment for the non-target lesions. 
PFS will be assessed in the Response-evaluable and As-treated populations.  


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Disease Control Rate (DCR) 
Disease control rate is defined as N (%) patients with CR, PR, or SD by 16 weeks on study 
using RECIST version 1.1.  For SD determination for DCR, the patient must have lack of 
progression for the first 16 weeks on study.  Disease control rate will be assessed in the 
Response-evaluable and As-treated populations.  
Overall Survival (OS) 
Overall survival is defined as the time from the date of start of IP treatment until death 
(+1 day) due to any cause.  Any patient not known to have died at the time of analysis will be 
censored based on the last recorded date on which the patient was known to be alive.  Overall 
survival will be assessed in the Response-evaluable and As-treated populations.  
8.4.2.1 
Pharmacokinetics and antibodies for durvalumab  
The actual sampling times will be used in the pharmacokinetic calculations.  Durvalumab 
concentration data and summary statistics will be tabulated.  Individual and mean serum 
durvalumab concentration-time profiles will be generated.   
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADA for durvalumab.  The immunogenicity 
titer will be reported for samples confirmed positive for the presence of ADA. 
8.5 
Methods for statistical analyses 
Demographic and baseline characteristics will be summarized with means, medians, standard 
deviations, ranges or percentages.   
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8.5.1 
Analysis of the primary variable(s) 
8.5.1.1 
Safety 
Safety will be summarized by the percentage of patients with AEs, with grading according to 
NCI CTCAE version 4.03 and attribution.  Summary statistics will also be provided for 
serious AEs, hematology, urinalysis, CPK, thyroid function testing, pregnancy test, ECG, vital 
sign, performance status, physical examinations and concomitant medications. 
8.5.2 
Analysis of the secondary variable(s) 
8.5.2.1 
Pharmacokinetic analysis 
Pharmacokinetic concentration data and summary statistics will be tabulated.  Individual and 
mean blood concentration-time profiles will be generated.  Due to the sparse pharmacokinetic 
sampling used in this study, formal non-compartmental analysis to derive pharmacokinetic 
parameters (e.g., terminal half-life) will not be conducted.  A population pharmacokinetic 
model may be developed with similar data from other studies to further characterize the 
pharmacokinetic properties of durvalumab when administered in combination with 
MEDI0457. 
8.5.2.2 
Anti-drug antibody analysis 
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADA for durvalumab.  The immunogenicity 
titers will be reported for samples confirmed positive for the presence of ADA.  The effect of 
immunogenicity on pharmacokinetic and its potential association with efficacy, safety and / or 
tolerability will be performed, if the data allow. 
8.5.2.3 
Anti-tumor analysis – objective response rate, disease control rate at 16 weeks, 
progression free survival and overall survival 
Summary statistics will be provided for ORR and DCR.  Progression free survival and OS will 
be estimated using the Kaplan-Meier method.  Median survival times and corresponding 95% 
confidence intervals will be provided. 
8.5.3 
Exploratory analysis   
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8.5.4 
Subgroup analysis 
Any subgroup analysis will be pre-planned and specified in the SAP. 
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9. 
STUDY AND DATA MANAGEMENT 
9.1 
Training of study site personnel 
Before the first patient is entered into the study, it is necessary for a representative of PRA to 
visit the investigational study site to: 
• 
Determine the adequacy of the facilities 
• 
Determine availability of appropriate patients for the study 
• 
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
MedImmune or its representatives.  This will be documented in the Clinical Study 
Agreement between PRA and the Investigator. 
Site personnel will be required to complete Electronic Data Capture training before the first 
patient is entered into the study. 
Before the first patient is entered into the study, a PRA representative will review and discuss 
the requirements of the Clinical Study Protocol and related documents with the investigational 
staff and also train them in any study specific procedures, and the WBDC system(s) utilized. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.2 
Monitoring of the study 
PRA will perform the monitoring of the study. 
During the study, a PRA representative will have regular contacts with the study site, 
including visits to: 
• 
Provide information and support to the investigator(s) 
• 
Confirm that facilities remain acceptable 
• 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks 
are being performed 


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• 
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients.  This 
will require direct access to all original records for each patient (e.g., clinic charts) 
• 
Ensure withdrawal of informed consent to the use of the patient’s biological 
samples is reported and biological samples are identified and disposed of / 
destroyed accordingly, and the action is documented, and reported to the patient. 
The PRA representative will be available between visits if the investigator(s) or other staff at 
the center needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Clinical Study Agreement for location of source data. 
9.2.2 
Study agreements 
The Principal Investigator at each / the center should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of 
any inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail. 
Agreements between MedImmune and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement. 
9.2.4 
Deviation from the clinical study protocol 
The investigator(s) must not deviate from or make any changes to the protocol without 
documented agreement between the Principal Investigator and MedImmune or the 
Institutional Review Board (IRB) approval based on its deliberations.  However, this shall not 
apply to cases where the deviation or change is necessary to avoid an immediate hazard to the 
patients or for other compelling medical reasons, or where the changes involve only logistical 
or administrative aspects of the clinical study (e.g., changes to the organization / structure of 
the MedImmune, the name / department name of the study site, the address or phone number 
of the study site or MedImmune, the job title of the investigator, and monitors).  
The investigator(s) should document any deviation from the protocol regardless of their 
reasons.  Only when the protocol was not followed in order to avoid an immediate hazard to 
the patients or for other medically compelling reason, the Investigator should prepare and 
submit the records explaining the reasons thereof to MedImmune and the head of study site, 
and retain a copy of the records.  


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The investigator(s) may deviate from or make a change to the protocol without documented 
agreement between the Principal Investigator and MedImmune or the IRB approval, only in 
the event of a medical emergency, e.g., it is only way to avoid an immediate hazard to the 
patients.  In such case, the Principal Investigator must notify details of the deviation or 
change, the reason, and a proposed revision in the protocol if required, to MedImmune and the 
head of the study site and IRB via the head of the study site as soon as possible, in order to 
obtain their approval.  A certificate of approval by the head of the study site as well as 
MedImmune should be obtained via the head of the study site. 
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 
The study started in Quarter 4 2016 and is expected to end by Quarter 4 2019. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  MedImmune 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with MEDI0457 and durvalumab. 
9.4 
Data management 
Data management will be performed by PRA Data Management Center staff according to the 
Data Management Plan.  
Data will be entered in the WBDC system at the study site.  Trained study staff will be 
responsible for entering data on the observations, tests and assessments specified in the 
protocol into the WBDC system and according to the CRF instructions.  The CRF instructions 
will also guide the study site in performing data entry.  Data entered in the WBDC system will 
be immediately saved to a central database and changes tracked to provide an audit trail.  The 
data will then be Source Data Verified, reviewed / queried and updated as needed.  The data 
will be validated as defined in the Data Management Plan. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.  Quality control procedures will be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly. 
Adverse events and medical / surgical history will be classified according to the terminology 
of the latest version of the MedDRA and the WHO Drug Reference Dictionary.  Medications 
will be classified according to the WHO Reference Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at PRA.  Note: the most current version of WHO 
Drug Reference Dictionary will be used.  Laboratory data will be coded using NCI CTCAE 
version 4.03. 
Relevant pain scale forms will be filled in by the patients or study staff according to 
age-appropriate guidelines within this protocol. 


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The data will be frozen and then locked to prevent further editing.  When all data have been 
coded, validated, signed, and locked, a clean file will be declared.  A copy of the completed 
CRFs will be archived at the study site when the study has been locked. 
Serious adverse event reconciliation 
Serious adverse event reconciliation reports are produced and reconciled with the Patient 
Safety database and / or the investigational site.  
Data management of genotype data 
Refer to Appendix C. 
Data associated with human biological samples 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to MedImmune. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation (ICH) 
/ GCP, applicable regulatory requirements and the MedImmune policy on Bioethics and 
Human Biological Samples. 
10.2 
Patient data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.3 
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the ICF and any other written information and / or materials to be provided to the patients.  
The Investigator will ensure the distribution of these documents to the applicable EC, and to 
the study site staff. 
The opinion of the EC should be given in writing.  The Investigator should submit the written 
approval to MedImmune before enrollment of any patient into the study.  
The EC should approve all advertising used to recruit patients for the study. 
PRA should approve any modifications to the ICF that are needed to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the EC annually. 


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Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
PRA will handle the distribution of any of these documents to the national Regulatory 
Authorities. 
PRA will provide Regulatory Authorities, ECs and Principal Investigators with safety updates 
/ reports according to local requirements. 
Each Principal Investigator is responsible for providing the ECs / IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP.  
PRA will provide this information to the Principal Investigator so that he / she can meet these 
reporting requirements. 
10.4 
Informed consent 
The Principal Investigator(s) at each center will: 
• 
Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study. 
• 
Ensure each patient is notified that they are free to discontinue from the study at any 
time. 
• 
Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided. 
• 
Ensure each patient provides signed and dated informed consent before conducting 
any procedure specifically for the study. 
• 
Ensure the original, signed ICF(s) is / are stored in the Investigator’s Study File. 
• 
Ensure a copy of the signed ICF is given to the patient. 
• 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the ICF that is approved by an EC. 
10.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 


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The amendment is to be approved by the relevant EC and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised protocols. 
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to EC see Section 10.3. 
If a protocol amendment requires a change to a center’s ICF, MedImmune and the center’s EC 
are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each EC. 
10.6 
Audits and inspections 
Authorized representatives of MedImmune, a regulatory authority, or an EC may perform 
audits or inspections at the center, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The Investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the center. 


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Pancreatic Cancers. Clinical Trials.gov Identifier:  NCT02327468 
Wolchok et al 2009 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the 
Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria.  
Clin Cancer Res 2009;15(23) December 1, 7412-20. 
Zandberg et al 2013 
Zandberg DP, Bhargava R, Badin S, Cullen KJ. The Role of Human Papillomavirus in 
Nongenital Cancers. CA Cancer J, 2013;Vol 63; No 1; January/February; 58-81. 
 
CCI


Clinical Study Protocol Appendix A 
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Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
135 (159) 
Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life-threatening 
‘Life-threatening’ means that the patient was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the patient’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a 
more severe form it might have caused death (e.g., hepatitis that resolved without hepatic 
failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal edema).  Hospital admissions and / or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
• 
Angioedema not severe enough to require intubation but requiring IV 
hydrocortisone treatment 
• 
Hepatotoxicity caused by acetaminophen overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 


Clinical Study Protocol Appendix A 
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Version 8.0 
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A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course.  Exposure to suspect drug.  Has the patient actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another etiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? MedImmune would not normally 
recommend or support a re-challenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


Clinical Study Protocol Appendix B 
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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Labeling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
three categories.  For transport purposes the classification of infectious substances according 
to Risk Groups was removed from the Dangerous Goods Regulations in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are e.g., Ebola, Lassa fever 
virus: 
• 
Are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2.  They are assigned the following UN number 
and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
Are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• 
Clinical trial samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging.  
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry ice content. 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable. 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 


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containment standards are encouraged wherever possible when road or rail transport 
is used. 


Clinical Study Protocol Appendix C 
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Appendix C 
Pharmacogenetics Research 
Background and Rationale 
MedImmune intends to perform genetic research in the MEDI0457 and durvalumab clinical 
development programme to explore how genetic variations may affect the clinical parameters 
associated with MEDI0457 and durvalumab.  Collection of DNA samples from populations 
with well described clinical characteristics may lead to improvements in the design and 
interpretation of clinical trials and, possibly, to genetically guided treatment strategies. 
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to MEDI0457 and durvalumab but also susceptibility to recurrent / metastatic 
head and neck cancer associated with HPV-16 and / or HPV-18 for which MEDI0457 and 
durvalumab may be evaluated.  Thus, this genetic research may involve study of additional 
un-named genes or gene categories, but only as related to disease susceptibility and drug 
action. 
Genetic Research Objectives 
The objective of this research is to collect and store DNA for future exploratory research into 
genes / genetic variation that may influence response (i.e., distribution, safety, tolerability and 
efficacy) to recurrent / metastatic head and neck cancer associated with HPV-16 and / or 
HPV-18.  
Genetic Research Plan and Procedures 
Selection of genetic research population 
Study selection record 
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study. 
Inclusion criteria 
For inclusion in this genetic research, patients must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: 
• 
Provide informed consent for the genetic sampling and analyses. 


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Exclusion criteria 
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following: 
• 
Previous allogeneic bone marrow transplant 
• 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection 
Discontinuation of patients from this genetic research 
Specific reasons for discontinuing a patient from this genetic research are: 
Withdrawal of consent for genetic research:  Patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study.  Voluntary discontinuation will not prejudice further treatment.  Procedures for 
discontinuation are outlined in Section 3.9 of the main Clinical Study Protocol. 
Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the patients at Week 1, Week 8, 
Week 10 and Week 16 (Table 3).  Although genotype is a stable parameter, early sample 
collection is preferred to avoid introducing bias through excluding patients who may withdraw 
due to an adverse event (AE), such patients would be important to include in any genetic 
analysis.  If for any reason the sample is not drawn at a scheduled visit at Week 1, Week 8, 
Week 10 and Week 16, it may be taken at any visit until the last study visit.  Samples will be 
collected, labeled, stored and shipped as detailed in the Laboratory Manual. 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
25 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached. 
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample.  The DNA sample will be assigned a unique number replacing the information 
on the sample tube.  Thereafter, the DNA sample will be identifiable by the unique DNA 
number only.  The DNA number is used to identify the sample and corresponding data at the 
MedImmune genetics laboratories, or at the designated contract laboratory.  No personal 
details identifying the individual will be available to any person (MedImmune employee or 
contract laboratory staff working with the DNA.) 
The samples and data for genetic analysis in this study will be single coded.  The link between 
the patient enrollment code and the DNA number will be maintained and stored in a secure 
environment, with restricted access within the Clinical Genotyping Group Laboratory 


Clinical Study Protocol Appendix C 
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Information Management System (LIMS) at MedImmune.  The link will be used to identify 
the relevant DNA samples for analysis, facilitate correlation of genotypic results with clinical 
data, allow regulatory audit and to trace samples for destruction in the case of withdrawal of 
consent. 
Ethical and Regulatory Requirements 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main Clinical Study Protocol. 
Informed consent 
All patients must sign the informed consent prior to any study-related procedures being 
performed.   
Patient data protection 
MedImmune will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, a MedImmune Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  Also Regulatory Authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate. 
Data management 
Any genotype data generated in this study will be stored in the MedImmune genotyping LIMS 
database, or other appropriate secure system within MedImmune and / or third party 
contracted to work with MedImmune to analyze the samples. 
The results from this genetic research may be reported in the Clinical Study Report for the 
main study, or in a separate report as appropriate. 
Genotype data will be transferred to the clinical database, and merged with the clinical data 
from the main study, prior to the statistical analysis and reporting of the study.  
Statistical methods and determination of sample size 
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A SAP will be 
prepared where appropriate. 


Clinical Study Protocol Appendix D 
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Appendix D 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  Hy’s Law criteria are met if there is no alternative explanation for the elevations in 
liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Product (IP).  
The Investigator is responsible for recording data pertaining to PHL / HL cases and for 
reporting adverse events (AEs) and serious adverse events (SAEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law 
A PHL case is defined as a study patient with an increase in serum aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) ≥ 3 x upper limit of normal (ULN) together with 
total bilirubin (TBL) ≥ 2 x ULN, irrespective of an increase in alkaline phosphatase (ALP), at 
any point during the study following the start of study medication.  
Hy’s Law 
A HL case is defined as a study patient with an increase in serum AST or ALT ≥ 3 x ULN 
together with TBL ≥ 2 x ULN, where no other reason, other than the IP, can be found to 
explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, 
another drug.   
For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 


Clinical Study Protocol Appendix D 
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Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 x ULN 
• 
AST ≥ 3 x ULN 
• 
TBL ≥ 2 x ULN 
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to MedImmune 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
• 
Notify the MedImmune representative. 
• 
Request a repeat of the test (new blood draw) by the central laboratory. 
• 
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result. 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
• 
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results).Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results). 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• 
Notify the MedImmune representative. 
• 
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits.  
Definitions within this Appendix for definition) by reviewing laboratory reports 
from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory CRF. 


Clinical Study Protocol Appendix D 
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Follow-up 
Potential Hy’s Law Criteria not Met 
If the patient does not meet PHL criteria the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
Potential Hy’s Law Criteria Met 
If the patient does meet PHL criteria the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Actions Required When Potential Hy’s Law Criteria are Met Before 
and After Starting Study Treatment). 
• 
Notify the MedImmune representative who will then inform the central Study 
Team.  
The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated.  
• 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  
• 
Complete the three Liver CRF Modules as information becomes available. 
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The MedImmune Medical Science Director and Global Safety Physician will also be involved 
in this review together with other patient matter experts as appropriate.   


Clinical Study Protocol Appendix D 
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According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
• 
If the alternative explanation is an AE / SAE, record the AE / SAE in the CRF 
accordingly and follow the AZ standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to MedImmune standard 
processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above. 
• 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review. 
Actions Required When Potential Hy’s Law Criteria are Met Before and After Starting 
Study Treatment  
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being met the Investigator will: 


Clinical Study Protocol Appendix D 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
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• 
Determine if there has been a significant change in the patients’ condition# 
compared with the last visit where PHL criteria were met#  
− 
If there is no significant change no action is required 
− 
If there is a significant change notify the MedImmune representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Potential Hy’s Law Criteria Met of this Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty. 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met 
found to be the disease under study e.g., chronic or progressing malignant disease, 
severe infection or liver disease, or did the patient meet PHL criteria prior to 
starting study treatment and at their first on study treatment visit as described in 
Actions Required When Potential Hy’s Law Criteria are Met Before and After 
Starting Study Treatment?  
If No: follow the process described in Potential Hy’s Law Criteria Met of this Appendix 
If Yes: 
Determine if there has been a significant change in the patient’s condition# compared with 
when PHL criteria were previously met 
• 
If there is no significant change no action is required. 
• 
If there is a significant change follow the process referred to in Appendix H. 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 


Clinical Study Protocol Appendix D 
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whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the Study Physician if there is any uncertainty. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 
  


Clinical Study Protocol Appendix E 
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Study Code D8860C00005 
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Appendix E 
CELLECTRA®5P Error Reporting Form 
 
Please complete the form and fax to 
 or scan the form to 
   
Protocol#_________ 
Site#______ 
Patient ID_________ 
Week#_______ 
Visit Date_______ 
DEVICE INFORMATION 
CELLECTRA®5P Serial No:  
Located on label on the front cover 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CELLECTRA®5P Applicator Serial No: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Located on label on the handle  
 
CELLECTRA® Array Lot No:  
Located on label on the package 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time of Electroporation (EP): 
_________ 
Location of Treatment/EP: ☐ Deltoid Right/Left __________ 
☐ Other Location, specify:_______________ 
IM-5P, was the EP Guide used? ☐ YES ☐ NO 
If EP Guide was used, please provide reason and include patient’s BMI. 
 
Was injection successful?  
☐ YES  
 
 ☐ NO 
If NO, please provide reason and include needle gauge and syringe volume used. 
 
Did the display on the device read Electroporation successful? ☐ YES 
 
 
 ☐ NO 
If NO, please check all complications that led to failure and describe complication below 
☐ Impedance Test Error message displayed, fill out Impedance Test Error section below 
☐ Electroporation Error message displayed, fill out Electroporation Error section below 
☐ EP aborted by trigger or keypad error message displayed 
☐ Battery level too low for EP message displayed 
☐ Difficulty inserting array into muscle or skin 
☐ Other, please specify below 
 
Describe device complication below (continue on back if necessary): 
 
 
 
 
Total # of arrays used: _____________ 
 
Impedance Test Error 
 
Was the array inserted in patient’s arm? 
☐ YES 
 ☐ NO 
Total # of attempts: __________ 
Were all attempts performed on the same day?  
☐ YES 
 ☐ NO  
(provide other date(s):___________) 
Was a different location used for each attempt? 
☐ YES  
 ☐ NO 
Was a new array used for each attempt? 
☐ YES  
 ☐ NO 
Please provide any additional information below (continue on back if necessary): 
 
 
 
 
Electroporation Error 
 
Were there 3 (IM) or 4 (ID) involuntary muscle contractions? 
 ☐ YES 
 ☐ NO (how many__________ 
Was the array fully inserted in the patient’s arm? 
 ☐ YES 
 ☐ NO 
Was the array inserted perpendicular to the patient’s skin? 
 ☐ YES 
 ☐ NO 
Did the needles of the array appear damaged in any way?  
 ☐ YES 
 ☐ NO 
If you were provided a sharps shuttle, please eject the array into a shuttle and ship to Inovio. 
Please provide any additional information below (continue on back if necessary): 
PPD
PPD


Clinical Study Protocol Appendix F 
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Appendix F 
Guidelines for Evaluation of Objective Tumor Response 
using RECIST version 1.1 Criteria (Response Evaluation 
Criteria in Solid Tumors) 
DEFINITION OF MEASURABLE, NON-MEASURABLE, TARGET AND NON-
TARGET LESIONS 
Only patients with measurable disease at baseline should be included in the study.  
Measurable disease is defined by the presence of at least one measurable lesion (by RECIST 
version 1.1) lesion which has not been previously irradiated.  A tumor lesion in a previously 
irradiated field can be assessed as measurable disease provided the lesion has been deemed to 
demonstrate progression. 
Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter [LD] to be recorded) as ≥ 20 mm with conventional techniques 
(computed tomography [CT], magnetic resonance imaging [MRI], x-ray) or as ≥ 10 mm with 
spiral CT scan.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
Non-measurable lesions 
All other lesions (or sites of disease), including small lesions (LD < 20 mm with conventional 
techniques or < 10 mm using spiral CT scan), are considered non-measurable disease.  Bone 
lesions, leptomeningeal disease, ascites, pleural / pericardial effusion, inflammatory breast 
disease, lymphangitis cutis / pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI) and cystic lesions are all non-measurable. 
Target lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 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 LD) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the LD for all target lesions will be calculated and 
reported as the baseline sum LD.  The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Non-target lesions include measurable lesions that exceed the 
maximum number per organ or total of all involved organs as well as non-measurable lesions.  
Measurements of these lesions are not required but the presence or absence of each should be 
noted throughout follow-up.  


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Guidelines for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
Note: Tumor lesions that are situated in a previously irradiate area might or might not be 
considered measurable.  Lesions progressing after previous irradiation are measurable; lesions 
not progressing after previous irradiation are not measurable. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the anti-tumor effect of treatment. 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI  These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and 
neck tumors and those of extremities usually required specific protocols.  
Positron Emission Tomography (PET)-CT  At present, the low dose or attenuation correction 
CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with intravenous and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which may 
bias an Investigator if it is not routinely or serially performed.   
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 


Clinical Study Protocol Appendix F 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
151 (159) 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostrate-specific antigen response (in recurrent prostate cancer) have 
been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and CR in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or SD is mandatory 
to differentiate between response or SD (an effusion may be a side effect of the treatment) and 
progressive disease (PD). 
Fludeoxyglucose (FDG)-PET  While FDG-PET response assessments need additional study, it 
is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease).  New lesions on 
the basis of FDG-PET imaging can be identified according to the following algorithm:  
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution / sensitivity. 


Clinical Study Protocol Appendix F 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
152 (159) 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
Response Criteria 
Evaluation of target lesions 
CR: 
Disappearance of all target lesions 
PR: 
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD 
PD: 
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions 
SD: 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
Evaluation of non-target lesions 
CR: 
Disappearance of all non-target lesions and normalization of tumor 
marker level 
Incomplete Response 
/ SD:  
Persistence of one or more non-target lesion(s) or / and maintenance 
of tumor marker level above the normal limits 
PD: 
Appearance of one or more new lesions and / or unequivocal 
progression of existing non-target lesions  
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
Note: If tumor markers are obtained and are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 


Clinical Study Protocol Appendix F 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
153 (159) 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression / recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response / 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note: Patients 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 CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate / biopsy) to confirm the CR status. 
Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed.  In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met.  Longer intervals as determined by the study protocol may also be 
appropriate.  


Clinical Study Protocol Appendix F 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
154 (159) 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol  
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever status is recorded first) until the first date that recurrence or PD is 
objectively documented, taking as reference for PD the smallest measurements recorded since 
the treatment started. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
The clinical relevance of the duration of SD varies for different tumor types and grades.  
Therefore, it is highly recommended that the protocol specify the minimal time interval 
required between two measurements for determination of SD.  This time interval should take 
into account the expected clinical benefit that such a status may bring to the population under 
study.  
Response review 
For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach.  
Reporting of results 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one 
of the following categories: 1) CR, 2) PR, 3) SD, 4) PD, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data). 
All of the patients who met the eligibility criteria should be included in the main analysis of 
the response rate.  Patients in response categories 4-9 should be considered as failing to 
respond to treatment (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific. 
All conclusions should be based on all eligible patients. 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 


Clinical Study Protocol Appendix F 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
155 (159) 
early discontinuation of treatment, major protocol violations, etc).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, 
and the reasons for excluding patients from the analysis should be clearly reported.   
The 95% confidence intervals should be provided. 


Clinical Study Protocol Appendix G 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
156 (159) 
Appendix G 
Guidelines for Evaluation of Progression Free Survival using 
Immune-related RECIST Criteria  
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH and Hodi FS.  Developing 
a Common Language for Tumor Response to Immunotherapy: Immune-Related Response 
Criteria Using Unidimensional Measurements.  Clin Cancer Res; 19(14) July 15, 2013 
For the immune-response response criteria (irRC), only index and measurable new lesions are 
taken into account (in contrast to conventional World Health Organization [WHO] criteria, 
which do not require the measurement of new lesions, nor do they include new lesion 
measurements in the characterization of evolving tumor burden).  
The longest diameter of each target lesion will be recorded.  Measurable lesions will be 
defined as ≥ 10 mm in the longest diameter as in RECIST as opposed to ≥5 x 5 mm2 in WHO / 
irRC.   
For unidimensional measurements, the cut-off values by RECIST (≥ 20% increase from the 
nadir for progression, ≥ 30% decrease from baseline for partial response, and disappearance of 
lesions for complete remission) will be used. 
 


Clinical Study Protocol Appendix H 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
157 (159) 
Appendix H 
Durvalumab Dose Modification for Toxicity Management  
Guidelines for the management of immune-mediated reactions, infusion-related reactions, and 
non-immune-mediated reactions for durvalumab monotherapy are provided in the Dosing 
Modification and Toxicity Management Guidelines. The most current version of these 
guidelines is an annex to this protocol and is also maintained within the Site Master File.  
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the immune-mediated AE. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an immune-mediated AE diagnosis. In the absence of a clear alternative etiology, 
events should be considered potentially immune related. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 6.12.1 of this protocol and the Dosing Modification and Toxicity 
Management Guidelines). 
Following the first dose of durvalumab subsequent administration of durvalumab can be 
modified based on toxicities observed as described in the Dosing Modification and Toxicity 
Management Guidelines. These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. 
These guidelines apply to AEs considered causally related to durvalumab monotherapy 
regimen by the reporting Investigator. 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician.


Clinical Study Protocol Appendix I 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
158 (159) 
Appendix I 
Administration Site Reaction Grading and Management   
 
Grading:  
• Grading should be done using two systems: Common Terminology Criteria for 
Adverse Events version 4.03 (which should be used for all dose delay / withdrawal 
decisions) and the system outlined below.  
• Table: Administration Site Reaction Grading Scale (adapted from “FDA Guidance for 
Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials”).  
 
Local Reaction to  
Injectable Product  
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Potentially 
Life  
Threatening  
(Grade 4)  
Pain  
Does not interfere  
with activity  
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity  
Any use of narcotic 
pain reliever or 
prevents daily  
activity  
Emergency 
room visit or  
hospitalization  
Tenderness  
Mild discomfort 
to touch  
Discomfort with 
movement  
Significant 
discomfort at rest  
Emergency 
room visit or 
hospitalization  
Erythema / Redness *  2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or 
exfoliative 
dermatitis  
Induration / 
Swelling**  
2.5 – 5 cm and 
does not interfere 
with activity  
5.1 – 10 cm or 
interferes with activity  
> 10 cm or prevents 
daily activity  
Necrosis  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration / Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement


Clinical Study Protocol Appendix I 
Drug Substance MEDI0457+Durvalumab  
Study Code D8860C00005 
Version 8.0 
Date 17 March 2021 
 
159 (159) 
 
Management: 
Grade from Table  
Dose Modification  
Management 
Any Grade  
For any grade:  
Per guidance below  
For any grade:  
• 
Manage per institutional standard at the discretion 
of investigator.  
• 
Monitor patients for signs and symptoms of 
administration site reactions.  
• 
Educate patients on infection control.  
Grade 1 
For Grade 1:  
No changes in dose or schedule are recommended  
For Grade 1:  
• 
Consider symptomatic treatment with over-the-
counter analgesics and supportive care (i.e., cold 
compress)  
Grade 2 
For Grade 2:  
If persistent injection site reaction lasting more than 10 days despite 
optimal management, MEDI0457 next dose of vaccine should be omitted.  
Durvalumab to continue dependent on discussion of Investigator with 
medial monitor.  
For second occurrence of Grade 2:  
In the setting of second occurrence of persistent ≥ Grade 2 injection site 
reaction for more than 7 days despite optimal medical management, 
permanently discontinue MEDI0457 and durvalumab.  
• 
Symptomatic treatment with over-the-counter 
analgesics (opioids should be avoided unless 
necessary) and supportive care (i.e. cold compress)   
• 
If pain persists for 3 days, contact Investigator  
Grade 3 or Grade 4 
For Grade 3:  
Injection should be held until the toxicity resolves to Grade 1 or baseline.  
• 
If resolution occurs within 5 days, consider continued dosing of 
MEDI0457 and durvalumab at the current schedule as long as 
the adverse event of concern was not considered life-threatening.  
• 
If the Grade 3 injection site toxicity only improves to Grade 2 
within 5 days then omit next dose of MEDI0147 and continue 
durvalumab dependent on discussion of Investigator with 
Medical Monitor. 
• 
If no change of Grade 3 reaction within 5 days, then permanently 
discontinue MEDI0457 and durvalumab.  
For Grade 4:  
Permanently discontinue MEDI0457 and durvalumab. 
For Grade 3 or Grade 4:  
• 
Consult Investigator for evaluation (rule out 
infection or other causes) and treatment (opioids 
may be considered)  
• 
Obtain dermatology / surgical consult 
• 
 Consider hospitalization  

SAP_003.pdf: 
Sponsor: MedImmune 
Statistical Analysis Plan v4.0
Protocol No: D8860C00005
Version Date: 21-Jun-2021
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Statistical Analysis Plan
Sponsor:
MedImmune, LLC/Ltd, a wholly owned subsidiary of AstraZeneca PLC
Protocol No:
D8860C00005
Version No. / Date:
8.0 / 17-Mar-2021
Title:
A Phase 1b/2a, Multi-Center Open-Label Study to Evaluate the Safety and
Efficacy of Combination Treatment with MEDI0457 (INO-3112) and
Durvalumab (MEDI4736) in Patients with Recurrent/Metastatic Human
Papilloma Virus Associated Head and Neck Squamous Cancer
CRF Version No. /
Date:
9.0 / 25-Sep-2020
PRA Project ID:
SAP Version No. /
Date:
4.0 / 21-Jun-2021


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Table of Contents
Approvals.................................................................................................................................................................................... 2
Table of Contents..................................................................................................................................................................... 3
1.0 Introduction ....................................................................................................................................................................... 5
1.1 Changes from Protocol.............................................................................................................................................. 5
2.0 Study Objectives ............................................................................................................................................................... 6
2.1 Primary Objectives ..................................................................................................................................................... 6
2.2 Secondary Objectives................................................................................................................................................. 6
3.0 Study Design....................................................................................................................................................................... 7
3.1 Overview......................................................................................................................................................................... 7
3.3 Randomization............................................................................................................................................................. 8
3.4 Screening Procedures................................................................................................................................................ 9
3.6 Administration Procedures...................................................................................................................................11
3.7 Follow-up Visit Procedures...................................................................................................................................13
4.0 Study Variables and Covariates................................................................................................................................14
4.1 Primary Variables .....................................................................................................................................................14
4.1.1 Safety......................................................................................................................................................................14
4.1.2 Efficacy..................................................................................................................................................................18
4.2 Secondary Variables.................................................................................................................................................20
4.2.1 Pharmacokinetics and Antidrug Antibodies..........................................................................................20
4.2.2 Efficacy..................................................................................................................................................................21
4.3 Other Variables...........................................................................................................................................................25
5.0 Definitions.........................................................................................................................................................................26
6.0 Analysis Sets.....................................................................................................................................................................31
6.1 As-treated Population .............................................................................................................................................31
6.2 DLT-Evaluable Population.....................................................................................................................................31
6.3 Response-Evaluable Population..........................................................................................................................31
6.4 Pharmacokinetics Population..............................................................................................................................31
6.5 Antidrug Antibodies Evaluable Population....................................................................................................31
7.0 Interim Analyses.............................................................................................................................................................32
7.1 Safety Data Monitoring Committee....................................................................................................................32
8.0 Data Review......................................................................................................................................................................33
8.1 Data Handling and Transfer..................................................................................................................................33
8.2 Data Screening............................................................................................................................................................33
9.0 Statistical Methods ........................................................................................................................................................34
9.1 Subject Disposition...................................................................................................................................................34
9.2 Protocol Deviations..................................................................................................................................................35
9.3 Treatments...................................................................................................................................................................35
9.3.1 Extent of Study Drug Exposure...................................................................................................................35
9.3.2 Concomitant Medications and Procedures ............................................................................................35


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9.3.3 Subsequent Anticancer Treatment............................................................................................................35
9.4 Demographic and Baseline Characteristics....................................................................................................35
9.5 Efficacy Analyses.......................................................................................................................................................36
9.5.1 Primary Efficacy Analysis..............................................................................................................................36
9.5.2 Secondary Efficacy Analyses........................................................................................................................36
9.5.3 Subgroup Efficacy Analyses..........................................................................................................................37
9.6 Safety Analyses...........................................................................................................................................................37
9.6.1 Adverse Events ..................................................................................................................................................37
9.6.2 Deaths and Serious Adverse Events..........................................................................................................38
9.6.3 Laboratory Data and other Observations Related to Safety ...........................................................38
9.7 Pharmacokinetics and Antidrug Antibodies..................................................................................................39
9.7.1 Pharmacokinetic Analysis.............................................................................................................................39
9.7.2 Immunogenicity Analysis..............................................................................................................................39
9.8 Exploratory Analyses...............................................................................................................................................39
9.9 Methods for Handling Dropouts and Missing Data.....................................................................................39
9.10 Multiplicity................................................................................................................................................................39
9.11 Pooling of Sites.........................................................................................................................................................39
10.0 Validation........................................................................................................................................................................40
References................................................................................................................................................................................40
Appendix 1 Glossary of Abbreviations .........................................................................................................................41




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2.0 Study Objectives
2.1 Primary Objectives 
Primary Objectives:
Outcome Measures:
To determine the safety profile of MEDI0457 in 
combination with durvalumab in patients with 
recurrent/metastatic head and neck cancer. 
x
Adverse events (AEs)/serious adverse events 
(SAEs)
x
Collection of hematology, serum chemistry, 
urinalysis, creatinine phosphokinase (CPK), 
thyroid function testing and pregnancy test
x
Electrocardiograms (ECGs). The following 
parameters will be recorded for each ECG: date 
and time of ECG, heart rate (HR) (beats/min), PR 
interval (ms), QRS interval (ms), RR interval 
(ms), QT interval (ms), QTcB interval (ms), QTcF 
interval (ms), sinus rhythm (yes/no), and overall 
evaluation (normal/abnormal)
x
Vital signs 
x
Physical examinations
x
Concomitant medications
x
World Health Organization (WHO)/Eastern 
Cooperative Oncology Group (ECOG)
performance status
To evaluate the anti-tumor activity of 
MEDI0457 in combination with durvalumab in 
patients with confirmed human papilloma virus 
(HPV) HPV-16 or HPV-18 associated 
recurrent/metastatic head and neck cancer
Objective response rate by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 
(Response-evaluable Population)
2.2 Secondary Objectives
Secondary Objectives:
Outcome Measures:
To evaluate the pharmacokinetics and 
anti-drug antibodies (ADAs) for durvalumab.
x
Serum concentrations of durvalumab
x
Anti-drug antibodies for durvalumab
To evaluate the anti-tumor activity of 
MEDI0457 in combination with durvalumab.
x
Objective response rate by RECIST version 1.1 
(As-treated Population) and immune-related 
RECIST (irRECIST)
x
Disease control rate (DCR) at 16 weeks by 
RECIST version 1.1
x
Overall survival (OS)
x
Progression free survival (PFS) as assessed by 
RECIST version 1.1 






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3.4 Screening Procedures
a
Magnetic resonance imaging scan of the brain will be performed at screening and also at each assessment if there are abnormalities at 
baseline. 
b
Vital signs at the screening visit include temperature, respiratory rate, pulse oximetry, blood pressure, HR, weight and height.
c
12-lead ECGs will be performed in triplicate (all three ECG assessments within a 5 minute time period)
d
Samples will be analyzed at local laboratories.
e
Historical tissue samples may be used; there is no need for additional samples / test for histological HPV assessment (p16) to be 
collected just for this protocol.
f
Free triiodothyronine (T3) and free thyroxine (T4) will only be measured if thyroid stimulating hormone (TSH) is abnormal.  They should 
also be measured if there is clinical suspicion of an AE related to the endocrine system. 
g
Serum pregnancy test will be performed for women of childbearing potential.
h
Hepatitis B and C testing is mandatory, while HIV serology is only required if clinically indicated.
i
Only for women of child bearing potential who may be post-menopausal. 
j
Samples will be analyzed at central laboratories.
k
At least three core samples are required if samples are collected are via a core needle of 18 gauge or larger or are collected as an excisional 
tumor biopsy sample.  When a smaller gauge needle is used, the number of required cores rises to four.  Note: a new baseline biopsy is 
required for all patients.  All patients should consent to pre-treatment biopsy of tumor if it can be done safely (as judged by the 
Investigator) during screening, otherwise archival tissue up to 3 years to study entry in all patients will be allowed except for a minimum 
10 of the first 20 patients who will be required to provide a paired biopsy (a fresh biopsy at screening and at Week 10).
Abbreviations:
AE=adverse event; APTT=activated partial thromboplastin time; CPK=creatine phosphokinase; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; ELISPOT=enzyme-linked immunospot; HIV=human immunodeficiency virus; HPV=human papilloma virus; 
IHC=KOOWPQJKUVQEJGOKUVT[ +04International Normalized Ratio; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating 
hormone; WHO=World Health Organization


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e
Electrocardiograms are to be collected in triplicate (all three ECG assessments within a 5 minute time period) within 
30 minutes before dosing of MEDI0457 and 30-60 minutes after dosing at Weeks 1, 3, 7 and 12 and thereafter single ECGs 
at pre-dose at subsequent dosing visits.  Triplicate (all three ECG assessments within a 5 minute time period) ECGs will be 
performed within 30 minutes before dosing of MEDI4736 at Week 4 and 30-60 minutes after dosing of MEDI4736 at 
Weeks 4 and 12.  An ECG assessment can also be performed if clinically indicated and according to the Investigator.
f
Free T3 and free T4 will only be measured if TSH is abnormal.  They should also be measured if there is clinical suspicion 
of an AE related to the endocrine system.
 
 
MEDI0457 post-treatment reactions will be assessed 30 to 60 minutes after study treatment and at post-treatment visits.
j
Core tumor biopsies will be collected.  At least three core samples are required if samples are collected are via a core 
needle of 18 gauge or larger or are collected as an excisional tumor biopsy sample.  When a smaller gauge needle is used, 
the number of required cores rises to four.  Either fresh tissue or formalin-fixed paraffin-embedded samples may be used.  
Archival tissue within 3 years prior to study entry in all patients will be allowed except for a minimum 10 of the first 
20 patients who will be required to provide a paired biopsy (a fresh biopsy at screening and at Week 10).  After 10 paired 
biopsies have been obtained then Week 10 on-treatment biopsy will be made optional but will be encouraged.  
k
Serum chemistry and hematology will be performed on Day 1, Week 7, Week 8 and Week 12, then every 4 weeks for the 
first 12 months and every 3 months thereafter until study discharge.  Thyroid function testing will be performed on Day 1, 
Week 4, Week 8 and Week 12, then every 4 weeks for the first 12 months and every 3 months thereafter until study 
discharge.  Thyroid function testing will be performed on Day 1, Week 4, Week 8 and Week 12, then every 4 weeks for the 
first 12 months and every 3 months thereafter until study discharge. Urinalysis will only be performed if clinically 
indicated.
l
After scan and durvalumab administration are completed in Week 8.  Disease status assessments should continue to be 
performed at every 8 weeks ± 5 days for 1 year if CR / PR / SD are achieved and then every 12 weeks ± 7 days until end of 
treatment (EOT). 
m
Additional baseline blood samples will be also collected in a 10 mL red top tube in order to have serum samples collected 
at baseline for future analysis which includes but is not limited to an autoimmune work-up (refer to the Laboratory Manual 
for the processing of this sample).
n
If physical examination, ECOG, weight or safety laboratory tests (hematology, chemistry, creatine phosphokinase, thyroid 
function testing and pregnancy tests) are performed within 3 days prior to Day 1, they do not need to be repeated.  Patients 
with a negative serum pregnancy test within 3 days prior to Day 1, do not require a Week 1 Day 1 pregnancy test to be 
performed.
o.
All visit windows will be ±3 days with the following exceptions: tumor biopsy assessments will have the visit window of ±7 
days; disease status assessments every 8 weeks (r 5 days) (relative to the date of the first MEDI0457 administration) for 1 
year.  After the first year on treatment, if CR / PR / SD are achieved then disease status assessments can be performed every 
12 weeks (r 7 days) until the EOT.  Disease status assessments will be performed once at the end of treatment if PD is 
observed, otherwise at end of treatment and then at Day 90 ± 7 days, every 3 months after Day 90 up to Month 12 ± 7 days 
then every 6 months after Month 12 ± 14 days until the death of the patient, withdrawal of consent or loss to follow-up.  
Abbreviations:
ADA=anti-drug antibody; AZ=AstraZeneca; CR=complete response; CT=computed tomography; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; ELISPOT=enzyme-linked immunospot; EP=electroporation; EOT=end of
treatment; HPV=human papilloma virus; IHC=immunohistochemistry; MRI=magnetic resonance imaging; 
PD=progressive disease; PR=partial response; SD=stable disease; T3=triiodothyronine; T4=thyroxine; TSH=thyroid 
stimulating hormone; WHO=World Health Organization 


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4.0 Study Variables and Covariates
4.1 Primary Variables
4.1.1 Safety 
4.1.1.1 Adverse Events
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. Medical condition/diseases present before starting the 
investigational drug will be considered AEs only if they worsen after starting study treatment. Please refer 
to the Protocol Section 6.1 for further definition of AEs. 
The following variables will be collected for each AE:
x
Adverse event (verbatim)
x
The date and time when the AE started and stopped
x
Each CTCAE grade for a repeated AE
x
Whether the AE is serious or not
x
Investigator causality rating against the investigational product (IP) (yes or no)
x
Action taken with regard to each IP
x
Administration of treatment for the AE
x
Outcome
x
Whether AE is of special interest, and if yes, which category per the AE CRF page 
x
Whether the AE is a DLT
x
Whether AE occurred before, during, or after dosing if occurred on same day of dosing 
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all events with an 
assigned CTCAE grading. For those events without assigned CTCAE grades, the recommendation in the 
CTCAE criteria that converts mild, moderate, and severe events into CTCAE grades should be used. 
Adverse events and SAEs will be collected from time of signature of informed consent, through 90 days 
after the last dose of the study treatment. Note: AEs/SAEs that occur post-signature but prior to IP 
administration are non-treatment-emergent AEs (non-TEAEs)/SAEs. AE’s for screen failure patients will 
not be recorded in the CRF unless they result from the screening biopsy procedure. 
4.1.1.2 Serious Adverse Events 
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes: death, a life-threatening AE, inpatient hospitalization 
or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered serious when 
based upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Please refer to the 
Protocol Section 6.2 for further definition of SAEs. 
The following variables, in addition to those mentioned above for AE, will be collected for SAEs:
x
Date AE met criteria for serious AE
x
Date Investigator became aware of serious AE
x
Seriousness criteria fulfilled
x
Date of hospitalization


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x
Date of discharge
x
Probable cause of death
x
Date of death
x
Whether an autopsy was performed
x
Causality assessment in relation to study procedure(s) and other medication(s)
x
Description of AE
4.1.1.3 Adverse Events of Special Interest
Adverse events of special interest (AESI) are those categorized on the CRF as AESI. These include the 
categories of diarrhea, colitis, pneumonitis, ALT/AST increases/hepatitis/hepatotoxicity, 
neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis/rash/pruritus, nephritis, pancreatitis,
myocarditis/pericarditis, uveitis, infusion-related reactions/hypersensitivity/analphylactic reactions, and 
administration site reactions. The same variables are collected for AESI as for other AEs.
4.1.1.4 Clinical Laboratory Tests
Local laboratory values will be graded according to CTCAE v4.03 criteria via PRA programming in Study 
Data Tabulation Model (SDTM) datasets. Please refer to the SDTM data specifications for lab grading 
criteria. 
Blood samples will be collected for hematology, serum chemistry, luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) (for select patients), CPK, thyroid function testing (if thyroid stimulating hormone 
(TSH) is abnormal then free triiodothyronine (T3) and free thyroxine (T4) will be required to be measured, if 
TSH is normal then free T3 and free T4 are not required to measured), coagulation tests (activated partial 
thromboplastin time [APTT] and either International Normalized Ratio [INR] or prothrombin time), hepatitis 
B and hepatitis C testing. Testing for HIV is only required if clinically indicated and is not mandatory for this 
study. A serum pregnancy test will be performed for women of childbearing potential at the screening visit
and a urine pregnancy test is required to be performed during the treatment period according to the 
administration procedures chart. The following laboratory variables will be measured for hematology, serum 
chemistry and urinalysis:
Hematology (whole blood)
Hemoglobin
White blood cell count
Absolute eosinophil count
Absolute lymphocyte count
Absolute neutrophil count
Platelet count


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a
Tests for ALT, AST, ALP and TBL must be conducted and assessed concurrently. ,I 7%/ LV  2 × ULN (and evidence of Gilbert’s 
syndrome) then fractionate into direct and indirect bilirubin.
b
It is preferable that both amylase and lipase parameters are assessed. For sites where only one of these parameters is routinely 
measured then either lipase or amylase is acceptable.
c
Bicarbonate (where available), chloride, gamma glutamyltransferase, magnesium, testing are to be performed at screening, on 
Day 0, and if clinically indicated.
Abbreviations:
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; 
TBL=total bilirubin; ULN=upper limit of normal
Urinalysis (dipstick)
Bilirubin
pH
Blood
Protein
Glucose
Specific gravity
Ketones
Color and appearance
4.1.1.5 Pregnancy Testing
For women of reproductive potential, a negative result for serum pregnancy test must be available at the 
screening visit and a urine beta-human chorionic gonadotropin (ȕ-HCG) pregnancy test is required to be 
performed during the treatment period at the frequency shown in the administration procedures table.  If at 
DQ\ SRLQW WKH ȕ-HCG (pregnancy) test is positive, indicating that the patient is pregnant, no additional IP 
will be administered, but the patient will be followed for the duration of the study and beyond to determine 
the outcome of the pregnancy (with the patient’s consent).
4.1.1.6 Electrocardiograms
An ECG will be performed at screening within 28 days of Day 0 for all patients to determine patient eligibility. 
Electrocardiograms are to be collected in triplicate (all three ECG assessments within a 5 minute time 
period) within 30 minutes before dosing of MEDI0457 and 30-60 minutes after dosing at Weeks 1, 3, 7 and 
12 and thereafter single ECGs at pre-dose at subsequent dosing visits. Triplicate (all three ECG 
assessments within a 5 minute time period) ECGs will be performed within 30 minutes before dosing of 
MEDI4736 at Week 4 and 30-60 minutes after dosing of MEDI4736 at Weeks 4 and 12.  An ECG 
assessment can also be performed if clinically indicated and according to the Investigator.
The following parameters will be recorded for each ECG: date and time of ECG, HR (beats/min), PR interval 
(ms), RR interval (ms), QRS interval (ms), QT interval (ms), QTcF interval (for Fridericia’s) (ms), QTcB 
interval (ms), sinus rhythm (yes/no), and overall evaluation (normal/abnormal).
Abnormal ECGs should be interpreted as clinically significant or not clinically significant.
Clinical Chemistry (serum)
Albumin
Glucose
ALP
Lactate dehydrogenase
ALTa
Lipaseb
AST
Magnesiumc
Amylaseb
Potassium
Bicarbonatec
Sodium
Calcium
Total bilirubin (TBL)a
Chloridec
Total protein
CPK
Urea or blood urea nitrogen, depending on local practice
Creatinine
Gamma glutamyltransferase


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4.1.1.7 Vital Signs, Height and Weight
Vital signs including temperature (C), respiration rate (respirations/minute), pulse oximetry (percentage), 
blood pressure (mmHg), pulse rate (beats/min) and weight(kg) will be measured according to the visits 
schedule in the administration procedures table. Height (cm) will be collected at the screening visit only. 
4.1.1.8 Physical Examinations
A complete physical examination will be performed and include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities) and neurological systems 
at screening and follow-up visits. A targeted physical examination to document changes in any medical 
condition since the last visit will be performed at all other visits.
The Investigator will assess local and systemic reactions post-treatment (within 30-60 minutes after study 
treatment) and at post-treatment visits.  Any reported local post-treatment reactions and systemic post-
treatment reactions will be graded per NCI CTCAE version 4.03 and all must be recorded on the CRFs.
4.1.1.9 Concomitant Medications and Procedures
Patients will be questioned by the Investigator regarding the occurrence of any concomitant medications 
during their clinic visits. The medication name, indication, reason, dose, dose unit, dose frequency, route 
of administration, start and end dates or whether ongoing will be collected on the CRF. Concomitant 
medications will be coded to the generic term using the current version of the World Health Organization 
Drug Dictionary.
Concomitant procedures will also be collected. The procedure name, indication, reason, start and end date 
or whether ongoing will be collected on the CRF. Concomitant procedures will not be coded using a 
dictionary. 
4.1.1.10 Performance Status 
A WHO / ECOG performance status will be conducted at screening, during IP administration and at 
follow-up.  A WHO / ECOG performance status will be performed at other visits as determined by 
Investigator or directed per patient complaints.
WHO/ECOG performance status (Oken et al 1982) will be assessed based on the following:
0=Fully active; able to carry out all pre-disease performance without restrictions.
1=Restricted in physically strenuous activity but ambulatory and able to carry out light work or work of a sedentary 
nature, e.g., light housework, office work.
2=Ambulatory and capable of self-care but unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4=Completely disabled. Unable to carry out any self-care and totally confined to bed or chair.
5=Dead












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4.2.2.3 Disease Control 
Disease control at 8, 16, and 24 weeks will be classified as values of CR, PR, and SD (SD maintained for 
 8, 16, and 24 weeks, respectively) as recorded on the disease response CRF page according to RECIST 
v1.1. 
4.2.2.4 Overall Survival
Overall survival is defined as the time from the date of start of IP treatment until death (+1 day) due to any 
cause. Any patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive. Date of death will be collected on the Statement 
of Death CRF page. Date last known alive is defined as the latest among the following dates recorded on 
the case report forms (CRFs):
• AE start and stop dates
• Admission and discharge dates of hospitalization
• Study treatment date
• Last dose date
• Laboratory test dates
• Date of vital signs, ECOG, concomitant medications, or sample collection dates
• Dates of evaluations for target, non-target, or new lesions
• Start and stop dates of alternative anticancer treatment
• Date last known alive on survival status CRF
• End of study disposition event date
4.2.2.5 Progression Free Survival
Progression free survival measures progression by growth of the primary tumor, nodal spread metastases, 
death from the cancer, or death from other causes. Progression free survival will be assessed by the 
periodic tumor assessment using imaging per the institutional guidelines at the schedules according to SAP 
section 3.6. All study evaluations for disease response must be based on RECIST version 1.1.
Progression free survival will be defined as the time from the date of start of IP treatment until the 
documentation of disease progression according to RECIST version 1.1 or death due to any cause, 
whichever occurs first (+1 day). Patients who have not progressed or died at the time of the analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST version 1.1 
assessment. However, if the patient progresses or dies after two or more missed visits, the patient will be 
censored at the time of the latest evaluable RECIST version 1.1 assessment prior to two missed visits.
The PFS time will always be derived based on scan/assessment/death dates and not visit dates.
RECIST version 1.1 assessment/scans contributing towards a particular visit may be performed on different 
dates. The following rules will be applied:
x
For investigator assessments, the date of progression will be determined based on the earliest of 
the RECIST version 1.1 assessment/scan dates of the component that indicates progression.
x
When censoring a patient for PFS, the patient will be censored at the latest of the dates contributing 
to a particular overall visit assessment.
PRA will not programmatically derive values of PD via RECIST v1.1. Rather, PD will be collected in a CRF-
derived field on the Disease Response page per sponsor standards. PD is defined as a value of 


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“Progressive Disease (PD)” in the field “Derived RECIST disease response”. The analysis of PFS does not 
require confirmation of progression. 
The date of PD will be the first date at which any objective diagnostic test provides data indicating PD. 
Specifically, the date of PD will be the earliest of the following 3 dates:
x
Date of PD as indicated by target lesions: If PD is triggered by a change in sum of diameters of 
target lesions, and the dates of evaluation of the target lesions vary for the same assessment, 
assign the first evaluation date among target lesions.
x
Date of PD as indicated by non-target lesions: If the dates of evaluation of the non-target lesions 
vary for the same assessment, assign the first evaluation date for which any non-target lesion 
exhibits a status of Unequivocal Progression.
x
Date of PD as indicated by new lesions: If multiple new lesions are identified and the dates of 
evaluation for the new lesions vary for the same assessment, assign the first evaluation date for 
which any new lesion is detected.
The following table includes the censoring and event rules that will be used for progression free survival:
Situation
Date of Progression or Censoring
Outcome*
Documented progression or death 
Date of PD or death, whichever comes 
first 
Event (unless 
the censoring 
rule specified 
below)
No PD or death at time of analysis or 
lost to follow-up
Date of last evaluable progression-free 
disease assessment
Censored
'HDWK RU 3' LPPHGLDWHO\ DIWHU  
consecutive missed or non-evaluable 
disease assessments
Date of the first dose of treatment or last 
evaluable progression-free disease 
assessment prior to missed or non-
evaluable assessments, whichever 
occurred last
Censored
No disease assessment at baseline
and no evidence of PD at first post-
baseline disease assessment
or 
No disease assessment post-baseline 
without death prior to second 
scheduled post-baseline disease 
assessment
Date of the first dose of treatment
Censored
New systemic anticancer treatment 
started without documented PD
Date of last evaluable progression-free 
disease assessment prior to start of new 
anticancer treatment 
Censored
Outcomes of deaths and progressions will be considered events for progression free survival. If a subject 
has two or more consecutive missed or non-evaluable assessments followed by an assessment showing 
no radiologic disease progression, then the assumption will be that the subject did not progress during the 
missed or non-evaluable assessments. Two or more consecutive assessments is defined as > 122 days


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within the first year or >182 days after the first year (two disease assessments including the + 5 or 7-day 
window as per protocol to allow for a late assessment) after the last evaluable post-baseline disease 
assessment.
4.2.2.6 Time to Response 
Time to response (TTR) is defined as the time from the first dose of IP until the first documentation of a 
subsequently confirmed objective response. Only subjects who have achieved confirmed objective 
response (CR or PR) will be evaluated for TTR. 
4.2.2.7 Duration of Response 
Duration of response (DOR) is defined as the time from the first documentation of objective response (CR 
or PR) until the first documentation of disease progression according to RECIST v1.1 or death due to any 
cause, whichever occurs first. Only subjects who have achieved confirmed objective response (CR or PR) 
will be evaluated for DOR. 
The date of PD/death or censoring should coincide with the date of progression or death from any cause 
used for the PFS endpoint. 
4.3 Other Variables 
Other variables will be collected for patient medical history, smoking history, alcohol use, tumor history and 
current status, prior anticancer treatments (cancer related surgery, radiation, systemic therapy or other), 
brain metastasis status at study entry and method of evaluation, pneumonitis questionnaire, pulmonary 
function tests, blood gases, serum interstitial lung disease (ILD) markers, bleeding event questionnaire, 
whether tumor biopsy collected, and subsequent anticancer treatments (cancer related surgery, radiation, 
systemic therapy or other). Medical history will be coded using MedDRA. 
If an AE is selected as Pneumonitis on the AE CRF, then the Pneumonitis Questionnaire CRF will be 
triggered to be completed. Blood Gases, Pulmonary Function Tests, and Serum ILD Markers CRF pages 
are triggered by responses on the Pneumonitis Questionnaire. These pages will be completed as required
and completed to the extent the information is available. 


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5.0 Definitions
Variable
Definition
Age
Date of birth is not collected. Age in years is recorded on the 
Demographics CRF page. 
Any ADA positive 
A subject is defined as Any ADA Positive if there are antidrug antibodies at 
any visit 
Any IP
At least one dose of either study drug 
Baseline
Baseline is defined as the last assessment prior to the first dose of either 
study drug.
Change from baseline
(for safety data)
Change from baseline will be defined as the maximum post-baseline value 
minus the baseline value where applicable (on a subject level). Change 
from baseline will only be calculated for subjects who have both baseline 
and at least one post-baseline value for any parameter. Note: Change 
from baseline for tumor assessments is defined below.


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Change from baseline 
(for tumor assessments)
Change from baseline (%) will be calculated for each disease assessment 
using RECIST v1.1 target lesion measurements. 
% change from baseline= (target lesion sum at postbaseline – target lesion 
sum at baseline)/(target lesion sum at baseline)]*100 
If at any time point one or more target lesions have an intervention or are 
not evaluable, then the tumor size change cannot be calculated at that 
time point. If target lesions split into more lesions, split lesion 
measurements will also be incorporated into the target lesion sum for that 
time point. If a target lesion is too small to measure, 5 mm will be used for 
that target lesion.
Maximum tumor size reduction: This will be defined as the maximum 
tumor size reduction (% change from baseline) up until the time of first 
RECIST v1.1 PD or start of systemic anticancer therapy. Note: If a patient 
experiences both tumor size increase and tumor size reduction, the 
greatest reduction will be taken for this variable.
Body Mass Index (BMI)
BMI will be calculated as Weight/(Height squared), with weight in kg and 
height in m.
Concomitant mediation
Any medication ongoing at the time of first dose of any IP or with a start 
date after first dose of any IP
Discontinuation of study
A subject will be considered discontinued from the study when an End of 
Study page is completed indicating the primary reason for discontinuation.
Disease Response
Refer to Sections 4.1.2.1
Disease Control Rate at 
8, 16, and 24 weeks
The percentage of subjects with a best Derived RECIST Disease 
Response of CR, PR, or SD (SD PDLQWDLQHG IRU  8, 16, or 24 weeks,
respectively) as recorded on the Disease Response CRF 
Dose intensity
(mg/week)
Dose intensity for each drug is defined as the cumulative dose received*
(in mg) divided by duration of exposure (in weeks).
*cumulative dose will be derived as the summation of the “prescribed dose 
(mg)” from the CRF page for each drug 
Example: If 3 MEDI0457 doses are received at 7mg each, and the 
duration of exposure to MEDI0457 is 90 days, then 
Dose intensity (MEDI0457)= (7+7+7)/ (90/7)= 1.63 mg/week 
(to be displayed to the number of decimal places shown in the table shells)
Actual duration of follow-
up (days)
Actual duration of follow-up will be calculated as the date of last contact or 
death minus date of first dose of any IP + 1 day. 


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Potential duration of 
follow-up (days)
Potential duration of follow-up will be calculated as the date of last contact
for subjects who were not deceased or the data cut-off date for deceased 
subjects minus date of first dose of any IP + 1 day. 
Duration of exposure 
(weeks)
Durvalumab: Duration of exposure is defined as the potential end date of
durvalumab treatment period plus 1 day minus first dose date. The 
potential end date of durvalumab treatment period is defined as 27 days 
after the last dose. For subjects who die prior to 27 days after the last 
dose, the potential end date is defined as date of death.  If database cutoff 
occurs prior to 27 days after the last dose and the subject remains alive, 
the potential end date is defined as date of database cutoff.  
MEDI0457: Duration of exposure is defined as the potential end date of 
MEDI0457 treatment period plus 1 day minus first dose date. The 
potential end date of MEDI0457 treatment period is defined as 13, 27, 34
and 55 days after the last dose if the last dose is on week1, 3, 7, and 
>=12, respectively. For subjects who die prior to the corresponding 
number of days after the last dose, the potential end date is defined as 
date of death.  If database cutoff occurs prior to the corresponding number 
of days after the last dose and the subject remains alive, the potential end 
date is defined as date of database cutoff.  
Duration of exposure to study treatment is defined as the later potential 
end date of either drug minus the earlier first dose date of either drug plus 
1 day. 
Duration will be converted to weeks by dividing by 7
Duration of response
(months)
DOR (months) = (Date of RECIST v1.1 PD/death or censoring – Date of 
first disease response per RECIST v1.1 + 1) / (30.4) among confirmed 
responders (CR,PR) only 
Duration of stable 
disease (months)
Duration of SD= (Date of RECIST v1.1 PD/death or censoring – Date of 
first dose of any IP + 1)/30.4. Duration of SD will use the same censoring 
rules as progression-free survival. 
End of Treatment (EOT)
EOT is defined separately for MEDI0457 injection and durvalumab infusion
using the End of Treatment CRF pages
Enrolled subject
An enrolled subject is a subject that is not a screen failure, who signs 
informed consent, and receives any IP
First line therapy
Subjects with only one line of therapy in a recurrent/metastatic setting.
This includes the study treatment. 
Height (cm)
Height that is recorded in inches (in) will be converted to centimeters (cm) 
for the TFLs
cm=in*2.54


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HPV-16/HPV-18 positive 
confirmed disease
A subject who is HPV16+ or HPV18+ by any confirmatory test at baseline 
or Week 10. Results reported in the CRF at baseline cannot be used for 
confirmatory status. Note: A subject could have confirmatory tests that 
were not available at baseline, but if subject has confirmatory positive 
results at Week 10 then subject will be assumed to have been positive at 
baseline. 
Line of therapy
Line of therapy is calculated from the “Prior anticancer treatment” page of 
CRF by taking number of lines and adding 1 (to account for study 
treatment). Subjects without a line of therapy (recorded as NA on the CRF 
page) count as 1L
Lymph node only disease
at baseline
Defined as at least one lesion in local lymph nodes or distant lymph nodes
among baseline target and non-target lesions and no other baseline target 
or non-target lesions in other sites
Measurable disease at 
baseline
For the purposes of deriving the evaluable population, measurable disease 
at baseline (Yes or No) will be defined among baseline target lesions as at 
least 1 target lesion that is >10mm (if solid tumor lesion*) or >15mm (if 
Local or Distant Lymph Nodes)
*a solid tumor lesion will be any lesion that is located in a site that is not 
the local lymph nodes or distant lymph nodes per the CRF 
Platinum Non- refractory
All subjects not meeting the definition for platinum refractory
Overall survival 
(months)
Refer to Section 4.2.2.4
(Date of death or date of censor – earliest date of either study drug + 1 
day)/30.4
Pharmacokinetics 
Variables
Geo=Geometric 
http://onbiostatistics.blogspot.com/2008/07/geometric-statistics-geometric-
cv-vs.html
CV% (not geometric)= (STD/Mean)*100% 


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Platinum-refractory
A finding of “Platinum Refractory” is specified on the Medical History CRF 
page. Only defined for those subjects in 1st line setting. 
Prior Cisplatin therapy
(any)
Defined as Yes if any prior therapy contained Cisplatin; otherwise No. 
Prior Carboplatin therapy
(any)
Defined as Yes if any prior therapy contained Carboplatin; otherwise No.  
Prior platinum therapy
(any)
Defined as Yes if any prior therapy contained Cisplatin or Carboplatin; 
otherwise No. 
Prior Platinum therapy 
intent
For summary table: if the setting is recurrent or metastatic, then it is 
palliative. Otherwise, curative.
Progression-free survival 
(months)
Refer to Section 4.2.2.5
(Date of progression, death, or censor – date of first dose of IP+ 1 
day)/30.4
Relationship to study 
treatment
AEs related to study treatment will be defined as those recorded on the 
CRF page as Related to either investigational product, study-related 
procedures, or device. 
MEDI0457 related includes any AE with relationship to MEDI0457; 
Durvalumab related includes any AE with relationship to Durvalumab; 
Treatment related total includes any AE with relationship to MEDI0457, 
Durvalumab, study procedures, or device. AEs with missing relation will be 
considered treatment related.
Relative dose density
Relative dose density is defined for Durvalumab only as the dose intensity
(defined above) divided by the planned dose intensity. 
The planned dose intensity for Durvalumab is 1500mg/every 4 weeks, 
unless the patient’s weight is <30kg at dosing. If the weight at dosing is 
<30kg, then the planned dose intensity will be 20mg/kg/every 4 weeks. 
Planned dose intensity will not be adjusted for dose delays, missed doses, 
or dose adjustments unless a Revised Dosing Schedule is implemented 
for all patients. 
Temperature
Temperature that is recorded as Fahrenheit (F) will be converted to 
Celsius (C) for the TFLs. 
C=(F – 32)/1.8
Time to response 
(months)
Time to response (months) = (Date of first disease response per RECIST 
v1.1 – Date of the first dose of IP  + 1) / (30.4) among confirmed 
responders (CR,PR) only
Treatment-emergent 
adverse event
An AE will be considered to be a TEAE if it begins or worsens on or after 
the first administration of either study drug up to 90 days following the last 
dose of the last study treatment. 


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Visceral metastases at 
baseline
Defined as at least one lesion in any of the following sites among baseline 
target and non-target lesions: adrenal, CNS, liver, lung, pleura, 
peritoneum, prostate, renal, pancreas, small bowel, stomach, ovary, 
uterus, cervix, colon, biliary tract, testicle, uveal. Subjects may have 
lesions in other sites as well but at least one lesion among these sites to 
be classified with visceral metastases at baseline 
Weight (kg) 
Weight that is recorded in pounds (lb) will be converted to) kilograms (kg) 
for the TFLs
kg= lb * 0.45359237
6.0 Analysis Sets
The analysis of data will be based on different subsets according to the purpose of the analysis, i.e., 
efficacy, safety and pharmacokinetic, respectively. Patients in the Safety Analysis Run-in period will be 
included in the analysis sets as applicable (i.e., meet the analysis set definitions). That is, patients in the 
Safety Analysis Run-in period will be included in any populations for which they meet the criteria. 
6.1 As-treated Population
Patients who receive any investigational product (defined as at least one dose of either study drug) will be 
included in the As-treated Population.
6.2 DLT-Evaluable Population
The DLT-Evaluable Population will include all patients enrolled in the safety run-in period who receive 
investigational product per protocol and complete the safety follow-up through the DLT-evaluation period 
(i.e. safety analysis run-in period) or experience any DLT during the DLT-evaluation period, as defined 
per protocol or revised by the Safety Data Monitoring Committee. At time of writing this SAP, the DLT 
population consists of the first three enrolled subjects. 
6.3 Response-Evaluable Population
This population will include all patients with confirmed HPV-16 or HPV-18 associated disease who have 
received one dose of both study drugs, have a baseline scan with measurable disease at baseline and at 
least one follow-up scan (includes discontinuations due to disease progression or death without follow-up 
scan) with the opportunity to be followed for  16 weeks. 
 
 
 
6.4 Pharmacokinetics Population
The Pharmacokinetic Analysis Set will include all patients who receive at least one dose of durvalumab 
and have at least one evaluable post-dose serum concentration measurement of durvalumab.
6.5 Antidrug Antibodies Evaluable Population
The ADA evaluable population will include subjects who have non-missing baseline ADAs and at least 
one non-missing post-baseline ADA result. 


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7.0 Interim Analyses
7.1 Safety Data Monitoring Committee
Approximately three to 12 patients (Safety Analysis Run-in patients) will be enrolled and assessed for 
safety before additional patients are enrolled at a recommended dose and schedule for the combination. 
Please refer to the Safety Data Monitoring Committee (SDMC) Charter for full details regarding the SDMC 
meeting frequency, composition, and requirements.


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8.0 Data Review
8.1 Data Handling and Transfer
Please refer to the Data Management Plan for details concerning data handling and transfer. 
8.2 Data Screening
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets, tables, figures, and listings (TFLs) provides additional data screening. Presumed data issues will 
be sent to Data Management.
Prior to database lock, data will first be frozen. The TFLs will be delivered based on data prior to the freeze 
(“pre-freeze”), after the freeze (“post-freeze”), and after database lock (final TFLs). Review of a pre-freeze 
TFL run on clean subjects and a post-freeze TFL run on the frozen database allow for further data screening 
prior to lock. The post-freeze TFL will be discussed with the sponsor in a data review meeting to identify 


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any final data issues and seek corrections prior to database lock. The PRA statistician and the sponsor 
must approve database lock.
9.0 Statistical Methods
All analyses will use SAS version 9.4 or higher. Unless otherwise noted, categorical variables will be 
summarized using counts and percentages. Percentages will be rounded to one decimal place, except 
100% will be displayed without any decimal places and percentages will not be displayed for zero counts. 
Continuous variables will be summarized using the number of observations (n), mean, standard deviation 
(SD), median, minimum and maximum. The median, minimum and maximum values will be displayed to 
the same level of precision as the raw data, the mean to a further decimal place and the SD to two additional 
decimal places.
Confidence intervals will be two-sided and use the exact binomial method at a 95% confidence level.
Time to event endpoints (PFS, OS) will be estimated using the Kaplan-Meier method and Kaplan-Meier 
figures will be provided. 
Selected TFLs as indicated in the TFL shells document may display results for subjects with and without 
confirmed HPV-18/HPV-18 positive disease as well as by the total number of subjects. Most shells will 
display by line of therapy and platinum-refractory/non-refractory for first line patients.
The following table details the primary and secondary efficacy endpoints and populations. At this time, these 
endpoints will be derived using the local assessments captured in the CRF.
Type of efficacy 
endpoint
Endpoint
Method
Population(s)
Co-primary1
ORR
RECIST version 1.1
Response-evaluable
Secondary
ORR
RECIST version 1.1 
As-treated
ORR
irRECIST
Response-evaluable and As-
treated
DCR-16w
RECIST version 1.1
Response-evaluable and As-
treated 
PFS
RECIST version 1.1, 
Kaplan-Meier
Response-evaluable and As-
treated
OS
Kaplan-Meier
Response-evaluable and As-
treated
Abbreviations
irRECIST=Immune-Related Response Evaluation Criteria in Solid Tumors, ORR=objective response rate, OS=overall survival, 
PFS=progression free survival, RECIST= Response Evaluation Criteria in Solid Tumors
1.
The other co-primary objective is the evaluation of safety. 
9.1 Subject Disposition
Tabulations of the number and percentage of subjects included in each analysis set, together with a 
breakdown of the reason for exclusion will be provided. Duration of actual and potential follow-up will be 
summarized. Subject entry by site will be tabulated.


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9.2 Protocol Deviations
Per PRA processes, protocol deviation data will be entered into our Clinical Trials Management System 
(CTMS). The study team and the sponsor will conduct on-going reviews of the protocol deviation data 
from CTMS. Important protocol deviations will be summarized in a table and all deviations will be listed.
Protocol deviations relating to the COVID-19 pandemic will also be summarized separately. 
9.3 Treatments
9.3.1 Extent of Study Drug Exposure
MEDI0457 intramuscular (IM) injection dosing and durvalumab IV infusion dosing will each be summarized. 
The number and percentage of subjects receiving at least one dose will be provided for each drug. 
For MEDI0457 injections, the total number of injections received, reason if injection was omitted,
percentage of doses where electroporation was delivered successfully, whether entire dose administered 
(and reason if not) will be summarized in a table and listing. Other details will be included the listing.
For durvalumab infusion, the total number of infusions and cumulative dose will be summarized. The date 
of dosing, and start and end times of infusion will be included in the listing.
Dose modifications for each drug such as reason if dose was omitted, whether entire dose was 
administered, reason if entire dose was not administered, whether dose interrupted and reason, number of 
interruptions, whether dose was reduced and why, whether dose was delayed and why, and whether dose 
increased and why will be summarized in a table and listing. 
The duration of exposure(in weeks and cycles), relative dose density and dose intensity for each drug will 
be calculated and summarized using descriptive statistics.
The lot numbers for each investigational product will be provided in a listing.
9.3.2 Concomitant Medications and Procedures
Concomitant medications will be coded to the generic term using the current version of the World Health 
Organization Drug Dictionary and will be tabulated and listed by subject in the As-treated Population.
Concomitant procedures will not be coded and will be listed by subject in the As-treated Population.
9.3.3 Subsequent Anticancer Treatment
Subsequent anticancer treatment including cancer related surgery, radiation, systemic therapy and other 
therapies will be summarized for subjects in the As-treated Population. Data that cannot be tabulated (e.g., 
start and end dates, times, etc.) will be displayed in listings by subject. 
9.4 Demographic and Baseline Characteristics
Demographic and baseline disease characteristics will be summarized in the As-treated Population. Data 
to be tabulated will include demographic features such as sex, age, ethnicity, race, weight and BMI, as well 
as disease-specific characteristics, such as but not limited to disease stage at initial diagnosis, tumor/lymph 
node/metastasis (TNM) staging at initial diagnosis, histologic grade at initial diagnosis, baseline ECOG 
status, and anatomical location of primary tumor. Medical history, smoking history, alcohol use, and prior 
anticancer treatments will also be tabulated. HPV, 
 status will be tabulated at baseline and 
in a shift table from baseline to Week 10. 


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9.5 Efficacy Analyses
9.5.1 Primary Efficacy Analysis
Objective response rate is defined as the number (%) of patients with confirmed CR or PR via RECIST 1.1 
and will be based on the patients in the Response-evaluable Population for the co-primary endpoint. The 
number and percentage of subjects with each response category will be displayed. The ORR estimate will 
be accompanied by a two-sided exact binomial 95% confidence interval. The confirmed CR rate as well as 
ORR including unconfirmed and confirmed CR and PR will also be provided and accompanied by a two-
sided exact binomial 95% confidence interval. This analysis may also be explored in the subset of patients 
in the Response-Evaluable population excluding patients with selected important protocol deviations. 
Protocol deviations leading to exclusion from analysis may include (but are not limited to): 
x
Inclusion criteria: Diagnosis not confirmed as per protocol
x
Informed consent: Failure to obtain Informed Consent
x
Study drug: Study drug prepared incorrectly
x
Study Drug: Administration error
x
Assessment of efficacy: Protocol defined evaluations not performed before administration of 1st
dose of study drug
x
Assessment of efficacy: Failure to use the same assessment method for disease assessment 
imaging
x
Assessment of efficacy: Missed determination of cancer progression
x
Assessment of efficacy: Assessment of tumor response not performed/documented as per 
protocol
x
Assessment of efficacy: Failure to obtain baseline radiology scan to document pre-therapy tumor 
size
x
Use of Prohibited co-medication
Decisions on subjects to be excluded will be made prior to database lock and recorded in the Data Review 
Meeting minutes. 
All RECIST v1.1 assessments, whether scheduled or unscheduled, will be included in the calculations but 
only those prior to the start of subsequent systemic anti-cancer therapy will be included in the calculations, 
regardless of treatment termination. 
At each visit, patients will be assigned a RECIST version 1.1 visit response of CR, PR, SD, NE or PD 
depending on the status of their disease compared with baseline and previous assessments by the 
Investigator-reported and derived results. Baseline will be assessed within the 28 days prior to enrollment. 
Lesions assessed by the investigator (target, non-target, and new lesions) and both investigator-reported
and derived RECIST v1.1 disease assessments will be presented in listings.
9.5.2 Secondary Efficacy Analyses
Objective response rate will be assessed as a secondary endpoint in the As-treated Population using 
RECIST version 1.1. Objective response rate will be also assessed in the Response-evaluable and As-
treated populations using irRECIST. The number and percentage of subjects with each response category 
will be displayed. The ORR estimates will be accompanied by a two-sided exact binomial 95% confidence 
interval. These tables will also be presented for subjects based on their line of therapy and platinum 
refractory status. Disease assessments per irRECIST will be provided in a listing.
PFS and OS will be summarized descriptively using the Kaplan-Meier method. Please refer to SAP Section
4.0 Variables and Section 5.0 Definitions for more details regarding event and censoring definitions. The
total number of censored patients and total number of patients with events will be provided. In addition, the 
median survival estimates (along with 95% confidence interval), 25th and 75th Kaplan-Meier percentiles, 


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and Kaplan-Meier survival rates at 3, 6, 9, 12, and 24 months (along with 95% confidence intervals) will be 
provided. These analyses will be performed for patients in the response-evaluable and as-treated 
population.
Disease control rate is defined as N (%) patients with CR, PR, or SD at 8, 16, and 24 weeks (SD maintained 
IRU  8, 16, or 24 weeks, respectively) using RECIST version 1.1. For SD determination for DCR, the patient 
must have lack of progression for the first X number of weeks on study, where X corresponds to 8, 16, and 
24 weeks as applicable. Disease control rate will be assessed in the Response-evaluable and As-treated 
populations. The estimate will be accompanied by a two-sided exact binomial 95% confidence interval. 
Time to response and duration of response according to RECISTv1.1 will be estimated using the Kaplan-
Meier method and summarized descriptively (median, percentiles, and 95% confidence interval). Kaplan-
Meier plots will be provided for the Response-Evaluable population, with separate curves for patients in 1L 
platinum-refractory, 1L platinum non-refractory and 2L+ groups, and 
. 
Time to response, duration of response, OS and PFS will be presented in listings. 
Spaghetti plot of tumor size change from baseline and waterfall plots of maximum tumor size reduction from 
baseline as assessed by the investigator according to RECISTv1.1 will be provided for the As-treated and 
Response Evaluable populations. 
 
 
 
 
 
 
9.6 Safety Analyses
9.6.1 Adverse Events
Adverse event data will be summarized by the count and percentage of patients with AEs. Adverse events 
(both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually by patient. 
AE occurring before treatment with IP (eg, non-treatment emergent) will be included in the data listings but 
will not be included in the summary tables of AEs. Any AE occurring after first dose of IP and within 90 days 
of last dose of IP will be included in the AE summaries.
A separate data listing of AEs occurring more than 90 days after last dose of IP will be included in the listing 
for non-treatment emergent AE. These events will not be included in AE summaries.
An AE will be considered to be a TEAE if it begins or worsens on or after the first administration of either 
study drug up to 90 days following the last dose of the last study treatment. AEs/SAEs that occur post 
informed consent signature but prior to IP administration are non-treatment-emergent AEs/SAEs. 
A summary of TEAEs, including the number of events reported, the number and percentage of patients
reporting at least one AE, the number and percentage of patients discontinuing due to an AE, the number 
and percentage of patients with at least one SAE, and the number and percentage of deaths will be 
presented. In reality all AEs which change in severity or relationship to study drug are assigned a new start 
date and captured as a new record. 
A breakdown of the number and percentage of patients reporting each AE, categorized by system organ 
class and preferred term coded according to the MedDRA dictionary v22.0, will be presented. Note that 


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counting will be by patients not event and patients are only counted once within each system organ class
or preferred term.
A further tabulation of these data, categorized by relationship to study drug, will be presented. Patients with 
multiple events within a particular system organ class or preferred term will be counted under the category 
of their related event within that system organ class or preferred term. Relationship will be categorized as 
MEDI0457-related, Durvalumab-related, study procedure related, device related, or treatment related (any 
relation or missing relation).
A summary of events reported, categorized by severity (CTCAE version 4.03
Grades 1-5) will also be 
provided. Patients with multiple events within a particular system organ class or preferred term will be 
counted under the category of their most severe event within that system organ class or preferred term.
Summaries of AEs leading to discontinuation from either study drug or modifications (delay, interruption, 
reduction, or omission) of either study drug will be provided, grouped by system organ class and preferred 
term.
Adverse events of special interest are categorized on the CRF and described in SAP Section 4.1.1.3. The 
number and percentage of patients reporting at least one AESI will be tabulated, as well as the number and 
percentage of patients in each category. Adverse events of special interest may be further tabulated by 
severity, treatment relation, and seriousness. Administration site reactions will be graded using CTCAE and 
the Administration Site Reaction Grading Scale (Mild: Grade 1, Moderate: Grade 2, Severe: Grade 3, 
Potentially life threatening: Grade 4) (See Appendix I of the protocol). 
A listing of DLTs will be provided.
A listing of AEs for patients that are any ADA positive will be provided.
A table of non-serious treatment-emergent AE occurring in greater than 5% of subjects will be provided by 
system organ class and preferred term. If there are no classes or terms with greater than 5% frequency, 
this percentage may be reduced to >2%.
9.6.2 Deaths and Serious Adverse Events
All deaths will be reported in a subject listing, which will include the date of death, primary cause of death, 
and date of first and last doses of study treatment. A table of mortality will be presented to indicate time of 
death while on study (<=90 days post-last dose, >90 days post-last dose) and cause of death in relation to 
investigational product. Another table will be presented for treatment-emergent AE resulting in death by 
system organ class and preferred term. 
The number and percentage of patients experiencing SAEs will be presented by SAE criteria and total.
Serious AE and treatment-related serious AE will be tabulated by system organ class and preferred term. 
9.6.3 Laboratory Data and other Observations Related to Safety
Descriptive statistics will be provided for the clinical laboratory results (chemistry, hematology, urinalysis 
and thyroid function testing) and vital signs and changes from baseline by visit for visits with more than 5 
subjects. Standard shift tables will be prepared for hematology and serum chemistry parameters presenting 
worst post-baseline CTCAE toxicity grade vs baseline. A shift table by reference range (low, normal, high) 
will be presented for other laboratory parameters that have references ranges but are not coded by CTCAE
version 4.03.
A table and listing will be provided for laboratory results for subjects with potential Hy’s law.
ECG change from baseline for minimum, maximum, and last record on treatment will be tabulated. The 
number and percentage of subjects meeting criteria for notable QTC intervals will be presented. For each 
planned visit for which a triplicate ECG is obtained, the average of the 3 values should be calculated for 
each parameter at each timepoint. The average values will be used for the ECG tables. Listings will include 
individual and averaged values.  


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A shift summary of ECOG performance status will be provided presenting worst post-baseline status vs 
baseline.
Laboratory and safety data will be listed by subject per the TFL shells. Where applicable and described in 
the TFL shells, change from baseline will be included in the listings. Pregnancy testing and physical exam 
data will be listed only. 
Bleeding and pneumonitis questionnaire data will be presented in listings. Blood gases, serum ILD markers, 
and pulmonary function tests will not be tabulated or listed (some of these data will be provided as part of 
the listings for questionnaires). Tumor biopsy sample collection from the CRF will also not be tabulated or 
listed. 
9.7 Pharmacokinetics and Antidrug Antibodies
Pharmacokinetics and immunogenicity data (secondary objectives) will be summarized and tabulated by 
PRA and will be reported in the PRA Clinical Study Report. 
9.7.1 Pharmacokinetic Analysis
Pharmacokinetic (PK) concentration data summary statistics will be tabulated by visit (including n, 
geometric mean and geometric CV%, minimum and maximum (list non-exhaustive)). Individual serum 
concentration-time profiles of durvalumab will be reported as listing. Due to the sparse PK sampling used 
in this study, formal non-compartmental analysis to derive PK parameters (e.g. terminal half-life) will not be 
conducted. A population PK model may be developed by Astrazeneca or vendor with similar data from 
other studies to further characterize the PK properties of durvalumab when administered in combination 
with MEDI0457 but will be reported outside of the CSR if conducted. 
9.7.2 Immunogenicity Analysis
Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of 
patients who develop detectable anti-durvalumab antibodies. The immunogenicity titers will be reported in 
the listing for samples confirmed positive for the presence of ADAs. The effect of immunogenicity on PK 
and safety may be performed, if the data allow, by Astrazeneca.
9.8 Exploratory Analyses 
. 
9.9 Methods for Handling Dropouts and Missing Data
There will be no imputation of missing data for analysis. It is expected that year will always be provided in 
the CRF; however, unknown day and unknown month is allowed for historic (pre-study) dates (medical 
history, prior anticancer treatment, pre-study concomitant medications). Missing day will be displayed as 
UN and missing month as UNK.
9.10 Multiplicity
There is no formal statistical testing in this study.
 
 
  
9.11 Pooling of Sites
Data will be pooled across centers for all analyses.


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10.0 Validation
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our quality 
control procedures will be documented separately in the study specific quality control plan. 
References
 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, 
S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe and J. Verweij 
(2009). "New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)." Eur J 
Cancer 45(2): 228-247.
 
 
Guidance for Industry and Investigators. Safety Reporting Requirements for INDs and BA/BE Studies. 
December 2012.
 
Oken MM, Creech R, Tormey DC, Horton J, Davis TE, McFadden ET al. Toxicity and Response Criteria of 
the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-55.




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HPV-16
Human Papilloma Virus Type 16
HPV-18
Human Papilloma Virus Type 18
HR
Heart rate
IHC
Immunohistochemistry
ILD
Interstitial Lung Disease
IM
Intramuscular
INR
International Normalized Ratio
IP
Investigational Product
irRECIST
Immune-Related Response Evaluation Criteria in Solid Tumors
IV
Intravenous
IVRS
Interactive Voice Response System
KM
Kaplan Meier
LH
Luteinizing Hormone
MTD
Maximum tolerated dose
MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease 
PK
Pharmacokinetic
PFS
Progression free survival 
PP
Per Protocol
PR
Partial response
PRA
PRA Health Sciences
PR interval
Interval on the electrocardiogram, from the start of the P wave to the start 
of the R wave
QRS interval
Interval on the electrocardiogram from the start of the Q wave to the end of 
the of the S wave
QT interval
Interval on the electrocardiogram, from the beginning of the QRS complex 
to the end of the T wave
QTcB interval
QT interval corrected for heart rate based on the Bazett formula
QTcF interval
QT interval corrected for heart rate based on the Fridericia formula


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RECISTv1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RR interval 
Interval on the electrocardiogram, time elapsing between two consecutive 
R waves 
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SCCHN
Squamous cell carcinoma of the head and neck 
SD
Stable disease 
SDMC
Safety Data Monitoring Committee 
SDTM
Study Data and Tabulation Model 
T3
Triiodothyronine
T4
Thyroxine
TBL
Total Bilirubin
TEAE
Treatment-Emergent Adverse Event 
TFL
Tables, Figures, and Listings
TNM
TNM Classification of Malignant Tumors
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WHO
World Health Organization