A Phase 2, Open-Label Study to Evaluate Efficacy of Combination Treatment With MEDI0457 (INO-3112) and Durvalumab (MEDI4736) in Patients With Recurrent/Metastatic Human Papilloma Virus Associated Cancers
Phase: PHASE2
Conditions: Human Papillomavirus-16 Positive, Human Papillomavirus-18 Positive, Metastatic Malignant Neoplasm, Recurrent Anal Canal Carcinoma, Recurrent Cervical Carcinoma, Recurrent Malignant Neoplasm, Recurrent Penile Carcinoma, Recurrent Vaginal Carcinoma, Recurrent Vulvar Carcinoma, Refractory Malignant Neoplasm, Stage IV Anal Cancer AJCC v8, Stage IV Cervical Cancer AJCC v8, Stage IV Penile Cancer AJCC v8, Stage IV Vaginal Cancer AJCC v8, Stage IV Vulvar Cancer AJCC v8, Stage IVA Cervical Cancer AJCC v8, Stage IVA Vaginal Cancer AJCC v8, Stage IVA Vulvar Cancer AJCC v8, Stage IVB Cervical Cancer AJCC v8, Stage IVB Vaginal Cancer AJCC v8, Stage IVB Vulvar Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

A Phase 2, Open-Label Study to Evaluate Efficacy of Combination Treatment with 
MEDI0457 (INO-3112) and Durvalumab (MEDI4736) in Patients with 
Recurrent/Metastatic Human Papilloma Virus Associated Cancers 
Investigational Drug Substances: Durvalumab, MEDI0457 
MDACC Study Number: 2017-0302 
AZ Study Number: ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
IND Sponsor: MD Anderson IND Office 
IND Number: 17919 
Supporters: AstraZeneca, Inovio 
PRINCIPAL INVESTIGATOR 
Michael Frumovitz, MD, MPH 
Professor and Fellowship Director 
MD Anderson Cancer Center 
Department of Gynecologic Oncology and 
Reproductive Medicine, Unit 1362 
1155 Pressler Drive, CPB6.3562 
Houston, TX 77030 
Phone: (713) 792-9599 
Fax: (713) 792-7586 
Email: mfrumovitz@mdanderson.org 
CO-PRINCIPAL INVESTIGATORS 
Van Morris, MD 
Professor 
Department of GI Medical Oncology 
MD Anderson Cancer Center 
Curtis Pettaway, MD 
Professor 
Department of Urology 
MD Anderson Cancer Center 
COLLABORATORS 
Translational Research 
Amir Jazaeri, MD 
Associate Professor 
Department of Gynecologic Oncology 
and Reproductive Medicine 
MD Anderson Cancer Center 
Chantale Bernatchez, PhD 
Assistant Professor 
Department of Melanoma Medical Oncology 
MD Anderson Cancer Center 
Cara Haymaker, PhD 
Instructor 
Department of Melanoma Medical Oncology 
MD Anderson Cancer Center 
Biostatistics 
Yuan Ying, PhD 
Professor 
Department of Biostatistics 
MD Anderson Cancer Center 
Bryan Fellman 
Research Statistical Analyst 
Department of Biostatistics 
MD Anderson Cancer Center 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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Radiology 
David Vining 
Professor 
Department of Diagnostic Radiology 
MD Anderson Cancer Center 
Leonardo Marcal 
Associate Professor 
Department of Diagnostic Radiology 
MD Anderson Cancer Center 
Pathology 
Ming Guo 
Professor 
Department of Anatomical Pathology 
MD Anderson Cancer Center 
Infectious Disease 
Bruno P. Granwehr, MD, MS 
Associate Professor 
Department of Infectious Diseases, 
Infection Control, and Employee Health 
MD Anderson Cancer Center 
Javier A. Adachi 
Professor 
Department of Infectious Diseases, 
Infection Control, and Employee Health 
MD Anderson Cancer Center 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................... 9 
1.1. 
Background and Rationale for Conducting This Study ............................................... 9 
1.2. 
Summary of Clinical Experience ................................................................................. 9 
1.3. 
Rationale for Study Design, Doses and Control Groups ............................................ 12 
1.4. 
Benefit/Risk and Ethical Assessment ......................................................................... 15 
1.5. 
Research Hypotheses.................................................................................................. 19 
1.6. 
Study Design .............................................................................................................. 19 
2. 
STUDY OBJECTIVES ........................................................................................... 20 
2.1. 
Primary ....................................................................................................................... 20 
2.2. 
Secondary ................................................................................................................... 20 
2.3. 
Exploratory ................................................................................................................. 21 
3. 
SUBJECT SELECTION AND PARTICIPATION ................................................ 21 
3.1. 
Inclusion Criteria ........................................................................................................ 21 
3.2. 
Exclusion Criteria ....................................................................................................... 22 
3.3. 
Patient Instructions ..................................................................................................... 25 
3.4. 
Discontinuation of Investigational Product ................................................................ 28 
3.5. 
Criteria for Withdrawal .............................................................................................. 29 
4. 
INVESTIGATIONAL PRODUCTS ....................................................................... 30 
4.1. 
Identity of Investigational Products ........................................................................... 30 
4.2. 
Labeling ...................................................................................................................... 32 
4.3. 
Study Drug Preparation .............................................................................................. 33 
4.4. 
Doses and Treatments ................................................................................................ 34 
4.5. 
Accountability and Disposition .................................................................................. 36 
5. 
STUDY PLAN ........................................................................................................ 36 
6. 
STUDY ASSESSMENTS ....................................................................................... 39 
6.1. 
Demographics............................................................................................................. 39 
6.2. 
Medical History .......................................................................................................... 39 
6.3. 
Efficacy Assessments ................................................................................................. 39 
6.4. 
HPV-16 or HPV-18 Testing ....................................................................................... 41 
6.5. 
Safety Assessments .................................................................................................... 41 
6.6. 
Biological Sampling Procedures ................................................................................ 43 
6.7. 
Management of IP-related Toxicities ......................................................................... 45 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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7.
SAFETY REPORTING .......................................................................................... 47
7.1.
Definition of adverse events ....................................................................................... 47
7.2.
Serious Adverse Event Reporting .............................................................................. 48
7.3.
Assessment of Safety Parameters ............................................................................... 49
7.4.
Recording and Reporting of AEs and SAEs .............................................................. 50
7.5.
Adverse Events of Special Interest............................................................................. 52
7.6.
Other events requiring reporting ................................................................................ 54
8.
STATISTICAL ANALYSES ................................................................................. 56
8.1.
Statistical Considerations ........................................................................................... 56
8.2.
Definitions of Analysis Sets ....................................................................................... 58
8.3.
Outcome Measures ..................................................................................................... 59
9.
ETHICAL AND REGULATORY REQUIREMENTS .......................................... 61
9.1.
Ethical Conduct of the Study ..................................................................................... 61
9.2.
Ethics and Regulatory Review ................................................................................... 61
9.3.
Informed Consent ....................................................................................................... 61
9.4.
Changes to the Protocol and Informed Consent Form ............................................... 61
9.5.
Protocol Review and Monitoring ............................................................................... 61
10.
STUDY DATABASE MANAGEMENT ............................................................... 62
10.1. Study Data .................................................................................................................. 62
10.2. Data Management ...................................................................................................... 62
11.
LIST OF REFERENCES ........................................................................................ 62
APPENDIX A.  International Airline Transportation Association (IATA) 6.2 Guidance Document
................................................................................................................................................... 67
APPENDIX B. ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW ..................................................... 68
APPENDIX C. CELLECTRA®5P Error Reporting Form ....................................................... 73
APPENDIX D. Durvalumab Dose Modification for Toxicity Management ............................ 74
APPENDIX E. Administration Site Reaction Grading and Management ................................ 91
APPENDIX F. Durvalumab Weight-Based Dose Calculation ................................................. 93
LIST OF FIGURES 
Figure 1. Overall Study Design Study Flow Chart ................................................................... 20
Figure 2. Examples of labeling for the CELLECTRA®5P ....................................................... 33
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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LIST OF TABLES 
Table 1. Supportive Medications .............................................................................................. 25
Table 2. Effective Methods of Contraception ........................................................................... 28
Table 3. Schedule of Study Procedures .................................................................................... 37
Table 4. Summary of Samples, Target, and Assays ................................................................. 44
Table 5. Operating Characteristics of Stopping Rules for Toxicity .......................................... 57
Table 6. A Summary of Efficacy Endpoints with Corresponding Methods of Assessment and 
Populations ................................................................................................................................ 58
Table 7. Treatment Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events (Durvalumab) .................................................................................................. 74
Table 8. Treatment Modification and Toxicity Management Guidelines for Infusion-related 
Reactions (Durvalumab) ........................................................................................................... 89
Table 9. Treatment Modification and Toxicity Management Guidelines for Non-immune-
mediated Reactions (Durvalumab) ........................................................................................... 90
LIST OF ABBREVIATIONS 
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 
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 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CRF 
Case Report Form (electronic) 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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Abbreviation or special term 
Explanation 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Event 
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) 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ELISPOT 
Enzyme-Linked Immunosorbent Spot 
EOS 
End of Study 
EOT 
End of Treatment 
EP 
Electroporation 
FACS 
Fluorescence Activated Cell Sorting 
FDA 
Food and Drug Administration 
FDG 
Fludeoxyglucose 
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 
IB 
Investigator’s Brochure 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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Abbreviation or special term 
Explanation 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon-Gamma 
IHC 
Immunohistochemistry 
IgG 
Immunoglobulin G 
IgG1 
Immunoglobulin G1 
ILD 
Interstitial Lung Disease 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
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 
LIMS 
Laboratory Information Management System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
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 
PI 
Principal Investigator  
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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Abbreviation or special term 
Explanation 
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 
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 
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 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBL 
Total Bilirubin 
TIL 
Tumor Infiltrating Lymphocytes 
TNF 
Tumor Necrosis Factor 
TNF-α 
Tumor Necrosis Factor-Alpha 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBDC 
Web Based Data Capture 
WHO 
World Health Organization 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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1.
INTRODUCTION
1.1. 
Background and Rationale for Conducting This Study 
Virtually all cervical cancers, most oropharyngeal and anal cancers, and a major proportion of 
penile, vaginal, and vulvar cancers are attributable to oncogenic types of human papillomavirus 
(HPV). Collectively, these cancers account for approximately 50,000 new cases, > 10,000 deaths, 
and approximately $1 billion in treatment costs annually in the U.S. Cervical cancer is a leading 
cause of cancer death in women in most of the developing world (number 1 in most of Africa). 
Anal cancer incidence in the U.S. is significantly increasing in both men and women. Penile 
cancer, though rare in developed countries, accounts for up to 10% of cancers in men in parts of 
the developing world. Additionally, HIV-positive individuals, including those treated with highly 
active antiretroviral therapy (HAART), remain at heightened risk of HPV-associated 
malignancies. For all HPV-related cancers, standard therapy for local regional disease does not 
always work, and no effective or established therapy is available for metastatic disease or even 
most local-regional recurrences.  
In these malignancies, 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 pRb 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 malignancies. HPV-16 and/or HPV-18 is found in 70% of all 
cervical cancers (de Sanjose et al 2010), 65% of anal cancers (Bosch et al 1995), and 70% of 
penile cancers (Maden et al 1993). 
1.2. 
Summary of Clinical Experience 
1.2.1. 
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.  
The clinical experience with VGX-3100 is obtained from two completed Phase 1 studies, HPV-
001 and HPV-002, which enrolled 18 and 13 patients, respectively, and a completed Phase 2 
study, HPV-003, which enrolled 167 patients.  There have been no significant safety findings.  
There were very few treatment-related Grade 3 adverse events (AEs) and no related Grade 4 AEs 
or serious adverse events (SAEs) after 551 doses given to 185 patients in these trials. 
Importantly, the safety profile of the DNA immunogen with electroporation (EP) remains 
consistently unremarkable in the 965 patients and more than 2500 doses in 23 different studies as 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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of January 15, 2016 (refer to the MEDI0457 Investigator’s Brochure [IB] for additional 
information).  
There is an ongoing clinical trial in more advanced cancer patients with HPV-16 and/or HPV-18 
associated head and neck cancers.  In this prospective Phase I/IIa trial (HPV-005 Study), adult 
patients with HPV-positive (assessed by p16) squamous cell carcinoma of the head and neck 
(SCCHN) were enrolled into two cohorts.  In Cohort 1, patients received MEDI0457 pre- and 
post-surgery.  In Cohort 2, patients received MEDI0457 after the completion of cisplatin based 
chemoradiation.  MEDI0457 (6 mg of VGX-3100 plus 1 mg of INO-9012) was delivered 
intramuscularly followed by EP with the CELLECTRA®5P device, once every 3 weeks for a total 
of four doses.  Patients were followed for 2 years.  As of December 2015, 20 patients had been 
enrolled and all patients have received four doses of MEDI0457, i.e., six Cohort 1 patients, and 14 
Cohort 2 patients.  MEDI0457 was well tolerated with no treatment-related Grade 3 AE, and no 
Grade 4 or higher AEs reported.  The most frequent AE was injection site pain (n=14), all of 
which were Grade 1.  Two patients had Grade 3 lymphopenia at baseline and no worsening during 
the trial.  Three unrelated SAEs have been reported in the trial; Grade 2 post-surgical procedure 
hemorrhage, a Grade 3 acute non-traumatic kidney injury, and Grade 3 dyspnea due to neck 
swelling.  Among samples tested, as compared to baseline, 4 of 5 evaluable patients showed 
increased anti-HPV-16/HPV-18 E6/E7 antibody titers and 9 of 10 evaluable patients exhibited 
increased HPV-specific cellular responses by interferon-gamma (IFN-γ) enzyme-linked 
immunosorbent spot (ELISPOT) assay demonstrating a vaccine response.  In addition, 7 of 
8 evaluable patients had HPV-specific CD8+ T-cell activation concurrent with increased lytic 
proteins (granzymes and perforin) by flow cytometric analysis.  
The application of EP via the CELLECTRA®5P device increases the expression of the E6 and E7 
antigens and interleukin-12 encoded by MEDI0457.  Electroporation utilizes a transmembrane 
electric field pulse to induce microscopic pathways (pores) in a bio-membrane.  The electric field 
allows macromolecules, ions, and water to pass from one side of the membrane to the other.  
In a small (10 healthy volunteers) pilot study, pain was evaluated immediately, 5, 15, 30 minutes 
and 1 hour after EP with the CELLECTRA®5P device (Diehl et al 2013).  Patients used a Visual 
Analog Scale questionnaire, 10 cm in length, anchored by word descriptors at each end, “No 
Pain” and “Worst Pain”, to mark their pain related to the treatment.  Patients reported a mean 
(±standard error of measurement) score of 6.3 (±0.7) immediately after treatment and 2.8 (±0.5) 
approximately 5 minutes after the procedure.  These data showed that the pain associated with EP 
was brief and diminished quickly (Diehl et al 2013). 
1.2.2. 
Durvalumab 
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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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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As of the data cut-off (DCO) date (12 July 2016), an estimated 5225 patients have been exposed 
to 1 or more doses of durvalumab in AstraZeneca or MedImmune sponsored studies, either as 
monotherapy or in combination, including 2878 patients in open label trials, and 2347 patients as 
an estimate based on the randomization scheme in studies where the treatment arm is blinded. 
Additionally, more than 1700 patients have been exposed to 1 or more doses of durvalumab in 
externally-sponsored/investigator-initiated clinical trials (ESR/IITs). Please refer to the 
durvalumab IB for detailed data. 
Safety data have been pooled for 4 durvalumab monotherapy studies (CD-ON-MEDI4736- 1108, 
D4190C00002, ATLANTIC and D4193C00001 [HAWK]) for patients who received a 
durvalumab dose of 10 mg/kg Q2W; a total of 1645 patients are included in this pooled data set. 

Overall, AEs reported in ≥10% of patients were fatigue (31.1%), decreased appetite
(22.5%), nausea (20.5%), dyspnea (17.9%), constipation (17.8%), cough (17.4%), diarrhea
(16.0%), anemia (15.3%), pyrexia (15.0%), vomiting (13.4%), back pain (12.5%), pruritus
(11.0%), arthralgia (10.6%) and abdominal pain (10.2%).

AEs that were considered by the investigator as related to durvalumab in ≥5% of patients
were fatigue (14.5%); nausea (7.3%); diarrhea (6.9%); hypothyroidism (6.6%); pruritus
(6.4%); decreased appetite (6.0%) and rash (5.2%).

A total of 820 patients (49.8%) reported AEs of Common Terminology Criteria for
Adverse Events (CTCAE) Grade 3 or higher: of these, 487 patients (29.6%) had events of
Grade 3, 63 patients (3.8%) had events of Grade 4 and 270 patients (16.4%) had Grade 5
(fatal) events. AEs of Grade 3 or higher considered related to durvalumab were reported in
164 patients (10.0%): of these, 144 patients (8.8%) had events of Grade 3, 12 patients
(0.7%) had events of Grade 4 and 8 patients (0.5%) had Grade 5 (fatal) events.

Grade 3 events occurring in ≥1% of patients were: anemia (5.5%); dyspnea (4.4%);
hyponatremia (4.1%); fatigue (2.9%); gamma-glutamyltransferase (GGT) increased
(2.7%); abdominal pain (2.0%); decreased appetite and back pain (1.9% each); pneumonia
(1.8%); aspartate aminotransferase (AST) increased and dehydration (1.6% each);
hypertension (1.3%); blood alkaline phosphatase (ALP) increased, hypokalemia, urinary
tract infection and vomiting (1.2% each); alanine aminotransferase (ALT) increased and
pleural effusion (1.1% each); bilirubin increased, asthenia, nausea and pulmonary
embolism (1.0% each). Grade 3 events considered related to durvalumab occurring in
≥0.5% patients were fatigue (1.2%), GGT increased (0.8%) and AST increased (0.6%).

The most commonly reported Grade 4 event was sepsis (15 patients [0.9%]). Other
commonly reported Grade 4 events were: GGT increased (9 patients [0.5%]); dyspnea,
hypercalcemia and respiratory failure (7 patients each [0.4%]) and pneumonia (5 patients
[0.3%]). All other Grade 4 events were reported in less than 5 patients each. Grade 4
events considered related to durvalumab occurring in ≥2 patients were GGT increased and
pneumonitis (0.1% each).

Grade 5 events occurred in the system organ class (SOC) of ‘neoplasms benign, malignant
and unspecified (including cysts and polyps)’ for 172 of the 270 patients with Grade 5
events (63.7%), with the highest number of events occurring for NSCLC (40 patients).
Amongst the other SOCs, the most common Grade 5 events were general physical health
deterioration (12 patients), respiratory failure (8 patients); Grade 5 events of pneumonia
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Drug Substances: Durvalumab, MEDI0457 
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Version Number: 1.8 
Date: July 26, 2019 
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and sepsis occurred in 5 patients each with the remainder of the Grade 5 events occurring 
in ≤4 patients for each event. The only Grade 5 event considered related to durvalumab 
occurring in ≥2 patients was pneumonitis (0.1%). 

A total of 134 patients (8.1%) discontinued from study treatment due to an AE. The most
common events leading to treatment discontinuation were: general physical health
deterioration (10 patients); pneumonitis (7 patients); pneumonia (6 patients); dyspnea and
NSCLC (5 patients each); all other discontinuation events occurred in ≤4 patients.

A total of 89 patients (5.4%) had serious treatment-emergent AEs (TEAEs) that were
considered by the investigator as related to durvalumab. The most common were:
pneumonitis (12 patients [0.7%]); fatigue (5 patients [0.3%]); colitis, infusion related
reaction and ILD (4 patients each [0.2%]); dehydration, diarrhea, nausea and nervous
system disorder (3 patients each [0.2%]); abdominal pain, acute kidney injury, adrenal
insufficiency, AST increased, bilirubin increased, dyspnea, hepatic function abnormal,
nephritis, transaminases increased, tumor hemorrhage and vomiting (2 patients each
[0.1%]).
A total of 854 patients (51.9%) experienced an adverse event of special interest (AESI) during the 
study. The most common grouped term AESI was diarrhea (263 patients [16.0%]; of whom 12 
patients [0.7%] had events of Grade ≥3). Other common AESIs (grouped term) were: selected 
hepatic events (248 patients [15.1%]; of whom 113 patients [6.9%] had events of Grade ≥3); 
dermatitis (237 patients [14.4%]; of whom 3 patients [0.2%] had events of Grade ≥3); rash (199 
patients [12.1%]; of whom 7 patients [0.4%] had events of Grade ≥3); hypothyroidism (170 
patients [10.3%]; of whom 2 patients [0.1%] had events of Grade ≥3); hyperthyroidism (93 
patients [5.7%]; of whom 1 patient [<0.1%] had events of Grade ≥3); and select renal events (87 
patients [5.3%]; of whom 16 patients [1.0%] had events of Grade ≥3). There were 6 patients who 
had AESIs of CTCAE Grade 5 (fatal events): three patients had hepatic events (autoimmune 
hepatitis; hepatic failure and hyperbilirubinemia); two patients had pneumonitis and 1 patient had 
immune thrombocytopenic purpura. 
1.3. 
Rationale for Study Design, Doses and Control Groups 
1.3.1. 
Rationale for the study 
Although HPV associated cancers appear to have a better prognosis at diagnosis, 
recurrent/metastatic HPV-associated cervical, rectal, and penile cancers are largely incurable with 
very few therapeutic options. For women with cervical, anal, and penile cancers, recurrence rates 
can be as high as 40%. (Leijte et al 2008, Uronis et al 2007)   For these cancers, current 
therapeutic options rarely achieve response rates >25% and 5-year survival after first recurrence is 
<5% for those patients not amenable to radical surgical resection or radiation salvage. There is a 
large unmet need for these patients with recurrent HPV-associated cancers. 
As HPV-associated tumors by nature involve evasion of the immune system for malignant 
transformation from pre-invasive to invasive disease, immunotherapy combinations are an 
appealing strategy for these malignancies. Immune checkpoint inhibitors are currently under 
investigation in many HPV associated tumors. In anal cancer, results of a phase II study with 
nivolumab has recently been presented showing response rates of 24% including 2 complete 
responses (CRs) and an additional 46% of patients with stable disease (SD) for an overall clinical 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
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benefit rate of 70%. (Morris et al 2016) The GOG/NRG recently completed a similar study of 
nivolumab in women with recurrent cervical cancer (GYN-002) although results are not yet 
known. Furthermore, as HPV-16 and/or HPV-18 subtypes are found in 70% of all cervical 
cancers, (deSanjose et al 2010) 65% of anal cancers, (Bosch et al 1995) and 70% of penile 
cancers, (Maden et al 1993) there is a strong rationale for combining an immune checkpoint 
inhibitor with a therapeutic HPV16/18 vaccine. 
MEDI0457 (INO-3112) is a plasmid DNA vaccine consisting of three plasmids expressing HPV-
16 and HPV-18 E6 and E7 proteins along with interleukin-12 as an adjuvant.  pGX3001 plasmid 
(also called HPV-16 DNA) consists of 3782 DNA base pairs and the pGX3002 plasmid (also 
called HPV-18 DNA) consists of 3824 base pairs.  pGX6001 (also called interleukin-12 DNA) 
plasmid is circular double-stranded DNA consisting of 6259 base pairs. The vaccine contains 3 
mg of pGX3001, 3 mg of pGX3002, and 1 mg of pGX6001. 
Interim data from the HPV-005 Phase I/IIa trial (HPV-005 Study) in patients with head and neck 
cancer showed that MEDI0457 was safe and associated with an immune response against the 
target antigens.  There were increases in anti-HPV-16/HPV-18 E7 antibody titers and 
HPV-16/HPV-18 E6/E7-specific T-lymphocytes following the administration of MEDI0457 
followed by EP (Aggarwal et al 2015).  
The proposed study is designed to study MEDI0457 in combination with durvalumab (also known 
as MEDI4736) in patients with cancers associated with HPV-16 and/or HPV-18. 
This combination is being studied for the first time in patients with HPV-16 and/or HPV-18 
associated recurrent/metastatic cancers.  Based on available scientific literature, including 
preliminary data and the non-redundant mechanism of action of each single agent, benefit is 
anticipated in this patient population.  It is anticipated that MEDI0457 and durvalumab will 
additively or synergistically enhance T-lymphocyte activities against cancers associated with 
HPV-16 and/or HPV-18 and thereby enhance their respective clinical anti-tumor effects. 
1.3.2. 
Rationale for endpoints 
In this study of MEDI0457 and durvalumab in combination, efficacy (response rate) will be the 
primary endpoint.  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.  Sample collection for pharmacokinetics analysis of durvalumab and for 
HPV-16/HPV-18 humoral and cellular immunogenicity testing will be done to inform further the 
safety and efficacy of combination treatment. 
1.3.3. 
Rationale for doses selected 
MEDI0457 (also known as INO-3112) at the proposed dose is being used in two ongoing studies 
(HPV-004 Study and HPV-005 Study) with >25 patients enrolled thus far.  There is a larger 
clinical experience with VGX-3100, a key component of MEDI0457, with two completed Phase 1 
studies that enrolled 18 and 13 patients respectively, and a completed Phase 2 study, which 
enrolled 169 patients in cervical intraepithelial neoplasm.  There have been no significant safety 
findings.  There were very few treatment-related Grade 3 AEs and no related Grade 4 AE’s or 
SAEs after 551 doses given to 185 patients in these trials.    
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Importantly, the safety profile of the DNA immunogen with EP remains consistently 
unremarkable in >1000 patients and more than 2500 doses in 23 different studies as of April 06, 
2016 (Refer to the MEDI0457 IB for additional information).  
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on the safety and 
immunogenicity data generated in the HPV-001 study, where 6 mg of DNA were delivered 
intramuscular (IM) followed by electroporation, which showed trends toward higher response 
rates and magnitudes of IFN-γ ELISpot responses in the high dose cohort compared to the low 
(0.6 mg) and mid- dose (2 mg) cohorts without significant safety issues (Bagarazzi et al., 2012). 
This dose-trend was consistent with prior expectation, a feature of the finding that suggests it is a 
“real” effect rather than random variation. Adverse events from previous human studies with 
closely related DNA plasmid products have been limited to injection site pain from the injection 
and electroporation procedure. No unexpected or severe adverse events were observed in any of 
the three dose cohorts tested in Study HPV-001. 
There were no significant safety findings in the 18 female subjects enrolled in HPV-001, the 
phase 1 study of VGX-3100, with only mild to moderate adverse events, injection  site  reactions  
and  laboratory  abnormalities  which  resolved  without sequelae. All subjects returned home 
after at least 30 minutes observation in the study unit post injection/electroporation. CPK and 
ECGs were unremarkable post electroporation. Study participants judged the injection/ 
electroporation to be relatively painful (mean VAS score 6.2 immediately after and 2.8 
approximately 5 minutes after EP) but transient, but did not preclude subsequent injection/ 
electroporation administration. There were no serious adverse events attributed to treatment in 
any of the subjects and there were no early discontinuations in the study. Thirteen women 
participated in HPV-002 in which a fourth dose (6 mg only) of VGX-3100 was evaluated and the 
safety findings were consistent with those observed in the parent study, HPV-001. 
The IL-12 plasmid dose is based on previous experience in the HVTN-080 study, where 1 mg was 
co-administered with PENNVAX®-B followed by electroporation. HIV- specific CD4+ T cell 
responses were generated in ~81% of PENNVAX®-B + IL- 12 recipients after three vaccinations, 
compared to 44% with PENNVAX®-B alone. Delivery of PENNVAX®-B via electroporation also 
increased the frequency of CD8+ T cell responses. CD8+ responses were detected in 33% of 
PENNVAX®-B and 52% of PENNVAX®-B + IL-12 recipients after 3 vaccinations. Six months 
after the third vaccination 43% of individuals were still able to respond to HIV peptide pools. 
Overall, 89% of individuals vaccinated with PENNVAX®-B + IL-12 plasmid followed by 
electroporation developed either a CD4+ or CD8+ T-cell response after the third vaccination. No 
unexpected or severe adverse events were observed in HVTN-080 or earlier studies of IL-12 
DNA delivered without electroporation. 
In summary, a total of 7 mg VGX-3100 + INO-9012 DNA was selected for this study based on 
the safety and immunogenicity data generated in HPV-001, the follow-on study HPV-002, and 
HVTN-080. 
Durvalumab (also known as MEDI4736) has an acceptable safety profile as detailed in Section 
1.2.2 and the durvalumab IB.   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. 
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1.3.3.1. 
Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
study (Study 1108; N=292; doses=0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). 
Population PK analysis indicated only minor impact of body weight (WT) on the PK of 
durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed 
dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median and 95th percentiles) using the population PK model. A fixed dose of 
750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 
1000 subjects were simulated using body WT distribution of 40–120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-subject variability with fixed dosing regimen.  
Similar findings have been reported by others (Ng et al 2006, Wang et al 2009, Zhang et al 2012, 
Narwal et al 2013). Wang and colleagues investigated 12 monoclonal antibodies and found that 
fixed and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-
subject variability in pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012).  
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, we 
considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 kg, a 
fixed dose of 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is included in the current 
study. 
1.3.4. 
Rationale for study population 
Recurrent HPV-associated cancers not amenable to surgical resection or radiation salvage are 
largely incurable with short overall survivals after recurrence. There is a large unmet need for 
therapeutics for these patients. Anti-PD1/PDL1 checkpoint inhibitors have been shown to have 
good activity in HPV associated cancers (Morris et al 2016). Furthermore, HPV-16 and/or HPV-
18 subtypes are found in 70% of all cervical cancers, (deSanjose et al 2010) 65% of anal cancers, 
(Bosch et al 1995) and 70% of penile cancers (Maden et al 1993). 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. 
1.4. 
Benefit/Risk and Ethical Assessment 
1.4.1. 
Potential benefits - MEDI0457 
The safety profile of MEDI0457 (INO-3112) with EP has been generally acceptable, although this 
statement 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; and (2) clinical benefits in patients with high grade cervical 
intraepithelial neoplasia, including viral clearance and improvement in pathological grade in the 
lesion area (Trimble et al 2015). 
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We expect to observe both an immune response to MEDI0457 and clinical benefits in most 
patients in this study. 
1.4.2. 
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 IB.  As of 12 July 2015, 456 of 
694 patients with advanced solid tumors treated with durvalumab 10 mg/kg every two weeks 
were evaluable for response (defined as having ≥ 24 weeks’ follow-up, measurable disease at 
baseline, and ≥ 1 follow-up scan, or discontinued due to disease progression or death without any 
follow-up scan).  In PD-L1 unselected patients, the ORR, based on investigator assessment per 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, ranged from 0% in uveal 
melanoma to 20.0% in bladder cancer, and DCR at 24 weeks (DCR-24w) ranged from 4.2% in 
triple negative breast cancer to 39.1% in advanced cutaneous melanoma.  PD-L1 status was 
known for 383 of the 456 response evaluable patients.  Across the PD-L1-positive tumors, ORR 
was highest (> 10%) for bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma 
(33.3% each), non-small cell lung cancer (26.7%), and SCCHN (18.2%).  In the PD-L1-positive 
subset, DCR-24w was highest (> 10%) in advanced cutaneous melanoma (66.7%), non-small cell 
lung cancer (36.0%), hepatocellular carcinoma and bladder cancer (33.3% each), and SCCHN 
(18.2%).  In the PD-L1-negative subset, ORR was 6.3% and DCR-24w was 25.3%.  For further 
details, please refer to the durvalumab IB. 
1.4.3. 
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. 
1.4.4. 
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.   
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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.  
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 the MEDI0457 IB for 
additional information). 
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 (Adorini 1999).  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 supporting companies.  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 E.  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. 
1.4.5. 
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, hepatitis/hepatotoxicity, endocrinopathy (hypothyroidism, hyperthyroidism, 
hypophysitis, and adrenal insufficiency), neuropathy/neuromuscular toxicity, nephritis, 
pancreatitis (elevated lipase/amylase), pneumonitis, and 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 
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toxicity management guidelines for this entire class of therapeutics (see Appendix D, Postow 
2015). 
For further details, please refer to the durvalumab IB. 
1.4.6. 
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 
1.4.4.  Mitigations in place to reduce the adverse effects of MEDI0457 with EP administration 
include the following: 

rotation of injection sites,

patients will be told 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 Common Terminology Criteria for Adverse Event (CTCAE) Grade 3 injection
site reactions that exist for > 5 days.
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 1.4.5.  It is reasonable to assume there is a risk of additive or synergistic 
toxicities with this combination.  Mitigations in place to detect and reduce the adverse effects of 
potential immune-mediated reactions include the following: 

eligibility criteria excluding certain auto-immune 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 toxicities and
management guidelines (Appendix D, 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 
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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 D, Postow 2015).  
1.5. 
Research Hypotheses 

MEDI0457 treatment in combination with durvalumab will be safe in patients with
recurrent/metastatic HPV-16 and/or HPV-18 associated cancers.

MEDI0457 treatment in combination with durvalumab will have good anti-tumor activity
as defined by response rate in patients with recurrent/metastatic HPV-16 and/or HPV-18
associated cancers.
1.6. 
Study Design 
This study will be an open label, multi-cohort, phase II trial for the combination therapy of 
MEDI0457 (INO-3112) and Durvalumab (MEDI4736) in patients with HPV-16 and/or -18 related 
malignancies. This study will enroll 3 cohorts of patients with HPV-16/18 (+) tumors. The three 
cohorts are: 
1. HPV-16/18 cervical cancer,
2. HPV-16/18 rare tumors (anal, penile, vulvar, vaginal), and
3. HIV (+) HPV-16/18 malignancies (any site).
Each cohort will have a two-stage design with predetermined stopping rules based on ORR after 
stage I and each cohort will function independently clinically. After each cohort completes 
accrual to stage I, only the two cohorts with the most responses will move on to stage 2. 
Therefore, accrual to stage 2 will not start till all three cohorts have completed stage I. However, 
if a single cohort has a high response rate (≥4 responses out of 9 patients), the second stage of 
accrual may proceed prior to other cohorts completing stage I. 
At the onset of the study, only patients with cervical, vulvar, or vaginal cancers will be enrolled 
for the first 3 slots. Once all 3 of these patients have completed the first 6 weeks of treatment, 
enrollment will be opened to all included cancer histotypes. 
Both MEDI0457 and durvalumab treatment will continue until confirmed disease progression or 
unacceptable toxicity.  Either treatment may be stopped by the investigator if a SAE is deemed to 
be related to that treatment while the other treatment continues.  
The target population consists of male or female patients 18 years of age or older with recurrent 
or metastatic HPV 16- or 18-associated cancers with persistent or progressive disease (PD) after 
initial standard-of-care treatment and lacking a curative treatment option.  
Eligible patients must have at least one "measurable target lesion"—according to RECIST version 
1.1—that has not been previously irradiated. In addition, if the primary lesion is not large enough 
for a biopsy without changing radiologic findings for following response, one additional lesion 
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that can be safely biopsied at screening and prior to the first dose of MEDI0457 at Week 1 will be 
required. 
All patients will receive combination treatment with MEDI0457 and durvalumab as per the 
Planned Dosing Schedule (Section 4.4.1, Figure 1, and Table 3). 
Figure 1. Overall Study Design Study Flow Chart 
 
In the case that the first stopping boundary is crossed (Section 8.1.3), a Revised Dosing Schedule 
will be decided by the Principal Investigators, collaborators, supporters, and IND Office Medical 
Monitor and will be used for the remaining patients. Two options are to decrease the number of 
doses of vaccine given from a total of 3 to either 1 or 2 during the first 7 weeks and/or decrease 
dose of durvalumab to 750 mg Q4W. Other options may also be considered based on toxicity 
profile. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary 
To evaluate the anti-tumor activity of MEDI0457 in combination with durvalumab. 
2.2. 
Secondary 
The secondary objectives are as follows: 
 To determine the safety profile of MEDI0457 in combination with durvalumab in patients 
with recurrent/metastatic HPV 16- or 18- associated cancer,  
 To evaluate the PFS and OS of patients with recurrent/metastatic incurable HPV-16/18 
positive solid malignancies receiving the combination of MEDI0457and durvalumab, 
Tumor Core Biopsy at screening & 
Week 10 
Planned Dosing Schedule: Durvalumab at Weeks 4, 8 and 12 and 
then every 4 weeks until disease progression or unacceptable toxicity 
Planned Dosing Schedule: MEDI0457 Vaccine at Weeks 1, 3, 7 and 12 
and then every 8 weeks, until disease progression or unacceptable toxicity 
E 
N 
R 
O 
L 
L 
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
To evaluate ORR by immune-related criteria of the combination of MEDI0457 and
durvalumab in patients with recurrent/metastatic incurable HPV-16/18 positive solid
malignancies, and

To evaluate the disease control rate at 24 weeks.
2.3. 
Exploratory 
The exploratory objectives are as follows: 

To determine the cellular and humoral immune response to immunotherapy with
MEDI0457 in combination with durvalumab,

To examine the correlation between anti-tumor activity and biomarkers including:
o
HPV-specific cellular and humoral responses
o
programmed death ligand 1 status
o
the number of tumor infiltrating lymphocytes
o
HPV 16/18 E6/E7 DNA levels and HPV 16/18 E6/E7 DNA sequence in biopsy tissue
and plasma.

To evaluate the pharmacokinetics and anti-drug antibodies (ADA) for durvalumab.
3.
SUBJECT SELECTION AND PARTICIPATION
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. 
Patients who fail to meet the eligibility criteria should not be enrolled or receive study 
medication.  Patients who are enrolled but subsequently found not to meet all the eligibility 
criteria must not be initiated on treatment and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is incorrectly started on-treatment, the 
investigator should discuss with the supporting company and the IND sponsor (MDACC IND 
Office) to determine whether to continue or discontinue the patient from treatment. 
3.1. 
Inclusion Criteria 
For inclusion in the study patients should fulfill the following criteria. 
1. Written informed consent in accordance with institutional guidelines.
2. Male and female patients age 18 years or older who are able and willing to comply with
all study procedures.
3. For patients who are not HIV positive, cervical, anal, penile, vulvar, or vaginal cancer
positive for HPV-16 and/or HPV-18 by the institutionally approved assay. For patients
who are HIV positive, histologically or cytologically confirmed diagnosis of cancer at any
site that is positive for HPV-16 and/or HPV-18 by the institutionally approved assay.
Tumors may be positive for more than 1 HPV subtype as long as HPV-16 and/or HPV-18
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is present. Note: For the first 3 patients, only cervical, vulvar, or vaginal cancers will be 
enrolled. 
4. Patients with cancer that is refractory to standard therapy, that have either relapsed after
standard therapy or has no standard therapy that increases survival by at least three
months, and/or that are not curable by salvage approaches including resection and/or re-
irradiation.
5. 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 v1.1 progression in the lesion
after such therapy.
6. All patients must consent to pre-treatment biopsy of the tumor if it can be done safely (as
judged by the investigator) during screening.  Week 10 on-treatment biopsies will be
required for a minimum 10 patients.  After 10 paired biopsies have been obtained then
Week 10 on-treatment biopsy will be made optional.
7. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1.
8. Adequate organ and bone marrow function within 28 days of Day 0.  Criteria “a” to “c”
cannot be met with recent (within 28 days of screening test except as noted below) blood
transfusions or require ongoing growth factor support:
a.
Hemoglobin ≥ 9 g/dL (Note: No Transfusion within 7 days of beginning study
treatment. Ongoing growth factor support is acceptable if on a stable dose for the past
56 days.),
b. Absolute neutrophil count ≥ 1,000/mm3,
c.
Platelet count ≥ 100,000/mm3 and no transfusion in prior 4 weeks,
d. Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) except patients with
documented Gilbert's syndrome (> 3 × ULN),
e.
Alanine aminotransferase (ALT) and aspartate aminotransferase (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), and
g. For HIV+ patients: Documented HIV-1 infection with CD4 count > 200 cells/mm3
and viral load < 75 copies/mL.
3.2. 
Exclusion Criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled. 
1. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment;
receipt of any investigational or approved anticancer therapy (chemotherapy, targeted
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therapy, biologic therapy, monoclonal antibodies, etc.) within 21 days or 5 half-lives, 
whichever is shorter, prior to the first dose of MEDI0457; concurrent enrollment in 
another clinical study, unless it is an observational (non-interventional) clinical study or 
during the follow-up period of an interventional study. 
2. 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.
3. Any unresolved toxicity (National Cancer Institute Common Terminology Criteria for
Adverse Event [CTCAE] version 4.03 [v4.03]) Grade 2 or greater from previous
anticancer therapy with the exception of alopecia, and the laboratory values defined in the
inclusion criterion 8.  Hearing loss of Grade 3 or lower and peripheral neuropathy of
Grade 2 or lower is allowed. Subjects with Grade ≥ 2 neuropathy will be evaluated on a
case-by-case basis after consultation with the Study Physician. Subjects with irreversible
toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be
included only after consultation with the Study Physician.
4. 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 physiologic doses not to exceed 10 mg/day of prednisone or equivalent.
Steroids as premedication for hypersensitivity reactions due to radiographic contrast
agents are allowed.
5. Patients requiring therapeutic anticoagulation and irreversible platelet inhibitors (e.g.
clopidogrel, prasugrel, or ticagrelor).  Low dose aspirin for cardiac prophylaxis is allowed.
6. History of primary immunodeficiency.
7. Patients who have had prior exposure to immune-mediated therapy, including but not
limited to prior exposure to T-cell and natural killer cell directed therapy, anti-PD-1, anti-
PD-L1, anti-CD137, and anti-CTLA4.
8. History of allogeneic organ transplantation.
9. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g. colitis, ulcerative colitis or Crohn's disease],
diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,
Sarcoidosis syndrome, 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, and

Patients with celiac disease controlled by diet alone.
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
24 
10. 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.
11. 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 criteria.

No concurrent treatment, inclusive of, but not limited to, surgery, radiation, and/or
corticosteroids. Note: patients are allowed on systemic steroids as detailed in
Exclusion Criterion 4 unless these are being administered to manage central nervous
system metastases.

Neurologic stability (lack of signs or symptoms greater than baseline prior to
radiotherapy) until the time of dosing of MEDI0457.

For radiation treatment, patients must be:
i. At least 14 days between last day of stereotactic radiosurgery or gamma-knife
treatment and Day 1 of protocol treatment,
ii. At least 28 days between last day of whole brain radiation therapy and Day 1 of
protocol treatment, and/or
iii. At least 14 days since last dose of corticosteroids and Day 1 of protocol treatment.
12. 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 OR a recent (< 3 months) CV event, including myocardial
infarction, unstable angina pectoris, or stroke.
13. Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from ECG using
Fridericia’s Correction by manual read.
14. Active tuberculosis (clinical evaluation that includes clinical history, physical examination
and radiographic findings, and tuberculosis testing in line with local practice) infection.
15. Presence of acute or chronic hepatitis B (HBV) or active hepatitis C (HCV). Patients with
a past or resolved HBV infection (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) are eligible.  Patients positive for HCV antibody are
eligible only if polymerase chain reaction is negative for HCV RNA.
16. 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.
17. Other untreated coexisting HIV related malignancies.
18. History of another primary malignancy except for:
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
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
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, or

adequately treated carcinoma in situ without evidence of disease.
19. Pregnant or breastfeeding female patients.
20. Known allergy or hypersensitivity to study treatment or any of the study drugs excipients.
21. 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.
22. Patients with active or prior digestive tract bleeding.
23. Patients with uncontrolled seizures.
24. 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.
25. Patients who are unable to provide informed consent, are incarcerated, or are unable to
follow protocol requirements.
3.3. 
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 4.4.3). 
3.3.1. 
Concomitant Medications 
3.3.1.1. 
Allowed 
Concomitant medications which are allowed while participating on this trial are listed in Table 1. 
Table 1. Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments (e.g. 
acetaminophen or diphenhydramine) deemed 
necessary to provide adequate prophylactic or 
supportive care, except for those medications 
identified as “prohibited,” as listed above  
To be administered as prescribed by the 
Investigator 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
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Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative 
radiotherapy to non-target lesions, etc.]) 
Should be used, when necessary, for all 
subjects 
Inactivated viruses, such as those in the 
influenza vaccine 
Permitted 
Highly active antiretroviral therapy (HAART) 
Patient remains stable on current HAART 
(Highly active antiretroviral therapy) while on 
study. Viral load<75 copies/mL. CD4 counts 
≥ 200 criteria at all times. Obtain routine 
outpatient ID consult for management of HIV 
prior to commencing study.   
3.3.1.2. 
Prohibited 
The following medications are considered exclusionary during the study, andexceptions to the 
exclusion are included. The MDACC IND Office must be notified if a patient receives any of 
these during the study. 
1. Any concurrent chemotherapy, radiotherapy, immunotherapy, IP, biologic, or hormonal
therapy for cancer treatment. Concurrent use of hormones for non-cancer-related
conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
Local treatment of isolated lesions, excluding target lesions, for palliative intent is
acceptable (e.g., by local surgery or radiotherapy).
2. Immunosuppressive medications including, but not limited to, systemic corticosteroids at
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and
tumor necrosis factor-alpha (TNF-α) blockers. Use of immunosuppressive medications for
the management of IP-related AEs, or in subjects with contrast allergies is acceptable). In
addition, use of inhaled, topical, and intranasal corticosteroids is permitted. 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.).
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. Drugs with laxative properties and herbal or natural remedies for constipation should be
used with caution through 90 days after the last dose of durvalumab during the study.
5. Sunitinib should not be given concomitantly or through 90 days after the last dose of
durvalumab (acute renal failure has been reported with combination therapy of
durvalumab and sunitinib).
6. Live attenuated vaccines should not be given through 30 days after the last dose of IP
(including SoC)
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
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3.3.2. 
Contraception 
Female subjects of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least one highly effective methods of effective contraception (Table 2) from 
the time of screening and must agree to continue using such precautions for 90 days after the last 
dose of IP. Cessation of birth control after this point should be discussed with a responsible 
physician. 
Females subjects of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal. 
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 luteinizing hormone and follicle-stimulating hormone 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 >6 months 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 are presented in Table 2. 
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Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8 
Date: July 26, 2019 
28 
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. 
3.3.3. 
Blood donation 
Subjects should not donate blood while participating in this study until 90 days after the last dose 
of IP. 
3.4. 
Discontinuation of Investigational Product 
An individual patient will not receive any further IP if any of the following occur. 

Initiation of subsequent anticancer therapy including another investigational agent.

Confirmed PD: the initial assessment of PD by RECIST v1.1 (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.

An AE that, in the opinion of the Investigator, supporting company, or the MDACC IND
Office, contraindicates further dosing.

Patient experienced a DLT as defined in Section 6.7.2.

Withdrawal of consent from further treatment with IP or lost to follow-up.
Table 2. Effective Methods of Contraception 
Barrier Methodsa,b 
Intrauterine Methods 
Hormonal Methods 
Male condom plus spermicide 
Cap plus spermicide 
Diaphragm plus spermicide 
e.g., Copper T intrauterine
deviced
Progesterone T intrauterine 
devicec 
Levonorgesterel-releasing 
intrauterine system (e.g., 
Mirena®c,d 
e.g., Implantsd
Hormone shot or injectiond 
Combined pilld 
Minipilla 
Patchd 
a.
Not highly effective (failure rate of = 1% per year)
b. A male condom plus cap, diaphragm, or sponge with spermicide (double barrier
methods) are also considered acceptable, but not highly effective, birth control methods
c.
Also considered a hormonal method
d. Highly effective (failure rate of < 1% per year)
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Drug Substances: Durvalumab, MEDI0457 
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Version Number: 1.8 
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
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 IP might
constitute a safety risk.

Pregnancy or intent to become pregnant.

Non-compliance with the study protocol that, in the opinion of the Investigator, supporting
company, or the MDACC IND Office, warrants withdrawal from treatment with IP (e.g.,
refusal to adhere to scheduled visits).

The treating Physician determines it is not in the best interest of the patient to continue.
At any time, patients are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments) without prejudice to further treatment. If a patient is withdrawn from study, see 
Section 3.5.2. 
3.5. 
Criteria for Withdrawal 
A patient will be considered to have completed the study when he/she completes all protocol 
specified scheduled study visits.  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 7. 
Patients who discontinue study treatment will be followed for: (1) up to 90 days after last study 
treatment with durvalumab and/or MEDI0457; (2) until AE/SAE resolution or an outcome is 
reached for all events (see Section 7.4.2); or (3) until patient initiates alternative anticancer 
therapy.  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 database (see Section 7.4.2 
for further details regarding the follow-up of unresolved AEs).   
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 assessments.  
Investigator should discuss the reason for any discontinuation of study treatment with the 
MDACC IND Office 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. 

Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of the
investigator for the best interest of the patient, are grounds for discontinuation.  This
includes serious and non-serious AEs regardless of relation to study treatment.
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Drug Substances: Durvalumab, MEDI0457 
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
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 in the database.  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.

Lack of Patient Compliance: 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 IND Office 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 supporting company.
3.5.1. 
Screen failures 
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be enrolled into the study.  These patients should have the reason the patient does not 
meet the required inclusion/exclusion criteria for study withdrawal recorded.  This reason for 
study withdrawal is only valid for screen failures. 
3.5.2. 
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 possible, they will 
be seen and assessed by an investigator(s), and AEs will continue to be followed (see Section 7). 
If a patient withdraws from participation in the study, then his/her enrollment number cannot be 
reused. 
4.
INVESTIGATIONAL PRODUCTS
4.1. 
Identity of Investigational Products 
4.1.1. 
MEDI0457 
MEDI0457 is a plasmid DNA vaccine consisting of three plasmids as a 3:3:1 (w/w) combination 
of pGX3001, pGX3002 and pGX6001. 
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Drug Substances: Durvalumab, MEDI0457 
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Version Number: 1.8 
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MEDI0457 will be supplied in a single pre-filled 2 mL glass vial containing all three components.  
The minimum fill volume for MEDI0457 vials is 1 mL. 
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. 
4.1.1.1. 
pGX3001 
Chemical name: Circular double-stranded DNA plasmid consisting of 3782 base pairs. 
Distinguishing name: Eukaryotic expression plasmid containing HPV-16 E6 and E7-encoding 
transcription unit controlled by a synthetic, cytomegalovirus promoter, and elements required for 
replication and selection in E. coli, namely a pUC origin of replication (pUC Ori) and a 
kanamycin resistance gene (Kan R). 
4.1.1.2. 
pGX3002 
Chemical name: Circular double-stranded plasmid DNA consisting of 3824 base pairs. 
Distinguishing name: Eukaryotic expression plasmid containing HPV-18 E6 and E7-encoding 
transcription unit controlled by a synthetic, cytomegalovirus promoter, and elements required for 
replication and selection in E. coli, namely a pUC origin of replication (pUC Ori) and a 
kanamycin resistance gene (Kan R). 
4.1.1.3. 
pGX6001 
Chemical name: Circular double-stranded plasmid DNA consisting of 6259 base pairs. 
Distinguishing name: Eukaryotic expression plasmid containing synthetic interleukin-12 p35 light 
chain and p40 heavy chain (pGX6001) controlled by a dual promoter vector, a bGH poly A tract, 
bacterial origin of replication to support production of the plasmid in E. coli, and a kanamycin 
resistance gene (Kan R).  
4.1.2. 
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 AstraZeneca/MedImmune or its designee as a 500 mg vial 
solution for infusion after dilution.  The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (w/v) polysorbate 80; it 
has a pH of 6.0.  The nominal fill volume is 10.0 mL. IP vials are stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Durvalumab must be used within the individually assigned expiry 
date on the label. 
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Drug Substances: Durvalumab, MEDI0457 
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Version Number: 1.8 
Date: July 26, 2019 
32 
4.1.3. 
CELLECTRA®5P device for in vivo electroporation 
The use of EP via the CELLECTRA®5P device increases the immunogenicity of MEDI0457.  
Electroporation utilizes a transmembrane electric field pulse to induce microscopic pathways 
(pores) in a bio membrane.  The electric field allows macromolecules, ions, and water to pass 
from one side of the membrane to the other.  The presence of a constant field influences the 
kinetics of directional translocation of the macromolecular plasmid, such that the plasmid delivery 
in vivo has been sufficient to achieve physiological levels of secreted proteins.  Intramuscular 
injection of plasmid followed by EP has been used very successfully to deliver therapeutic genes 
that encode for a variety of hormones, cytokines or enzymes in a variety of species (Prud'homme 
et al 2006, Prud'homme et al 2007).  The design of software that enables constant current EP to 
deliver plasmids allows for the individual resistance of the treated muscle to be taken into 
consideration and yields highly efficient in vivo plasmid expression (Khan et al 2005). 
The target organ for EP is skeletal muscle.  The skeletal musculature is an excellent candidate for 
the target tissue of gene expression, because muscle fibers have a long lifespan and can be 
transduced by circular plasmids, allowing the gene to be expressed efficiently in 
immunocompetent hosts (Davis et al 1993, Tripathy et al 1996).  Furthermore, muscle is well 
vascularized, allowing the newly produced transgene product to gain access to the circulation. 
The CELLECTRA®5P) device and its components bear labels that identify the device name and 
place of business of the manufacturer.  The CELLECTRA®5P User Manual describes all relevant 
contraindications, hazards, adverse effects, interfering substances or devices, warnings, and 
precautions.  Each CELLECTRA®5P Pulse Generator has a unique serial number and each 
CELLECTRA®5P Applicator has a unique serial number.  Each CELLECTRA®5P Array has a 
Lot Number, Manufacture Date and Expiration Date. 
The CELLECTRA®5P device, and its components, will be shipped directly from the 
manufacturer to 1) the study site or 2) the study depot prior to shipping to the study site.  The 
investigational labels in Section 4.2 below are presented as examples. Please note, information 
such as expiration date, lot and serial numbers (as applicable) is included at the time of 
manufacture and may vary from these examples.  The information found on the actual device 
labels should always be used to manage, track and record IP accountability during study conduct. 
4.2. 
Labeling 
This study is open-labeled; therefore, the patient, the investigator’s site personnel, supporting 
company representative, and the MDACC IND Office 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. 
Example labels for the CELLECTRA®5P Device (Pulse Generator, Applicator and Array) are 
shown in Figure 2. 
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Drug Substances: Durvalumab, MEDI0457 
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Version Number: 1.8 
Date: July 26, 2019 
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Device Component 
Example Label 
CELLECTRA® 5P Pulse 
Generator
Model 14510
Part Number: 
M01-003188 
CELLECTRA® 5P 
Applicator
Model 14506
Part Number: M01-
002535
CELLECTRA® IM Array 
REF: M01-002537
Figure 2. Examples of labeling for the CELLECTRA®5P 
4.3. 
Study Drug Preparation 
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. 
4.3.1. 
MEDI0457 
Vial contents must be thawed at ambient room temperature and must be administered within 4 
hours of removal from freezer.    
The study personnel will draw 1 mL of MEDI0457 from the pre-filled vials using a syringe.  This 
syringe will be used to administer IP to the patients IM through the CELLECTRA®5P device. 
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Drug Substances: Durvalumab, MEDI0457 
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Date: July 26, 2019 
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The syringe must be labeled with the date and time it was removed from the freezer and a 4-hour 
expiration date and time from the time the vial is removed from the freezer.  The label should also 
contain the words “administer as soon as possible”. 
4.3.2. 
Durvalumab 
All doses will be prepared in infusion bags under aseptic conditions by trained personnel; it 
should not be prepared on the ward. No incompatibilities between Durvalumab and 
polyvinylchloride or polyolefin IV bags have been observed.  
Durvalumab will be administered using an IV bag containing 0.9% (w/v) saline, 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. 
For patients ≥30 kg, remove 30.0 mL of IV solution from the IV bag prior to addition of 
Durvalumab. Next, 30.0 mL of Durvalumab (i.e., 1500 mg of Durvalumab) is added to the IV bag 
such that final concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL). Mix the 
bag by gently inverting to ensure homogeneity of the dose in the bag. 
For patients < 30 kg, calculate the dose volume of Durvalumab and number of vials needed for 
the subject to achieve the accurate dose according to Appendix F. 
4.4. 
Doses and Treatments 
4.4.1. 
Planned Dosing Schedule 
All patients will receive combination treatment with MEDI0457 and durvalumab as per the 
following Planned Dosing Schedule (treatment should be given at the beginning of the week, 
unless otherwise specified) as detailed in Figure 1 and Table 3. 
Durvalumab will be administered at a fixed dose of 1500 mg q4wk for patients that are ≥30 kg. 
For patients who weigh <30 kg, weight-based dosing will be used at a dose of 20 mg/kg q 4 
weeks, and if their weight increases to ≥30 kg they can be switched to durvalumab at 1500 mg 
every 4 weeks. 
Patients will receive 7 mg MEDI0457 delivered by IM followed by EP on Day 1 (Week 1), 
Week 3, Week 7, Week 12 and then every 8 weeks until disease progression or unacceptable 
toxicity.  Durvalumab will be administered on Week 4, Week 8, Week 12 and then every 4 weeks 
until disease progression or unacceptable toxicity.  On days when both MEDI0457 and 
durvalumab administrations will occur on the same day (Week 12 then every 8 weeks), 
MEDI0457 will be administered first, and durvalumab IV infusion will start approximately 1 hour 
after MEDI0457 is delivered intramuscularly followed by EP. 
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. 
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4.4.2. 
Durvalumab 
Durvalumab will be administered at a fixed dose of 1500 mg q4w in the combination and 
monotherapy arms for patients weighing ≥30 kg. For patients weighing <30 kg, the dose will be 
20 mg/kg. The maximum number of doses of checkpoint inhibitor therapy will equal 13. 
The duration will be approximately 1 hour (± 5 minutes) for each durvalumab infusion.  A 1- hour 
observation period is required after the first infusion of durvalumab is administered.  If no 
clinically significant infusion reactions are observed during or after the first dose, subsequent 
infusion observation periods can be at the investigator’s discretion (suggested 30 minutes after 
each durvalumab infusion). 
Patients will be monitored during and after the infusion with assessment of vital signs at the times 
specified in the study protocol. 
See Section 6.7.1 dose administration changes in the event of Grade 1 or 2 infusion-related 
reactions. 
4.4.3. 
MEDI0457 
The DNA vaccine is administered in two steps.  In step 1 the vaccine is injected intramuscularly 
through the CELLECTRA®5P device.  Step 2 follows immediately as the CELLECTRA®5P 
device delivers a sequence of electroporation pulses to the injection area. 
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.  The use of 
any narcotic (including Tylenol® [acetaminophen] with codeine) for pain meets the 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 in the database. 
The instructions for use of the CELLECTRA®5P device are located in the Operations Manual.  
Each clinical site will receive training for the use of the CELLECTRA®5P device.  The following 
specifications will be used during the study: 
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36 

Number of pulses=3

Current Strength=0.5 Amp

Electroporation pulse duration=52 milliseconds/pulse

Interval separating pulses=1 second
The injection/EP procedure must be performed by qualified personnel.  Any individual designated 
to perform the procedure should be permitted by the relevant local authorities to administer 
parenteral medications to patients in addition to receiving device training from Inovio personnel.  
Individuals whose credentials do not meet the relevant local requirements may perform the 
injection/EP procedure under the conditions below: 

The procedure must be performed under the direct supervision of the Principal
Investigator or an approved Sub-Investigator who has already been trained by the
supporting company’s designated personnel.

The curriculum vitae and any relevant qualifications of the individual have been reviewed
and approved by the Inovio or its designee to perform the procedure.
Any deviation from the above procedures must be approved by Inovio and MDACC IND Office 
or its designee. 
4.4.4. 
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 Inovio or designee by e mail to 
CELLECTRAdata@inovio.com.  Instructions on how to download the data are provided 
separately.  Training will be provided. 
4.5. 
Accountability and Disposition 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF). See the CTEP home page at http://ctep.cancer.gov for the Procedures for Drug 
Accountability and Storage or to obtain a copy of the DARF. Any deviation or error in use of 
CELLECTRA®5P device must be reported error reporting form (Appendix C) 
The site will account for all investigational study drug dispensed and also for appropriate 
destruction. Certificates of delivery and destruction must be signed. 
5.
STUDY PLAN
All study procedures will be performed according to Table 3. 
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37 
Table 3. Schedule of Study Procedures 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4a 
Cycle 5a 
EOTb 
Follow-upc 
Week of Study 
- 
1 
3 
4 
7 
8 
10 
12 
16 
20 
- 
- 
Procedures 
Day of Week 
-28 to -1
1 
±7 days (unless otherwise noted) 
Informed consent 
X 
Demographics 
X 
Medical historiesd 
X 
Inclusion/exclusion criteria 
X 
X 
Physical examinatione 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease statusg 
Xh 
Xi 
Xi,j 
X 
Xk 
Hepatitis/HIV screeningl 
X 
Vital signsm 
Xg 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
Xf 
X 
X 
Xn 
X 
HPV typingo 
X 
Hematologyp 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xq 
X 
Serum chemistryr 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Xq 
X 
Coagulation testings 
X 
As clinically indicated. 
Thyroid function testingt 
X 
Xf 
X 
X 
X 
X 
Xq 
X 
Urinalysisu 
X 
As clinically indicated. 
Pregnancy testv 
Xw 
Xx 
X 
X 
X 
X 
X 
X 
MEDI0457 administrationy 
X 
X 
X 
X 
X 
MEDI0457 post-treatment reactionz 
X 
X 
X 
X 
X 
Download EP data 
X 
X 
X 
X 
X 
Durvalumab administrationaa 
X 
X 
X 
X 
X 
Tumor biopsybb 
X 
Xcc 
Xdd 
Immune Profiling/HPV Serology Research Bloodee 
X 
X 
X 
X 
Xff 
X 
Pharmacokinetics/ADA Research Bloodgg 
X 
X 
Xhh 
Viral loadii 
X 
X 
X 
X 
X 
X 
X 
HBV DNA/Hep BsAgjj 
X 
X 
X 
X 
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38 
Drug Substances: Durvalumab, MEDI0457 
Study Numbers: 2017-0302, ESR-16-12202 
Version Number: 1.8  
Date: July 26, 2019 
a Patients can continue on the study until progression or unacceptable toxicity as long as the physician feels the patient is receiving benefit. Cycles 4 and 5 should be repeated to continue this 
treatment. b End of treatment (EOT) is defined as the last visit where the decision is made to discontinue protocol directed treatment. 
c A clinic visit is not required for follow-up. Patients who are taken off study due to disease progression or intolerable toxicities will be followed for vital status every 6 months via phone and/or 
review of medical record. 
d Histories include medical history, history of prior cancer treatment, history of procedures 
e Complete physical examination during Screening and at the Follow-up visit; targeted physical examination at all other visits. 
f If performed within 3 days prior to Day 1, they do not need to be repeated. 
g The preferred method of disease assessment is CT with contrast. The same method is preferred for all subsequent tumor assessments for the same patient. Patients discontinued from treatment for 
reasons other than PD will continue disease assessments until confirmed PD or start of subsequent anticancer therapy. 
h Magnetic resonance imaging scan of the brain will be performed only at screening or at each assessment if the patient is neurologically symptomatic during treatment outside of the setting where the 
patient has known central nervous system metastases. 
i If possible, disease status assessments will be performed on the day prior to scheduled drug administration. 
j Disease status assessments will be performed every 8 weeks ( 3 days) (relative to the date of the first MEDI0457 administration) for 1 year, if CR/PR/SD are achieved then disease status 
assessments should be performed every 12 weeks ( 7 days) until the EOT. 
k If no PD, disease assessment should be performed on Day 90 (± 7 days) after EOT, every 3 months (± 7 days) after Day 90 up to Month 12, and then every 6 months (± 14 days) after Month 12 until 
the end of study (EOS). 
l Hepatitis screening tests include: HBV-DNA, HCV-Ab, HBsAg, HBcAB, and HBsAb.
m Temperature, respiratory rate, pulse oximetry, blood pressure, HR and weight. Height will be measured only during Screening. See Section 6.5.7 for details. 
n Every 12 weeks until end of treatment.
o Historical tissue samples may be used; there is no need for additional samples/test for the HPV 16/18 test to be collected just for this protocol.
p Hematology panel includes: basophils, eosinophils, hematocrit, hemoglobin, lymphocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume,
monocytes, neutrophils, platelet count, red blood cell count, total white cell count. For patients in the HIV(+) cohort, CD4 and CD8 counts will be performed.
q Every 4 weeks for first 12 months and every 3 months thereafter until study discharge.
r Serum Chemistry panel includes: albumin, alkaline phosphatase, ALT, AST, bicarbonate, calcium, chloride, glucose, lactate dehydrogenase, magnesium, potassium, sodium, total bilirubin (if Total 
bilirubin is ≥2xULN [and no evidence of Gilbert’s syndrome] then fractionate into direct and indirect bilirubin), total protein, creatinine, creatinine phosphokinase, blood urea nitrogen, uric acid, 
amylase and lipase. Please note: GGT to be collected at baseline and as clinically indicated.
s Prothrombin time, APTT and INR.
t Free triiodothyronine (T3) and free thyroxine (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.
u Urinalysis panel includes: bilirubin, blood, glucose, ketones, pH, protein, specific gravity, and color/appearance.
v Only for women of childbearing potential.
w To include luteinizing hormone and follicle-stimulating hormone only for women of child bearing potential who may be post-menopausal. 
x 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.
y A window of ±3 days for all time points except C1D1. For Cycles 1 and 2, an interval of 7 days must occur between MEDI0457 and durvalumab treatments. 
z MEDI0457 post-treatment reactions will be assessed 30 to 60 min after study treatment.
aa A window of ±3 days applies to all time points.
bb Core tumor biopsies will be collected as per Section 6.6.1.
cc ± 3 days. Biopsies at this time point are required until 10 subjects have provided tissue and then are optional for all subsequent subjects.
dd At time of confirmed disease progression; Optional
ee See Section 6.6.2.1 for HPV Serology Research Blood details.
ff Week 16 and then every 8 weeks until end of treatment.
gg See Section 6.6.2.2 for Pharmacokinetics/ADA details.
hh Week 16 only.
ii For HIV(+) patients, viral load will be drawn at baseline, every month for the first 3 months, then every 3 months thereafter while on therapy.
jj For patients with inactive Hepatitis B (Hep B core Ab(+)/HepB sAg (-)),HBV DNA and Hep BsAg will be monitored every month for the first 3 months, then every 3 months thereafter while on
therapy.
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39 
6.
STUDY ASSESSMENTS
The Prometheus system will be used as the database for data collection and query handling. This 
database system was developed at MD Anderson for conduction of phase II and phase III clinical 
trials. The investigator will ensure that data are recorded in the database 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. 
6.1. 
Demographics 
The demographics (date of birth, sex and race) details for each patient will be collected at the 
screening visit. 
6.2. 
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 disease e.g., past surgical and/or radiation regimens.  Any prior chemotherapy or 
immunotherapies, adjuvants, etc. should be recorded in the electronic medical record. 
Illnesses first occurring or detected after the first protocol specific intervention 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 in the database. 
6.3. 
Efficacy Assessments 
RECIST v1.1 will be used to assess patient response to treatment by determining ORR, Disease 
Control Rate at 24 weeks (DCR-24w), and PFS.  Objective response rate will also be assessed 
using immune-related RECIST (irRECIST).  OS will also be evaluated. 
The methods of assessment of tumor burden used at baseline are CT and/or MRI scans, 
preferably with IV contrast imaging, of the chest, abdomen, and pelvis.  Any other areas of 
disease involvement should be additionally imaged based on the signs and symptoms of 
individual patients. 
Radiologists at the MD Anderson Cancer Center have developed a multimedia structured reporting 
system, called ViSion, which will be used to capture the key images and metrics recorded by a radiologist 
for tumor response assessment.  The captured images are tagged by a radiologist with metadata referenced 
to the SNOMED-CT ontology to indicate the anatomical location and radiological observation/diagnosis 
of each finding. The ViSion system displays serial image findings linked in graphical disease timelines. 
Target and non-target lesions may be designated by a radiologist from which the calculation and display 
of disease response criteria (e.g., RECIST) is automated. The radiologist’s actual image analysis is 
performed using the institution’s FDA-cleared Philips iSite picture archiving and communications system 
(PACS) display that is enabled with electronic calipers – ViSion only captures the annotated key images 
and metrics for subsequent storage, analysis and display. The ViSion database is housed within the 
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institutional firewall on an MD Anderson server, and the system is HIPAA-compliant requiring 
institutional passwords for controlled access. 
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 ( 3 days) 
(relative to the date of the first MEDI0457 administration) for 1 year, if CR/partial response 
(PR)/SD are achieved then disease status assessments should 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 ± 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.  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. 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following: 
 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, and/or 
 SD while on immunotherapy may be durable and represent clinical benefit. 
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 anti-
cancer compounds, this study will include the following in addition to standard RECIST 1.1 
criteria: 
 RECIST will be modified so that PD must be confirmed with a second radiologic 
assessment, preferably, 5 weeks (+/- 7 days) after the initial assessment of PD in the 
absence of clinically significant deterioration. Treatment with study regimen should 
continue between the initial assessment of progression and confirmation for progression 
at outlined in Tables 4.  
 In addition, subjects may continue to receive the study regimen beyond confirmed PD in 
the absence of clinically significant deterioration and if investigators consider that 
subjects may be deriving benefit from treatment and there are no more suitable 
alternative treatments available for the subject.  
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Modification of RECIST as described is meant to discourage the early discontinuation of the 
study regimen and provide a more complete evaluation of its anti-tumor activity than would be 
seen with conventional response criteria. Nonetheless, the efficacy analysis will be conducted by 
programmatically deriving each efficacy endpoint based on the first evidence of progression (by 
modified RECIST 1.1 criteria described below) when progression is confirmed by a second scan. 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than the study regimen or other 
symptomatic progression that requires urgent medical intervention (e.g., central nervous system 
metastasis, respiratory failure due to increasing malignant pleural effusion, or development of 
mechanical bowel obstruction due to carcinomatosis or tumor compression) 
6.4. 
HPV-16 or HPV-18 Testing 
Patients will be enrolled into the study based on a fresh or historical sample that has been tested 
and is positive for HPV-16 or HPV-18 positive by the institutionally approved assay. Please refer 
to section 6.6.1 for details regarding tissue collection. 
6.5. 
Safety Assessments 
6.5.1. 
Laboratory safety assessments 
Clinical laboratory tests (blood and urine) will be performed as detailed in the Schedule of Study 
Procedures (Table 3). 
6.5.2. 
Serology 
Antibodies to HBV and HCV will be measured.  Antibodies to HIV will only be measured if 
clinically indicated.     
Patients with a positive HBV surface antigen (HBsAg) test at screening are not eligible for the 
study. 
Patients who are HBsAg and HBV core antibody (HBcAb) negative but are positive for HBsAb 
may be included in the study provided that all other eligibility criteria are satisfied.   
A HBV DNA test will be performed if the patient is HBsAg negative but HBcAb positive 
(regardless of HBsAb status).   
If the HBV DNA test is positive, the patient will be excluded.   
If the HBV 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.   
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6.5.3. 
Pregnancy testing 
For women of childbearing potential, a negative result for serum pregnancy test (β-HCG) must 
be available at the screening visit, prior to the collection of the tumor biopsy, and prior to each 
administration of IP.  If at any point, the 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). 
6.5.4. 
Physical examination 
A complete physical examination will be performed at screening and follow-up visits and will 
include an assessment of the following: general appearance, respiratory, CV, abdomen, skin (for 
signs of injection site reactions due to MEDI0457 or EP), lymph nodes, abdomen, pelvis, 
musculo-skeletal, and neurological systems.  A targeted physical examination to document 
changes in any medical condition since the last visit will be performed at all other visits. 
6.5.5. 
WHO/ECOG performance status 
A WHO/ECOG performance status will be conducted at screening 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. 
6.5.6. 
Post-treatment reaction assessment 
The investigator will assess local and systemic reactions post-treatment (within 30-60 minutes 
after study treatment).  Any reported MEDI0457 local post-treatment reactions and systemic 
post-treatment reactions will be graded per NCI CTCAE version 4.03 and all must be recorded in 
the database. See Appendix E for more information. 
6.5.7. 
Vital signs 
Vital signs including temperature, respiration rate, pulse oximetry, blood pressure, HR and 
weight will be measured at all the study visits. 
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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 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 the first infusion of
durvalumab is administered.
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 in the database.  Additional monitoring with assessment of vital 
signs is at the discretion of the investigator per standard clinical practice or as clinically 
indicated. 
6.5.8. 
Electrocardiogram 
An ECG will be performed at screening within 28 days prior to Cycle 1 Day 1 for all patients to 
determine patient eligibility and as clinically indicated throughout the study.  One 12-lead ECG 
recordings is required 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), 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. 
6.6. 
Biological Sampling Procedures 
A summary of the samples collected and planned analyses for the study is presented in Table 4. 
The approaches to perform these research assays are rapidly evolving in the laboratories at the 
MD Anderson Cancer Center and across the world. Thus, we will perform these analyses with 
the current state-of-the-art assays available at the time of analysis. 
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44 
6.6.1. 
Tumor biopsies 
Patients will have a pre-treatment tumor biopsy if it can be done safely (as judged by the 
investigator) during screening. Week 10 Day 1 (± 3 days) tumor biopsies will be required until 
10 subjects who completed a pre-treatment biopsy have successfully been biopsied again, and 
then the Week 10 biopsy will be made optional.  Optional biopsies upon confirmed PD will be 
collected if clinically feasible (i.e., repeat biopsy does not pose unacceptable medical risk to a 
subject as determined by the investigator).  If additional clinically indicated biopsies will be 
performed (e.g., for mixed responses), additional tissue will be collected for research purposes 
(optional). All optional biopsies will be discussed with the subject at the time of initial consent. 
To confirm eligibility, tumor tissue from the subject must be confirmed positive for HPV-16 or 
HPV-18 according to the institutionally approved HPV 16/18 assay. Archival tissue, if available, 
may be used for this assay, else tissue from the screening tumor biopsy will be used.  
Fresh tumor biopsies should be preferentially obtained from tumor tissues that are safely 
accessible as determined by the investigator and are not obtained from sites that require 
significant risk procedures, which include, but are not limited to, biopsies of the brain, lung, 
mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or 
bowel wall. 
The biopsied tumor lesion should not be used as a RECIST target lesion.  When feasible and 
depending on the tumor volume, up to 5 cores (18 GA or larger) will be obtained and processed 
in the following preferential order: 1) FFPE, 2) fresh frozen, 3) FFPE, 4) fresh frozen, and 5) 
fresh frozen. 
6.6.2. 
Research Blood 
Research blood sample will be collected at the time points listed in the Schedule of Procedures 
(Table 3). These samples will be used for pharmacokinetics, pharmacogenetics, ADA, 
biomarker, and other analyses as described in Section 6.6. 
Table 4. Summary of Samples, Target, and Assays 
Sample 
Target 
Assay 
Tumor (Archival/Biopsy) 
HPV-16/HPV-18 genotyping 
HPV16/18 assay 
Tumor (Biopsy) 
HPV-16/HPV-18 DNA sequence 
DNA sequencing 
Tumor (Biopsy) 
PD-L1, p16 expression and 
exploratory biomarkers 
IHC, Nanostring, RNAseq, or 
Affymetrix expression analysis 
Serum 
HPV-16/HPV-18 E6/E7 
antibodies, PK, ADA  
Serology assays 
PBMCs 
HPV-16/HPV-18 E6/E7 T-cells 
IFN- ELISPOT and FACS 
Plasma 
HLA type, Tumor cell DNA and 
HPV-16/HPV-18 DNA  
High resolution class I HLA, 
PCR and DNA sequencing 
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6.6.2.1. 
Immune Profiling and HPV serology 
At the time points listed in Table 3, up to 70 mL of blood will be collected in vacutainer tubes 
(containing heparin and/or serum separating agent) for the isolation of PBMCs, plasma, and 
serum. 
6.6.2.2. 
PK and ADA 
At the time points listed in Table 3, up 10 mL of blood will be collected in vacutainer tubes 
(containing serum separating agent) for the isolation of serum for PK and ADA analyses. 
6.6.3. 
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, the 
researchers are not obliged to destroy the results of this research. 
6.7. 
Management of IP-related Toxicities 
6.7.1. 
Dose Management 
Either treatment may be stopped by the investigator while the other treatment continues. 
MEDI0457 doses should not be modified.   
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).

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 D, Postow 2015). 
Following the first dose of durvalumab, subsequent administration of durvalumab can be 
modified based on toxicities observed (Appendix D, 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 
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46 
(hypothyroidism, hyperthyroidism, hypophysitis, and adrenal insufficiency), 
neuropathy/neuromuscular toxicity, nephritis, pancreatitis (elevated lipase/amylase), 
pneumonitis, and colitis should be considered to be immune-related.   
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.  In the event of Grade ≤ 2 
infusion-related reaction, the infusion rate of durvalumab may be decreased by 50% or 
interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate 
until completion of the infusion.  In patients experiencing Grade ≤ 2 infusion-related reaction, 
subsequent infusions may be administered at 50% of the initial rate.  If a patient experiences an 
infusion-related reaction, acetaminophen and/or an antihistamine (e.g., diphenhydramine) and/or 
corticosteroid or equivalent medications per institutional standard may be administered prior to 
subsequent infusions at the discretion of the investigator for secondary prophylaxis of infusion-
related reactions.  If the infusion-related reaction is Grade 3 or higher in severity, treatment with 
durvalumab 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. 
6.7.2. 
Dose-limiting Toxicities 
Grading of DLTs will be according to the NCI CTCAE version 4.03. 
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 the 
initial six patients), 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 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the
initiation of maximal supportive care is a DLT.
e.
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.
f.
Any ≥ Grade 3 cardiotoxicity (to include but not limited to arrhythmias, myocarditis with
cardiomyopathy, ventricular dysfunction) irrespective of duration is a DLT.
g. Any ≥ Grade 3 ocular toxicity (including but not limited to iritis, uveitis, significant
vision changes) irrespective of duration is a DLT.
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h. 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.
i.
AST or ALT elevation > 8 × ULN or TBL > 5 × ULN.
j.
Any ≥ Grade 3 non-irAE, except for the exclusions listed below.
k. Grade 3 or greater injection site reaction that is persistent beyond 5 days or does not
downgrade to ≤ Grade 1 in 14 days.
l.
Grade 3 or greater fever, not associated with above listed events (a to f), assessed by
Principal Investigator as related to study treatment.
m. Grade 3 or greater systemic symptoms, not associated with above listed events (a to e),
assessed by Principal Investigator as related to study treatment.
n. Any Grade 3 or greater anaphylaxis related to study treatment.
o. Death that is at least possibly related to the study treatment.
The DLT definition excludes the following conditions: 
a.
Grade 3 fatigue lasting ≤ 7 days.
b. 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.
c.
Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g.,
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.).
d. Concurrent vitiligo or alopecia of any AE grade.
e.
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid
prophylaxis) that resolves within 6 hours with appropriate clinical management.
f.
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.
g. Grade 3 or 4 lymphopenia.
h. 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.
i.
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. 
7.
SAFETY REPORTING
7.1. 
Definition of adverse events 
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
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treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s 
preexisting condition. An abnormal laboratory finding (including ECG finding) that requires an 
action or intervention by the investigator, or a finding judged by the investigator to represent a 
change beyond the range of normal physiologic fluctuation, should be reported as an AE. 
Adverse events may be treatment emergent (i.e., occurring after initial receipt of IP) or 
nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, or 
other untoward medical event that begins after written informed consent has been obtained but 
before the subject has received IP.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
7.2. 
Serious Adverse Event Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the MDACC IND Office, it results in any of the following outcomes: 

Death

A life-threatening adverse drug experience – any adverse experience that places the
patient, in the view of the initial reporter, at immediate risk of death from the adverse
experience as it occurred. It does not include an adverse experience that, had it occurred
in a more severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions.

A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience 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 (21 CFR 312.32). 
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1. Important medical events as defined above, may also be considered serious adverse
events. Any important medical event can and should be reported as an SAE if deemed
appropriate by the Principal Investigator or the MDACC IND Office.
2. All events occurring during the conduct of a protocol and meeting the definition of a SAE
must be reported to the IRB in accordance with the timeframes and procedures outlined
in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board
Policy for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs
and Devices”. Unless stated otherwise in the protocol, all SAEs, expected or unexpected,
must be reported to the IND Office, regardless of attribution (within 5 working days of
knowledge of the event).
3. All life-threatening or fatal events, that are unexpected, and related to the study drug,
must have a written report submitted within 24 hours (next working day) of knowledge of
the event to the Safety Project Manager in the IND Office.
4. Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety
reporting to the IND Office and MDACC IRB.
5. Serious adverse events will be captured from the time of the first protocol-specific
intervention, until 90 days after the last dose of drug, unless the participant withdraws
consent. Serious adverse events must be followed until clinical recovery is complete and
laboratory tests have returned to baseline, progression of the event has stabilized, or there
has been acceptable resolution of the event.
6. Additionally, any serious adverse events that occur after the 90-day time period that are
related to the study treatment must be reported to the IND Office. This may include the
development of a secondary malignancy.
7.3. 
Assessment of Safety Parameters 
7.3.1. 
Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of AEs 
and SAEs. Severity will be graded according to the NCI CTCAE v4.03. 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.

Grade 2 (moderate): An event that is usually alleviated with additional specific
therapeutic intervention. The event interferes with usual activities of daily living, causing
discomfort but poses no significant or permanent risk of harm to the subject.

Grade 3 (severe): An event that requires intensive therapeutic intervention. The event
interrupts usual activities of daily living, or significantly affects the clinical status of the
subject.
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
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 subject to perform activities of daily living (eating, ambulation,
toileting, etc.).

Grade 5 (fatal): Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 10.1. A Grade 3 AE 
need not necessarily be considered an SAE. For example, a Grade 3 headache that persists for 
several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 
7.3.2. 
Relationship 
The investigator will provide an assessment of relationship of AEs and SAEs to the IP. 
An event will be considered “not related” to use of the IP if any of the following tests are met: 

An unreasonable temporal relationship between administration of the IP and the onset of
the event (e.g., the event occurred either before, or too long after, administration of the IP
for it to be considered product-related),

A causal relationship between the IP and the event is biologically implausible (e.g., death
as a passenger in an automobile accident), and/or

A clearly more likely alternative explanation for the event is present (e.g., typical adverse
reaction to a concomitant drug and/or typical disease-related event).
 “Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (i.e., there are facts, evidence, or arguments to suggest possible 
causation). 
7.4. 
Recording and Reporting of AEs and SAEs 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all AEs and assigning the attribution for all AEs for subjects enrolled. 
AEs and SAEs will be recorded according to the NCI suggested criteria as listed below. 
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Attribution Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Possible 
Phase I 
Phase II  
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Probable 
Phase I 
Phase II 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Definitive 
Phase I 
Phase II 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II  
Phase III 
Phase I 
Phase II 
Phase III 
Phase I 
Phase II  
Phase III 
7.4.1. 
Study recording period and follow-up for AEs and SAEs 
AEs and SAES will be recorded from time of first protocol-specific intervention throughout the 
treatment period and including the follow-up period (90 days after the last dose of Durvalumab 
and/or MEDI0457). For physical exams, only abnormal findings will be recorded.  
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
If a subject 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 assessments. 
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
7.4.2. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the case report 
form. After 90 days, only subjects with ongoing IP-related SAEs will continue to be followed for 
safety. 
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
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7.4.3. 
Reporting to FDA 
Serious adverse events will be forwarded to FDA by the MDACC IND Office (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s and supporting companies’ guidelines, and Institutional Review Board 
policy. 
7.4.4. 
Investigator Communications with AstraZeneca 
A copy of the SAE report must be sent to AstraZeneca at the time the event is reported to the 
FDA. SAE report forms should be forwarded with supporting relevant source documents (e.g. 
history and physical [H&P], hospital discharge summary, autopsy report when available, results 
of relevant diagnostic tests completed to evaluate the event) to AstraZeneca’s designated 
mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com.  
Transmission of the SAE report Form should be confirmed by the site personnel submitting the 
report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to AstraZeneca as soon as it is available; these reports can be submitted using 
the MD Anderson eSAE Report Form. 
7.5. 
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 supporting companies.  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.  
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Adverse events of special interest observed with MEDI0457 and durvalumab include: 

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, adrenal insufficiency, type 1 diabetes, and
hyper- and hypothyroidism),

Dermatitis,

Nephritis,

Pancreatitis (or laboratory tests suggestive of pancreatitis - increased serum lipase,
increased serum amylase),

Infusion-related reactions, and

Administration site reactions.
Adverse events of special interest are required to be reported within 24 hours of knowledge of 
the event in the database, even if the event is considered to be non-serious. 
Further information on these risks (e.g., presenting symptoms) can be found in the subsections 
below and the current versions of the IBs. More specific guidelines for their evaluation and 
treatment are described in detail in Appendix D. 
7.5.1. 
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 in Appendix D. 
7.5.2. 
Pneumonitis 
AEs of pneumonitis are also of interest for the Supporter.  Initial work-up should include high-
resolution CT scan, ruling out infection, and pulse oximetry.  Pulmonary consultation is highly 
recommended.  Guidelines for management of patients with pneumonitis are outlined in 
Appendix D. 
7.5.3. 
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 
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reactions may include hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, 
angioedema, hypotonia, urticaria, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, 
headache, hypertension, myalgia, vomiting and unresponsiveness.  Guidelines for management 
of patients with hypersensitivity reactions (including anaphylactic reactions) are outlined in 
Appendix D. 
7.5.4. 
Infusion-related reactions 
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to the 
supporting companies 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.  All infusion 
reactions should be documented in the database, and all infusions-related reaction SAEs should 
be reported as described in Section 7.4.  Guidelines for management of patients with infusion-
related reactions are outlined in Appendix D.  
7.5.5. 
Administration site reactions 
Adverse events of administration site reactions are of special interest to the supporting company.  
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) of grade ≥ 3 pair or any other 
administration site reaction.  Guidelines for the grading and management of administration site 
reactions are outlined in Appendix E. 
7.6. 
Other events requiring reporting 
7.6.1. 
Overdose 
An overdose is defined as a subject receiving a dose of Durvalumab and/or MEDI0457 in excess 
of that specified in the IB, 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 supporting companies’  designee and 
the MDACC IND Office.  If the overdose results in an AE, the AE must also be recorded as an 
AE.  
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.  There is currently no specific treatment in the event of an overdose of either 
MEDI0457 or durvalumab. 
The investigator will use clinical judgment to treat any overdose. 
7.6.2. 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the IPs 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 
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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 appropriate AstraZeneca representatives within 1 day, i.e., immediately, but 
no later than 24 hours of when he or she becomes aware of it.  
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site 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. 
7.6.3. 
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.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) should be followed up and documented.   
If any pregnancy occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate AstraZeneca representatives within 1 or 5 days. 
7.6.4. 
Hepatic Function Abnormality 
Hepatic function abnormality (i.e., TBL, ALT, or AST outside of the levels defined in the 
inclusion criteria) 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 MDACC IND Office and supporting companies 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 supporting companies. 
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7.6.5. 
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 B for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law (HL). 
7.6.6. 
Events requiring reporting within 72 hours 
The following events must be reported to MDACC IND Office and supporting companies 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 6.7.2,
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 6.7.2, assessed by Principal Investigator as related to study treatment.
8.
STATISTICAL ANALYSES
8.1. 
Statistical Considerations 
Summary statistics will be provided to summarize response, toxicity, and other clinical and 
demographic variables.  Objective response rate and disease control rate by RECIST 1.1 criteria 
will be estimated with 95% confidence interval.  Progression free survival and OS will be 
summarized using the method of Kaplan and Meier and Cox proportional hazards models.  All 
analysis will be done across all cohorts along with subset analysis within each cohort. 
8.1.1. 
Sample size estimate 
Up to 77 evaluable patients will be enrolled in this study.  
The design requires a maximum of 34 evaluable subjects per cohort.  Nine subjects will be 
treated in the first stage.  If 1 or fewer responses are seen, enrollment into that cohort will be 
stopped for futility.  If there are 2 or more responses, an additional 25 subjects will be enrolled 
into the second stage.  If there are 9 or more responses out of 34, the combination will be deemed 
worthy of further study. The two cohorts with the best response rates after completion of accrual 
into stage 1 for all 3 cohorts will move on to stage 2. The maximum total sample size is 77 (9 x 1 
cohorts + 34 x 2 cohorts) evaluable subjects.  
After each cohort completes accrual to stage I, only the two cohorts with the most responses will 
move on to stage 2. Therefore, accrual to stage 2 will not start till all three cohorts have 
completed stage I. However, if a single cohort has a high response rate (≥4 responses out of 9 
patients), the second stage of accrual may proceed prior to other cohorts completing stage I. 
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8.1.2. 
Efficacy futility assessments 
We will use a Simon’s two-stage optimal design targeting an alternative hypothesis ORR of 0.35 
versus a null hypothesis ORR of 0.15 with 80% power and a one-sided 0.05 significance level.  
This will be conducted independently in each of the three cohorts. ORR will be assessed every 8 
weeks and will be defined using RECIST 1.1 criteria. During the interim, the accrual will be 
halted until the go/no-go decision can be made. 
8.1.3. 
Toxicity monitoring 
DLT will be monitored continuously in cohorts of 6 subjects for all 34 subjects to ensure safety 
using the methods by Thall et al.  Cohorts will be monitored independently.  The trial will be 
stopped early for toxicity if the Pr(DLT > 30% | data) > 0.90 using a prior of beta(0.6, 1.4) for 
toxicity.  Stopping boundaries corresponding to this probability criterion are to halt the trial if (# 
of patients with DLT) / (# patients evaluated) ≥ 4/6, 6/12, 9/18, 11/24, and 13/30.  The operating 
characteristics of this rule is found in table below. 
Table 5. Operating Characteristics of Stopping Rules for Toxicity 
True 
toxicity P(stop) p10 p25 p50 p75 p90 
Avg # 
subjects 
Avg # 
toxicities 
0.10 
0.002 
34 
34 
34 
34 
34 
33.9 
3.4 
0.20 
0.035 
34 
34 
34 
34 
34 
33.2 
6.7 
0.30 
0.196 
12 
34 
34 
34 
34 
29.9 
9.0 
0.40 
0.549 
6 
12 
30 
34 
34 
23.2 
9.2 
0.50 
0.877 
6 
6 
12 
24 
34 
15.5 
7.8 
The Investigator is responsible for completing toxicity/efficacy summary reports and submitting 
them to the IND office Medical Affairs and Safety Group for review.  These should be submitted 
as follows:  
Toxicity Assessment: After the first 6 evaluable patients per cohort, complete 4 weeks of 
study treatment, and every 6 evaluable patients thereafter. 
Efficacy Assessment: After the first 9 evaluable patients per cohort, complete 8 weeks of 
study treatment, and every 5 evaluable patients thereafter, until enrollment is complete. On 
every report submission, the response information from previous reported patients will need 
to be updated. 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”.  
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8.2. 
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. 
8.2.1. 
Efficacy analysis set 
Response-evaluable Population: The co-primary endpoint of ORR by RECIST v1.1 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 any dose of both study drugs, have a 
baseline scan with measurable disease, and have at least one follow-up scan (includes 
discontinuations due to disease progression or death without follow-up scan) with ≥ 16 weeks 
follow-up.  
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 6 provides a summary of the efficacy endpoints with their corresponding methods of 
assessment and populations. 
Table 6. A Summary of Efficacy Endpoints with Corresponding Methods of Assessment 
and Populations 
Type of efficacy 
endpoint 
Endpoint 
Method 
Population(s) 
Primary 
ORR 
RECIST version 1.1 
Response-evaluable 
 
 
 
 
Secondary 
ORR 
RECIST version 1.1  
As-treated  
 
ORR 
irRECIST 
Response-evaluable and As-treated  
 
DCR-24w 
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 
8.2.2. 
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). 
8.2.3. 
Pharmacokinetics analysis set 
The pharmacokinetic analysis set will include all patients who receive at least one dose of 
durvalumab and have any post-dose data available and have at least one post dose plasma 
concentration measurement at a scheduled time point without any important protocol deviations 
or violations thought to significantly affect the pharmacokinetic of the drug. 
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8.3. 
Outcome Measures 
8.3.1. 
Primary 
The primary objective will be measured by ORR by RECIST v1.1. The ORR will be estimated 
along with corresponding 95% confidence interval.  All analysis will be done within each cohort 
as well as across all cohorts. 
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.  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). 
8.3.2. 
Secondary 
The secondary objectives will be measured by the following: 

AEs/SAEs;

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, QRS,
RR interval, QT (ms), QTcF (ms), sinus rhythm (yes/no), and overall evaluation
(normal/abnormal);

Vital signs;

Physical examinations;

Concomitant medications;

OS;

PFS as assessed by RECIST v1.1;

ORR by RECIST v1.1;

Immune-related RECIST; and

Disease control rate at 24 weeks by RECIST v1.1.
Safety will be summarized by the percentage of patients with AEs, with grading( according to 
CTCAE v4.03) and attribution.  Summary statistics will also be provided for serious AEs, 
hematology, urinalysis, CPK, thyroid function testing, pregnancy test, ECG, vital sign, physical 
examinations and concomitant medications. 
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8.3.2.1. 
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. 
8.3.2.2. 
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 v1.1. 
Progression free survival will be defined as the time from the date of start of IP treatment until 
the date of objective disease progression or death (+1 day) (by 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. 
8.3.2.3. 
Disease Control Rate (DCR) 
Disease control rate is defined as N (%) patients with CR, PR, or SD by 24 weeks on study using 
RECIST version 1.1.  For SD determination for DCR, the patient must have lack of progression 
for the first 24 weeks on study.  Disease control rate will be assessed in the Response-evaluable 
and As-treated populations.  
8.3.2.4. 
Overall Survival (OS) 
OS 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 
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last recorded date on which the patient was known to be alive.  OS will be assessed in the 
Response-evaluable and As-treated populations.  
8.3.3. 
Exploratory 
The exploratory objectives as detailed in Section 6.6 will be analyzed descriptively with 
summary statistic generation and correlation to survival or other statistics as appropriate. 
9.
ETHICAL AND REGULATORY REQUIREMENTS
9.1. 
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 ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection. 
9.2. 
Ethics and Regulatory Review 
This study will be subject to subject to local IRB and federal oversight. 
9.3. 
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in the 
medical record or research file. 
9.4. 
Changes to the Protocol and Informed Consent Form 
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed and approved by the IRB and AstraZeneca. Any changes made to 
the protocol must be submitted as amendments and must be approved by the IRB and 
AstraZeneca prior to implementation. Any changes in study conduct must be reported to the IRB 
and AstraZeneca. 
9.5. 
Protocol Review and Monitoring 
The study team, including the PI, research nurse, and data coordinator, will perform monthly 
reviews of case histories and regulatory documents.  
The MD Anderson IND Office will monitor this study. 
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10.
STUDY DATABASE MANAGEMENT
10.1. 
Study Data 
Clinical study data for this trial will be collected and managed using the Prometheus database 
system. 
10.2. 
Data Management 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other 
records transmitted outside the clinical site will be identified by a subject’s identification number 
or coded number and age. All study records, source medical records, and code sheets or logs 
linking a subject’s name to an SID number will be kept in a secure location. Study records may 
be maintained electronically and require the same security and confidentiality as paper. Clinical 
information will not be released without written permission of the subject/legal representative, 
except as specified in the ICF(s) (e.g., necessary for monitoring by regulatory authorities or the 
MDACC IND Office of the clinical study). The investigator must also comply with all applicable 
privacy regulations (e.g., HIPAA 1996, EU Data Protection Directive 95/46/EC). 
Study documents (including subject records, copies of data submitted to the MDACC IND 
Office, study notebook, and pharmacy records) must be kept secured in accordance with the 
specific data retention periods that are described in the clinical study site agreement and based 
upon local requirements. Study documents must not be destroyed without prior written approval 
of the MDACC IND Office. 
11.
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APPENDIX A.  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 containment standards are encouraged wherever 
possible when road or rail transport is used. 
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APPENDIX B. 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 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 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. 
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 
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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. 
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: 
Request a repeat of the test (new blood draw) by the central laboratory. 
Complete the appropriate unscheduled laboratory database 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: 
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 database. 
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). 
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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.  
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.   
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 database. 
If the alternative explanation is an AE/SAE, record the AE/SAE in the database accordingly. 
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 MD Anderson IRB/DSMB 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: 
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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: 
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 
# 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: 
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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 described in Appendix D, Table 7. 
# 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. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM174090.pdf 
 
 
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APPENDIX C. CELLECTRA®5P ERROR REPORTING FORM 
Please complete the form and fax to (267) 440-4242 or scan the form to EPerror@inovio.com  
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): 
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APPENDIX D. DURVALUMAB DOSE MODIFICATION FOR TOXICITY MANAGEMENT 
Table 7. Treatment Modification and Toxicity Management Guidelines for Immune-related Adverse Events (Durvalumab) 
Event 
Grade of the Event 
(NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Immune-related 
adverse events 
(overall 
management for 
toxicities not 
noted below) 
Drug administration modifications of 
study drug/study regimen will be made to 
manage potential immune-related adverse 
events (irAEs) based on severity of 
treatment-emergent toxicities graded per 
NCI CTCAE v4.03. 
•
In addition to the criteria for
permanent discontinuation of study
drug/regimen based on Common
Terminology Criteria (CTC)
grade/severity (table below),
permanently discontinue study
drug/study regimen for the following
conditions: Inability to reduce
corticosteroid to a dose of ≤ 10 mg of
prednisone per day (or equivalent)
within 12 weeks after last dose of
study drug/regimen
•
Recurrence of a previously
experienced Grade 3 treatment-related
adverse event (AE) following
resumption of dosing.
It is recommended that management of irAEs follow the guidelines 
presented in this table 
•
Subjects should be thoroughly evaluated to rule out any
alternative etiology (e.g., disease progression, concomitant
medications, infections, etc.).
•
In the absence of a clear alternative etiology, all events should
be considered potentially immune-related.
•
Symptomatic and topical therapy should be considered for low
grade (Grade 1 or 2, unless otherwise specified) events.
•
For persistent (greater than 3 to 5 days) low grade (Grade 2) or
severe (Grade ≥ 3) events promptly start prednisone oral
1-2 mg/kg/day or intravenous (IV) equivalent.
•
If symptoms recur or worsen during corticosteroid tapering
28 days of taper), increase the corticosteroid dose (prednisone
dose [e.g. up to 2-4 mg/kg/day or IV equivalent]) until
stabilization or improvement of symptoms, then resume
corticosteroid tapering at a slower rate (> 28 days of taper).
•
More potent immunosuppressives such as tumor necrosis
factor (TNF) inhibitors (e.g., infliximab) – (also refer to the
individual sections of the irAE for specific type of
immunosuppressive) should be considered for events not
responding to systemic steroids.
•
Discontinuation of study drug is not mandated for
Grade 3/Grade 4 inflammatory reactions attributed to local
tumor response (e.g., inflammatory reaction at sites of
metastatic disease, lymph nodes etc.).  Continuation of study
drug in this situation should be based upon a benefit/risk
analysis for that subject.
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
•
If toxicity worsens then treat as
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Grade 3 or Grade 4 
•
If toxicity improves to baseline, then
treat at next scheduled treatment date
Study drug/study treatment can be 
resumed at the next scheduled dose once 
event stabilizes to Grade ≤ 1 and 5-7 days 
have passed after completion of steroid 
taper. 
Subjects with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 1) the event stabilizes and is 
controlled, 2) the subject is clinically 
stable as per Investigator or treating 
physician’s clinical judgment, and 3) doses 
of prednisone are at less than or equal to 
10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen.  Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study 
regimen. 
Note: For Grade 3 and above asymptomatic amylase or lipase levels hold study drug/regimen and if complete work-up shows no evidence 
of pancreatitis, may continue or resume study drug/regimen 
Pneumonitis/ 
interstitial lung 
disease (ILD) 
Grade of 
pneumonitis 
(CTCAE version 
4.03)  
Any Grade 
•
Monitor subjects for signs and symptoms of pneumonitis or
ILD (new onset or worsening shortness of breath or cough).
Subjects should be evaluated with imaging and pulmonary
function tests including other diagnostic procedures as
described below.
•
Initial work-up may include clinical evaluation, monitoring of
oxygenation via pulse oximetry (resting and exertion),
laboratory work-up and high-resolution computed tomography
(CT) scan.
Grade 1  
(asymptomatic, 
clinical or 
diagnostic 
observations only, 
No dose modification required.  However, 
consider holding study drug/study regimen 
dosing as clinically appropriate and during 
diagnostic work-up for other etiologies. 
•
For Grade 1 (radiographic changes only)
-
Monitor and closely follow-up in 2-4 days for clinical
symptoms, pulse oximetry (resting and exertion) and
laboratory work-up and then as clinically indicated.
-
Consider pulmonary and infectious disease consult.
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1 ASCO Educational Book 2015. Michael Postow MD. “Managing Immune Checkpoint Blocking Antibody Side Effects” 
intervention not 
indicated) 
Grade 2  
(symptomatic, 
medical intervention 
indicated, limiting 
instrumental 
activities of daily 
living [ADL]) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
•
If toxicity worsens then treat as
Grade 3 or Grade 4
Study drug/study treatment can be 
resumed based upon treating physician’s 
clinical judgment at the next scheduled 
dose once event stabilizes to Grade ≤ 1 or 
baseline and 5-7 days have passed after 
completion of steroid taper. 
•
For Grade 2 (mild to moderate new symptoms)
-
Monitor symptoms daily and consider hospitalization.
-
Promptly start systemic steroids (e.g., prednisone
1-2 mg/kg/day or IV equivalent).
-
Reimaging as clinically indicated.
-
If no improvement within 3-5 days, additional work-up
should be considered and prompt treatment with
IV methylprednisolone 2-4 mg/kg/day started.
-
If still no improvement within 3-5 days despite
IV methylprednisone at 2-4 g/kg/day, promptly start
immunosuppressive therapy such as TNF inhibitors
(e.g., infliximab at 5 mg/kg every 2 weeks).  Caution:
Important to rule out sepsis and refer to infliximab
label for general guidance before using infliximab.
-
Once improving, gradually taper steroids over
≥ 4 weeks and consider prophylactic antibiotics,
antifungal or anti-pneumocystis pneumonia (anti PCP)
treatment (refer to current National Comprehensive
Cancer Network (NCCN) guidelines for treatment of
cancer-related infections (Category 2B
recommendation)1.
-
Consider pulmonary and infectious disease consult.
-
Consider as necessary discussing with Study Physician.
Grade 3 or 4  
(Grade 3: severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated 
Grade 4: life 
threatening 
respiratory 
compromise, urgent 
intervention 
indicated [e.g. 
Permanently discontinue study drug/study 
regimen. 
•
For Grade 3 or 4 (severe or new symptoms, new/worsening
hypoxia, life threatening)
-
Promptly initiate empiric IV methylprednisolone 1 to
4 mg/kg/day or equivalent.
-
Obtain pulmonary and infectious disease consult.
-
Hospitalize the subject.
-
Supportive Care (oxygen, etc).
-
If no improvement within 3-5 days, additional work-up
should be considered and prompt treatment with additional
immunosuppressive therapy such as TNF inhibitors (e.g.,
infliximab at 5 mg/kg every 2 weeks dose) started.
Caution: rule out sepsis and refer to infliximab label for
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tracheostomy or 
intubation])  
general guidance before using infliximab. 
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and in
particular, anti PCP treatment (please refer to current
NCCN guidelines for treatment of cancer-related infections
(Category 2B recommendation)2.
Diarrhea/ 
enterocolitis 
Grade of diarrhea 
(CTCAE 
version 4.03) 
Any grade 
•
Monitor for symptoms that may be related to
diarrhea/enterocolitis (abdominal pain, cramping, or changes
in bowel habits such as increased frequency over baseline or
blood in stool) or related to bowel perforation (such as sepsis,
peritoneal signs and ileus).
•
Subjects should be thoroughly evaluated to rule out any
alternative etiology (e.g., disease progression, other
medications, infections including testing for Clostridium
difficile toxin, and stool for ova and parasites (O+P).etc.).
•
Steroids should be considered in the absence of clear
alternative etiology, even for low grade events, in order to
prevent potential progression to higher grade event.
•
Use analgesics carefully; they can mask symptoms of
perforation and peritonitis.
Grade 1 diarrhea 
(stool frequency of 
< 4 over baseline 
per day)  
No dose modification 
•
For Grade 1 diarrhea:
-
Close monitoring for worsening symptoms.
-
Consider symptomatic treatment including hydration,
electrolyte replacement, dietary changes (e.g., American
Dietetic Association colitis diet), and loperamide.  Use of
probiotics as per treating physician’s clinical judgment.
Grade 2 diarrhea 
(stool frequency of 
4-6 over baseline
per day)
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
•
If toxicity worsens then treat as
Grade 3 or Grade 4
•
If toxicity improves to baseline then
treat at next scheduled treatment date
will be based upon treating
physician’s clinical judgment
Study drug/study treatment can be 
resumed based upon treating physician’s 
clinical judgment at the next scheduled 
•
For Grade 2 diarrhea:
-
Consider symptomatic treatment including hydration,
electrolyte replacement, dietary changes (e.g., American
Dietetic Association colitis diet), and loperamide and/or
budesonide.
-
Promptly start prednisone 1 to 2 mg/kg/day or
IV equivalent.
-
If event is not responsive within 3-5 days or worsens
despite prednisone at 1-2 mg/kg/day or IV equivalent,
gastrosintestinal (GI) consult should be obtained for
consideration of further work-up such as imaging and/or
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dose once event stabilizes to Grade ≤ 1 or 
baseline and 5-7 days have passed after 
completion of steroid taper. 
colonoscopy to confirm colitis and rule out perforation, 
and prompt treatment with IV methylprednisolone 
2-4 mg/kg/day started.
-
If still no improvement within 3-5 days despite
2-4 mg/kg IV methylprednisolone, promptly start
immunosuppressives such as (infliximab at 5 mg/kg once
every 2 weeks3).  Caution: important to rule out bowel
perforation and refer to infliximab label for general
guidance before using infliximab.
-
Consult Study Physician if no resolution to ≤ Grade 1 in
3-4 days.
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and
anti PCP treatment (please refer to current NCCN
guidelines for treatment of cancer-related infections
[Category 2B recommendation]).
Grade 3 or 4 
diarrhea 
(Grade 3: stool 
frequency of ≥ 7 
over baseline per 
day  
Grade 4: life 
threatening 
consequences) 
Permanently discontinue study drug/study 
regimen. 
•
For Grade 3 or 4 diarrhea:
-
Promptly initiate empiric IV methylprednisolone 2 to
4 mg/kg/day or equivalent.
-
Monitor stool frequency and volume and maintain
hydration.
-
Urgent GI consult and imaging and/or colonoscopy as
appropriate.
-
If still no improvement within 3-5 days of
IV methylprednisolone 2 to 4 mg/kg/day or equivalent,
promptly start further immunosuppressives (e.g.,
infliximab at 5 mg/kg once every 2 weeks).
-
Caution: ensure GI consult to rule out bowel perforation
and refer to infliximab label for general guidance before
using infliximab.
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and
anti PCP treatment (please refer to current NCCN
guidelines for treatment of cancer-related infections
[Category 2B recommendation]).
Hepatitis 
(elevated liver 
Grade of liver 
function test 
•
Monitor and evaluate liver function test: aspartate
aminotransferase (AST), alanine aminotransferase (ALT),
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function tests 
[LFTs]) 
Infliximab 
should not be 
used for 
management of 
immune-related 
hepatitis 
elevation (CTCAE 
version 4.03) 
Any grade 
alkaline phosphatase (ALP), and total bilirubin (TBL) 
•
Evaluate for alternative etiologies (e.g., viral hepatitis, disease
progression, concomitant medications).
Grade 1  
(AST or ALT 
> upper limit of
normal [ULN] to
3 times ULN and/or
TBL > ULN to 1.5
times ULN)
No dose modification. 
If it worsens, treat as Grade 2 event. 
•
For Grade 1 AST or ALT and/or TBL elevation
-
Continue LFT monitoring per protocol.
Grade 2 
(AST or ALT > 3 to 
5 times ULN and/or 
TBL > 1.5-3.0 times 
ULN) 
Hold study drug/study regimen dose until 
Grade 2 resolution to ≤ Grade 1 
•
If toxicity worsens then treat as
Grade 3 or Grade 4
Study drug/study treatment can be 
resumed based upon treating physician’s 
clinical judgment at the next scheduled 
dose once event stabilizes to Grade ≤ 1 or 
baseline and 5-7 days have passed after 
completion of steroid taper. 
•
For Grade 2 AST or ALT and or TBL elevation:
-
Regular and frequent checking of LFTs (e.g., every
1-2 days) until elevations of these are improving or
resolved.
-
If no resolution to ≤ Grade 1 in 1-2 days, discuss with
Study Physician.
-
If event is persistent (> 3-5 days) or worsens, promptly
start prednisone 1-2 mg/kg/day or IV equivalent.
-
If still no improvement within 3-5 days despite
1-2 mg/kg/day of prednisone or IV equivalent, consider
additional work-up and prompt treatment with
IV methylprednisolone 2-4 mg/kg/day started.
-
If still no improvement within 3-5 days despite
2-4 mg/kg/day of IV methylprednisolone, promptly start
immunosuppressives (mycophenolate mofetil)4.  Discuss
with Study Physician if mycophenolate mofetil is not
available.  Infliximab should NOT be used.
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and
anti PCP treatment (please refer to current NCCN
guidelines for treatment of cancer-related infections
[Category 2B recommendation]).
Grade 3 
(AST or ALT 
> 5-20 times ULN
and/or TBL >
3.0-10 times ULN
For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 × ULN 
•
Hold study drug/study regimen dose
until resolution to ≤ Grade 1 or
baseline
•
For Grade 3 or 4 AST or ALT and/or TBL elevation:
-
Promptly initiate empiric IV methylprednisolone at 1 to
4 mg/kg/day or equivalent.
-
If still no improvement within 3-5 days despite 1 to
4 mg/kg/day methylprednisolone IV or equivalent,
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5 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 
•
Resume study drug/study regimen
administration at the next scheduled
dose if elevations downgrade ≤
Grade 1 or baseline
•
Permanently discontinue study
drug/study regimen if the elevations
do not downgrade to ≤ Grade 1
For elevations in transaminases > 8 × ULN 
or elevations in bilirubin > 5 × ULN, 
discontinue study drug/study regimen  
•
Permanently discontinue study
drug/study regimen for any case
meeting Hy’s Law criteria (ALT > 3 ×
ULN + bilirubin > 2 × ULN without
initial findings of cholestasis (i.e.,
elevated alkaline P04) and in the
absence of any alternative cause5
promptly start treatment with immunosuppressive 
therapy (mycophenolate mofetil).  Discuss with Study 
Physician if mycophenolate is not available.  Infliximab 
should NOT be used. 
-
Hepatology consult, abdominal work-up, and imaging as
appropriate.
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and
anti PCP treatment (please refer to current NCCN
guidelines for treatment of cancer-related infections
[Category 2B recommendation]).
Grade 4  
(AST or ALT > 
20 times ULN 
and/or TBL > 
10 times ULN)  
Permanently discontinue study drug/study 
regimen. 
Nephritis or 
renal 
dysfunction 
(elevated serum 
creatinine)  
Grade of elevated 
serum creatinine 
(CTCAE version 
4.03) 
Any grade 
•
Consult with nephrologist.
•
Monitor for signs and symptoms that may be related to changes
in renal function (e.g., routine urinalysis, elevated serum blood
urea nitrogen and creatinine, decreased creatinine clearance,
electrolyte imbalance, decrease in urine output, proteinuria, etc).
•
Subjects should be thoroughly evaluated to rule out any
alternative etiology (e.g., disease progression, infections etc).
•
Steroids should be considered in the absence of clear alternative
etiology even for low grade events (Grade 2), in order to prevent
potential progression to higher grade event.
Grade 1 [serum 
creatinine > 1-1.5 × 
baseline; > ULN to 
1.5 × ULN]  
No dose modification 
•
For Grade 1 elevated creatinine:
-
Monitor serum creatinine weekly and any accompanying
symptom

If creatinine returns to baseline, resume its regular
monitoring per study protocol.
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81 

If it worsens, depending on the severity, treat as
Grade 2 or Grade 3 or 4.
-
Consider symptomatic treatment including hydration,
electrolyte replacement, diuretics, etc.
Grade 2 [serum 
creatinine > 1.5-3.0 
× baseline; > 1.5 × 
3.0 × ULN] 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
•
If toxicity worsens then treat as
Grade 3 or Grade 4
Study drug/study treatment can be 
resumed based upon treating physician’s 
clinical judgment at the next scheduled 
dose once event stabilizes to Grade ≤ 1 or 
baseline and 5-7 days have passed after 
completion of steroid taper. 
•
For Grade 2 elevated creatinine:
-
Consider symptomatic treatment including hydration,
electrolyte replacement, diuretics, etc.
-
Carefully monitor serum creatinine every 2-3 days and as
clinically warranted. 
-
Consult nephrologist and consider renal biopsy if clinically
indicated.
-
If event is persistent (> 3-5 days) or worsens, promptly start
prednisone 1 to 2 mg/kg/day or IV equivalent.
-
If event is not responsive within 3-5 days or worsens
despite prednisone at 1-2 mg/kg/day or IV equivalent,
additional work-up should be considered and prompt
treatment with IV methylprednisolone at 2-4 mg/kg/day
started.
-
Once improving gradually taper steroids over ≥ 28 days and
consider prophylactic antibiotics, antifungals and anti PCP
treatment (please refer to current NCCN guidelines for
treatment of cancer-related infections [Category 2B
recommendation]).
-
When event returns to baseline, resume study drug/study
regimen and routine serum creatinine monitoring per study
protocol.
Grade 3 or 4  
(Grade 3: serum 
creatinine > 3.0 × 
baseline; > 3.0-6.0 × 
ULN 
Grade 4: serum 
creatinine > 6.0 × 
ULN)  
Permanently discontinue study drug/study 
regimen. 
•
Carefully monitor serum creatinine on daily basis.
•
Consult Nephrologist and consider renal biopsy if clinically
indicated.
•
Promptly start prednisone 1 to 2 mg/kg/day or IV equivalent.
•
If event is not responsive within 3-5 days or worsens despite
prednisone at 1-2 mg/kg/day or IV equivalent, additional
work-up should be considered and prompt treatment with
IV methylprednisolone 2-4 mg/kg/day started.
•
Once improving, gradually taper steroids over ≥ 28 days and
consider prophylactic antibiotics, antifungals and anti PCP
treatment (please refer to current NCCN guidelines for
treatment of cancer-related infections [Category 2B
recommendation]).
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82 
Rash (excluding 
bullous skin 
formations) 
Grade of skin rash  
(please refer to  NCI 
CTCAE v4.03 for 
definition of 
severity/grade 
depending on type 
of skin rash)  
Any grade 
•
Monitor for signs and symptoms of dermatitis (rash and
pruritus)
-
**IF THERE IS ANY BULLOUS FORMATION, THE
STUDY PHYSICIAN SHOULD BE CONTACTED
AND STUDY DRUG DISCONTINUED**
Grade 1 
No dose modification 
•
For Grade 1:
-
Consider symptomatic treatment including oral
antipruritics (e.g., diphenhydramine or hydroxyzine) and
topical therapy (e.g., urea cream).
Grade 2 
For persistent (> 1- 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to ≤ Grade 1 or 
baseline.  
•
If toxicity worsens then treat as
Grade 3
•
If toxicity improves then resume
administration at next scheduled dose
Study drug/study regimen can be resumed 
at the next scheduled dose once event 
stabilizes to Grade ≤ 1 or baseline and 
5-7 days have passed after completion of
steroid taper.
•
For Grade 2:
-
Obtain dermatology consult.
-
Consider symptomatic treatment including oral
antipruritics (e.g., diphenhydramine or hydroxyzine) and
topical therapy (e.g., urea cream).
-
Consider moderate strength topical steroid.
-
If no improvement of rash/skin lesions occurs within
3-5 days or is worsening despite symptomatic treatment
and/or use of moderate strength topical steroid, discuss 
with Study Physician and promptly start systemic 
steroids prednisone 1-2 mg/kg/day or IV equivalent. 
-
Consider skin biopsy if persistent for > 1-2 weeks or
recurs.
Grade 3 
•
Hold study drug/study regimen until
resolution to ≤ Grade 1 or baseline
•
Resume study drug/study regimen
administration at the next scheduled
dose if elevations downgrade
≤ Grade 1 or baseline
•
For Grade 3 or 4:
-
Consult dermatology.
-
Promptly initiate empiric IV methylprednisolone 1 to
4 mg/kg/day or equivalent.
-
Consider hospitalization.
-
Monitor extent of rash [Rule of Nines].
-
Consider skin biopsy (preferably more than 1) as
clinically feasible.
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and
anti PCP treatment (please refer to current NCCN
guidelines for treatment of cancer-related infections
[Category 2B recommendation]).
-
Discuss with Study Physician.
Grade 4 
Permanently discontinue study drug/study 
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83 
regimen. 
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
hypopituitarism, 
adrenal 
insufficiency, 
etc.) 
Any grade  
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 for 
defining the CTC 
grade/severity)  
•
Consult Endocrinologist.
•
Monitor subjects for signs and symptoms of endocrinopathies.
Non-specific symptoms include headache, fatigue, behavior
changes, changed mental status, vertigo, abdominal pain,
unusual bowel habits, hypotension and weakness.
•
Subjects should be thoroughly evaluated to rule out any
alternative etiology (e.g., disease progression including brain
metastases, infections, etc).
•
Monitor and evaluate thyroid function tests: thyroid
stimulating hormone (TSH), free triiodothyronine and free
thyroxine (T4) and other relevant endocrine labs depending on
suspected endocrinopathy.
•
If a subject experiences an AE that is thought to be possibly of
autoimmune nature (e.g., thyroiditis, pancreatitis,
hypophysitis, diabetes insipidus), the investigator should send
a blood sample for appropriate autoimmune antibody testing.
Grade 1 
(depending on the 
type of 
endocrinopathy, 
refer to NCI 
CTCAE v4.03 for 
defining the CTC 
Grade 1) 
No dose modification 
•
For Grade 1: (including those with asymptomatic TSH
elevation)
-
Monitor subject with appropriate endocrine function tests
-
If TSH < 0.5 × lower limit of normal, or TSH > 2 × ULN
or consistently out of range in 2 subsequent
measurements, include free T4 at subsequent cycles as
clinically indicated and consider endocrinology consult.
Grade 2  
(depending on the 
type of 
endocrinopathy, 
refer to  NCI 
CTCAE v4.03 for 
defining the CTC 
grade/severity 2) 
•
For Grade 2 endocrinopathy other
than hypothyroidism, hold study
drug/study regimen dose until subject
is clinically stable.
-
If toxicity worsens then treat as
Grade 3 or Grade 4
-
If toxicity improves to baseline
then treat at next scheduled
treatment date
•
Study drug/study regimen can be
resumed at the next scheduled dose
once event stabilizes to Grade ≤ 1 and
5-7 days have passed after completion
of steroid taper
•
For Grade 2: (including those with symptomatic
endocrinopathy)
-
Isolated hypothyroidism may be treated with
replacement therapy without treatment interruption and
without corticosteroids.
-
Initiate hormone replacement as needed for management.
-
Evaluate endocrine function, and as clinically indicated,
consider pituitary scan.
-
For subjects with abnormal endocrine work-up, except for
those with isolated hypothyroidism, consider short-term,
corticosteroids (e.g., 1-2 mg/kg/day methylprednisolone or
IV equivalent) and prompt initiation of treatment with
relevant hormone replacement (e.g., levothyroxine,
hydrocortisone, or sex hormones).
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84 
•
Subjects with endocrinopathies who
may require prolonged or continued
steroid replacement can be retreated
with study drug/study regimen on the
following conditions: 1) the event
stabilizes and is controlled, 2) the
subject is clinically stable as per
Investigator or treating physician’s
clinical judgment, and 3) doses of
prednisone are at less than or equal to
10mg/day or equivalent.
-
Once improving, gradually taper steroids over ≥ 28 days
and consider prophylactic antibiotics, antifungals and
anti PCP treatment (please refer to current NCCN
guidelines for treatment of cancer-related infections
[Category 2B recommendation]).
-
For subjects with normal endocrine work-up (laboratory or
magnetic resonance imaging [MRI] scans), repeat
laboratory assessments/MRI as clinically indicated.
Grade 3 or 4 
(depending on the 
type of 
endocrinopathy, 
refer to  NCI 
CTCAE v4.03 for 
defining the CTC 
grade/severity 3 or 
4)  
•
For Grade 3 or 4 endocrinopathy other
than hypothyroidism, hold study
drug/study regimen dose until
endocrinopathy symptom(s) are
controlled
•
Resume study drug/study regimen
administration if controlled at the next
scheduled dose
•
Study drug/study treatment can be
resumed based upon treating
physician’s clinical judgment at the
next scheduled dose once event
stabilizes to Grade ≤ 1 or baseline and
5-7 days have passed after completion
of steroid taper
•
For Grade 3 or 4:
-
Consult endocrinologist.
-
Isolated hypothyroidism may be treated with
replacement therapy without treatment interruption and
without corticosteroids.
-
Promptly initiate empiric IV methylprednisolone 1 to
2 mg/kg/day or equivalent.
-
Administer hormone replacement therapy as necessary.
-
For adrenal crisis, severe dehydration, hypotension, or
shock: immediately initiate IV corticosteroids with
mineralocorticoid activity.
-
Once improving, gradually taper immunosuppressive
steroids over ≥ 4 weeks and consider prophylactic
antibiotics, antifungals and anti PCP treatment (please
refer to current NCCN guidelines for treatment of
cancer-related infections [Category 2B
recommendation]).
-
Discuss with Study Physician.
Immune 
mediated  
neurotoxicity (to 
include but not 
limited to limbic 
encephalitis. 
autonomic 
neuropathy, 
excluding 
myasthenia 
Grade of 
neurotoxicity  
Depending on the 
type of 
neurotoxicity, refer 
to  NCI CTCAE 
v4.03 for defining 
the CTC grade/ 
severity 
Any grade 
•
Subjects should be evaluated to rule out any alternative etiology
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85 
gravis and 
Guillain-Barré) 
(e.g., disease progression, infections, metabolic syndromes and 
medications, etc). 
•
Monitor subject for general symptoms (headache, nausea,
vertigo, behavior change, or weakness).
•
Consider appropriate diagnostic testing (e.g., electromyogram
and nerve conduction investigations).
•
Symptomatic treatment with neurological consult as
appropriate.
Grade 1 
No dose modifications 
- See “Any Grade” recommendations above.
Grade 2 
•
For acute motor neuropathies or
neurotoxicity, hold study drug/study
regimen dose until resolution to
≤ Grade 1
•
For sensory neuropathy/neuropathic
pain, consider holding study
drug/study regimen dose until
resolution to ≤ Grade 1.
-
If toxicity worsens then treat as
Grade 3 or Grade 4
-
If toxicity improves to baseline
then treat at next scheduled
treatment date
•
Study drug/study regimen can be
resumed at the next scheduled dose
once event stabilizes to Grade ≤ 1 and
5-7 days have passed after completion
of steroid taper
•
Discuss with the Study Physician.
•
Obtain Neurology Consult.
•
Sensory neuropathy/neuropathic pain may be managed by
appropriate medications (e.g., gabapentin, duloxetine, etc).
•
Promptly start systemic steroids prednisone 1-2 mg/kg/day or
IV equivalent.
•
If no improvement within 3-5 days despite 1-2 mg/kg/day
prednisone or IV equivalent consider additional work-up and
promptly treat with additional immunosuppressive therapy
(e.g., IVIG).
Grade 3 
•
Hold study drug/study regimen dose
until resolution to ≤ Grade 1
•
Resume study drug/study regimen
administration at the next scheduled
dose if elevations downgrade
≤ Grade 1 or baseline
•
For Grade 3 or 4:
-
Discuss with Study Physician.
-
Obtain Neurology Consult.
-
Consider hospitalization.
-
Promptly initiate empiric IV methylprednisolone 1 to
2 mg/kg/day or equivalent.
-
If no improvement within 3-5 days despite
IV corticosteroids, consider additional work-up and
promptly treat with additional immunosuppressants (e.g.,
IVIG).
-
Once stable, gradually taper steroids over ≥ 4 weeks.
Grade 4 
Permanently discontinue study drug/study 
regimen 
Immune-
Any grade 
•
The prompt diagnosis of immune-mediated peripheral
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86 
mediated 
peripheral 
neuromotor 
syndromes, such 
as Guillain-Barré 
and myasthenia 
gravis 
neuromotor syndromes is important, since certain subjects 
may unpredictably experience acute decompensations which 
can result in substantial morbidity or in the worst case, death. 
Special care should be taken for certain sentinel symptoms 
which may predict a more severe outcome, such as prominent 
dysphagia, rapidly progressive weakness, and signs of 
respiratory insufficiency or autonomic instability. 
•
Subjects should be evaluated to rule out any alternative
etiology (e.g., disease progression, infections, metabolic
syndromes and medications, etc).  It should be noted that the
diagnosis of immune-mediated peripheral neuromotor
syndromes can be particularly challenging in subjects with
underlying cancer, due to the multiple potential confounding
effects of cancer (and its treatments) throughout the neuraxis.
Given the importance of prompt and accurate diagnosis, it is
essential to have a low threshold to obtain a neurological
consult.
•
Neurophysiologic diagnostic testing (e.g., electromyogram
and nerve conduction investigations, and “repetitive
stimulation” if myasthenia is suspected) are routinely
indicated upon suspicion of such conditions and may be best
facilitated by means of a neurology consultation.
•
Important to consider that the use of steroids as the primary
treatment of Guillain-Barré is not typically considered
effective.  Subjects requiring treatment should be started with
IVIG and followed by plasmapheresis if not responsive to
IVIG.
Grade 1 
No dose modification 
•
Discuss with the Study Physician.
•
Care should be taken to monitor subjects for sentinel
symptoms of a potential decompensation as described above.
•
Obtain a neurology consult unless the symptoms are very
minor and stable.
Grade 2 
•
Hold study drug/study regimen dose
until resolution to ≤ Grade 1
•
Resume study drug/study regimen
administration at the next scheduled
dose if elevations downgrade
≤ Grade 1 or baseline
•
Grade 2:
-
Discuss with the Study Physician.
-
Care should be taken to monitor subjects for sentinel
symptoms of a potential decompensation as described
above.
-
Obtain a Neurology Consult.
-
Sensory neuropathy/neuropathic pain may be managed
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87 
by appropriate medications (e.g., gabapentin, duloxetine, 
etc). 
◦
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat
Myasthenia Gravis.  Important to consider that
steroid therapy (especially with high doses) may
result in transient worsening of myasthenia and
should typically be administered in a monitored
setting under supervision of a consulting
neurologist.
o
Subjects unable to tolerate steroids may be
candidates for treatment with plasmapheresis or
IVIG.  Such decisions are best made in
consultation with a neurologist, taking into account
the unique needs of each subject.
o
If Myasthenia Gravis-like neurotoxicity present,
consider starting acetylcholinesterase (AChE)
inhibitor therapy in addition to steroids. Such
therapy, if successful, can also serve to reinforce
the diagnosis.
◦
GUILLAIN-BARRÉ:
o
Important to consider here that the use of steroids
as the primary treatment of Guillain-Barré is not
typically considered effective. Subjects requiring
treatment should be started with IVIG and
followed by plasmapheresis if not responsive to
IVIG.
Grade 3 
•
Hold study drug/study regimen dose
until resolution to ≤ Grade 1
•
Resume study drug/study regimen
administration at the next scheduled
dose if elevations downgrade
≤ Grade 1 or baseline
•
For severe or life threatening (Grade 3 or 4) events:
-
Discuss with Study Physician.
-
Recommend hospitalization.
-
Monitor symptoms and obtain neurological consult.
◦
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat
Myasthenia Gravis.  It should typically be
administered in a monitored setting under
supervision of a consulting neurologist.
o
Subjects unable to tolerate steroids may be
candidates for treatment with plasmapheresis or
IVIG.
Grade 4 
Permanently discontinue study drug/study 
regimen. 
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88 
o
If Myasthenia Gravis-like neurotoxicity present,
consider starting AChE inhibitor therapy in
addition to steroids. Such therapy, if successful,
can also serve to reinforce the diagnosis.
◦
GUILLAIN-BARRÉ:
o
Important to consider here that the use of steroids as the
primary treatment of Guillain-Barré is not typically
considered effective. Subjects requiring treatment should
be started with IVIG and followed by plasmapheresis if
not responsive to IVIG.
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89 
Table 8. Treatment Modification and Toxicity Management Guidelines for Infusion-related Reactions (Durvalumab) 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any grade 
•
Management per institutional standard at the discretion of investigator.
•
Monitor subjects for signs and symptoms of infusion-related reactions (e.g.,
fever and/or shaking chills, flushing and/or itching, alterations in heart rate
and blood pressure, dyspnea or chest discomfort, skin rashes etc) and
anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, hypotension,
tachycardia, etc).
Grade 1 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event. 
•
For Grade 1 or Grade 2:
-
Acetaminophen and/or antihistamines may be administered per
institutional standard at the discretion of the investigator.
-
Consider premedication per institutional standard prior to subsequent
doses.
Grade 2 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution 
of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
Grade 3/4 
Permanently discontinue study drug/study regimen. 
•
For Grade 3 or 4:
- Manage severe infusion-related reactions per institutional standards
(e.g., intramuscular epinephrine, followed by intravenous
diphenhydramine and ranitidine, and intravenous glucocorticoid).
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90 
Table 9. Treatment Modification and Toxicity Management Guidelines for Non-immune-mediated Reactions (Durvalumab) 
CTC Grade/Severity 
Dose Modification 
Toxicity Management 
Any grade 
Note: dose modifications are not required for adverse events (AEs) not deemed to be related to 
study treatment (i.e., events due to underlying disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly as per 
institutional standard. 
1 
No dose adjustment. 
Treat accordingly as per 
institutional standard. 
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline. 
Treat accordingly as per 
institutional standard. 
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline, resume 
study drug/study regimen administration at next scheduled dose based upon treating 
physician’s clinical judgment.  Otherwise, discontinue study drug/study regimen. 
Treat accordingly as per 
institutional standard. 
4 
Discontinue study drug/study regimen (Note for Grade 4 labs, decision to discontinue would be 
based on accompanying clinical signs/symptoms and as per Investigator’s clinical judgment 
and in consultation with the MDACC IND Office and supporting companies). 
Treat accordingly as per 
institutional standard. 
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Drug Substances: Durvalumab, MEDI0457 
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Version Number: 1.8 
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91 
APPENDIX E. ADMINISTRATION SITE REACTION GRADING AND 
MANAGEMENT 
Grading: 

Grading should be done using two systems: Common Terminology Criteria for Adverse
Event 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. 
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92 
Grade 
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
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93 
APPENDIX F. DURVALUMAB WEIGHT-BASED DOSE CALCULATION 
For durvalumab dosing done depending on subject weight. Weight-based dosing should be 
utilized for patients < 30 kg who would have otherwise received a 1500mg fixed dose.  
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag:
Dose (mL) = XY mg / 50 (mg/mL)
where 50 mg/mL is durvalumab nominal concentration.
The corresponding volume of durvalumab should be rounded to the nearest tenth mL
(0.1 mL). Dose adjustments for each cycle are only needed for greater than 10% change
in weight.
5. The number of vials required for dose preparation is the next greatest whole number of
vials from the following formula:
Number of vials = Dose (mL) / 10.0 (mL/vial) 
Example:  
1. Cohort dose: 20 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 600 mg = 20 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag:
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL
5. The number of vials required for dose preparation:
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials
Bagarazzi, M. L., Yan, J., Morrow, M. P., Shen, X., Parker, R. L., Lee, J. C., . . . Sardesai, N. Y. 
(2012). Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular 
immune responses. Sci Transl Med, 4(155), 155ra138. doi:10.1126/scitranslmed.3004414 
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