Prospective Study of HPV Specific Immunotherapy in Subjects With HPV Associated Head and Neck Squamous Cell Carcinoma (HNSCCa)
Phase: PHASE1
Conditions: Head and Neck Squamous Cell Cancer
Sponsor: Inovio Pharmaceuticals

 
Official Title: 
PROSPECTIVE STUDY OF HPV SPECIFIC IMMUNOTHERAPY IN SUBJECTS WITH 
HPV ASSOCIATED HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCCa) 
NCT Number: 
NCT02163057 
 
Document Date: 
 
Protocol Version 2.1: 08 April 2016 
 
 
 
 
 
 
 
 

CLINICAL RESEARCH PROTOCOL 
Prospective Study of HPV Specific Immunotherapy in Subjects with HPV 
Associated Head and Neck Squamous Cell Carcinoma (HNSCCa) 
Principal Investigator: 
, MD, MPH 
Protocol Version 2.1 
Medical Oncology 
, MD 
, MD 
, MD 
Head and Neck Surgery 
 Jr, MD 
, MD 
, MD 
, MD 
, MD 
Radiation Oncology 
, MD 
, MD 
, MD 
Basic Science Expert 
, PhD 
Drug Manufacturer/Sponsor 
Inovio Pharmaceuticals, Inc. 
660 W Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
Research Correlative Studies 
, PhD 
Biostatistics 
, PhD 
Medical Monitor 
, MD  
IND # 15946, under Inovio, Inc.
 
Research Correlative Studies 
, MD, PhD 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio Pharmaceuticals and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review Board/Ethics 
committee approval and informed consent, or as required by local regulatory authorities. Persons to whom 
this information is disclosed must be informed that this information is privileged and confidential and that it 
should not be further disclosed without the written permission of Inovio Pharmaceuticals. Any supplemental 
information added to this document is also confidential and proprietary information of Inovio 
Pharmaceuticals and must be kept in confidence in the same manner as the contents of this document. 

INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
SUMMARY OF CHANGES 
The following is a list of significant protocol changes from v2.0 dated June 25, 2015 to v2.1 
dated April 8, 2016. All other changes are administrative and do not significantly affect the 
safety of subjects, study scope, or scientific quality of the protocol.  
 
1. The long term follow up period post last dose is changed from "2 years from screening” 
to “6 months post the last dose of immunotherapy”. It is mainly because to date, safety 
profile from 19 subjects who have been followed for more than 6 months does not show 
any study treatment related adverse safety events, therefore it is considered an undue 
burden on subjects to continue the follow up for an extended time period.  
Following sections of the protocol are affected: 
 
• Protocol Synopsis 
• Tables S1 and S2 Schedule of Events 
• Section 3, Study Design 
• Section 6.1.7 Cohort I Long Term Follow Up 
• Section 6.2.4 Cohort II, Long Term Follow Up 
 
 
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
PROTOCOL ACKNOWLEDGEMENT 
 
 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or 
Independent Ethics Committee overseeing the conduct of the study and approved or given 
favorable opinion before implementation. 
 
The signature of the Principal Investigator and Sponsor below constitute their approval of this 
protocol and proved the necessary assurances that this study will be conducted according to The 
Declaration of Helsinki, GCP, ICH guidelines, local legal and regulatory regulations as well as to 
all stipulations of the protocol in both the clinical and administrative sections, including 
statements regarding confidentiality. 
 
 
 
 
______________________                  _______________             _________________ 
Investigator’s printed name                  Signature 
 
 
Date 
 
 
 
_________________________________ 
 
 
_________________ 
Medical Monitor  
 
 
 
 
 
Date 
 
 
 
 
Protocol Number: HPV-005 
Site Number:  
Version Number/Version Date: v2.1 /8-April-2016 
 
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
 
Table of Contents 
 
SUMMARY OF CHANGES .........................................................................................................2 
CLINICAL PROTOCOL SYNOPSIS .........................................................................................7 
TABLE S1:  COHORT I SCHEDULE OF EVENTS ........................................................................ 13 
TABLE S2: COHORT II SCHEDULE OF EVENTS ........................................................................ 15 
1 
INTRODUCTION................................................................................................................17 
1.1 
BACKGROUND ................................................................................................................ 17 
1.1.1 HPV RELATED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK ...................... 17 
1.1.2 RATIONALE FOR HPV SPECIFIC IMMUNOTHERAPY WITH A THERAPEUTIC HPV VACCINE
 
18 
1.1.3 RATIONALE 
FOR 
IMMUNOTHERAPY 
WITH 
SYNTHETIC DNA 
DELIVERED 
BY 
ELECTROPORATION ................................................................................................................ 18 
1.1.4 RATIONALE FOR ADDITION OF IL-12 PLASMID DNA MOLECULAR ADJUVANT ............ 19 
1.1.5 RATIONALE FOR ELECTROPORATION (EP) WITH CELLECTRA® DEVICE ................... 19 
1.2 
INVESTIGATIONAL AGENTS ............................................................................................ 20 
1.2.1 VGX-3100 (COMMON NAME) .................................................................................... 20 
1.2.2 INO-9012 (COMMON NAME) ..................................................................................... 20 
1.2.3 CELLECTRA®5P DEVICE FOR INTRAMUSCULAR ELECTROPORATION ....................... 20 
1.3 
PRECLINICAL DATA ....................................................................................................... 20 
1.3.1 VGX-3100 PRECLINICAL DATA ................................................................................. 20 
1.3.2 INO-9012 PRECLINICAL DATA................................................................................... 20 
1.4 
CLINICAL DATA ............................................................................................................. 21 
1.4.1 VGX-3100 CLINICAL DATA ....................................................................................... 21 
1.4.2 INO-9012 CLINICAL DATA ........................................................................................ 21 
1.4.3 CELLECTRA® DEVICE CLINICAL USE ..................................................................... 21 
1.5 
DOSE RATIONALE AND RISK/BENEFITS.......................................................................... 22 
1.5.1 DOSE RATIONALE ....................................................................................................... 22 
1.5.2 RISKS/BENEFIT ASSESSMENT ..................................................................................... 23 
2 
STUDY OBJECTIVES ........................................................................................................23 
2.1 
PRIMARY OBJECTIVES .................................................................................................... 23 
2.2 
SECONDARY OBJECTIVES ............................................................................................... 24 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................... 24 
3 
STUDY DESIGN ..................................................................................................................24 
3.1 
GENERAL DESIGN .......................................................................................................... 24 
3.2 
STUDY ENDPOINTS ......................................................................................................... 26 
3.2.1 PRIMARY ENDPOINT ................................................................................................... 26 
3.2.2 SECONDARY ENDPOINT .............................................................................................. 26 
3.2.3 EXPLORATORY ENDPOINTS: CLINICAL RESPONSE CRITERIA AS DETERMINED BY: ....... 28 
4 
SUBJECT SELECTION AND WITHDRAWAL .............................................................28 
4.1 
INCLUSION CRITERIA ..................................................................................................... 28 
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UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
4.2 
EXCLUSION CRITERIA .................................................................................................... 29 
4.3 
SUBJECT RECRUITMENT AND SCREENING ...................................................................... 29 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .............................................................................. 30 
4.4.1 WHEN AND HOW TO WITHDRAW SUBJECTS ............................................................... 30 
4.4.2 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS ............................ 30 
5 
STUDY DRUG .....................................................................................................................31 
5.1 
DESCRIPTION ................................................................................................................. 31 
5.2 
PACKAGING ................................................................................................................... 31 
5.3 
RECEIVING, STORAGE, DISPENSING AND RETURN.......................................................... 32 
5.3.1 RECEIPT OF DRUG SUPPLIES ....................................................................................... 32 
5.3.2 STORAGE .................................................................................................................... 32 
5.3.3 DISPENSING OF STUDY DRUG ..................................................................................... 32 
5.3.4 PRECAUTIONS WITH INVESTIGATIONAL MEDICINAL PRODUCT ................................... 33 
5.3.5 PREPARATION OF INVESTIGATIONAL PRODUCT .......................................................... 33 
5.3.6 RETURN OR DESTRUCTION OF STUDY DRUG .............................................................. 34 
5.4 
USE OF CELLECTRA ELECTROPORATION DEVICE..................................................... 35 
5.4.1 INVESTIGATIONAL DEVICE ACCOUNTABILITY ............................................................ 35 
6 
STUDY PROCEDURES AND TREATMENTS ...............................................................35 
6.1 
COHORT I ....................................................................................................................... 35 
6.1.1 PRE TREATMENT EVALUATION (SCREENING; DONE WITHIN 28 DAYS OF FIRST DOSE)35 
6.1.2 VISIT FOR IMMUNOTHERAPY (PRE AND POST SURGERY: EVERY 3 WEEKS ± 3 DAYS).. 36 
6.1.3 SURGERY .................................................................................................................... 37 
6.1.4 POST SURGERY 2 WEEK FOLLOW UP (± 7 DAYS) .......................................................... 37 
6.1.5 INSPECTION VISIT 4 WEEKS POST-SURGERY (±7 DAYS) ............................................. 37 
6.1.6 2 WEEK FOLLOW UP POST LAST DOSE OF IMMUNOTHERAPY (±3 DAYS) ................... 37 
6.1.7 LONG TERM FOLLOW UP (EVERY 3 MONTHS ±7 DAYS FOR 6 MONTHS)/END OF STUDY 
VISIT 38 
6.2 
COHORT II ..................................................................................................................... 38 
6.2.1 PRE-TREATMENT EVALUATION (SCREENING; WITHIN 28 DAYS OF FIRST DOSE) .......... 38 
6.2.2 VISIT FOR IMMUNOTHERAPY (4 DOSES EVERY 3 WEEKS ±3 DAYS) ............................ 39 
6.2.3 2 WEEK FOLLOW UP POST LAST DOSE OF IMMUNOTHERAPY (± 3 DAYS) ................... 39 
6.2.4     LONG TERM FOLLOW UP (EVERY 3 MONTHS ± 7 DAYS FOR 6 MONTHS)/END OF STUDY 
VISIT 39 
6.3 
TIMING AND EVALUATION ............................................................................................. 40 
6.3.1 INFORMED CONSENT .................................................................................................. 40 
6.3.2 ASSIGNMENT OF SUBJECT NUMBERS .......................................................................... 40 
6.3.3 MEDICAL HISTORY/EXISTING EVENTS/ILLNESSES ..................................................... 40 
6.3.4 SAFETY ASSESSMENTS ............................................................................................... 40 
6.4 
OPTIONAL COLLECTION OF LEFTOVER TUMOR TISSUE SAMPLE ..................................... 42 
6.5 
HLA TESTING ................................................................................................................ 42 
6.6 
INJECTION OF INO-3112 FOLLOWED BY ELECTROPORATION ......................................... 42 
6.6.1 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE .................................. 43 
6.6.2 ASSESSMENT OF INJECTION SITE REACTIONS ............................................................. 43 
7 
STATISTICAL PLAN .........................................................................................................44 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................... 44 
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UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
7.2 
STATISTICAL METHODS ................................................................................................. 44 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................... 44 
8 
SAFETY AND ADVERSE EVENTS .................................................................................44 
8.1 
DEFINITIONS .................................................................................................................. 44 
8.1.1 UNANTICIPATED PROBLEMS INVOLVING RISK TO SUBJECTS OR OTHERS ................... 44 
8.1.2 ADVERSE EVENT ........................................................................................................ 45 
8.1.3 SERIOUS ADVERSE EVENT .......................................................................................... 45 
8.1.4 ADVERSE EVENT REPORTING PERIOD ........................................................................ 46 
8.1.5 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS .................... 47 
8.1.6 PREEXISTING CONDITION ........................................................................................... 48 
8.1.7 GENERAL PHYSICAL EXAMINATION FINDINGS ........................................................... 48 
8.1.8 POST-STUDY REPORTING REQUIREMENTS .................................................................. 48 
8.1.9 ABNORMAL LABORATORY VALUES ........................................................................... 48 
8.1.10 HOSPITALIZATION, PROLONGED HOSPITALIZATION OR SURGERY .............................. 49 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................. 49 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............... 50 
8.3.1 EVENTS REQUIRING EXPEDITED REPORTING .............................................................. 50 
8.3.2 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) ............................................... 51 
8.3.3 INVESTIGATOR REPORTING: INOVIO PHARMACEUTICALS, INC. ................................... 51 
8.3.4 INVESTIGATOR REPORTING: THE PENN IRB ............................................................... 52 
8.3.5 OTHER REPORTABLE EVENTS: .................................................................................... 53 
8.4 
REPORTABLE EVENTS .................................................................................................... 53 
8.5 
REPORTING OF DEVICE RELATED COMPLAINTS ............................................................. 54 
9 
DATA HANDLING AND RECORD KEEPING ..............................................................54 
9.1 
CONFIDENTIALITY ......................................................................................................... 54 
9.2 
SOURCE DOCUMENTS .................................................................................................... 54 
9.3 
CASE REPORT FORMS .................................................................................................... 54 
9.4 
RECORDS RETENTION .................................................................................................... 54 
10 STUDY MONITORING, AUDITING, AND INSPECTING ..........................................55 
10.1 
STUDY MONITORING ...................................................................................................... 55 
10.2 
MEDICAL MONITOR ....................................................................................................... 55 
10.3 
AUDITING AND INSPECTING ........................................................................................... 55 
11 ETHICAL CONSIDERATIONS ........................................................................................56 
12 STUDY FINANCES.............................................................................................................56 
12.1 
FUNDING SOURCE .......................................................................................................... 56 
12.2 
CONFLICT OF INTEREST .................................................................................................. 56 
13 PUBLICATION PLAN .......................................................................................................56 
14 LIST OF ABBREVIATIONS .............................................................................................57 
15 REFERENCES .....................................................................................................................59 
 
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
 
CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study: Prospective Study of HPV Specific Immunotherapy in Subjects with HPV 
Associated Head and Neck Squamous Cell Carcinoma (HNSCCa) 
 
Number of Study Centers and Countries/Regions: 1 Site (United States) 
 
Research Hypothesis: This protocol proposes to study the safety and the immune effects 
of immunotherapy with INO-3112 that contains VGX-3100, synthetic plasmid DNA 
encoding human papillomavirus (HPV)-16 and HPV-18 E6/E7 antigens and INO-9012, a 
recombinant IL-12 molecular adjuvant administered.  
 
The safety and effects of immunotherapy will be studied in following two populations: 
1. In  chemo- and radiation-naïve subjects who undergo definitive surgery and 
2. In subjects after chemoradiation therapy  
 
Study Objectives:  
Primary: Evaluate safety of treatment with INO-3112. 
Secondary: 
1. Evaluate humoral and cellular immune response post to administration of INO-3112 
in chemo- and radiation-naïve subjects who undergo definitive surgery: 
a. Pre- and Post-immunotherapy tissue analysis to evaluate infiltration of T 
cells in the tumor 
b. Evaluate effect of number of doses on immune responses 
c. Evaluate immune response duration 
 
2. Evaluate humoral and cellular immune response to administration of INO-3112 in 
subjects after chemoradiation therapy: 
- 
Evaluate immune response duration 
 
Exploratory: 
1. Explore anti-tumor response  
2. Explore progression free survival  
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
Sample Size:  
 
A minimal of 20, and no more than 25 subjects will be enrolled in this study. 
 
Study Design: 
This will be a prospective, open-label, Phase I/IIa study of immunotherapy of INO-3112 in 
subjects with HPV-positive HNSCCa. Subjects will receive a course of treatment as 
described below and will be followed for safety as well as immune and clinical responses 
for 6 months from the last dose of immunotherapy.  
The safety and effects of immunotherapy will be studied in following two populations: 
1. In  chemo- and radiation-naïve subjects who undergo definitive surgery and 
2. In subjects after chemoradiation therapy  
Doses of INO-3112 are based on safety experience in prior and on-going clinical trials. 
Based on the prior experience with these agents, dose escalation will not be conducted in 
this trial.  
The study is divided into the following treatment cohorts: 
I. 
INO-3112 (6 mg VGX-3100 + 1 mg INO-9012) will be given to subjects before and 
after definitive surgery  
II. 
INO-3112 (6 mg VGX-3100 + 1 mg INO-9012) will be given to subjects after  
chemoradiation therapy 
Cohort I: Immunotherapy will be given both before and after definitive surgery. Each 
subject will receive a total of 4 doses of treatment. Each treatment will be 6 mg of VGX-
3100 and 1 mg INO-9012 (INO-3112) delivered IM followed by electroporation (EP). A 
minimum of 5 eligible subjects will be enrolled to this cohort. 
Pre-Surgery: 
1. Subjects will be enrolled if they have confirmed HPV-positive HNSCCa. Tumor 
tissue sample must be available to perform immunological correlates prior to 
definitive surgery. 
2. After providing informed consent and being deemed eligible, subjects will receive 
immunotherapy. Up to 2 doses may be administered approximately once every 3 
weeks (± 3 days) prior to definitive surgery. 
3. The number of pre-surgery immunotherapies (one vs. two injections) will be based 
on the estimated time interval between pre-surgery evaluation and definitive surgery. 
Time to surgery according to standard practice is usually 2- 4 weeks; however, this 
varies due to ordinary logistical considerations independent of a clinical trial. 
4. Surgery will not be delayed to allow for immunotherapy. 
 
Post-Surgery:  
 
1. Subjects will be seen approximately 2 weeks (± 7 days) post-surgery for follow up. 
2. Subjects will undergo visual inspection to document healing by surgeon 
approximately 4 weeks post-surgery. 
3. Post-surgery immunotherapy will proceed only after approval of the surgeon. 
 
 
 
 
 
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
Post-Surgery (conti.):  
4. Subjects will receive up to 3 doses given 3 weeks (± 3 days) apart. A total of 4 
doses (pre- and post- surgery) will be administered. 
5. Immunotherapy will be administered prior to adjuvant chemotherapy and/or 
radiation that may be indicated.  
6. Adjuvant therapy will not be delayed due to immunotherapy. 
7. Subjects will be followed for tumor status as per institutional standard of care. 
Cohort II: Immunotherapy will start approximately 2-6 months after completion of 
definitive or adjuvant chemoradiation therapy in order to allow recovery from the 
treatment side effects of chemoradiation. INO-3112 will be delivered by IM injection 
followed by EP approximately once every 3 weeks for a total of 4 doses. A minimum of 10 
eligible subjects will be enrolled into this cohort. 
1. Subjects will be enrolled if they have HPV-16 and/or HPV-18 positive HNSCCa, 
and have completed chemoradiation therapy. Adequate tissue must be available to 
perform immunological correlates studies. Confirmation of HPV-16 and/or HPV-
18 positivity is required prior to first dose of immunotherapy. 
2. Subjects will be followed for tumor status as per normal institutional standard of 
care. 
 
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
Study Endpoints:  
Primary Endpoints: Safety and tolerability based on standard laboratory and clinical 
adverse event monitoring. 
1. Adverse events will be measured and graded according to “Common Terminology 
Criteria for Adverse Events (CTCAE)”, NCI version 4.03 issued by the US 
Department of Health and Human Services. 
2. Frequency and severity of injection site reactions including administration site 
pain, skin erythema, induration, bleeding tenderness and infection. 
Secondary Endpoints: Immune response after immunotherapy based on correlative 
measures. 
1. Measure HPV-16 and HPV-18 specific antibody levels. 
2. Using Antigen-specific IFN-γ ELISpot assays, determine the number of antigen-
specific spot forming units (SFU) in response to stimulation with HPV-16 and 
HPV-18. 
3. Evaluate cytotoxic T cells in response to HPV specific immunotherapy by flow 
cytometry. 
4. Evaluate tumor infiltrating lymphocytes (TILs) by Immunohistochemistry (IHC) on 
pre-surgical and surgical samples. 
5. Evaluate phenotypes of cultured TILs. 
Exploratory Endpoints: Clinical response criteria as determined by:  
1. Any evidence of anti-tumor response as assessed by the Investigator 
2. Progression free survival  
 
 
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INO-3112 
 
 
UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
Study Population: 
     Inclusion Criteria 
 
1. Signed and dated written Ethics Committee approved informed consent. 
2. Age ≥18 years. 
3. Histologically confirmed HPV-positive mucosal squamous cell head and neck 
cancer. Tumor tissue samples and the HPV test results must be available prior to 
first dose of Study Treatment: 
• For pre-surgical subjects, p16 positivity must be confirmed prior to first 
dose 
• For subjects post chemoradiation therapy, HPV-16 and/or HPV-18 
positivity (as assessed by p16 IHC AND oncogenic HPV ISH or PCR) 
must be confirmed prior to first dose.  
4. Adequate bone marrow, hepatic, and renal function. ANC (Absolute Neutrophil 
Count) ≥ 1.5x109 cell/ml, platelets ≥75,000 /mm3, hemoglobin ≥9.0 g/dL, total 
serum bilirubin within 1.5 x upper limit of normal (ULN), AST, ALT, CPK within 
2.5 x ULN and performed within 4 weeks prior to the first administration of Study 
Treatment. 
5. ECG with no clinically significant findings as assessed by the investigator. 
6. No history of clinically significant autoimmune disease, HIV infection or other 
immunosuppressive disease. 
7. ECOG (Eastern Cooperative Oncology Group) performance status of 0-1. 
8. Women of childbearing potential must have a negative serum pregnancy test and 
agree to remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), 
or use two medically effective methods of contraception (e.g. oral contraception, 
barrier methods, spermicide, intrauterine device (IUD)). Males with reproductive 
potential must be willing to use a condom and have their female sexual partners 
use another form of contraception such as an IUD, spermicidal 
foam/gel/film/cream/suppository, diaphragm with spermicide, oral contraceptive, 
injectable progesterone, sub-dermal implant or a tubal ligation if the female partner 
could become pregnant. This requirement should be followed from screening 
through 24 weeks after last dose of immunotherapy. 
9. Able and willing to comply with all study procedures. 
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UPCC # 39313 / HPV-005 
Inovio Pharmaceuticals, Inc 
 
   Clinical Protocol 
Study Population: (continued): 
     Exclusion Criteria 
1. Pregnant or breast-feeding subjects. 
2. Anticipated concomitant immunosuppressive therapy (excluding non-
systemic inhaled, topical skin and/or eye drop-containing corticosteroids). 
3. Any concurrent condition requiring the continued use of systemic steroids 
(>10 mg prednisone or equivalent per day) or the use of immunosuppressive 
agents. All other corticosteroids must be discontinued at least 4 weeks prior 
first dose of study treatment. 
4. Known history of hepatitis B or C with active viral replication. 
5. Administration of any vaccine within 6 weeks of first dose of study 
treatment. 
6. Tattoos, scars, or active lesions/rashes within 2 cm of the intended site of 
injection 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. 
7. Participation in another interventional clinical trial within 30 days before 
receiving first dose of study treatment. However, the subject may participate 
in observational studies. 
8. Any cardiac pre-excitation syndromes, e.g. Wolff-Parkinson-White 
syndrome. 
9. Active drug or alcohol use or dependence that, in the opinion of the 
investigator, would interfere with adherence to study requirements. 
10. Prisoners or subjects who are compulsorily detained (involuntarily 
incarcerated) for treatment of either a psychiatric or physical (i.e. infectious 
disease) illness must not be enrolled into this study. 
11. Any illness or condition that in the opinion of the investigator may affect the 
safety of the subject or the evaluation of any study endpoint. 
12. Any other conditions judged by the investigator that would limit the 
evaluation of a subject. 
 
 
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INO-3112                                                                                                                                        UPCC # 39313 / Inovio HPV-005 
Inovio Pharmaceuticals, Inc                                                                                                                                      Clinical Protocol 
 
Table S1:  Cohort I Schedule of Events 
Pre-surgery (Up to 2 doses of immunotherapy  3 weeks apart ± 3 days) 
Post-surgery (Up to 3 doses of immunotherapy, 3 weeks apart; ± 3 days).   
Subjects will receive no more than 4 doses of Immunotherapy (to include both pre and post-surgery dosing). 
  
Screening1 
Pre 
Dose 
Post 
Dose 
Surgery 
2 wk Post 
surgery 
Inspection 
Visit2 
2 wk f/u 
post last 
dose  
LTFU/
EOS3 
Procedures 
  
  
  
  
  
  
 
  
Informed Consent 
X 
  
  
  
  
  
 
  
Medical History 
X 
 
  
  
 
 
 
 
Physical Exam4/Assessment 
X 
X 
  
  
X 
X 
X 
X 
Performance Status (ECOG) 
X 
X 
  
  
X 
X 
X 
X 
Concomitant Medications 
X 
X 
  
  
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
  
X 
X 
X 
X 
Injection site assessment 
  
  
X5 
  
 
  
X 
  
Wound healing Inspection 
  
  
  
  
  
X 
 
  
Tumor evaluation 
X 
 
 
 
 
 
 
 
Clinical Labs 
  
  
  
  
  
  
 
  
CBC w diff (4ml) 
X 
 X6 
  
  
  
  
X 
X 
Chemistry (5ml)7 
X 
 X6 
  
  
  
  
X 
X 
PT-INR/PTT  (4ml) 
X 
  
  
  
  
  
 
  
B-hCG (1ml)8 
X 
 X 
  
  
  
  
 
  
Viral Serology (5ml)9 
X 
  
  
  
  
  
 
  
CPK (1ml) 
X 
 
 
 
 
 
X 
 
Other Clinical Procedures 
  
  
  
  
  
  
 
  
ECG 12-lead 
X 
  
  
  
  
  
 
  
Research Immunology 
  
  
  
  
  
  
 
  
Serum and Whole Blood  
(1 Red Top and 4 ACD 
tube)10 
X 
X 
  
X 
X 
X 
 
 
X 
X 
Tissue Sample11 
X 
  
  
X 
  
  
 
  
HLA Testing (no action 
required) 
 
X12 
IMMUNOTHERAPY  
  
X 
  
  
  
  
 
  
Download EP Data 
  
 
 X 
  
  
  
 
  
Patient Reminder Card 
  
 
 X 
  
  
  
 
  
1- Screening to be done within 28 days prior to first dose. If a subject is rescreened, the screening clinical labs and 12-
lead ECG must be repeated unless they will occur within 4 weeks of the subject’s first dose.  All other screening 
procedures do not need to be repeated. 
2- Inspection visit occurs 4 weeks post-surgery (± 7 days)  
3- LTFU: Long term follow up: every 3 months (±7 days) for 6 months from the last dose of immunotherapy, End of 
Study (EOS) defined as last LTFU visit 
4- Includes weight, vital signs, oxygen saturation (height will be collected as part of Screening visit). Assessment includes 
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INO-3112                                                                                                                                        UPCC # 39313 / Inovio HPV-005 
Inovio Pharmaceuticals, Inc                                                                                                                                      Clinical Protocol 
 
 medical/clinical assessment  
5- To be done 30-45 minutes post dose  
6- If clinical screening labs (CBC and Chemistry) were performed within 72 hours prior the subject’s first dose, these labs 
are not required to be redrawn prior to the subject’s first dose  
7- Total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum creatinine, serum electrolytes, serum 
calcium, serum albumin. 
8- Women of childbearing potential. Serum β-hCG at screening and Urine β-hCG within 72 hours of each dose. 
9- Antibody to human immunodeficiency virus (HIV-Ab), Hepatitis B surface antigen (HBsAg), antibody to Hepatitis C 
virus (HCV) 
10- At least 34 mL (4 x 8.5 mL ACD tubes) whole blood and 4 mL serum per time point to be collected. A total of at least 
68 mL whole blood and 4 mL serum should be collected prior dosing on Day 0. 
11- Paraffin-embedded tumor tissue or unstained slides for IHC and ISH. Fresh cut primary tumor tissue at the time of 
surgery. 
12- To be performed using available PBMC from whole blood immunology sample. 
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Table S2: Cohort II Schedule of Events  
Immunotherapy starts ~2-6 months post chemoradiation. Doses are q3 weeks (± 3 days). 
  
Screening1 
Pre Dose 
Post Dose 
2 wk f/u 
post last 
dose 
LTFU/EOS2 
Procedures 
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Exam3/Assessment 
X 
X 
 
X 
X 
Performance Status (ECOG) 
X 
X 
 
X 
X 
Concomitant Medications 
X 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
Injection site assessment 
 
 
X4 
 
 
Clinical Labs 
 
 
 
 
 
CBC w diff (4ml) 
X 
X5 
 
X 
X 
Chemistry (5ml)6 
X 
X5 
 
X 
X 
PT-INR/PTT  (4ml) 
X 
 
 
 
 
B-hCG (1ml)7 
X 
X 
 
 
 
Viral Serology (5ml)8 
X 
 
 
 
 
CPK (1ml) 
X 
 
 
X 
 
Other Clinical Procedures 
 
 
 
 
 
ECG 12-lead 
X 
 
 
 
 
Research Immunology 
 
 
 
 
 
Serum and Whole Blood  
(1 Red Top and 4 ACD tube)9 
X 
X 
 
X 
X 
Tissue Sample10 
X 
 
 
 
 
HLA Testing (no action 
required) 
 
X11 
IMMUNOTHERAPY  
 
X 
 
 
 
Download EP Data 
 
 
X 
 
 
Patient Reminder Card 
 
 
X 
 
 
1- Screening to be done within 28 days prior to first dose. If a subject is rescreened, the screening 
clinical labs and 12-lead ECG must be repeated unless they occur within 4 weeks of the subject’s first 
dose.  All other screening procedures do not need to be repeated. 
2- LTFU: Long term follow up: every 3 months (±7 days) for 6 months from the last dose of 
immunotherapy, End of Study (EOS) defined as last LTFU visit 
3- Includes weight, vital signs, oxygen saturation  
4- To be done 30-45 minutes post dose  
5- If clinical screening labs (CBC and Chemistry) were performed within 72 hours prior the subject’s 
first vaccination, these labs are not required to be redrawn prior to the subject’s first dose  
6- Total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum creatinine, serum 
electrolytes, serum calcium, serum albumin. 
7- Women of childbearing potential only. Serum β-hCG at screening and Urine β-hCG within 72 hours 
of each dose 
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8- HIV, Hepatitis BsAg, Hepatitis C 
9- At least 34 mL (4 x 8.5 mL tubes) whole blood and 4 mL serum per time point to be collected.  A 
total of at least 68 mL whole blood and 4 mL serum should be collected prior to dosing on Day 0. 
10- Paraffin-embedded tumor tissue or unstained slides for IHC and ISH. Confirmation of HPV-16 and/or 
HPV-18 positivity prior to first dose.  
11- To be performed using available PBMC from whole blood immunology sample. 
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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 Background 
1.1.1 HPV related squamous cell carcinoma of the head and neck  
Squamous cell carcinoma of the head and neck (HNSCC) is diagnosed in over 500,000 patients 
worldwide each year, accounting for 5% of all malignancies [1]. A significant subset of HNSCCa 
is now known to be caused by oncogenic human papilloma virus (HPV) infection. HPV-
associated SCCa arises predominantly in the oropharynx and occurs in patients (strong male 
predominance) without a strong tobacco and/or alcohol consumption history. In a retrospective 
study, tumor tissues from 253 patients with newly diagnosed or recurrent HNSCCa were tested 
for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, 
Southern blot hybridization, and in situ hybridization (ISH). The viral E6 coding region was 
sequenced to confirm the presence of tumor-specific viral isolates. HPV was detected in 62 (25%) 
of 253 cases. High risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive 
tumors. HPV-16 was localized specifically by ISH within the nuclei of cancer cells in pre-
invasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent 
with viral integration. Poor tumor grade and oropharyngeal site independently increased the 
probability of HPV presence [2].  
The molecular and clinical profiles of HPV positive tumors are distinct from those of HPV 
negative cancers. In the typical HPV negative squamous cell carcinomas, p53 mutations are 
frequent along with decreased p16 and increased levels of pRb [3]. By contrast, HPV positive 
carcinomas are associated with wild type (albeit dysregulated) p53, down regulation of pRb, and 
up-regulation of p16, the latter serving as a surrogate marker for the disease itself. As compared 
with HPV-negative oropharyngeal cancers, HPV positive oropharyngeal cancers are less likely to 
occur among moderate to heavy drinkers and smokers, have characteristic basaloid morphology, 
and have improved disease-specific survival [2]. 
The HPV viral oncoproteins, E6 and E7, are predominantly responsible for oncogenesis. Like 
many viral oncoproteins, E6 and E7 are expressed early in the course of infection and have 
multifunctional roles. 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 drive rapid cellular proliferation, 
suppress or downregulate key tumor suppressor proteins, and lead to cellular immortality. In 
addition, E6/E7 expression is vital for malignancy and is required to maintain a malignant 
transformed phenotype [4]. It has been shown that persistence of malignant cells requires the 
continuous expression of the human papillomavirus type 16 oncogenes [5]. 
Tumor HPV status is a strong and independent prognostic factor for survival among patients with 
oropharyngeal cancer. HPV related tumors are generally more responsive to chemotherapy and 
radiation compared to non-HPV related HNSCCa [6]. In a landmark retrospective analysis of 
RTOG0129, Ang et al. described that patients with HPV related tumors had superior 3-year rates 
of overall survival compared to non-HPV related tumors.  After adjusting for age, race, tumor and 
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nodal stage, tobacco exposure, and treatment assignment, patient with HPV-related HNSCCa had 
a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). Smoking history 
had a significant impact on survival in this otherwise favorable prognosis population; the risk of 
death increased significantly with each additional pack-year of tobacco smoking [6]. 
Despite the availability of highly curative treatments, at least 10-30% of patients with HPV 
related HNSCCa (depending on smoking status and other unknown variables) will eventually 
develop locally recurrent and/or metastatic disease. The prognosis of patients with locally 
recurrent or metastatic HNSCCa is dismal, and palliative treatment options remain extremely 
limited. A few patients with recurrent disease are candidates for salvage therapies, including 
potentially curative surgery [7]. Highly selected patients in this setting may benefit from re-
irradiation although the morbidity of this approach is substantial [8]. Palliative systemic therapy 
remains the mainstay for most patients. Despite the availability of cytotoxic chemotherapy and 
targeted agents like cetuximab, median survival for patients with incurable HNSCCa is around 
10.5 months [9].  
1.1.2 Rationale for HPV specific immunotherapy with a therapeutic HPV vaccine  
Current treatment of HPV related HNSCC could potentially be improved with addition of 
immunotherapy. Commercially available preventive HPV vaccines generate neutralizing 
antibodies against HPV major capsid protein L1, but they do not exert therapeutic effects on 
existing lesions and are unlikely to have an effect on HPV associated malignancy because they do 
not engender a cytolytic T-cell response [10]. HPV specific immunotherapy, on the other hand, 
may eliminate preexisting lesions and infections by generating cellular immunity against HPV 
infected cells. HPV E6 and E7 oncoproteins represent ideal targets for therapeutic intervention 
because of their constitutive expression in HPV associated tumors and their crucial role in the 
induction and maintenance of HPV associated disease [10]. 
One therapeutic approach is to modify the virus itself and use it as an immunogen.  In a recent 
study, Wieking et al. described the generation of a mutant non-oncogenic HPV16 E6D/E7D 
construct. This construct, expressed either as a stable integrant or in the [E1-, E2b-] adenovirus, 
lacks the ability to transform human cells but retains the ability to induce an HPV-specific 
immune response. In a mouse model, vaccination with Ad5 [E1-, E2b-]-E6D/E7D in immune 
competent mice enhanced immune related clearance in vivo during standard therapy for HPV 
related cancer with cisplatin and radiation [11].  
1.1.3 Rationale for immunotherapy with synthetic DNA delivered by electroporation 
The delivery of synthetic DNA using electroporation represents another approach that offers 
several potential advantages. Synthetic DNA in the form of a plasmid are not known to elicit anti-
vector immune responses, providing the capacity for repeated administrations that may be 
required to achieve and maintain effective immune responses. Furthermore, the plasmids can be 
engineered to express a variety of HPV related antigenic peptides and/or proteins [10]. 
Inovio has developed a novel immunotherapeutic from synthetic HPV-16/18 E6 and E7 DNA 
sequences. Phase 1 clinical results with VGX-3100 delivered by in vivo electroporation (EP) were 
recently published [12]. Eighteen women previously treated for cervical intraepithelial neoplasia 
(CIN) grade 2 or 3 were treated with a three-dose (intramuscular) regimen of a highly engineered 
DNA (VGX-3100) in a dose escalation study (0.3, 1, and 3 mg per plasmid). HPV specific CD8+ 
T cells were shown to exhibit full cytolytic functionality in all cohorts. VGX-3100 was shown to 
drive robust immune responses to E6 and E7 from high-risk HPV serotypes and could thereby 
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contribute to elimination of HPV infected cells and subsequent regression of the HPV induced 
dysplastic process [12]. 
Because E6 and E7 are responsible for the transformation of cancer cells and are required for 
maintenance of HPV associated HNSCC, we hypothesize that generation of robust T-cell 
immunity to E6 or E7 will lead to down-regulation of cancer survival pathways and disease 
stabilization or regression.  
1.1.4 Rationale for addition of IL-12 plasmid DNA molecular adjuvant 
DNA vaccines primarily elicit CD4+ T-cell responses in humans, and there has been interest in 
discovering ways to boost the immune response post vaccination. In addition to electroporation, 
Inovio has also shown that IL-12 DNA can be used as a molecular adjuvant to enhance immune 
responses. This is done by co-delivering DNA plasmids expressing immune modulators. The IL-
12 DNA adjuvant is a dual promoter expression plasmid expressing the genes encoding human 
IL-12 proteins p35 and p40 under separate regulatory control.  
In a clinical study with a similarly designed HIV DNA immunogen, co-administration of IL-12 
DNA with DNA encoding antigenic proteins was associated with an enhanced CD8 vaccine 
immune response [13, 14]. The use of IL-12 DNA was associated with expansion of antigen-
specific IFN-γ positive effector cells as well as granzyme B production. The immunity induced 
included both a CD8 as well a CD4 component [15, 16]. The evaluation of recombinant IL-12 
DNA has yielded a wealth of safety information to date in humans and forms the preliminary 
basis for the predicted safety profile for the use of IL-12 plasmid as an adjuvant component of the 
vaccine in the proposed clinical study. 
1.1.5 Rationale for electroporation (EP) with CELLECTRA® device  
The use of EP with the CELLECTRA device has been shown to increase the expression of 
VGX-3100. EP is the use of 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 [17]. 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 [18].  
Ten healthy adults were electroporated using CELLECTRA, to evaluate the pain following EP 
in 10 healthy subjects, was evaluated immediately after, and at 5, 15, 30 minutes and 1 hour after 
the procedure. Subjects used a Visual Analog Scale (VAS) 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. Subjects reported a mean (±sem) score of 6.3 (±0.7) immediately after treatment 
and 2.8 (±0.5) approximately 5 minutes after the procedure [19]. These data show that the pain 
associated with electroporation is acute and diminishes quickly. Therefore, the risk to subjects is 
minimal, and benefit outweighs the risk. 
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In this proof of concept study, we propose to evaluate the safety and immune effects of the 
immunotherapy with VGX-3100, synthetic plasmid DNA encoding HPV-16 and HPV-18 E6/E7 
antigens co-administered with a recombinant IL-12 molecular adjuvant (INO-9012).  
1.2 Investigational Agents 
1.2.1 VGX-3100 (Common Name) 
Chemical Name: Circular, double stranded, deoxyribonucleic acid consisting of 3782 base pairs 
for the pGX3001 plasmid and 3824 base pairs for the pGX3002 plasmid. 
Distinguishing Name: Eukaryotic expression plasmids containing HPV-16 and -18 E6 & E7-
encoding transcription unit controlled by a synthetic, CMV 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). 
1.2.2 INO-9012 (Common Name) 
Chemical Name: Circular, double stranded, deoxyribonucleic acid consisting of 6259 base pairs 
for the pGX6001 (also called IL-12 DNA) plasmid. 
Distinguishing Name: Eukaryotic expression plasmids containing synthetic IL-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). 
 
VGX-3100 and INO-9012 combination is referred to as INO-3112 in this protocol. 
1.2.3 CELLECTRA®5P device for intramuscular electroporation 
The CELLECTRA®5P device is a portable, battery powered medical device designed to generate 
a minimally controlled electric field which temporarily and reversibly increases cellular 
membrane permeability without damaging the tissue. During the period of increased permeability, 
an injected plasmid DNA formulation can be injected into the cells. Additional information on the 
investigational device is available in the manual. 
1.3 Preclinical Data 
1.3.1 VGX-3100 Preclinical Data 
DNA plasmids for HPV-16 (pCon16E6E7) and HPV-18 (pCon18E6E7) have been studied for 
pre-clinical expression and immunogenicity.  Preclinical GLP toxicology and biodistribution 
studies with VGX-3100 have demonstrated an acceptable safety profile in New Zealand white 
rabbits (Refer to INO-3112 IB for details). 
1.3.2 INO-9012 Preclinical Data 
IL-12, a dendritic cell (DC)-produced cytokine, is a strong stimulator of NK cells as well as of T 
lymphocyte activity. IL-12 supports the differentiation of antigen specific CD4 T cells to produce 
Th1 cytokines including IFN-gamma and triggers the expansion of antigen specific CD8 T cells 
to express cytotoxic mediators, such as granzyme B/perforin [20-23]. The use of IL-12 DNA (e.g. 
INO-9012) as an immune adjuvant has proven effective at improving immune priming ex vivo as 
well as in animal models [24-26]. See Section 4 of the INO-3112 IB for details. 
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1.4 Clinical Data  
1.4.1 VGX-3100 Clinical Data 
VGX-3100 has been tested in 2 Phase I clinical trials (HPV-001 and HPV-002) in adult females 
post-surgical or ablative treatment of grade 2 or 3 cervical intraepithelial neoplasia (CIN) to 
evaluate safety and immunogenicity [12]. Safety data showed only mild to moderate Grade 1 and 
2 adverse events, mainly injection site local reactions and non-clinically significant laboratory 
abnormalities. There were no serious adverse events attributed to treatment in any of the subjects 
enrolled and no study subjects discontinued early.  
 VGX-3100 is being evaluated in an ongoing Phase II study in women with high grade CIN 
(HPV-003). VGX-3100 was immunogenic and efficacious against CIN 2/3 without any 
significant safety concerns (Refer to INO-3112 IB for details). 
1.4.2 INO-9012 Clinical Data 
The safety profile associated with IM administration of IL-12 plasmid DNA alone or followed by 
EP has been acceptable in previous clinical studies. Clinical results from three different studies 
substantiate the safety and tolerability profile of IL-12 plasmid DNA. IL-12 plasmid DNA has 
been used in several cohorts in the following four phase I clinical protocols.   
Protocol # 
Co-administered with 
# subjects received IL-12 DNA 
HVTN-060 
HIV-1 gag p37 
80 
HVTN-063 
HIV-1 gag p37 
30 
HVTN-070 
PENNVAX®-B (gag, pol, env) 
30 
HVTN-080 
PENNVAX®-B (gag, pol, env) 
30 
IL-12 DNA was delivered without EP in HVTN-060, -063 and -070 but was followed by EP in 
HVTN-080. In the protocol HVTN-080, PENNVAX®-B or placebo were delivered via IM 
injection followed by electroporation with the CELLECTRA®-5P device in 48 healthy volunteers. 
The regimen consisted of 3 mg of PENNVAX®-B with or without plasmid encoding IL-12 at 
months 0, 1 and 3. This study established that a highly engineered DNA vaccine delivered 
intramuscularly followed by EP can induce frequent and robust T-cell responses in humans. 
In summary of above clinical studies, no pattern of systemic AEs emerged, and no SAEs related 
to the study products were observed. The plasmid DNA vaccine co-administered with IL-12 
plasmid DNA as a cytokine adjuvant were well-tolerated (Refer to INO-3112 IB for details). 
1.4.3 CELLECTRA® Device Clinical Use 
Clinical Experience with Inovio Plasmid DNA-based Immunotherapy Delivered by 
Electroporation using CELLECTRA® device: 
The underlying basis for all studies of plasmid DNA vaccines is the fairly substantial safety 
database that exists for the varied plasmid DNA vaccine candidates that have now been studied in 
humans. The plasmid DNA platform has been utilized for vaccine candidates for a variety of 
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disease indications and infectious agents (e.g., HIV, HPV, Influenza, SARS, West Nile virus, 
Ebola among others) in addition to plasmid cytokine adjuvants such as IL-2, IL-12 and IL-15. 
Four separate GLP toxicology and biodistribution studies have been performed for eight 
additional plasmid DNA vaccine candidates developed by Inovio Pharmaceuticals, Inc. with 
identical backbones delivered by electroporation yielding similar toxicity and biodistribution 
profiles. 
As of April 7, 2015, 587 human subjects had been treated with electroporation using the Inovio 
CELLECTRA® device in more than 14 different studies. The total includes more than 1300 
injections (IM or ID) of DNA followed by EP and approximately 186 injections of placebo 
followed by EP (refer to Investigator Brochure for details) without any clinically significant 
safety issues. 
1.5 Dose Rationale and Risk/Benefits 
1.5.1 Dose Rationale 
The doses selected are based on previous human experience and preclinical data with VGX-3100 
and other DNA vaccines. 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 IM followed by EP, 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 (Table 1.1) without significant safety issues [12]. 
This dose-trend was consistent with prior expectations, suggesting that it may be 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 3 
dose cohorts.  
Table 1.1: Percent of subjects responding and average SFU/106 PBMC in responders for 
each antigen by cohort in Protocol HPV-001 Interferon-γ ELISpot  
 
Cohort 
Low (0.6 mg) 
Mid (2 mg) 
High (6 mg) 
Antigen 
%RR 
AVG 
%RR 
AVG 
%RR 
AVG 
16E6 
33% 
107 
50% 
243 
50% 
1341 
16E7 
17% 
198 
50% 
104 
67% 
143 
18E6 
50% 
359 
50% 
338 
83% 
664 
18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
RR = Response Rate 
The IL-12 plasmid dose is based on previous experience in the HVTN 080 study, where 1 mg of 
IL-12 plasmid was co-administered with PENNVAX®-B followed by EP. HIV-specific CD4+ T 
cell responses were generated in 67.9% (19/28) of PENNVAX®-B + IL-12 recipients after two 
vaccinations, compared to 30.0% (3/10) with PENNVAX®-B alone. Co-administration with IL-12 
resulted in CD4+ T cell responses in ~81% vs. 44% without IL-12 after three doses. Delivery of 
PENNVAX®-B via EP increased the frequency of CD8+ T cell responses even more dramatically. 
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 
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able to respond to HIV peptide pools. Overall, 71% of individuals vaccinated with PENNVAX®-
B + IL-12 plasmid followed by EP developed either a CD4+ or CD8+ T-cell response after the 
second vaccination and 89% developed CD4+ or CD8+ T-cell responses after the third 
vaccination.  As noted above the addition of the IL-12 plasmid to the vaccine did not alter the 
safety profile. We do not anticipate any significant risks with the administration of this dose. 
1.5.2 Risks/Benefit Assessment 
In accordance with the International Conference on Harmonisation (ICH), this study has been 
designed to minimize risk to study subjects. Potential risks of study products and administration 
from studies using similar plasmids with the identical DNA backbone are listed in Table 1.2.  
The potential side effects of treatment with the investigational products may include discomfort 
related to the electroporation technique such as local edema, swelling, or pain. Systemic side 
effects with vaccines based on the identical SynCon® backbone have been demonstrated to be 
generally safe in more than 580 subjects (data as of May 15, 2015). The potential benefit of this 
study is to determine whether this immunotherapy will generate protective levels of antibodies 
and cytotoxic T-cells as treatment for those with HPV associated HNSCCa. 
Table 1.2: Summary of Reported Adverse Events from previous clinical trials and Potential 
Risks of DNA based immunotherapy delivered IM+EP with CELLECTRA®  
Common 
• 
Mild to moderate administration site pain, erythema, tenderness, swelling, 
induration   
• 
Malaise/fatigue, myalgia, or headache in the first few days following injection 
Less common 
• 
Injection site hematoma, bruising/ecchymosis, laceration, other transient lesions, or 
bleeding related to the injection procedure 
• 
Arthralgia or nausea 
Uncommon or 
rare 
• 
Severe administration site pain or tenderness 
• 
Rash following injection/EP  
• 
Vasovagal reaction/lightheadedness/dizziness related to the injection/EP procedure 
• 
Transient changes in clinical laboratory values 
Unknown 
frequency or 
theoretical 
potential risks 
• 
Severe localized administration site reaction, such as sterile abscess or secondary 
bacterial infection  
• 
Allergic reaction, including urticaria, angioedema, bronchospasm, or anaphylaxis  
• 
Muscle damage at the administration site 
• 
Autoimmune disease 
• 
Electrical injury  
• 
Disruption of function of implanted electronic medical devices 
• 
Exacerbation of cardiac arrhythmia 
• 
Effects on the fetus and on pregnancy 
 
2 Study Objectives 
2.1 Primary Objectives 
 
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Evaluate safety of treatment with INO-3112. 
2.2 Secondary Objectives 
1. Evaluate humoral and cellular immune response to administration of INO-3112 in chemo- 
and radiation-naïve subjects who undergo definitive surgery: 
a. Pre- and Post-immunotherapy tissue analysis to evaluate infiltration of T cells in 
the tumor. 
b. Evaluate effect of number of doses on immune responses. 
c. Evaluate immune response duration. 
 
2. Evaluate humoral and cellular immune response to administration of INO-3112 in subjects 
after chemoradiation therapy: 
- 
Evaluate immune response duration. 
2.3 Exploratory Objectives  
1. Explore anti-tumor response  
2. Explore progression free survival 
3 Study Design 
This will be a prospective, open-label, Phase I/IIa study of immunotherapy with INO-3112 in 
subjects with HPV-positive HNSCCa. Subjects will receive a course of treatment as described 
below and will be followed for safety as well as immune and clinical responses for 6 months from 
the last dose of immunotherapy.  
 
The safety and effects of immunotherapy will be studied in two populations:  
1. In  chemo- and radiation-naïve subjects who undergo definitive surgery and 
2. In subjects after chemoradiation therapy.  
 
Doses of INO-3112 are based on safety experience in prior and on-going clinical trials. Based on 
the prior experience with these agents, dose escalation will not be conducted in this trial.  
The study is divided into the following treatment cohorts: 
I. INO-3112 (6 mg VGX-3100 + 1 mg INO-9012) will be given to subjects before and after 
definitive surgery. 
II.  INO-3112 (6mg VGX-3100 + 1 mg INO-9012) will be given to subjects after 
chemoradiation therapy.  
3.1 General Design 
Study Schema: Eligible subjects will receive highly engineered plasmid DNA encoding HPV-16 
and HPV-18-E6 & E7 transcription unit antigens (VGX-3100) combined with the DNA encoding 
IL-12 (INO-9012) followed by EP with the CELLECTRA®5P device.  
COHORT I: Immunotherapy will be given both before and after definitive surgery. Each subject 
will receive a total of 4 doses of treatment, 1-2 of them pre-surgery.  Each treatment will be 6 mg 
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of VGX-3100 and 1 mg INO-9012 (INO-3112) delivered IM followed by EP. A minimum of 5 
eligible subjects will be enrolled to this cohort. 
Pre-Surgery:   
1) Subjects will be enrolled if they have confirmed HPV positive mucosal HNSCCa. Tumor 
tissue samples must be available to perform immunological correlates prior to definitive 
surgery. 
2) After providing informed consent and being deemed eligible, subjects will receive 
immunotherapy. Up to 2 doses may be administered approximately once every 3 weeks 
(±3 days) prior to definitive surgery. 
3) The number of pre-surgery immunotherapies (one vs. two injections) will be based on the 
estimated time interval between pre-surgery evaluation and definitive surgery. Time to 
surgery according to standard practice is usually 2- 4 weeks; however, this varies due to 
ordinary logistical considerations independent of a clinical trial.   
4) Surgery will not be delayed to allow for immunotherapy. 
Post-Surgery:  
1) Subjects will be seen approximately 2 weeks (±7 days) post-surgery for follow up. 
2) Subjects will undergo visual inspection to document healing by surgeon approximately 4 
weeks post-surgery. 
3) Post-surgery immunotherapy will proceed only after approval of the surgeon. 
4) Subjects will receive up to 3 doses given 3 weeks (±3 days) apart. A total of 4 doses (pre- 
and post-surgery) will be administered. 
5) Immunotherapy will be administered prior to adjuvant chemotherapy and/or radiation that 
may be indicated.  
6) Adjuvant therapy will not be delayed for immunotherapy. 
7) Subjects will be followed for tumor status as per institutional standard of care. 
COHORT II: Immunotherapy will start approximately 2-6 months after completion of definitive 
or adjuvant chemoradiation therapy in order to allow recovery from the treatment side effects of 
chemoradiation. INO-3112 (6 mg of VGX-3100 and 1 mg INO-9012) will be delivered by IM 
injection with EP once every 3 weeks (±3 days) for a total of 4 doses. A minimum of 10 subjects 
will be enrolled into this cohort. 
1) Subjects will be enrolled if they have HPV-16 and/or HPV-18 positive HNSCCa 
confirmed by ISH or PCR, and have completed chemoradiation therapy. Adequate tissue 
must be available to perform immunological correlates studies. Confirmation of HPV-16 
and/or HPV-18 positivity is required prior to first dose of immunotherapy. 
2) Subjects will be followed for tumor status as per normal institutional standard of care.  
Sample Size: A minimal of 20 but no more than 25 eligible subjects will be enrolled in this study. 
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3.2 Study Endpoints 
3.2.1 Primary Endpoint 
The primary study endpoint is safety and tolerability based on standard laboratory and clinical 
adverse event monitoring: 
1. Adverse events will be measured and graded according to “Common Terminology Criteria 
for Adverse Events (CTCAE)”, NCI version 4.03 issued by the US Department of Health 
and Human Services. 
2. Frequency and severity of injection site reactions including administration site pain, skin 
erythema, induration, bleeding, tenderness and infection. 
3.2.2 Secondary Endpoint 
The secondary endpoints is immune response after immunotherapy based on correlative 
measures: 
1. Measure HPV-16 and HPV-18 specific antibody levels.  A standardized binding ELISA 
will be performed to measure the anti–HPV16/18 E6 or E7 antibody response induced by 
VGX-3100 and INO-9012. 96-well enzyme immunoassay plates will be coated with 
HPV16 or HPV18 E6 or E7 proteins (1 μg/ml) (recombinant HPV16/18 E7 and HPV16 
E6 procured from ProteinX Lab, HPV18 E6 from Impact Biologicals). Subject sera will be 
diluted with 1% bovine serum albumin in PBS and tested in triplicate with an automated 
and calibrated plate washer and read on a kinetic microplate reader (Molecular Devices). 
Samples will be scored as positive if the average optical density (OD) was greater than 
0.15 absorbance units and greater than the average OD before preimmunization plus 2.5 
times the standard deviation of the OD compared to corresponding preimmunized samples 
at the same dilution.  
2. Using Antigen-specific IFN-γ ELISpot assays, determine the number of antigen-specific 
spot forming units (SFU) in response to stimulation with HPV16 and HPV18.  T cell 
responses will be assessed using an HPV IFN-γ ELISpot assay. PBMCs will be thawed 
and plated at 200,000 cells/well. Cells will be incubated with HPV16 and HPV18 peptides 
corresponding to E6 and E7 proteins of HPV. The three sets of peptides, each contain 15–
amino acid residues overlapping by 8 amino acids representing the entire consensus E6/E7 
fusion protein sequence of HPV16 or HPV18, and are pooled at a concentration of 2 μg/ml 
per peptide into two pools [12]. After an overnight incubation, IFN-gamma release will be 
detected using standard procedures. The average number of SFU counted in R10 wells 
will be subtracted from the average in individual HPV peptide wells and then adjusted to 1 
× 106 PBMCs for each HPV peptide pool. Additionally, PBMC responses against a pool 
of known antigenic epitopes combined from Cytomegalovirus, Epstein Barr Virus and 
Influenza (CEF) will be tested in order to track general cellular immune competence 
during the study in the same manner as HPV responses described above. 
3. Evaluate cytotoxic T cells in response to HPV specific immunotherapy by flow cytometry.  
Additional assessment of cellular immune activity will occur via the application Flow 
Cytometry. Flow Cytometric assays will include an examination the influence of 
immunotherapy on the ability of patient T cells to exhibit phenotypic markers associated 
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with cytolytic potential after short-term stimulation by HPV E6 and E7 of VGX-3100 
antigen (hereafter referred to as “CTL Phenotyping”), the ability of patient T cells to 
remain active in the presence of long-term antigen exposure and efficiently synthesize 
proteins used in lytic activity (hereafter referred to as “Lytic Granule Loading”) and the 
ability of patient T cells to effectively employ Granzyme B for the purposes of lytic 
degranulation and killing of target cells expressing HPV E6 and E7 (hereafter referred to 
as “Killing”).  These panels may vary as newer information becomes available within the 
literature. 
i. 
The assay for CTL Phenotyping will employ a 6-hour in vitro stimulation of 
unfractionated patient PBMCs using peptides spanning VGX-3100 antigens as 
described above, an irrelevant peptide control (OVA) and a positive control 
(Staphylococcal Enterotoxin B or a combination of phorbol 12-myristate 13-
acetate and Ionomycin).  The CTL Phenotyping assay will examine the following 
external cellular markers: CD3, CD4, CD8 (T cell identification), CD45RO, CCR7 
(memory subset identification), and CD107a.  The CTL Phenotyping assay will 
additionally analyze the following intracellular markers: Interferon Gamma (Th1 
biasing cytokine), Tumor Necrosis Factor Alpha, Granzyme A, Granzyme B and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). This 
panel of markers may vary as new information becomes available. 
ii. 
The Lytic Granule Loading assay will employ a 120-hour in vitro stimulation of 
unfractionated patient PBMCs using peptides spanning VGX-3100 antigens, an 
irrelevant peptide control (OVA) and a positive control (Concanavalin A).  The 
Lytic Granule Loading assay will examine the following external cellular markers: 
CD3, CD4, CD8 (T cell identification), and CD137 (also known as 41BB – marker 
of T cell activation).  The Lytic Granule Loading assay will additionally analyze 
the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential).  This 
panel of markers may vary as new information becomes available.   
iii. 
The Killing assay will employ a 120-hour in vitro stimulation of unfractionated 
patient PBMCs using peptides spanning VGX-3100 antigens.  Stimulated whole 
PBMCs or CD8+ T cells isolated after the 120-hour incubation will be co-
incubated for 60 minutes with target cells that have received a membrane stain that 
differentiates them from patient PBMCs/CD8+ T cells and have additionally been 
pulsed with a reagent which is activated only when the cell is actively in apoptosis 
(programmed cell death).  At the end of this time cells will be washed and target 
cells identified using the membrane stain and analyzed for the presence of the 
active substrate as a measure of functional cytolytic degranulation and killing 
Employment of this assay may change pending readouts from the Lytic Granule 
Loading assay. Description of previous use of these assays or variants thereof can 
be found in Bagarazzi et al. Immunotherapy against HPV16/18 [12]. The 
construction of this assay may vary as new information becomes available.   
 
4. Evaluate tumor infiltrating lymphocytes (TIL) by Immunohistochemistry (IHC) on pre-
surgical and surgical samples. HPV immunotherapy prior to surgery will provide us with a 
unique opportunity to determine if the VGX-3100 induced immune response can directly 
target the HPV positive tumor cells. Therefore, we will perform immunohistochemistry on 
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samples obtained prior to or at study entry as well as on samples that will be obtained 
from resection of the primary tumor in Cohort I.  
5. Evaluate phenotypes of cultured TILs.  In addition, for Cohort I we will use any remaining 
fresh (unfixed) tissue 1) isolate TILs and 2) isolate tumor cells to use for in vitro 
stimulation of lymphocytes isolated from the periphery.  In order to determine if HPV E6 
and E7 specific lymphocytes have migrated to the tumor we will isolate TILs by standard 
procedures 
from 
tumor 
pre- 
and 
post-immunotherapy. 
We 
will 
utilize 
Affymetrix/Panomics Luminex Plex System to define the immunological transcriptome. 
This gene analysis will incorporate analysis of Perforin, IFN-gamma, IL-2, IL-10 and IL-4 
to account for antigen specific CD8 and CD4 T cells as well as Treg upregulation.  In 
addition, confirmatory genes will be included.  Such genes are transcription factors for 
these cell types; Tbet, GATA2, FOXP2 and RORC.  
Secondly, during digestion of the tumor with collagenase for lymphocytes we will save 
and cryopreserve tumor cells as well.  These tumor cells can be used in in vitro assays to 
stimulate lymphocytes isolated from the periphery of the respective subject.  We expect 
that we will observe an immune response to peptides.  However, stimulation with tumor 
cells will provide information about lymphocytes ability to target the tumor cells.  
3.2.3 Exploratory Endpoints: Clinical response criteria as determined by: 
1. Any evidence of anti-tumor response as assessed by the Investigator  
2. Progression free survival  
4 Subject Selection and Withdrawal 
Exceptions to eligibility will not be granted for this study. 
4.1 Inclusion Criteria 
1. Signed and dated written Ethics Committee approved informed consent. 
2. Age ≥18 years. 
3. Histologically confirmed HPV-positive mucosal squamous cell head and neck cancer. 
Tumor tissue samples and the HPV test results must be available prior to first dose of 
Study Treatment. 
• For pre-surgical subjects, p16 positivity must be confirmed prior to first dose 
• For subjects post chemoradiation therapy, HPV-16 and/or HPV-18 positivity (as 
assessed by p16 IHC AND oncogenic HPV ISH or PCR) must be confirmed prior 
to first dose. 
4. Adequate bone marrow, hepatic, and renal function. ANC (Absolute Neutrophil Count) ≥ 
1.5x109 cell/ml, platelets ≥75,000 /mm3, hemoglobin ≥ 9.0 g/dL, concentrations of total 
serum bilirubin within 1.5 x upper limit of normal (ULN), AST, ALT, CPK within 2.5 x 
ULN, and performed within 4 weeks prior to the first administration of Study Treatment. 
5. ECG with no clinically significant findings as assessed by the investigator. 
6. No history of clinically significant autoimmune disease, HIV infection or other 
immunosuppressive disease. 
7. ECOG (Eastern Cooperative Oncology Group) performance status of 0-1. 
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8. Women of childbearing potential must have a negative serum pregnancy test and agree to 
remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), or use two 
medically effective methods of contraception (e.g. oral contraception, barrier methods, 
spermicide, intrauterine device (IUD)). Males with reproductive potential must be willing 
to use a condom and have their female sexual partners use another form of contraception 
such as an IUD, spermicidal foam/gel/film/cream/suppository, diaphragm with 
spermicide, oral contraceptive, injectable progesterone, sub-dermal implant or a tubal 
ligation if the female partner could become pregnant. This requirement should be followed 
from screening through 24 weeks after last dose of immunotherapy. 
9. Able and willing to comply with all study procedures. 
4.2 Exclusion Criteria 
1. Pregnant or breast-feeding subjects. 
2. Anticipated concomitant immunosuppressive therapy (excluding non-systemic inhaled, 
topical skin and/or eye drop-containing corticosteroids). 
3. Any concurrent condition requiring the continued use of systemic steroids (>10 mg 
prednisone or equivalent per day, see above) or the use of immunosuppressive agents. All 
other corticosteroids must be discontinued at least 4 weeks prior to first dose of study 
treatment. 
4. Known history of hepatitis B or C with active viral replication. 
5. Administration of any vaccine within 6 weeks of first dose of study treatment. 
6. Tattoos, scars, or active lesions/rashes within 2 cm of the intended site of injection 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. 
7. Participation in another interventional clinical trial within 30 days before receiving first 
dose of study treatment. However, the subject may participate in an observational studies. 
8. Any cardiac pre-excitation syndromes, e.g. Wolff-Parkinson-White syndrome. 
9. Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements 
10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness must not be 
enrolled into this study. 
11. Any illness or condition that in the opinion of the investigator may affect the safety of the 
subject or the evaluation of any study endpoint. 
12. Any other conditions judged by the investigator that would limit the evaluation of a 
subject. 
4.3 Subject Recruitment and Screening 
Subjects will be identified through the clinical practices of the co-investigators or sub-
investigators in the Division of Medical Oncology, Division of Radiation Oncology and Division 
of Otolaryngology at the Hospital of the University of Pennsylvania and its affiliated hospitals 
and through referrals from outside hospitals and physicians. The trial will be publicized on the 
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website of the Abramson Cancer Center of the Hospital of the University of Pennsylvania. This 
protocol will also be listed in ClinicalTrials.gov database. Subjects will be required to give 
written consent of study participation before any screening tests or evaluations are conducted.  
 
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects who do not complete the study protocol will be considered to have prematurely 
discontinued the study. The reasons for premature discontinuation (for example, voluntary 
withdrawal, toxicity, death) must be recorded on the case report form (CRF). Final study 
evaluations will be completed at the time of discontinuation if it is possible. Reasons for 
withdrawal include, but are not limited to the following: 
1. Inter-current illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree or require discontinuation of study; 
2. Unacceptable toxicity: Subjects will be followed until resolution or stabilization; 
3. Disease progression;  
4. Subject withdraws consent; 
5. Treatment delay greater than four weeks for any toxicity; 
6. Subjects who do not have satisfactory compliance with study procedures; 
7. Major protocol violations, including, but not limited to: 
a. failure to meet major inclusion/exclusion criteria; 
b. failure to complete full evaluations as required by protocol; 
c. use of concomitant therapies. 
If any subject in a cohort discontinues early for reasons other than toxicity from immunotherapy, 
consideration will be given for replacement. 
If a subject discontinues Study Treatments before completion of long term follow up for 6 months 
post the last dose of immunotherapy, all assessments for the end of Study Treatment visit and/or 
end of study visit should be performed. 
Subjects who have disease progression confirmed and/or start new anti-cancer therapy will be 
discontinued from the study. In both Cohorts, subjects who progress in their disease, once 
confirmed, will be required to come for the end of the study visit. All subjects will be followed 
for survival status regardless of the cause of death. 
In the case of a fatal outcome, all relevant information (including cause of death, autopsy report, 
ER/hospital record, concomitant medication, and relationship to Study Treatment or underlying 
disease) will be collected.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Subjects taken off study due to treatment related toxicity will be followed until resolution or 
stabilization. All subjects will be followed for survival status regardless of the cause of death. 
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5 Study Drug  
5.1 Description 
Investigational product is defined as a pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in the study. 
VGX-3100, the active investigational product to be used in this study, is a mixture of two separate 
DNA plasmids encoding E6 and E7 proteins of HPV types 16 and 18. INO-9012 is a DNA 
plasmid expressing the p35 and p40 human IL-12 subunits off of separate promoters within the 
same plasmid. VGX-3100 and INO-9012 combination is referenced as INO-3112. 
INO-3112 (6 mg VGX-3100 + 1 mg INO-9012) is delivered by IM with EP for subjects in Cohort 
I and Cohort II. INO-3112 will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 5.1 Investigational Products 
Product 
Concentration 
Dosage Form & Route of Administration 
Dosea 
(mL) 
VGX-3100 
6 mg/mL* 
Sterile water for injection with 1% poly-L-
glutamate sodium salt via IM injection 
1.1# 
INO-9012 
10 mg/mL* 
Sterile water for injection via IM injection 
*Target concentration of the DNA plasmid. The actual concentration may vary slightly in the lot used for 
this study.  
aVGX-3100 and INO-9012 combined to deliver 1.1 mL (Cohorts I and II). 
# There is no exception on dosing change in immunotherapy for any cohort 
5.2 Packaging 
VGX-3100 and INO-9012 vials will be shipped directly from the manufacturer or its designee to 
each individual study site or regional depot. Each vial will be labeled with a single panel label. 
Vials will only be handled by designated personnel (e.g. pharmacist) at each site. When a subject 
is eligible for enrollment, personnel will combine the appropriate investigational products as 
detailed in section 5.3.5 (Preparation of Investigational Product) then provide to the clinical 
personnel. Sample vial text for each investigational product is provided below: 
 
VGX-3100 
SynCon™ VGX-3100 [6mg/mL] 1 mL/vial 
Lot: VGX-3100. xxxxxx 
Date of Manufacture: DD MMM YY     
Final Retest Date: DD MMM YY  
Store frozen at or below -15C 
CAUTION: New Drug – Limited by Federal Law to Clinical Trial Use Only 
Inovio Pharmaceuticals Inc  660 W Germantown Pike, Plymouth Meeting, 
PA 19462 USA 
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INO-9012 
SynCon™ INO-9012 [10 mg/mL] 
0.2 mL/vial Single Use Vial 
Lot: INO-9012.xxxxxx 
Date of Manufacture: DD MMM YY 
Final Retest Date: DD MMM YY 
Store frozen at or below -15°C 
CAUTION: New Drug – Limited by Federal 
Law to Investigational Use. 
Inovio Pharmaceuticals Inc.  Rev 000 
5.3 Receiving, Storage, Dispensing and Return 
5.3.1 Receipt of Drug Supplies 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the investigational 
product is adequate for the duration of the trial. Unless otherwise specified, the product will be 
shipped frozen on dry ice. If there is no dry ice remaining in the shipment container when the 
shipment is received Inovio, or its designee should be contacted immediately.  
5.3.2 Storage 
Investigational product(s) should be stored in a secure area according to local regulations. The 
product should be transferred from the shipping container to the appropriate storage conditions 
(frozen at -15ºC or below) upon arrival.  
Freezer and refrigerator temperature logs must be maintained at the clinical site and temperatures 
must be recorded and monitored regularly. 
 
The principal investigator and study team will ensure that a current record of investigational 
product disposition is maintained at the study site where investigational product is inventoried and 
disposed. Records or logs must comply with applicable regulations and guidelines, and should 
include: 
 
• Amount received and placed in storage area; 
• Amount currently in storage area; 
• Label ID number or batch number and use date or expiry date; 
• Dates and initials of person responsible for each investigational product inventory 
entry/movement; 
• Amount dispensed to each subject, including unique subject identifiers; 
• Amount transferred to another area/site for dispensing or storage; 
• Amount returned to Sponsor; 
• Amount destroyed at study site, if applicable. 
5.3.3 Dispensing of Study Drug 
It is the responsibility of the Investigator to ensure that product is only dispensed to study 
participants. It must be dispensed only from official study sites by authorized personnel according 
to local regulations. The site will identify a dedicated investigational pharmacist to dispense IP. 
Their duties will include the receipt, storage, preparation and maintenance of records for the IP. 
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The VGX-3100 and INO-9012 vials should be removed from the freezer and thawed at room 
temperature to ensure complete thaw. The thawed product must be used within 4 hours of 
removal from freezer. All material removed from the freezer must not be re-frozen. 
 
5.3.4 Precautions with Investigational Medicinal Product 
A dose of the study product known or suspected to have been taken (accidentally or intentionally) 
exceeding the dose mandated by the protocol, and any misuse or abuse of study products or any 
other product taken as a concomitant medication, whether or not associated with an adverse 
experience, must be reported to Inovio Pharmaceuticals within 24 hours. Any clinical sequelae in 
association with the overdose should be reported as an AE or SAE. Details of signs or symptoms, 
clinical management, and outcome should be reported, if available. 
5.3.5 Preparation of Investigational Product 
Prior to administering to subjects the investigational products will be combined by authorized 
personnel into a single syringe using the following procedure: 
 
Required Materials: 
(1) or (2) vials SynConTM VGX-3100, thawed 
(1) vial SynConTM INO-9012, thawed 
(1) 2 mL sterile empty vial 
(1) 0.5 mL or 1.0 mL syringes 
(2) 3 mL syringes 
(1) 21 gauge, 2” needle 
(2) 21 gauge, 1.5” needles  
 
Note: The second vial of SynConTM VGX-3100 should only be thawed if less than 1.1 mL 
is withdrawn from the first vial in Step (1) below: 
1. Using aseptic technique, withdraw the entire contents from the vial SynConTM VGX-
3100 with a 3 mL syringe and a 2” 21 gauge needle; a needle of a minimum length of 2” is 
recommended to be able to withdraw the entire contents of the larger vial. 
2. If the volume of VGX-3100 in the syringe is less than 1.1 mL, perform Formulation 
Instruction Set A. 
3. If the volume of VGX-3100 in the syringe is exactly 1.1 mL, perform Formulation 
Instruction Set B. 
4. If the volume of VGX-3100 in the syringe is 1.2 mL or more, perform Formulation 
Instruction Set C. 
Formulation Instruction Set A (less than 1.1 mL VGX-3100 withdrawn): 
1. Thaw a second vial of SynConTM VGX-3100. 
2. Once the vial is thawed, using the same syringe/needle from the first vial, withdraw a 
sufficient volume of VGX-3100 from the second vial to total at least 1.2 mL of VGX-
3100 in the syringe. 
3. Inject 1.2 mL of VGX-3100 into an empty sterile vial; set this “mixing” vial which now 
contains 1.2 mL of VGX-3100 aside. 
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4. Using a new 0.5 or 1.0 mL syringe with a 1.5” 21 gauge needle, withdraw 0.12 mL from 
the vial SynConTM INO-9012 and add the 0.12 mL to the “mixing” vial containing 1.2 mL 
of VGX-3100. The final volume of this vial should now be approximately 1.32 mL of 
VGX-3100 and INO-9012. 
5. Ensure the contents of the “mixing” vial are well mixed by gently inverting the vial 
several times. 
6. Using a 3 mL syringe with a 1.5” 21 gauge needle, withdraw 1.1 mL of VGX-3100 and 
INO-9012 from the “mixing” vial. This syringe will be used for dosing of subjects. 
Formulation Instruction Set B (exactly 1.1 mL VGX-3100 withdrawn): 
1. Inject 1.1 mL of VGX-3100 into an empty sterile vial; set this “mixing” vial which now 
contains 1.1 mL of VGX-3100 aside. 
2. Using a new 0.5 or 1.0 mL syringe with a 1.5” needle, withdraw 0.11 mL from the vial 
SynConTM INO-9012 and add the 0.11 mL to the “mixing” vial containing 1.1 mL of 
VGX-3100. The final volume of this vial should now be approximately 1.21 mL of VGX-
3100 and INO-9012. 
3. Ensure the contents of the “mixing” vial are well mixed by gently inverting the vial 
several times. 
4. Using a 3 mL syringe with a 1.5” 21 gauge needle, withdraw 1.1 mL of VGX-3100 and 
INO-9012 from the “mixing” vial. This syringe will be used for dosing of subjects. 
Formulation Instruction Set C (1.2 mL or more of VGX-3100 withdrawn): 
1. Inject 1.2 mL of VGX-3100 into an empty sterile vial; set this “mixing” vial which now 
contains 1.2 mL of VGX-3100 aside. 
2. Using a new 0.5 or 1.0 mL syringe with a 1.5” needle, withdraw 0.12 mL from the vial 
SynConTM INO-9012 and add the 0.12 mL to the “mixing” vial containing 1.2 mL of 
VGX-3100. The final volume of this vial should now be approximately 1.32 mL of VGX-
3100 and INO-9012. 
3. Ensure the contents of the “mixing” vial are well mixed by gently inverting the vial 
several times. 
4. Using a 3 mL syringe with a 1.5” 21 gauge needle, withdraw 1.1 mL of VGX-3100 and 
INO-9012 from the “mixing” vial. This syringe will be used for dosing of subjects. 
Replace the 1.5” needle with 2” 21 gauge needle of the syringe for dosing of subjects. The syringe 
must be labeled with a four-hour expiration time from the time the vial is removed from the 
freezer. The label should also contain the words “administer as soon as possible”. 
5.3.6 Return or Destruction of Study Drug 
Upon completion or termination of the study, all unused and/or partially used investigational 
product must be returned to Inovio Pharmaceuticals, Inc., or its designee, if not authorized by 
Inovio Pharmaceuticals, Inc. to be destroyed at the site. All investigational products returned to 
Inovio Pharmaceuticals, Inc., or its designee, must be accompanied by the appropriate 
documentation. Returned supplies should be in the original containers. Empty containers should 
not be returned to Inovio Pharmaceuticals, Inc. It is the Investigator’s responsibility to arrange for 
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disposal for all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. The return of unused 
investigational product(s) should be arranged by the responsible Study Monitor. 
If investigational products are to be destroyed on site, it is the Investigator’s responsibility to 
ensure that arrangements have been made for the disposal, written authorization has been granted 
by Inovio Pharmaceuticals, Inc., or its designee, procedures for proper disposal have been 
established according to applicable regulation and guidelines and institutional procedures, and 
appropriate records of the disposal have been documented. The unused investigational products 
can only be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. representative. 
5.4 Use of CELLECTRA Electroporation Device  
The instructions for use of the CELLECTRA device are located in the Operations Manual. Each 
clinical site will receive training for the use of the CELLECTRA device. The following 
specifications will be used during the study: 
Number of pulses per treatment = 3 
Maximum Current Strength = 0.5 Amperes 
Maximum Voltage Strength = 200 Volts 
Electroporation pulse duration = 52 milliseconds/pulse 
Interval separating pulses = 1 second 
EP needle array length (injection depth) 
~12 mm (with array guide in place)  
~18 mm (without array guide) 
5.4.1 Investigational Device Accountability 
Each clinical site is responsible for maintaining investigational device accountability.  This 
includes recording the CELLECTRA®5P serial number, applicator serial number, and array lot 
number used for electroporation of each subject. 
6 Study Procedures and Treatments 
6.1 Cohort I 
Immunotherapy will be performed prior to and after definitive surgery. Up to 2 doses may be 
administered approximately once every 3 weeks (+/-3 days), depending on the planned interval 
between pre-surgery evaluation and definitive surgery according to standard practice.  Up to 3 
doses will be given post-surgery. All subjects will receive a total of 4 doses of immunotherapy. 
6.1.1 Pre treatment evaluation (Screening; Done Within 28 days of First Dose) 
1. Signed written informed consent. 
2. Complete medical history including prior and current medications/treatments. 
3. Complete physical examination including, but not limited to vital signs, height, weight and 
oxygen saturation. 
4. ECOG Performance Status. 
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5. Tumor Evaluation: Confirmation of diagnosis by histology and confirmation of p16 positivity. 
While biopsy tissue samples are undergoing confirmation of p16 positivity, the subject may 
proceed to other screening procedures and tests. However, the subject will be dosed only upon 
confirmation of p16 positivity or other pathological evidence of oncogenic HPV infection. 
Confirmation of diagnosis of surgically resectable HNSCCa.  
6. 12-lead ECG. 
7. Clinical laboratory testing including, but not limited to: CBC with differential and platelet 
count, PT, INR/PTT, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), 
serum creatinine, serum electrolytes, serum calcium, serum albumin and CPK.  
Note: If clinical lab testing is performed within 28 days prior to study Day 0 as standard of 
care, the results can be used for screening and eligibility assessment.  
8. Serology (HIV Ab, HCV Ab, HBsAg). 
9. Serum beta HCG (for women of child bearing potential). 
10. Adverse Events 
11. Whole blood and serum for baseline immunologic assays. 
12. Paraffin-embedded tumor tissue or unstained slides for ISH and IHC. 
On the rare occasions where a subject is re-screened, the clinical labs and 12-lead ECG must be 
repeated unless they occur within 4 weeks of the subject’s first dose.  All other screening 
procedures do not need to be repeated. 
6.1.2 Visit for Immunotherapy (Pre and Post surgery: Every 3 weeks ± 3 days) 
Subjects may receive up to 2 doses of immunotherapy prior to surgery and 1-3 doses post-surgery 
as previously described. All sequential doses will be administered three weeks (±3 days) apart. 
The following study evaluations will be performed prior to immunotherapy: 
1. Confirmation of p16 positivity or other pathological evidence of oncogenic HPV infection. 
2. Medical/Clinical assessment including concomitant medications/treatments. 
3. Focused physical examination including, but not limited to vital signs, weight and oxygen 
saturation. 
4. ECOG Performance Status. 
5. Review of adverse events. 
6. Clinical laboratory testing including, but not limited to: CBC with differential and platelet 
count, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum 
creatinine, serum electrolytes, serum calcium and serum albumin. 
NOTE: If clinical screening labs (CBC and Chemistry) were performed within 72 hours prior 
to the subject’s first immunotherapy, these labs are not required to be redrawn prior to the 
subject’s first immunotherapy. 
7. Urine β-HCG (for women of child bearing potential) up to 72 hours prior to visit. 
8. Whole blood and serum for baseline immunologic assays. 
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The following study evaluations will be performed on the same day post-immunotherapy: 
1. Injection site reaction assessment within 30-45 minutes after EP. 
2. Review of adverse events. 
3. Data should be downloaded from the EP device. 
4. Distribute participant reminder card to be reviewed at the next visit. 
6.1.3 Surgery 
At the time of definitive surgery, fresh resected tumor specimens not needed for diagnostic 
purposes and unstained slides will be collected and will be used for correlative studies and 
evaluation of immune responses. Prior to surgery whole blood and serum will also be collected 
for immunologic assays. 
6.1.4 Post surgery 2 week follow up (± 7 days) 
1. Medical/Clinical assessment including concomitant medications/treatments. 
2. Complete physical examination including, but not limited to vital signs, weight and 
oxygen saturation. 
3. ECOG Performance Status. 
4. Review of adverse events. 
5. Whole blood and serum for immunologic assays. 
6.1.5 Inspection Visit 4 Weeks Post-Surgery (±7 days) 
1. Medical/Clinical assessment including concomitant medications/treatments 
2. Complete physical examination including, but not limited to vital signs, weight and 
oxygen saturation. 
3. ECOG Performance Status. 
4. Review of adverse events. 
5. Visual Inspection of wound healing. 
6. Whole blood and serum for immunologic assays. 
6.1.6 2 Week Follow Up Post Last Dose of Immunotherapy (±3 Days) 
1. Medical/Clinical assessment including concomitant medications/treatments 
2. Complete physical examination including, but not limited to vital signs, weight and 
oxygen saturation. 
3. ECOG Performance Status  
4. Review of adverse events. 
5. Clinical laboratory testing including, but not limited to: CBC with differential and platelet 
count, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum 
creatinine, serum electrolytes, serum calcium, serum albumin and CPK. 
6. Injection site reaction assessment. 
7. Whole blood and serum for immunologic assays. 
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6.1.7 Long term follow up (every 3 months ±7 days for 6 months)/End of study visit 
Long term follow up for 6 months from the last dose of immunotherapy. End of study 
visit will be the last long term follow up visit. 
1. Medical/Clinical assessment including concomitant medications/treatments. 
2. Complete physical examination including, but not limited to vital signs, weight and 
oxygen saturation. 
3. ECOG Performance Status. 
4. Review of adverse events. 
5. Clinical laboratory testing including, but not limited to: CBC with differential and platelet 
count, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum 
creatinine, serum electrolytes, serum calcium and serum albumin. 
6. Whole blood and serum for immunologic assays. 
6.2 Cohort II 
Immunotherapy will start approximately 2-6 months after completion of chemoradiation therapy.  
6.2.1 Pre-treatment evaluation (Screening; within 28 days of first dose) 
1. Signed written informed consent. 
2. Complete medical history including prior and concurrent medications/treatments. 
3. Complete physical examination including, but not limited to vital signs, height, weight and 
oxygen saturation. 
4. ECOG Performance Status. 
5. Tumor Evaluation: Confirmation of diagnosis by histology and confirmation of p16 and 
HPV -16 and/or -18 (by PCR or ISH assay) positivity.  
6. 12-lead ECG (performed up to 4 weeks prior to Dose 1). 
7. Clinical laboratory testing including, but not limited to: CBC with differential and platelet 
count, PT, INR/PTT, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT 
(SGPT), serum creatinine, serum electrolytes, serum calcium and serum albumin and CPK  
Note: If these testing are performed within 28 days prior to study Day 0 as standard of care, 
the results can be used for screening and eligibility assessment.  
8. Serology (HIV Ab, HCV Ab, HBsAg). 
9. Serum beta HCG (for women of child bearing potential)  
10. Whole blood and serum for baseline immunologic assays. 
11. Paraffin-embedded tumor tissue or unstained slides for IHC. 
If clinical screening labs (CBC and Chemistry) were performed within 72 hours prior to the 
subject’s first immunotherapy, these labs are not required to be redrawn prior to the subject’s first 
immunotherapy. 
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6.2.2 Visit for Immunotherapy (4 doses Every 3 Weeks ±3 days) 
The following study evaluations will be performed prior to immunotherapy: 
1. Medical/Clinical assessment including concurrent medications/treatments. 
2. Focused physical examination including, but not limited to vital signs, weight and oxygen 
saturation. 
3. ECOG Performance Status. 
4. Review of adverse events. 
5. Clinical laboratory testing including but not limited to: CBC with differential and platelet 
count, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum 
creatinine, serum electrolytes, serum calcium and serum albumin. Urine β-HCG (for 
women of child bearing potential). 
NOTE: If clinical screening labs (CBC and Chemistry) were performed within 72 hours prior 
to the subject’s first immunotherapy, these labs are not required to be redrawn prior to the 
subject’s first immunotherapy. 
6. Whole blood and serum for baseline immunologic assays. 
The following study evaluations will be performed on the same day post-immunotherapy: 
1. Injection site reaction assessment within 30-45 minutes after EP. 
2. Review of adverse events. 
3. Data should be downloaded from the EP device  
4. Distribute participant reminder card to be reviewed at the next visit. 
6.2.3 2 Week Follow Up Post Last Dose of Immunotherapy (± 3 days) 
1. Medical/Clinical assessment including concurrent medications/treatments. 
2. Complete physical examination including, but not limited to vital signs, weight and 
oxygen saturation. 
3. ECOG Performance Status. 
4. Review of adverse events. 
5. Injection site reaction assessment. 
6. Clinical laboratory testing including but not limited to: CBC with differential and platelet 
count, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum 
creatinine, serum electrolytes, serum calcium, serum albumin and CPK. 
7. Whole blood and serum for immunologic assays. 
6.2.4     Long Term Follow Up (Every 3 Months ± 7 Days for 6 months)/End of study visit 
Long term follow up for 6 monthss post the last dose of immunotherapy. End of study visit 
will be the last long term follow up visit 
 
1. Medical/Clinical assessment including concurrent medications/treatments. 
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2. Complete physical examination including, but not limited to vital signs, weight and 
oxygen saturation. 
3. ECOG Performance Status. 
4. Review of adverse events. 
5. Clinical laboratory testing including, but not limited to: CBC with differential and platelet 
count, total serum bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), serum 
creatinine, serum electrolytes, serum calcium and serum albumin. 
6. Whole blood and serum for immunologic assays. 
6.3 Timing and Evaluation 
6.3.1 Informed Consent 
Study personnel will meet with prospective study subjects, explain the study, and provide them 
with an informed consent form (ICF) that describes the screening tests, eligibility criteria for 
entering the study, and study treatments and follow-up procedures. The subjects must sign the 
ICF before the study can commence. 
6.3.2 Assignment of Subject Numbers 
Study personnel will screen subjects and assign allocation numbers as appropriate. Each subject 
who consents will be assigned a patient identification number (PIN) which identifies the subject 
for all study-related procedures for the duration of their participation in the study. Once assigned, 
PINs cannot be reused for any reason 
6.3.3 Medical History/Existing Events/Illnesses 
Investigators should document all relevant and clinically significant non-cancer related illnesses 
that the subject has experienced within 5 years prior to screening and all prior cancer related 
illnesses as Medical History. The determination of the relevance includes, but not limited to, the 
history related to HNSCCa and treatment for HNSCCa, major surgery and procedures, on-going 
medical conditions that require continuous treatment or close follow up/monitoring, history of 
hypersensitivity and allergic events.  
Illnesses’ first occurring or detected after the ICF is signed or during the study and/or worsening 
of an existing illness during the study are to be documented as AEs on the CRF. 
Prior treatments, defined as administered prior to first immunotherapy treatment, should be 
recorded in the CRF as prior medications. Concomitant treatments, defined as treatments 
continued by the subject upon entry into the study and new treatments taken after the first 
immunotherapy treatment, should be recorded in the CRF as concomitant medications. 
The subject’s previous anti-cancer treatments, including detailed information about their therapy 
directed against HNSCCa (e.g. past surgical and/or radiation regimens) should be documented. 
Additionally, information about any non-cancer treatments should also be noted. 
6.3.4 Safety Assessments 
The following subject evaluations for safety will be performed. 
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6.3.4.1 Participant Reminder Card  
Subjects record any post treatment reactions and enter this information on the participant 
reminder card. The study staff will review the reminder card and assess the reported events for 
clinical significance.  
Study staff should evaluate each unique reminder card entry according to CTCAE guidelines 
(Version 4.03) and Table 6.1 of the protocol, “Grading Scale for Injection Site Reactions.” Any 
reminder card entry determined to meet the criteria for a Grade 1 or higher adverse event should 
be documented as an adverse event unless deemed part of the subject’s ongoing medical history. 
If the reminder card entry does not meet the criteria of a Grade 1 or higher AE as per the CTCAE 
guidelines, clinical judgment can be used to determine whether the entry should be recorded as an 
AE and documented accordingly in the site’s source. For cases where the reminder card entry and 
final AE reporting (i.e. grading) do not agree, the reasoning should be recorded in the source 
documents. 
6.3.4.2 Medical/Clinical Assessments and concomitant medications 
New onset disease and concomitant medications will be queried from the first time reported 
through to the end of study visit/discharge. 
Assessment of adverse events will be collected from the time of informed consent through End of 
Study visit and will be assessed using the “Common Terminology Criteria for Adverse Events 
(CTCAE)”, version 4.03 issued by the US Department of Health and Human Services on June 14, 
2010.  
6.3.4.3 Physical Assessments 
A complete physical examination will be conducted at specified visits. A targeted physical 
assessment will be performed at other visit as determined by the Investigator or directed per 
subject complaints. The injection site is to be assessed by the study personnel within 30 – 45 
minutes after EP, and during subsequent clinic visits as specified in the schedule of events (Tables 
S1 and S2). 
6.3.4.4 Vital Signs 
Vital signs may include but are not limited to, body temperature, oxygen saturation, blood 
pressure and heart rate will be measured at specified visits.  
6.3.4.5 Weight and Height 
Weight (kg) and height (cm) will be collected at specified visits. The information can be used for 
body mass index (BMI) calculations.  
6.3.4.6 12-Lead ECGs 
An ECG will be performed within 28 days of the first dose of immunotherapy for eligibility.  
6.3.4.7 Pregnancy Test 
Women of reproductive potential must have a negative serum β-HCG test at screening and a 
negative serum or urine (with sensitivity of at least 25 mIU/mL) β-HCG within 72 hours prior to 
administration of immunotherapy.  If at any point the β-HCG test is positive, indicating that the 
subject is pregnant, no additional immunotherapy will be administered, but the subject will be 
followed for the duration of the study and beyond to determine the outcome of the pregnancy 
(with the subject’s consent). 
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6.3.4.8 Eastern Cooperative Oncology Group (ECOG) 
ECOG performance status will be measured at specified visits. 
6.3.4.9 Laboratory Evaluations 
Blood samples will be taken to be tested for serum chemistry and complete blood count as 
specified in the Schedule of Events (Tables S1 and S2). 
Complete Blood Count 
White blood cell (WBC) count with differential, Red blood cell (RBC) count, Hemoglobin, 
Hematocrit, Platelet count and PT, INR/PTT (screening only).  
Serum Chemistry  
Bilirubin, alkaline phosphatase, SGPT (serum glutamic-pyruvic transaminase)/ALT, SGOT 
(serum glutamic-oxaloacetic transaminase)/AST, creatinine, electrolytes, calcium, albumin and 
CPK (at screening and at 2 weeks after the last dose of immunotherapy only). 
Serology (screening only): 
Antibody to human immunodeficiency virus (HIV-Ab), hepatitis B surface antigen (HBsAg), 
antibody to hepatitis C virus (HCV) 
6.4 Optional collection of Leftover Tumor Tissue Sample 
Leftover tumor tissue samples may be collected through subject’s standard of care during the 
course of the study. The tumor tissue samples will be used for immunological and correlative 
assessments.  
6.5 HLA Testing 
HLA testing will be performed on PBMC from any single blood sample collected for 
immunogenicity analysis after screening visit. If the subject has a record of previous high 
resolution HLA testing and access to results, this HLA testing is not required.  
 
The DNA extracted from the blood sample will be used to determine if alleles at the MHC locus 
affect the immune response to study treatment. Data arising from this study will be subject to 
same confidentiality as the rest of the study. This specimen will be destroyed immediately after 
the analysis and the results checked. 
6.6 Injection of INO-3112 Followed by Electroporation 
INO-3112 will be administered, mixed in a volume of 1.1 mL by IM injection in the deltoid 
followed immediately by EP. If the deltoid is not a suitable location, the IM injection should be in 
the lateral quadriceps followed immediately by EP. Vaccination/EP must not be given within 2 
cm of a tattoo, scar, or active lesion/rash or on the same side of the body where an implanted 
device is located. The timing of the initial dose will be as outlined above. 
The vaccination/electroporation procedure will be performed by qualified personnel. An 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to subjects (licensed health care professionals who 
have appropriate credentials, e.g. MD, DO, RN, NP, PA) in addition to satisfactorily completing 
device training from device company personnel. Individuals whose credentials do not meet the 
relevant local requirements may perform the /electroporation procedure under one or both of the 
conditions below: 
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1. The procedure must be performed under the direct supervision of the Principal 
Investigator or an approved Sub-Investigator who has already been trained by device 
company personnel. 
2. The CV and any relevant qualifications of the individual have been reviewed and 
approved by the device company or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the Inovio Pharmaceuticals, Inc. 
or its designee. 
6.6.1 Management of anxiety and pain due to EP procedure 
Subjects will be offered topical anesthetic (e.g. EMLA), to limit significant discomfort from the 
vaccination/EP 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 vaccination/EP.  Subjects will be offered an analgesic (e.g. ibuprofen, ketorolac) 
after vaccination/EP. In case subjects are anxious for the procedure, they will be offered a mild 
sedative (e.g. 0.5-1.0 mg lorazepam), or equivalent, as a mild sedative for anxiety related to the 
vaccination/EP procedure. Mild sedatives may be administered approximately 1 hour prior to EP. 
Subjects who receive a mild sedative should not operate a motor vehicle for 3-4 hours after 
receiving medication and should have arranged transportation to depart the study site. Subjects 
who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a mild sedative 
will be offered a suitable alternative. 
6.6.2 Assessment of Injection Site Reactions 
When evaluating injection site reactions throughout the study, the investigator or designee will be 
instructed to use the following grading scale (Table 6.1): 
Table 6.1: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild(1) 
Moderate(2) 
Severe(3) 
Potentially Life 
Threatening(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 
(ER) visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER 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 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
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*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 
7 Statistical Plan 
7.1 Sample Size Determination 
A minimal of 20 but no more than 25 eligible subjects will be enrolled, as described above.  This 
study is an estimation study, and as such, a power calculation is not applicable.  Regarding the 
primary analysis, 20 subjects will provide 95% confidence that the true incidence of SAEs is 
<17% if 0 SAEs are observed.  If more than one subject in a cohort discontinues early for reasons 
other than toxicity from the immunotherapy, consideration will be given for replacement. 
7.2 Statistical Methods 
The primary analysis will estimate safety parameters.  The incidence of SAEs and the incidence 
of injection site reactions will be estimated along with exact Clopper Pearson 95% confidence 
intervals.  Toxicity experience will also be recorded and summarized. 
In secondary analyses, immune response parameters will be estimated.  For continuous outcomes, 
the mean and 95% confidence interval will be calculated using a t-distribution approach, and for 
binary outcomes, the proportion and exact Clopper Pearson 95% confidence interval will be 
calculated. 
In exploratory analyses, we will also estimate the distributions of progression-free survival (PFS) 
and overall survival (OS) will be estimated, and any observed anti-tumor responses will be 
summarized.  PFS and OS will be measured from the time of instillation of the initial dose of 
immunotherapy.  Both The variables will be potentially censored by the end of the subject’s 
observation.  These distributions will be summarized using Kaplan-Meier survival curves and 
estimated median time to event of each type. Anti-tumor response category frequencies will be 
calculated. 
 
7.3 Subject Population(s) for Analysis 
Any subject who receives at least one dose of treatment will be included in the safety analyses.  
For immunogenicity and survival/anti-tumor analyses, the main analyses will utilize subjects who 
received their assigned number of doses. 
8 Safety and Adverse Events 
8.1 Definitions 
8.1.1 Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc) 
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• Related or possibly related to participation in the research (i.e. possibly related means there 
is a reasonable possibility that the incident experience, or outcome may have been caused 
by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
8.1.2 Adverse Event 
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body, or worsening of a pre-existing condition, temporally 
associated with the use of a product whether or not considered related to the use of the product. In 
this study, such changes will be monitored, classified, and summarized, as Clinical or Laboratory 
AEs. Medical condition/diseases present before starting the investigational drug will be 
considered adverse events only if they worsen after starting Study Treatment. An unexpected AE 
is one not identified in the Clinical Investigator’s Brochure (CIB) or otherwise not expected from 
the characteristics of the clinical material.  
AEs include the following: 
• 
Pre- or post-treatment complications that occur as a result of protocol mandated procedure 
during or after the first screening visit (before the administration of study drug) 
• 
Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an 
AE 
• 
Complications and termination of pregnancy; 
• 
All AEs that occur from the screening visit onwards and throughout the duration of the 
study, including the follow-up off study treatment period should be recorded as an AE 
AEs do not include the following: 
• 
Medical or surgical procedures other than the definitive surgical procedure for Cohort I 
(e.g., surgery, endoscopy, tooth extraction, transfusion) performed; the condition that 
leads to the procedure is an AE 
• 
Pre-existing diseases or conditions or laboratory abnormalities present or detected before 
the screening visits that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions). 
• 
Overdose without clinical sequelae 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history CRF 
• 
Uncomplicated pregnancy (documented on a pregnancy CRF) 
• 
An induced elective abortion to terminate a pregnancy without medical reason 
(documented on a pregnancy CRF) 
8.1.3 Serious Adverse Event 
A serious adverse event (SAE) is any AE that meets one of the following conditions: 
• 
Death during the period of surveillance defined by the protocol; 
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• 
Is immediately life-threatening (e.g., subject was, in the view of the Investigator, at 
immediate risk of death from the event as it occurred). This does not include an AE that, 
had it occurred in a more serious form, might have caused death; 
• 
An event requiring inpatient hospitalization or prolongation of existing hospitalization 
during the period of protocol defined surveillance (including any overnight stay in the 
hospital, regardless of the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE (see Section 8.1.12); 
• 
Results in congenital anomaly or birth defect; 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalization, but based upon appropriate medical judgment, may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse; development of malignancies. 
Clarification of Serious Adverse Events 
• 
Death is an outcome of an AE, and not an adverse event in itself 
• 
The subject may not have been on investigational medicinal product at the occurrence of 
the event. Dosing may have been given as treatment cycles or interrupted temporarily 
before the onset of the SAE, but may have contributed to the event 
• 
“Life-threatening” means that the subject was at immediate risk of death from the event as 
it occurred. This does not include an event that might have led to death if it had occurred 
with greater severity 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE 
• 
Inpatient hospitalization means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department 
The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be documented 
as the AE and/or SAE and not the individual signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution. The reporting period 
for SAEs is described in Section 8.3. 
8.1.4 Adverse Event Reporting Period 
0-3 days after each Study Treatment. Study subjects will be directly observed by study personnel 
for 30-45 minutes after administration of Study Treatment for immediate reactions. The 
occurrence and severity of any AE during this period or the lack of same will be recorded. After 
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that, subjects will be given an oral thermometer and a Participant Reminder Diary. They will be 
asked to take and record their body temperature daily at the same time and to note and 
characterize in their own words any local or systemic events they experience, during this 3 day 
period after each Study Treatment. 
Throughout the Study. In addition to the daily record of oral temperature, administration site 
reactions, and systemic complaints recorded for 3 days after Study Treatment or until resolution, 
subjects will be queried at each study visit regarding the occurrence of any SAE or other AE that 
may have occurred since the last study visit. They will be reminded to contact study personnel 
and immediately report any such event that occurs during the course of the study. These events 
will be recorded on the CRFs.  
The investigator will grade laboratory AEs and clinical AEs (based on discussions with study 
participants) with respect to the following levels of severity as defined in the document “Common 
Terminology Criteria for Adverse Events (CTCAE)”, NCI version 4.03 issued by the US 
Department of Health and Human Services: 
• 
Mild (Grade 1) 
• 
Moderate (Grade 2) 
• 
Severe (Grade 3) 
• 
Potentially Life Threatening (Grade 4) 
• 
Deaths (Grade 5) 
Adverse events should be captured once on the CRF at the maximum severity reported. 
8.1.5 Causal Relationship of Clinical Material to Adverse Events 
A related AE is one judged to have a suspected relationship to the administration of the clinical 
material, (INO-3112) and the investigational CELLECTRA® device. An AE may also be assessed 
as not related to the investigational product. The Investigator is responsible for reporting adverse 
events and causality (judging the relationship between the administration of the clinical material 
and a subsequent AE) because the investigator is knowledgeable about the subject (e.g., medical 
history, concomitant medications), administers the investigational product, and monitors the 
subject’s response to the investigational product. The Investigator is aware of the subject’s 
clinical state and thus may be sensitive to distinctions between events due to the underlying 
disease process versus events that may be product related and may have observed the event. The 
Sponsor will assess the overall safety of the investigational product and determine whether to 
report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the Study Subject, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether or not an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" accordingly. 
Causality should be assessed by the Investigator as “yes, related” or “no, unrelated” by the 
following criteria: 
• 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
• 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
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• 
Temporal relationship of event onset to the initiation of study drug; 
• 
Course of the event, considering especially the effects of dose reduction, discontinuation 
of study drug, or reintroduction of study drug (where applicable); 
• 
Known association of the event with the study drug or with similar treatments; 
• 
Known association of the event with the disease under study; 
• 
Presence of risk factors in the Study Subject or use of concomitant medications known 
to increase the occurrence of the event; 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
For Study Subject receiving combination therapy, causality may be assessed individually for each 
protocol-mandated therapy or for the combination. 
8.1.6 Preexisting Condition 
A preexisting condition is one that is present at the time of signing of Informed consent.  A 
preexisting condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
8.1.7 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  
At the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
8.1.8 Post-study Reporting Requirements 
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study (including any protocol-required post-treatment follow-up). 
Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for 
subjects. However, if the investigator learns of an AE or SAE that occurs after the completion of 
termination visit and the event is deemed by the investigator to be related to the study treatment 
(following the guidelines in Section 8.1.5), he/she should promptly document and report the event 
to Inovio Pharmaceuticals. 
8.1.9 Abnormal Laboratory Values 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, coagulation, CPK) independent of the underlying 
medical condition that require medical or surgical intervention or lead to investigational 
medicinal product interruption or discontinuation must be recorded as an AE, as well as an SAE, 
if applicable. In addition, laboratory or other abnormal assessments (e.g., electrocardiogram, vital 
signs) that are associated with signs and/or symptoms must be recorded as an AE or SAE if they 
meet the definition of an AE (or SAE) as described in Sections 8.1.2 and 8.1.3. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the 
laboratory result (e.g., decreased hemoglobin).  
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
• 
Requires therapeutic intervention or diagnostic tests 
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• 
Leads to discontinuation of study treatment 
• 
Has accompanying or inducing symptoms or signs 
• 
Is judged by the investigator as clinically significant 
Grade is an essential element of these criteria. Each CTCAE grading term in the current version is 
a unique representation of a specific event used for medical documentation and scientific analysis 
and is a single MedDRA Lowest Level Term (LLT).  
Investigators are asked to take the CTCAE grading criteria into account when assessing if a 
laboratory abnormality qualifies as a laboratory AE.  Their clinical judgment ultimately 
determines whether the abnormality in question is “clinically significant (CS)” or “not clinically 
significant (NCS)” and the severity of the event. CTCAE grading can be used as a reference when 
making this determination. It is the responsibility of the Investigators to ensure all AEs are 
accurately reported and graded. 
8.1.10 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event as detailed in 8.1.3.  Any condition related to 
surgery should be documented as an adverse event if the condition meets the criteria for an 
adverse event.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document, though should be 
grouped under one diagnosis. 
All adverse events occurring during the study period must be recorded. Adverse events will be 
measured and graded in accordance with the document entitled “Common Terminology Criteria 
for Adverse Events (CTCAE)”, NCI version 4.03 issued by the US Department of Health and 
Human Services on June 14, 2010. 
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All AEs, regardless of severity, seriousness, or presumed relationship to study treatment, must be 
recorded using medical terminology in source documents and on the CRF. Whenever possible, a 
diagnosis should be documented, in lieu of symptoms. The source document and the CRF must 
contain the investigator’s opinion concerning the relationship of the AE to study treatment. 
AEs should be described with the following attributes: 
• 
Duration (start and end dates) 
• 
Seriousness 
• 
Severity 
• 
Causality 
• 
Action(s) taken 
• 
Outcome 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must confirm to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible, but at a minimum 
those events that must be reported are those that are: 
• related to investigational product(s), 
• unexpected, and  
• serious or involve risks to subjects or others (see definitions, section 8.1).   
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the grade and 
association between the event and study 
treatment 
 
8.3.1 Events Requiring Expedited Reporting 
Events requiring expedited reporting (ERER) will be defined as treatment- or EP-related 
adverse events including any of the following:  
1. Grade 3 or greater injection site pain, tenderness, erythema, and/or induration recorded 
≥ 1 hour after study treatment (see Table 6.1) 
2. Grade 3 or greater fever within 7 days of study treatment 
3. Grade 3 or greater systemic symptoms within 7 days of study treatment 
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as defined in the “Common Terminology Criteria for Adverse Events (CTCAE)”, version 
4.03 issued by the US Department of Health and Human Services on June 14, 2010. The 
worst grade for that particular event is to be documented on the CRFs. 
Sites should inform Inovio of any ERER within 72 hours to discuss whether further dosing 
should continue for that participant. 
8.3.2 Stopping Rules (Criteria for Pausing of Study) 
8.3.2.1 If at any time during the study one third (1/3) or more subjects experience an 
ERER assessed as possibly, probably or definitely related to study treatment, 
further enrollment and study treatments will be on hold immediately until a 
thorough investigation has been conducted by the Medical Monitors of Inovio and 
Principal Investigator. 
8.3.2.2 Any SAE, potentially life threatening AE or death assessed as possibly, probably 
or definitely related to study treatment, further enrollment and study treatments 
will be on hold immediately until a thorough investigation has been conducted by 
the Medical Monitors of Inovio and Principal Investigator and IRB (if applicable). 
8.3.2.3 If three or more subjects in this study, experience the same grade 3 or 4 adverse 
event, assessed as possibly, probably or definitely related to study treatment, 
further enrollment and study treatments will be on hold immediately until a 
thorough investigation has been conducted by the Medical Monitors of Inovio and 
Principal Investigator. 
8.3.2.4 In the event of any unexpected Grade 4 toxicities, assessed as possibly, probably 
or definitely related to study treatment, further enrollment and study treatments 
will be on hold immediately until a thorough investigation has been conducted by 
the Medical Monitors of Inovio and Principal Investigator and IRB (if applicable). 
8.3.2.5 The study will be on hold for any report of Grade 3 anaphylaxis from 
immunotherapy/EP  in two or more subjects (as graded per “Common 
Terminology Criteria for Adverse Events (CTCAE)”, version 4.03 issued by the 
US Department of Health and Human Services on June 14, 2010). Occurrence in 
three or more subjects will lead to an immediate halt of enrollment and further 
immunotherapy until full discussion has been conducted by the Medical Monitors 
of Inovio and Principal Investigator, IRB (if applicable) and the FDA. 
8.3.3 Investigator reporting: Inovio Pharmaceuticals, Inc. 
Any study-related unanticipated problem posing risk of harm to subjects or others, and any type 
of serious adverse event, must be reported to Inovio within 24 hours of the event.  To report such 
events, the SAE worksheets or a MedWatch 3500a form must be completed by the investigator 
and faxed/emailed to Inovio within 24 hours. The investigator will keep a copy of this SAE form 
on file at the study site. Report serious adverse events by facsimile/email to: 
TELEPHONE:  
 
EMAIL:  
safety@inovio.com 
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If there is a need to directly contact the medical monitor, please contact: 
 MEDICAL MONITOR: 
, MD or designee 
MAILING ADDRESS: 
TELEPHONE: 
 office 
Inovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, 
Suite 110 
Plymouth Meeting, PA 19462 
  
 Mobile 
FACSIMILE (FAX): 
 
EMAIL: 
  
As soon as available, the investigator must provide further information on the serious adverse 
event or the unanticipated problem in the form of a written narrative. This should include an 
updated MedWatch Form, and any other diagnostic information that will assist the understanding 
of the event. Significant new information on ongoing serious adverse events should be provided 
promptly to Inovio. 
Inovio will be responsible for reporting any applicable events to the U.S. Food and Drug 
Administration (FDA) per their reporting requirements. 
8.3.4 Investigator Reporting: the Penn IRB 
The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events 
related to study participation that are unforeseen and indicate that participants or others are at 
increased risk of harm.  The Penn IRB will not acknowledge safety reports or bulk adverse event 
submissions that do not meet the criteria outlined below.  The Penn IRB requires researchers to 
submit reports of the following problems within 10 working days from the time the investigator 
becomes aware of the event: 
• Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-
site) that occurs any time during or after the research study, which in the opinion of the 
principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and package 
inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.) 
Deaths occurring for subjects on-study and within 30 days of study drug administration that are 
considered unforeseen and indicates participants or others are at increased risk of harm (i.e. 
unexpected and probably/definitely related), must be reported to the IRB within 24 hours of 
notification. Copies of each report and documentation of IRB notification and receipt will be kept 
in the Clinical Investigator’s study file. 
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8.3.5 Other Reportable Events: 
For clinical drug trials, the following events are also reportable to the Penn IRB: 
• Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
– An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected. 
– A paper is published from another study that shows that an arm of your research study 
is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants at 
increased risk, or affects the rights or welfare of subjects. 
The IRB will accept other reports when the investigator is unsure whether the event should be 
reported, and the IRB will review such reports to determine whether the event meets the threshold 
for an unanticipated event presenting risk to the participant. 
 
, Institutional Review Board 
 
Phone: 
 
Fax: 
 
 
8.4 Reportable Events 
Deviation 
A one-time unintentional action or process that departs from the IRB approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on 
the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the 
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safety and welfare or the subjects, the deviation must be reported to the Sponsor (Inovio) as soon 
as possible. 
8.5 Reporting of Device Related Complaints 
Any problems experienced during the treatment procedure including potential malfunctions of the 
CELLECTRA® device, error messages displayed on the device screen following treatment or 
errors that occur during the treatment procedure should be reported to the Sponsor or designee 
immediately for evaluation via email to 
. The Error Reporting Form 
provided will be completed and sent to Inovio or its designee. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data 
are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained. If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
If the item is not applicable to the individual case, write “N/A”.   
9.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
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contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the drug manufacturer.  In 
such an instance, it is the responsibility of the drug manufacturer to inform the 
investigator/institution as to when these documents no longer need to be retained.  
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring 
Monitoring of the clinical trial will be performed by experienced monitors, who will report to the 
Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be monitored. 
The following clinical site monitoring tasks will be performed at all sites: 
• 
Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure compliance with all applicable requirements 
• 
All clinical site monitoring visits will be documented 
• 
Periodic site visits will be performed throughout the study 
• 
The site monitor will be responsible for addressing and documenting the following study 
conduct activities and obligations and will: 
○ Assure that the study is being conducted in accordance with the protocol, applicable 
regulatory agency regulations, and IRB/EC policies 
○ Discuss study conduct issues and incidents of noncompliance with the Investigator 
and/or study personnel and document them on the resolution trip report. Report any 
significant unresolved problems immediately to the sponsor 
○ Remind the Investigator as necessary of the obligation to immediately report all 
serious adverse events (SAE) and provide subsequent follow-up report of the final 
outcome to the IRB/EC 
○ Inspect all Case Report Form (CRF) pages for completeness, logic, and internal 
consistency throughout the study 
○ Assure that the study facilities continue to be acceptable 
○ Compare the study CRFs with source documents to assure that the data are accurate 
and complete and that the protocol is being followed 
○ Assure that test article accountability and reconciliation records are complete and 
accurate 
○ Assure that all subject specimens are being stored and forwarded properly for testing 
10.2 Medical Monitor 
The medical monitor for this study will be Dr. 
 from Inovio Pharmaceuticals or a 
designee.   
10.3 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
IND Sponsor or its designee, government regulatory bodies, and University compliance and 
quality assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
11 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval 
of the study conduct.  The decision of the IRB concerning the conduct of the study will be made 
in writing to the investigator and a copy of this decision will be provided to Inovio 
Pharmaceuticals before commencement of this study. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
and CTSRMC for the study.  The formal consent of a subject, using the IRB-approved consent 
form, must be obtained before that subject undergoes any study procedure.  The consent form 
must be signed by the subject and the investigator-designated research professional obtaining the 
consent.  
12 Study Finances 
12.1 Funding Source 
The study will be supported by funds through the Abramson Cancer Center’s EARLY PHASE 
CLINICAL RESEARCH SUPPORT. Funding for immunological correlatives and vaccine will be 
provided by Inovio Pharmaceuticals, Inc.  We will not be receiving additional funding through 
Inovio. 
12.2 Conflict of Interest 
Investigators on this protocol do not have a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) All 
University of Pennsylvania investigators will follow the University conflict of interest policy. 
13 Publication Plan 
Publication policy shall be as provided in Section 4.3 of the Clinical Trial Agreement between the 
University of Pennsylvania and Inovio Pharmaceuticals, Inc.  
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14 List of Abbreviations 
AE 
 
 
Adverse Event 
ALT (SGPT)  
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) 
ANC  
 
Absolute Neutrophil Count 
AST (SGOT)  
Aspartate Aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
CBC  
 
Complete Blood Count 
Chemo XRT  
Chemoradiation Therapy 
CIN 
 
 
Cervical Intraepithelial Neoplasia 
CMI 
 
 
Cell Mediated Immunity 
CPK  
 
Creatine Phosphokinase 
CRF 
 
 
Case Report Form 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
DNA  
 
Deoxyribonucleic Acid 
ECG  
 
Electrocardiogram 
ECOG  
 
Easter Cooperative Oncology Group 
EP 
 
 
Electroporation 
FDA  
 
Food and Drug Administration 
HBsAg 
 
Hepatitis B Surface Antigen 
HNSCCa 
 
Head and Neck Squamous Cell Carcinoma 
HCG  
 
Human Chorionic Gonadotropin 
HIV 
 
 
Human Immunodeficiency Virus 
HPV  
 
Human Papillomavirus 
ICH 
 
 
International Conference on Harmonisation 
IEC 
 
 
Independent Ethics Committee 
IRB 
 
 
Institutional Review Board 
ISH 
 
 
In Situ Hybridization 
IUD 
 
 
Intrauterine Device 
IM 
 
 
Intramuscular 
IP 
 
 
Investigational Product 
LFT 
 
 
Liver Function Test 
PBMC  
 
Peripheral Blood Mononuclear Cells 
PCR 
 
 
Polymerase Chain Reaction 
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RBC  
 
Red Blood Cells 
SAE 
 
 
Serious Adverse Event 
SFU 
 
 
Spot Forming Units 
SOC  
 
System Organ Class 
TILs 
 
 
Tumor Infiltrating Lymphocytes 
ULN  
 
Upper Limit of Normal 
WBC  
 
White Blood Cells  
 
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