Conditions: Vulvar High Grade Squamous Intraepithelial Lesion (HSIL) Vulvar Dysplasia Vulvar Intraepithelial Neoplasia (VIN) VIN2 VIN3 Pre-cancerous Lesions of the Vulva Human Papillomavirus (HPV)
Keywords: HPV-16 HPV-18
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the safety and efficacy of an investigational immunotherapy VGX-3100, in combination with a study device, to treat women with vulvar high-grade squamous intraepithelial lesion (HSIL) \[vulval intraepithelial neoplasia 2 or 3 (VIN 2 or VIN 3)\] associated with human papilloma virus (HPV) types 16 and/or 18. VGX-3100 is being assessed as an alternative to surgery with the potential to clear the underlying HPV infection. For more information visit our study website at: www.VINresearchstudy.com

Detailed description:

Arms:
arm 1: Participants with histologically confirmed vulvar high-grade squamous intraepithelial lesion (HSIL) associated with human papilloma virus (HPV) 16 and/or 18, received four doses of 6 mg VGX-3100 as an intramuscular (IM) injection on Day 0, Week 4, Week 12, and Week 24 followed by electroporation (EP) using the CELLECTRA™ 2000 device. Participants with vulvar HSIL who had a reduction in lesion size or no increase in lesion size at Week 48, received a fifth dose of VGX-3100 at Week 52. arm 2: Participants with histologically confirmed vulvar HSIL associated with HPV-16 and/or 18, received four doses of 6 mg VGX-3100 as an IM injection on Day 0, Week 4, Week 12, and Week 24 followed by EP using the CELLECTRA™ 2000 device. Participants with vulvar HSIL who had a reduction in lesion size or no increase in lesion size at Week 48, received a fifth dose of VGX-3100 at Week 52. In addition, participants applied imiquimod 5% cream to the vulvar lesion three times per week for 20 weeks.

Interventions: intervention 1: VGX-3100 intervention 2: Imiquimod 5% Cream intervention 3: CELLECTRA™ 2000
Intervention descriptions: intervention 1: One milliliter (1 mL) VGX-3100 injected IM and delivered by EP using CELLECTRA™ 2000 on Day 0, Week 4, Week 12 and Week 24. intervention 2: Participants applied imiquimod 5% cream to the vulvar lesion three times per week for 20 weeks. intervention 3: IM injection of VGX-3100 was followed by EP with the CELLECTRA™ 2000 device.

Protocol document:
Prot_000.pdf: 
Official Title: 
NCT Number: 
NCT03180684 
Document Dates:
Protocol Version 5.0: 19 December 2019 
Protocol Version 3.0: 26 March 2019 
Protocol Version 2.1: 01 December 2017 
Protocol Version 2.0: 20 November 2017 
Protocol Version 1.3: 21 April 2017 
Protocol Version 1.2: 24 January 2017 
Protocol Version 1.1: 20 January 2017 
Protocol Version 1.0: 13 January 2017
A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation With CELLECTRA™ 2000 Alone or in 
Combination With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 
Related High Grade Squamous Intraepithelial Lesion (HSIL) of the Vulva


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA® 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
U.S. BB-IND #13683 
 
 
 
 
Version 1.0 
13 January 2017 
 
 


VGX-3100
HPV-201
Inovio Pharmaceuticals, Inc.
Clinical Protocol
Medical Monitor Approval Page
Drug:
VGX-3100
Sponsor:
lnovio Pharmaceuticals, Inc.
660 W. Germantown Pike, Suite 110
Plymouth Meeting, PA 19462
Medical Monitor:
, M.D., Ph.D.
lnovio Pharmaceuticals, Inc.
Approval Signature:
M.D., Ph.D.
Date
lnovio Pharmaceuticals, Inc.
CONFIDENTIAL
The information in this document is considered privileged and confidential by lnovio
Pharmaceuticals and may not be disclosed to others except to the extent necessary to
obtain Institutional Review BoardlEthics 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 lnovio Pharmaceuticals. Any
supplemental information added to this document is also confidential and proprietary
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner
as the contents of this document.
Version Date: 13Jan2017
CONFIDENTIAL
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VGX-3100 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI’s approval of this 
protocol and provides the necessary assurances that this trial will be conducted in 
accordance with ICH/GCP and ISO guidelines, local legal and regulatory requirements, 
and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
____________________________________  
_________________________ 
<Insert Principal Investigator Printed Name>  
        Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


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Clinical Protocol 
 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................................... 4 
CLINICAL PROTOCOL SYNOPSIS ....................................................................................................... 9 
STUDY SCHEDULE OF EVENTS ........................................................................................................ 22 
1. 
INTRODUCTION ......................................................................................................................... 24 
1.1 
Background ..................................................................................................................... 24 
 
Human Papillomavirus and Infection ............................................................. 24 
 
Vulvar Cancer .................................................................................................... 24 
 
Vulvar Intraepithelial Neoplasia (VULVAR HSIL) ......................................... 24 
 
Recurrent Disease with Current Therapeutic Options ................................. 25 
 
Psychological and Physical Impacts of Current Therapeutic Options ...... 26 
 
Impact of Vulvar HSIL Upon Activities of Daily Living ................................. 26 
 
Limitations of Prophylactic HPV Vaccines .................................................... 26 
 
Enhanced Monitoring Plan ............................................................................... 27 
 
VGX-3100 ........................................................................................................... 27 
  Electroporation .................................................................................................. 27 
  Imiquimod Cream, 5% ...................................................................................... 28 
  Study Rationale ................................................................................................. 28 
  Dose and Regimen Rationale for VGX-3100 ................................................ 28 
  Rationale for imiquimod ................................................................................... 28 
  Potential Risks of investigational products .................................................... 29 
  Potential Benefits of Study Participation ....................................................... 29 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ........................................................................... 29 
2.1 
Primary Objective and Endpoint .................................................................................. 30 
2.2 
Secondary Objectives and Associated Endpoints .................................................... 30 
2.3 
Exploratory Objectives and Associated Endpoints ................................................... 32 
3. 
STUDY DESIGN ......................................................................................................................... 33 
3.1 
Treatment Regimens ..................................................................................................... 33 
3.2 
Efficacy Assessment ...................................................................................................... 34 
 
Definition of Responder and Non-Responder ............................................... 35 
3.3 
Safety Assessment ........................................................................................................ 36 
 
Data Safety & Monitoring Board ..................................................................... 36 
3.4 
Immunogenicity Assessment ........................................................................................ 37 
3.5 
Virologic Assessment .................................................................................................... 37 


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4. 
SELECTION OF SUBJECTS .................................................................................................... 37 
4.1 
Inclusion Criteria ............................................................................................................. 37 
4.2 
Exclusion Criteria ........................................................................................................... 38 
4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................... 40 
 
Criteria for Discontinuation of Investigational Product ................................ 40 
 
Criteria for Withdrawal from the Study ........................................................... 41 
 
Sponsor Notification of Discontinuation/Withdrawal .................................... 41 
 
Reason for Discontinuation/Withdrawal ......................................................... 42 
5. 
STUDY TREATMENT ................................................................................................................ 42 
5.1 
Investigational Products ................................................................................................ 42 
5.2 
Packaging and Labeling ................................................................................................ 43 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................... 43 
5.3 
Handling and Storage .................................................................................................... 44 
5.4 
Preparation and Dispensing ......................................................................................... 45 
 
Dispensing of VGX-3100 ................................................................................. 45 
 
Dispensing and Use of Imiquimod .................................................................. 45 
5.5 
Investigational Product Accountability ........................................................................ 45 
5.6 
Return and Destruction of Investigational Product ................................................... 46 
5.7 
Use of Investigational Device ....................................................................................... 46 
5.8 
Packaging and Labeling of Investigational Device ................................................... 47 
5.9 
Investigational Device Accountability .......................................................................... 49 
5.10 
Return of Investigational Devices ................................................................................ 49 
6. 
STUDY PROCEDURES AND TREATMENTS ....................................................................... 50 
6.1 
Before Treatment Procedures ...................................................................................... 50 
 
Screening evaluations ...................................................................................... 50 
 
Ultrasound Measure of Skin-to-Muscle and Related Thicknesses ............ 51 
6.2 
During Treatment Procedures by Visit ........................................................................ 52 
 
Day 0 ................................................................................................................... 52 
 
8-14 Days Post Dose 1 Phone Call ................................................................ 53 
 
Week 4 ................................................................................................................ 53 
 
8-14 Days Post Dose 2 Phone Call ................................................................ 54 
 
Week 12 .............................................................................................................. 54 
 
Week 15 .............................................................................................................. 55 
 
Week 24 .............................................................................................................. 55 
 
Week 27 .............................................................................................................. 56 


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Week 48 .............................................................................................................. 56 
  Week 52 .............................................................................................................. 57 
  Week 74 .............................................................................................................. 57 
  Week 78 .............................................................................................................. 58 
  Week 96 .............................................................................................................. 58 
  Week 100 ........................................................................................................... 59 
6.3 
Evaluations and Procedures ........................................................................................ 60 
 
Informed Consent .............................................................................................. 60 
 
Assignment of Subject Identification Numbers ............................................. 60 
 
Safety Evaluations ............................................................................................ 60 
6.4 
Injection and Electroporation (EP) ............................................................................... 62 
 
Risks of Treatment Procedures ...................................................................... 63 
 
Management of Anxiety and Pain Due to EP Procedure ............................ 64 
6.5 
Assessment of Laboratory Abnormalities ................................................................... 65 
6.6 
Assessment of Clinical Study Adverse Events .......................................................... 65 
6.7 
Assessment of Injection Site Reactions ..................................................................... 65 
6.8 
Assessment of Patient Reported Outcomes .............................................................. 66 
6.9 
Peripheral Blood Immunogenicity Assessments ....................................................... 67 
6.10 
Tissue Immunogenicity Assessment ........................................................................... 67 
6.11 
HLA Typing...................................................................................................................... 67 
6.12 
Vulvar HPV Testing ........................................................................................................ 68 
6.13 
Colposcopy, PAP Smears and HPV Testing ............................................................. 68 
6.14 
Vulvoscopy, Photographs, and Biopsies .................................................................... 68 
6.15 
Concomitant Medications/Treatments ........................................................................ 69 
6.16 
Restrictions...................................................................................................................... 69 
  Other Restrictions ............................................................................................. 69 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY .................................... 70 
7.1 
Safety Parameters ......................................................................................................... 70 
 
Adverse Events ................................................................................................. 70 
 
Serious Adverse Events ................................................................................... 71 
 
Clarification of Serious Adverse Events ........................................................ 71 
 
Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ...................................................................... 72 
 
Unexpected Adverse Drug Reactions and Expedited Reporting ............... 72 
 
Unanticipated (Serious) Adverse Device Effect (UADE) ............................ 73 


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Assessing Severity (Intensity) ......................................................................... 73 
 
Casual Relationship of Clinical Material to Adverse Events ....................... 73 
 
Abnormal Laboratory Value ............................................................................. 74 
  Post-Trial Reporting Requirements ................................................................ 74 
  Procedures for Documenting Pregnancy During Study .............................. 74 
7.2 
Methods and Timing of Collection of Safety Data ..................................................... 75 
7.3 
Safety and Toxicity Management ................................................................................ 75 
 
Adverse Events of Special Interest ................................................................ 76 
 
Stopping Rules (Criteria for Pausing of Study) ............................................. 76 
7.4 
Adverse Experience Reporting .................................................................................... 77 
 
Trial Reporting Period of Adverse Events ..................................................... 77 
 
Trial Reporting Period of Serious Adverse Events ...................................... 77 
 
Notification of Serious Adverse Events ......................................................... 78 
 
Reporting of Device Related Complaints ...................................................... 78 
7.5 
Trial Discontinuation ...................................................................................................... 79 
8. 
STATISTICAL ANALYSIS PLAN ............................................................................................ 79 
8.1 
General Considerations ................................................................................................ 79 
8.2 
Randomization and blinding ......................................................................................... 79 
8.3 
Sample Size/Power ........................................................................................................ 79 
8.4 
Analyses Populations .................................................................................................... 80 
8.5 
Subject Disposition ........................................................................................................ 80 
8.6 
Demographic and Other Baseline Characteristics .................................................... 80 
8.7 
Medical History ............................................................................................................... 80 
8.8 
Prior and Concomitant Medications ............................................................................ 80 
8.9 
Efficacy Analysis ............................................................................................................ 81 
8.10 
Immunogenicity Analysis .............................................................................................. 81 
8.11 
Safety analyses .............................................................................................................. 81 
  Adverse events .................................................................................................. 81 
  Laboratory data ................................................................................................. 82 
  Vital Signs .......................................................................................................... 82 
  Physical Examination ....................................................................................... 82 
  Patient Reported Outcomes ............................................................................ 82 
  Missing Values .................................................................................................. 82 
  Interim Analysis ................................................................................................. 82 
9. 
ETHICS ......................................................................................................................................... 83 


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9.1 
Investigator and Sponsor Responsibilities ................................................................. 83 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ...................................... 83 
9.3 
Office of Biotechnology Activities (OBA) .................................................................... 83 
9.4 
Compliance with Informed Consent Regulations ...................................................... 83 
9.5 
Compliance with IRB/EC Requirements ..................................................................... 84 
9.6 
Compliance with Good Clinical Practice ..................................................................... 84 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 .......................................................................................................................................... 84 
9.8 
Compliance with Protocol ............................................................................................. 84 
9.9 
Changes to the Protocol ................................................................................................ 84 
10. 
DATA COLLECTION, MONITORING AND REPORTING ................................................... 84 
10.1 
Confidentiality and Privacy ........................................................................................... 84 
10.2 
Source Documents ........................................................................................................ 85 
10.3 
Records Retention ......................................................................................................... 85 
10.4 
Safety and Quality Monitoring ...................................................................................... 86 
  Data & Safety Monitoring Board ..................................................................... 86 
  Pathology Adjudication Committee ................................................................ 86 
  Clinical Monitoring ............................................................................................. 86 
11. 
PUBLICATION POLICY ............................................................................................................ 87 
12. 
LIST OF ABBREVIATIONS ...................................................................................................... 88 
13. 
REFERENCES ............................................................................................................................ 90 
 
 
 


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Clinical Protocol 
 
 
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CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA® 2000  Alone or in Combination 
With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 20 sites in the 
United States (US) 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-
16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000  given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA® 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3X) from Day 0 through Week 202 
No. of Subjects 
Approximately 36 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic clearance 
of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar HSIL3 
and no evidence of HPV-16/18 at Week 48 in vulvar tissue 
samples (i.e. collected via biopsy or excisional treatment)4 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3  No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
4  A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive non-study related medication for treatment of 
VIN lesions. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, AIS, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions.   


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Clinical Protocol 
 
 
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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar  HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/186 in vulvar tissue samples at 
Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL and no evidence of 
condyloma on histology (i.e. biopsies or 
excisional treatment) at the Week 48 visit
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion 
of 
subjects 
with 
no 
progression7 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of vulvar 
lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 48, 74 
and 96 compared to baseline8. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
                                                     
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
6 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
7 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
8 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96  
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects who did not have 
complete lesion resolution at Week 48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 74 and/or 
Week 96 compared to baseline9. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior  
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 
infiltrating cells10.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the vulva  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from other 
anatomic locations without surgical 
intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week  48 
                                                     
9 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
10 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Assess 
skin-to-muscle, 
skin-to-bone, 
and 
muscle thicknesses via ultrasound measure of 
deltoid (or quadriceps if applicable) and the 
correlation of needle depth into muscle with 
efficacy. 
7.  Ultrasound-measured skin-to-muscle, 
skin-to-bone, and muscle thicknesses  
8. Describe patient reported outcomes for subjects 
treated with VGX-3100 and VGX-3100 with 
imiquimod 
8.  Patient-reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and 
following each of the first four doses, 
and at Weeks 48, 74, 96, and 100. 
 
 


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Study Design: 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered with 
CELLECTRA® 2000 alone or in combination with imiquimod in adult women with histologically confirmed 
vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled.  
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-3100 
and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass Index 
(BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-5D-5L 
(EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvar Neoplasia) and two additional 
PRO questions assessing quality of life after surgery or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of a 4 mm vulvar 
punch biopsy/biopsies with lesion remaining, and photographs of the acetowhite vulvar lesion(s) at the 
time of screening. In the case of multifocal disease, the two regions of potentially most advanced and 
severe disease, as judged by the investigator, should be chosen for biopsy using vulvoscopy and 
documented using standardized high resolution photography with a digital single-lens reflex (SLR) 
camera, on the case report form. Biopsy slides or tissue will be sent to a Pathology Adjudication 
Committee (PAC) for evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must 
assign the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar 
tissue specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study.
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of VGX-
3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject’s biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of VGX-
3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic and 
lesion area changes.  The first dose will be administered on Day 0, the second at Week 4, the third at 
Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 48 
(Subgroups A and B) will receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator.  Subjects in Subgroup E may receive surgical treatment per the 
judgement of the Investigator.  All subjects are scheduled to be followed to Week 100.  
 
 
 


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Figure 1: Study Visit Schedule 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will apply imiquimod 
5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to apply imiquimod 
cream three times per week for 20 weeks (inclusive of administration in the evening of VGX-3100 
dosing).  Subjects unable to tolerate imiquimod treatment may reduce their dosing frequency, and will 
document their use on the imiquimod dosing diary provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by visual inspection with vulvoscopy is insufficient evidence 
to confirm disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74, and 96. Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), 
defined as areas that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0, and 
Weeks 4, 12, 27, 48, 74 and 96. Using standardized high resolution digital imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 3 
for Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC there is no 
evidence of HSIL (Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and biopsy 
adjacent to the site of the initial biopsy. Repeat biopsies that are indicated beyond Week 48 must be 
taken from the same lesion, adjacent to the prior biopsy site(s) within the boundaries of the original 
lesion.  
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size or no change 
in lesion size from baseline (Subgroups C or D), the Investigator has the option to give the subject a 5th 
dose of VGX-3100 at Week 52, and the subject will continue on study with vulvoscopy and biopsy at 


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Week 74.  Alternatively, the Investigator may choose to treat the subject with surgical or standard 
treatment, and the subject will continue on study without further biopsy.   
 
Figure 2: Decision process at Week 52  
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as follows: 
At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion as study 
start, but adjacent to the original site within the boundaries of the original lesion (see Table 3). If after 
evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject 
will continue to Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at Week 
78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, the 
Investigator may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy.   
 
 
 
 
 
 
 


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Figure 3: Decision Process at Week 78 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 3). 
If there is no vulvar HSIL (Subgroups A or B), no further procedures are required. If after evaluation of 
biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), 
the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 


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In the event of worsening disease at any time (ie, Subgroup E – any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per the 
Investigator’s judgement and will continue on study through Week 100 with vulvoscopy, but without 
further biopsy.  For a finding of carcinoma, subjects will receive surgical treatment, and be discontinued 
from study treatment.  The event will be reported as an SAE per section 7.1.4.  If wide excision is 
required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder: 
Responder and non-responder definitions (Table 4) take into account both histopathologic regression 
of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since HPV persistence is an 
important factor in the clinical progression of HSIL. A treatment responder is defined as a subject with 
no histologic evidence of vulvar HSIL and no evidence of HPV-16 or HPV-18 in vulvar tissue at 
evaluation and who did not receive non-study related medication for treatment of VIN lesions.  A 
treatment non-responder is a subject with histologic evidence of vulvar HSIL, adenocarcinoma-in-situ, 
or vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions. Any case of 
histologically confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. No formal interim 
analysis is planned. The following stopping rules will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, assessed 
as related to study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal Investigator 
for the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding the outcome of 
any investigation stemming from a Study Pause.  


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Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (both Screening as well 
as Day 0 prior to dosing) and at Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and at Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize HPV infection at Screening, 
Week 48, 74 and 96. Cervical samples, oropharyngeal rinse samples, vaginal, and intra-anal tissue 
swab samples will be obtained to characterize HPV infection in samples from study subjects taken at 
Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and intra-anal only) and at Weeks 
27, 48, 74, and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks will be collected for immunohistochemistry (IHC) 
and in situ hybridization (ISH) for the presence of HPV-16/18. Whenever possible, these studies will be 
performed on tissue sections from the diagnostic biopsy (pre-dose) and from tissue obtained post-dose 
(Week 48, 74 and 96). 
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above; 
3. 
Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. 
Vulvar tissue specimen/slides provided to the Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
5. 
Histologic evidence of vulvar HSIL as confirmed by the PAC at screening; 
6. 
Must be judged by investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
7. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system; 
iv) Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject. 
10. Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 


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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing treatment for CIN;
5) Biopsy-proven differentiated VIN; 
6) More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day of first 
dose (i.e. Day 0); 
7) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
8) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
9) Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into cervical 
canal at screening; 
10) History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, or insufficient 
for diagnosis (ECC is not performed as part of study screening) and did not receive definitive 
treatment; 
11) Treatment for genital warts within 4 weeks prior to screening; 
12) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
13) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last dose 
of investigational product; 
15) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the investigator; 
16) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying drugs such as 
TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
17) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
18) Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
20) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the investigator; 
21) Current or history of clinically significant, medically unstable disease which, in the judgement of the 
investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results (e.g. chronic renal failure, angina, 
myocardial ischemia or infarction, class 3 or higher congestive heart failure, cardiomyopathy, or 
clinically significant arrhythmias); 
22) Malignancy or treatment for malignancy within 2 years of screening, with the exception of superficial 


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skin cancers that only require local excision; 
23) Acute or chronic bleeding or clotting disorder that would contraindicate IM injections or use of blood 
thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 
24) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic agents; 
25) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at Screening or 
Day 0; 
27) Prior major surgery within 4 weeks of Day 0; 
28) Participated in an interventional study with an investigational compound or device within 4 weeks of 
signing informed consent (participation in an observational study is permitted); 
29) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
30) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
31) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in 
ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
32) Metal implants or implantable medical device within the intended treatment site (i.e. electroporation 
area);  
33) Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with 
adherence to study requirements; 
34) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (i.e. infectious disease) illness; 
35) Active military service personnel; 
36) Study-related staff or family members of study-related staff; 
37) 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.  


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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X
Inclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X---------------------------------------------------------------------------------------------------X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Vital signs 
Xb 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xe 
 
Xf
 
Xe 
 
Xe
 
Xe 
 
HLA testing g 
 
X 
Cervical cytology, ThinPrep™ h 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject  VGX-3100 +EP m 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing diary n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing diary 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Review PD o 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X-----------------------------------------------------------------------------------------------------------X 
Ultrasound Measure of skin-to-
muscle and related thicknesses 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X
Abbreviations: OP; oropharynx 


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a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE. 
b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared).  Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 30 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27. 
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrepTM cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected.  Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j Standardized high resolution digital imaging of the vulva and the associated acetowhite stained lesion(s) 
must be performed prior to and after biopsy, and at all vulvoscopy examinations. Additionally, 
standardized high resolution digital imaging should be obtained during examinations of the vagina if 
lesions are identified, for documentation. 
k Tissue specimen and slides from all excised tissue must be reviewed by the PAC and residual vulvar 
tissue from entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) should be 
sent to the central pathology laboratory for immunohistochemistry (IHC) and HPV testing.   
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing diary to document their use of imiquimod.  
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36, EQ-5D-5L, WOMAN-PRO) plus two additional questions will be assessed as 
described in Section 6.8.     
 
 
 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, 
and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the most 
significant amongst high-risk types since they are responsible for most HPV-caused 
cancers [1].   
HPV-16 is involved in more than 85% of HPV-associated vulvar HSIL cases in the U.S.[1]. 
Persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions 
(HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oro-pharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS)[2].  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 5,950 new cases and 1,110 
attributable deaths annually for year 2016 in the United States [3]. Vulvar cancers consist 
largely of squamous cell carcinomas and accounts for approximately 5% of all female 
genital malignancies [4]. Differentiated VIN, which is typically not caused by HPV infection 
and is more typically found in older women, is more likely to progress to cancer more 
rapidly than HPV-associated-VIN. The five year overall relative survival for vulvar cancer 
in the U.S. is 70.7% [3].  Recurrent vulvar cancer occurs in an average of 24% of cases 
after primary treatment, after surgery with or without radiation [5].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia.  The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance of 
pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [6]    
In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) replaced 
the three grade classification system with the current single grade classification for which 


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only high grade VIN (2/3) is classified as VIN [7]. In 2012, the Lower Anogenital Squamous 
Terminology (LAST) Standardization Project for HPV-associated lesions applied the term 
high grade squamous intraepithelial lesion (HSIL) to encompass high grade dysplasia [8].  
Therefore, for the purpose of this study, the term vulvar HSIL will be used, which 
encompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to encompass what 
was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [9]. Over time, typically years, vulvar HSIL can progress to invasive 
cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group and median 
13.8 years in another group [10], and from VIN3 patients, mean = 2.5 years, range: 4 – 
216 months [11].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity against 
vulvar HSIL and have not achieved universal uptake, leaving a population of susceptible 
and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to visual 
inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for vulvar 
HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, often 
requiring multiple, repeat treatments. Progression to vulvar cancer following current vulvar 
HSIL treatments can also occur within 1 year of treatment and for up to 20 years post 
treatment. The current treatment options for vulvar HSIL are surgical excision, laser 
ablation, and off-label medical therapy. The rate of HPV-associated vulvar HSIL 
recurrence after surgical treatment is high; post-treatment recurrence rates exceed 30-
50% with all currently available treatment regimens [12, 13].   
Wide local excision is the ‘preferred initial intervention’ by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation.  Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues with 
body image and sexual dysfunction.  Medical therapies have been investigated as a 
means to avoid these negative outcomes.  Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food and 
Drug Administration for this indication.  Inconsistent treatment efficacy results have been 
shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 
of recurrence is slightly higher compared to wide local excision. Laser treatment of vulvar 
HSIL requires destruction of cells through the entire thickness of the epithelium including 
hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation should 


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extend through the dermis. Post-treatment recurrence rates exceed 30% (for all treatment 
regimens), and is higher with positive excision margins [14]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low rate 
of spontaneous resolution.  According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is suspected 
(even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is wide local 
excision (i.e. surgery) [15].  When occult invasion is not a concern, vulvar HSIL can be 
treated with excision, laser ablation, or topical imiquimod as an off-label medical therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [14].  Therefore, many patients have a fear 
of recurrence and progression to cancer [16].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks.  
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid use of toilet paper and to rather rinse with warm water.  
During recovery, common effects include pain in urinating and wiping, soreness, difficulty 
sitting, and feeling tired [17]. In the first week after hospital discharge, common patient-
reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [18].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-being 
[17].  The symptoms and signs of vulvar HSIL can be moderate to severe and include 
painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating [18]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than age-
matched healthy women [19]. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor’s office all the time [17]. 
 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid HPV-associated vulvar HSIL 
and subsequent vulvar cancer. The US-licensed prophylactic HPV vaccines are indicated 
for girls and women ages 9 through 26 years for Gardasil® and Gardasil®9 (Merck & Co. 
Inc.), and ages 9 through 25 years for Cervarix® (GlaxoSmithKline). The early portions of 


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these age ranges are generally before sexual debut and thus can allow immunologic 
protection against the anticipated earliest normal exposures to HPV infection. HPV 
prophylactic vaccination is highly effective and safe, and routine vaccination is 
recommended for females in the United States starting at age 11 or 12 years [20]. 
However, the prophylactic vaccines have no therapeutic effect upon existing HPV infection 
or existing HPV-related intraepithelial neoplasia [21]). 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan is used in this study to address the risk of a potential delay 
in treatment of vulvar HSIL.  The feasibility of this approach was demonstrated in the 
Phase 2b study of cervical HSIL.  Given that vulvar disease progresses slowly to vulvar 
cancer if untreated, the proposed enhanced monitoring plan is expected to maintain the 
safety of trial subjects for this study.  First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study investigators.  Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, by 
two independent expert pathologists (pathology adjudication committee). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
[22], is specifically excluded from study entry.  By contrast, HPV-associated vulvar HSIL 
does not progress rapidly, typically taking years to manifest and progress, making 
enhanced monitoring feasible.   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.14).  Colposcopy will also be 
done at baseline and during the study given that concurrent disease in the lower genital 
tract can occur.   A Data Safety Monitoring Board will be utilized to review subject safety 
data and advise on any study-level safety concerns. Investigators always have the option 
of performing ad hoc vulvar biopsies to rule out disease progression.  Additional treatment 
(e.g., additional excision, ablation, or medical therapy) may be carried out, if deemed 
necessary according to Investigator judgement. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA® device represent an integrated investigational 
product designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, 
CIN3) via an immune response directed against HPV-16/18.  Further information about 
VGX-3100 is provided in the Investigator’s Brochure. 
 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA® in vivo electroporation (EP) device. EP is 
a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [23, 24]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 


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10 to 100 fold [25, 26]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as shown 
by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [27].  
This study will use the CELLECTRA® 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no significant 
safety issues identified.  Further information about the CELLECTRA® 2000 device can be 
found in the Investigator’s Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device.  Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 250 
mg of the cream, equivalent to 12.5 mg of imiquimod.  The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod.  The overall aim is to determine if treatment with VGX-3100 could allow women 
with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of concept that 
VGX-3100 can induce resolution of both HPV-associated dysplastic lesions and the 
underlying HPV 16/18 infection was shown in a Phase 2b study of cervical intraepithelial 
neoplasia (CIN).  The similar underlying pathogenic mechanisms between cervical and 
vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could be a non-
surgical therapeutic option for the treatment of vulvar HSIL, which is a significantly under 
met medical condition.  A VGX-3100 with imiquimod-administration arm is also included, 
given the prevalent use of imiquimod as a topical medical treatment of vulvar lesions, to 
investigate if a more robust immune response is achieved with VGX-3100, to potentially 
increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 
responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [28].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Imiquimod may be able to be used synergistically with 
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Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG).  Published regimens include three times weekly 
application to affected areas for 12 – 20 weeks, with colposcopic assessment at 4-6 week 
intervals during treatment [15].  
The current study will include an imiquimod arm with VGX-3100, to evaluate 
histopathologic regression of vulvar HSIL and virologic clearance of HPV-16/18, compared 
to the current body of knowledge in imiquimod alone.     
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 
reported at the application site [29].  The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity.  In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure including 
anesthesia, post-operative bleeding, infection, or damage to surrounding structures such 
as the clitoris, urethra, or anus. The other potential benefit is that the response to VGX-
3100 is systemic and may clear the underlying HPV infection, which is the root cause of 
vulvar HSIL.  Consequently, there is the potential to reduce the risk of recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL  associated with HPV-16 and/or HPV-18 (HPV-16/18), 
will result in a higher percentage of women with regression of HSIL of the vulva based on 
histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from 
vulvar tissue compared with historical control. 
 
 
 


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2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional treatment).  
2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL11 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/1812 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression13 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
                                                     
11 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
12 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
13 Progression is defined as advancement to carcinoma according to the Pathology Adjudication Committee by 
histology. 


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6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
48, 74 and 96 compared to baseline14. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion size of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).  
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone 
or in combination with imiquimod,  post dose 
3, post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes 
at baseline and Weeks 15, 27, 48, 74 and 
96 visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 
                                                     
14 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe 
the 
efficacy 
of 
VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects without a 
complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
74 and/or Week 96 compared to baseline15. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in lesion 
area of 0-25%), partial lesion area resolution 
(>25% and <100% reduction), and complete 
lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6  doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, 
as 
measured 
by 
virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 infiltrating 
cells16.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the 
vulva   
5. Proportion of subjects who have cleared HPV-
16/18 on specimens from other anatomic 
locations 
without 
surgical 
intervention 
(inclusive of cervix, oropharynx, vagina and 
intra-anus) at Week  48 
6. Characterize 
HLA 
haplotypes 
and 
the 
correlation with efficacy 
6.  Proportion of subjects with regression of HSIL 
on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Assess skin-to-muscle, skin-to-bone, and 
muscle thicknesses via ultrasound measure 
of deltoid (or quadriceps if applicable) and the 
correlation of needle depth into muscle with 
efficacy. 
7. Ultrasound-measured skin-to-muscle, skin-
to-bone, and muscle thicknesses.  
8. Describe patient reported outcomes for 
subjects treated with VGX-3100 and VGX-
3100 with imiquimod 
8. A patient-reported outcome (PRO) endpoint 
may be obtained prior to first dose (Day 0), 
following each of the first doses, and at 
Weeks 74, and 96. 
                                                     
15 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
16 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA® 2000 alone or in combination with 
imiquimod in adult women with histologically confirmed vulvar HSIL associated with HPV-
16/18. Approximately 36 subjects will be enrolled.  Twenty-four subjects will receive VGX-
3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at 
screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category 
(<45 years vs. ≥45 years). 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be provided and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with 
vulvar Neoplasia) and two additional PRO questions assessing quality of life after surgery 
or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of 
a 4 mm vulvar punch biopsy/biopsies with lesion remaining, and photographs of the 
acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, the 
two regions of most advanced and severe disease, as judged by the investigator, should 
be chosen for biopsy using vulvoscopy and documented using standardized high 
resolution photography with a digital single-lens reflex (SLR) camera on the case report 
form. Biopsy slides or tissue will be sent to a Pathology Adjudication Committee (PAC) for 
evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must assign 
the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a 
vulvar specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation 
in the study. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 mg 
of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-16/18 
status and all other eligibility criteria but no more than 10 weeks following collection of the 
subject’s biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid, preferred site, 
or anterolateral quadriceps, alternate site) followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes.  The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  


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Subjects with HSIL at Week 74, who have a reduction in lesion size or no increase in 
lesion size from baseline (Subgroups C or D), may receive a sixth dose of VGX-3100 
administered IM with EP at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgement of the Investigator.  All 
subjects will complete the study at Week 100. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will 
apply imiquimod 5% cream to the vulvar lesion beginning in the evening on Day 0, and 
will continue to apply treatment three times per week for 20 weeks (inclusive of 
administration in the evening of VGX-3100 dosing).  Subjects unable to tolerate imiquimod 
treatment may reduce their dosing frequency, and will document their use on the 
imiquimod dosing diary provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital imaging, vulvar lesion(s) will also be quantitatively 
measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 
mm in length. Visible lesion must remain after screening biopsy to ensure measurement 
on study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3 for Minimally Required Biopsy 
Procedures). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Figure 2, Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and 
biopsy adjacent to the site of initial biopsy.     
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size 
or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the Investigator 
has the option to give the subject a 5th dose of VGX-3100 at Week 52, and the subject will 
continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator 
may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3). If after evaluation of biopsy tissue by 
the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to 
Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no increase in lesion size from 
baseline (Subgroups C or D), the Investigator has the option to give the subject a 6th dose 


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of VGX-3100 at Week 78, and the subject will continue on study with vulvoscopy and 
biopsy at Week 96. Alternatively, the Investigator may choose to treat the subject with 
surgical or standard treatment, and the subject will continue on study without further 
biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3). If there is no vulvar HSIL (Subgroups 
A or B), no further procedures are required. If after evaluation of biopsy tissue by the PAC 
there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), the subject 
will receive surgical or other standard treatment. 
In the event of worsening disease (ie, Subgroup E - any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per 
the Investigator’s judgement and will continue on study through Week 100 with 
vulvoscopy, but without further biopsy.  For a finding of carcinoma, subjects will receive 
surgical treatment, and be discontinued from study treatment.  The event will be reported 
as an SAE per section 7.1.4. If wide excision is required, the sample obtained will be sent 
to the PAC for evaluation.  
 
Table 3:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original biopsy site within the boundaries of the original 
lesion; 
Acetowhite Lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original site within the boundaries of the original lesion; 
biopsy of lesion must include suspected area of most 
advanced disease  
Multiple acetowhite lesions 
Vulvar punch biopsies and imaging; biopsy should be 
conducted of the same two lesions as study entry but 
adjacent to the original site within the boundaries of the 
original lesion; biopsies must include area of most advanced 
and severe disease as determined at screening  
 
  
 DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 4) take into account both histopathologic 
regression of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since 
HPV persistence is an important factor in the clinical progression of HSIL.  
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive non-study related medication for treatment of VIN lesions.  A treatment non-
responder is a subject with histologic evidence of vulvar HSIL, adenocarcinoma-in-situ, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, 


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or a subject who received non-study related medications for treatment of VIN lesions. Any 
case of histologically confirmed progression is considered a non-responder. Progression 
is defined as advancement to carcinoma by histology. 
Table 4: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSILa  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive non-study 
related medication for treatment of VIN 
lesions. 
 
Subject with histologic evidence of vulvar HSIL, 
Adenocarcinoma-in-situ (AIS), vulvar carcinoma at 
evaluation 
  
AND/OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related 
medication for treatment of VIN lesions 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight.  
The DSMB will meet quarterly to review safety data. The DSMB will be charged with 
advising the Sponsor if there appears to be a safety issue. No formal interim analysis is 
planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, Principal Investigator for the trial, and the DSMB. 


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 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately until 
a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) and at 
Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and at Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize HPV infection at Screening, Week 48, 74 
and 96. Cervical samples, oropharyngeal (OP) rinse samples, vaginal, and intra-anal 
tissue swab samples will be obtained to characterize HPV infection in samples from study 
subjects taken at Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and 
intra-anal only) and at Weeks 27, 48, 74 and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then unstained slides and/or the relevant paraffin blocks will be collected for 
immunohistochemistry (IHC) and in situ hybridization (ISH) for the presence of  
HPV-16/18. Whenever possible, these studies will be performed on tissue sections from 
the diagnostic biopsy (pre-dose) and from tissue obtained post-dose (Week 48, 74 and 
96).  
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. Vulvar tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
5. Histologic evidence of vulvar HSIL as confirmed by PAC at screening; 
6. Must be judged by investigator to be an appropriate candidate for the protocol-specified 


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procedure (i.e. excision or biopsy) required at Week 48; 
7. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 
adequate size to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months 
or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 12 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method 
with failure rate of less than 1% per year when used consistently and correctly from 
screening until 6 months following the last dose of investigational product. Acceptable 
methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into 
the study, and this male is the sole partner for that subject. 
10. Normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment 
for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. More than 10 weeks have elapsed between date of initial tissue biopsy for screening 
and day of first dose (i.e. Day 0); 
7. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
8. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after 
biopsy; 


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9. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension 
high into cervical canal at screening; 
10. History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, 
or insufficient for diagnosis (ECC is not performed as part of study screening) and 
did not receive definitive treatment; 
11. Treatment for genital warts within 4 weeks prior to screening; 
12. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 
4 weeks prior to screening; 
13. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
15. Presence of any abnormal clinical laboratory values greater than Grade 1 per Common 
Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or 
less than Grade 1 but deemed clinically significant by the investigator; 
16. Immunosuppression as a result of underlying illness or treatment including: 
a. History of or positive serologic test for HIV at screening;  
b. Primary immunodeficiencies; 
c. Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d. Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e.  History of solid organ or bone marrow transplantation; 
f. 
 Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
17. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
18. Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of 
Day 0; 
20. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the investigator; 
21. Current or history of clinically significant, medically unstable disease which, in the 
judgement of the investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the study 
results (e.g. chronic renal failure, angina, myocardial ischemia or infarction, class 3 or 
higher congestive heart failure, cardiomyopathy, or clinically significant arrhythmias); 
22. Malignancy or treatment for malignancy within 2 years of screening, with the exception 
of superficial skin cancers that only require local excision; 


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23. Acute or chronic bleeding or clotting disorder that would contraindicate IM injections 
or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
24. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
25. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 
mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
27. Prior major surgery within 4 weeks of Day 0; 
28. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
29. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
30. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment 
site; 
31. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) 
that is located in ipsilateral deltoid injection site (unless deemed acceptable by a 
cardiologist); 
32. Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
33. Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
34. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
35. Active military service personnel; 
36. Study-related staff or family members of study-related staff; 
37. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study treatment/EP 
but will be encouraged to continue follow-up safety assessment through study discharge 
and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that subject. 


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 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw from 
study participation at any time. A subject may be withdrawn at any time at the discretion 
of the investigator for any maternal obstetrical or medical complications after consultation 
with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report form 
(eCRF) and the subject’s source document 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule for 
follow-up and treatment of VIN, and ascertain whether or not the subject wishes to and/or 
should continue in the study based on previous noncompliance. In cases where the 
subject does not return for the rescheduled visit or cannot be reached to reschedule the 
missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls to the subject should be made and if that fails, then a certified letter is sent 
to the subject’s last known mailing address) so that they can be considered withdrawn 
from the study for disposition purposes. These contact attempts should be documented in 
the subject’s medical record. Should the subject continue to be unreachable, then and 
only then will she be considered to have withdrawn from the study with a primary reason 
of “Lost to Follow-up.” For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). At 
a minimum, the investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100).  A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The investigator or study coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the study 
or is withdrawn from the study prior to study completion, all applicable activities scheduled 
for the final study visit should be performed at the time of discontinuation. The investigator 
will make every effort to have all scheduled immune assessment blood samples collected 
as indicated in the Schedule of Events in the synopsis, Table 1. Any AEs and/or SAEs 
present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in section 7.1 – Safety Parameters. 


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 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 
 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs regardless 
of relation to study drug. 
 
 Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical 
need to withdraw. If the subject gave a reason for withdrawal, it must be recorded 
on the eCRF. This reason does not allow for further data collection and should not 
be selected if follow-up data collection of this subject is anticipated by the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation should 
be discussed with the Sponsor’s Medical Monitor prior to discontinuation of study 
treatments or study withdrawal. 
 
 Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter sent 
by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon®) technology.  The VGX-
3100 formulation to be used in this study is described in Table 5 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum.  There are 24 single-use packets of imiquimod in one box.  The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older.  Although it is not approved by the US Food 
and Drug Administration for the treatment of vulvar HSIL, imiquimod is currently 


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recommended as a non-surgical, off-label treatment option for vulvar dysplasia by the 
American College of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 5. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  Imiquimod Cream, 5% will have both the original 
manufacturer's label on individual packets and the back of the carton, and an 
investigational label on the front of the carton.  The labels will contain, at minimum, the 
information shown in Figure 6.   


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Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  
 
Figure 6. Example labels for imiquimod 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Opthalmic Use. 
Keep out of reach of children.  This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer’s instructions. Avoid freezing.    


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5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. The 
product must be used within 4 hours of removal from the refrigerator. All material removed 
from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 
 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations.  Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks.  Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water.  Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. 
Subjects will be provided with an imiquimod dosing diary to record their use and side 
effects during the 20 week treatment period.  The imiquimod dosing diary should be 
brought to the clinic with the used imiquimod box, at Week 4, 12, and 24 for review with 
study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 


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5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to 
be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 IP can only 
be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer.  The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, adverse effects, interfering substances 
or devices, warnings, and precautions.  Each CELLECTRA® 2000 Pulse Generator has a 
unique serial number, and each CELLECTRA® 2000 Applicator has a unique serial 
number. Each CELLECTRA® 2000 Array has a Lot Number, Manufacture Date, and 
Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local authorities 
to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to successfully 
completing device training from sponsor personnel. Individuals whose credentials do not 
meet the relevant local requirements may perform the treatment procedure under both of 
the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or 
an approved Sub-Investigator who has already been trained by the sponsor’s 
personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and 
approved by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its 
designee. 


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5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 7 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers (as 
applicable) is included at the time of manufacture and may vary from these examples. The 
information found on the actual device labels should always be used to manage, track and 
record investigational product accountability during study conduct. 
 
 
 
 
 
 
 
 


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Table 7. Example Labels for the CELLECTRA® 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA® 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA® 
2000 5P  
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA® IM 
Array 
 
REF: M01-
002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. This 
includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA® 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA® 2000 IM Applicator is intended to be used multiple times on the same 
subject and then disposed after final use in accordance with accepted medical practice 
and any applicable local, state, and federal laws and regulations. Once the IM applicator 
is assigned to a subject, it may NOT be used on another subject. The used sterile 
disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.10 
RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the responsible Study 
Monitor. 
If product is to be destroyed on site, it is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted 


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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected 
prior to consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the samples 
sent to the central pathology lab for review by the PAC to assess eligibility.  There will be 
a maximum allowable window of 10 weeks from the date of collection of the qualifying 
biopsy sample(s) (i.e. slides/samples(s) reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be obtained 
within a reasonable timeframe, an additional biopsy sample should be collected during 
screening following the consent of the subject. The 10 week screening window begins 
upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets other 
eligibility criteria). Subjects whose vulvar specimens also test positive for other HPV 
genotypes are not excluded as long as they have a positive result for HPV-16 and/or HPV-
18.  
The assessments during the screening period will determine the subjects’ eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, which 
must be performed within 30 days prior to Day 0. All screening assessment values must 
be reviewed prior to study treatment. 
 
Signed informed consent 
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG (within 30 days prior to Day 0) 
 
Baseline laboratory evaluations (includes complete blood count [CBC), serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine aminotransferase 
[ALT], creatine phosphokinase [CPK], and urinalysis) to be performed within 30 days 
prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be performed 
once) 
 
Cervical cytology and ThinPrep™ for cervical HPV type 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical areas 
should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photographs of the vulva and the associated lesion must be collected prior to 
and after biopsy at screening.  
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC. If residual vulvar 
tissue is available from entry either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 ULTRASOUND MEASURE OF SKIN-TO-MUSCLE AND RELATED 
THICKNESSES 
Subjects who consent to participate in the ultrasound sub-study will have both right and 
left deltoids and one (either) quadriceps measured. The precise site of the ultrasound 


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within the deltoid and quadriceps will align with where EP is administered. The ultrasound 
measure will be performed at each of those three body sites in two manners: with no 
pressure applied by the technician through the probe to the tissue and separately, and 
with EP-like pressure applied by the technician through the probe to the tissue and 
separately. The “EP-like pressure” is defined as a firm push against the skin resulting in 
puckering of the skin by the ultrasound probe. The rationale for the differing pressures is 
to determine if and how much the thickness being measured will change. For each body 
site and pressure, three triplicate measures will be performed.  The type and number of 
ultrasound images and replicates taken for each body site for each patient would be as 
follows: 
 
   Table 8. Type and Number of Ultrasound Images, by Muscle and Probe Pressure 
 
Right 
Deltoid
Left 
Deltoid
Either 
Quadricep
s 
Total 
No pressure of the ultrasound probe on tissue 
site 
 
3 
 
3 
 
3 
 
9 
EP-like pressure of the ultrasound probe on 
tissue site 
 
3 
 
3 
 
3 
 
9 
Total number of replicate measures 
6 
6 
6 
18 
 
Ultrasound measures will be performed during the screening period, i.e. before enrollment 
and hence before any administrations of VGX-3100, and will thus include both enrolled 
and screen-failed subjects.   
Locally stored images of each ultrasound measure will be measured via digitizer or simple 
scale to obtain the following cross-sectional distances, for each replicate image: 
- 
Skin to muscle distance (i.e. depth of the beginning of the muscle) = “S-M” 
- 
Skin to bone distance (i.e. depth of the beginning of the bone) = “S-B” 
- 
Muscle thickness (i.e. distance of the beginning to end of the muscle) = “MT”, a 
calculated field with the following equation: 
 
  
MT = “S-B” - “S-M” 
The ultrasound measures will be performed on all screened patients in this trial, thus 
including both enrolled patients and ultimately screen-failed patients in these sub-
analyses.    
 
Last, each patient would be asked for their handedness, i.e. whether they are they right-
handed, left-handed, or ambidextrous.   
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment.  Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 


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 
Review of concomitant medications and adverse events 
 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP rinse, vaginal and intra-anal swabs 
 
Baseline vulvoscopy  
 
Vulvar lesion photography 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing diary (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 4 
The following study evaluations will be performed at Week 4 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing diary and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 


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 
Vulvoscopy  
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression. 
 
Vulvar lesion photography  
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after study 
treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing diary (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 
The following study evaluations will be performed at Week 12 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing diary and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 and Week 94 unless PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression 


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 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing diary to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 
The following study evaluations will be performed at Week 15 (± 7 days): 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay 
 WEEK 24 
The following study evaluations will be performed at Week 24 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing diary and usage (accountability of returned product) for 
subjects in the imiquimod arm  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 


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 WEEK 27 
The following study evaluations will be performed at Week 27 (± 7 days): 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 or Week 96 unless the PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression.  
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 WEEK 48 
The following study evaluations will be performed at Week 48 (± 7 days): 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 


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 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected. 
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
 If residual vulvar tissue is available from entry and/or Week 48 
specimen(s) either paraffin blocks or unstained slides should be sent to 
the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 
Patient Reported Outcomes 
 WEEK 52  
Subjects will have a Week 52 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 74 
The following study evaluations will be performed at Week 74 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 


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 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 78 
Subjects will have a Week 78 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 
 WEEK 96 
The following study evaluations will be performed at Week 96 (± 14 days): 
 
Review of concomitant medications and adverse events 


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 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical 
areas should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 100 
The following study evaluations will be performed at Week 100 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 


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6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, study 
objectives, potential benefits and risks, discomforts/inconveniences, and the subject’s 
rights and responsibilities. The subject is then requested to sign and date the ICF. A copy 
of the signed informed consent documentation must be provided to the subject. The 
qualified study personnel will document the process of obtaining informed consent within 
the source record. Signed ICFs are maintained in the subject’s source records and must 
be accessible for verification at any time. 
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all study-related procedures. SIDs are a combination of a 
up to two alpha letters study code, two alpha letter Country code, two digit site number, 
plus 3-digit subject number starting with 001 (e.g., VNUS01001). Once assigned, SIDs 
cannot be reused for any reason. Information regarding the SID and screen date must be 
documented on a Screening log/system and in the Interactive Response Technology 
(IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated allocation 
schedule.  
 SAFETY EVALUATIONS 
6.3.3.1 PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100).  It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems.   
A targeted physical assessment will be performed at other visits as determined by 
the investigator or directed per subject complaints. 
6.3.3.2 VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 


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 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.3.3 WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.3.4 MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be obtained 
at screening. All relevant (as judged by the investigator) past and present 
conditions, as well as prior surgical procedures will be recorded for the main body 
systems.  
6.3.3.5 SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, history 
of prior cervical dysplasia, and pregnancy history will be obtained at Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to document 
any change from screening. 
6.3.3.6 LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 


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6.3.3.7 PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.3.8 ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has been 
in a supine position for 10 to 15 minutes. The ECG should include measurements 
of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, Twave as 
well as an investigator assessment of whether the ECG is normal or abnormal 
(automated interpretations of ECG should not be used). Abnormal ECGs should 
be interpreted as “clinically significant (CS)” or “not clinically significant (NCS)” by 
the investigator. 
6.3.3.9 POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after the 
study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.3.10 
IMIQUIMOD DOSING DIARY 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the dosing diary during the 20 week treatment period. Subjects will 
record their symptoms, the severity of their symptoms, and the duration of 
symptoms and return the diary at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA® 2000. Study treatment plus EP must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is implanted 


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metal within the same limb. Any device implanted in the chest (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal) excludes the use of the deltoid 
muscle on the same side of the body. The timing of the initial dose will be designated Day 
0 with the subsequent doses scheduled for administration at Weeks 4, 12, 24, and at 
Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 RISKS OF TREATMENT PROCEDURES TO VGX-3100 
Table 9 summarizes reported AEs and potential risks of VGX-3100. 
Table 9. Summary of Reported Adverse Events and Potential Risks of VGX-3100 Delivered 
IM EP with CELLECTRA® 2000 
Very Common  
 
Mild to moderate injection site pain or tenderness 
 
Malaise/fatigue, myalgia, or headache in the first few days following 
injection 
 
Upper respiratory tract infection 
 
Brief muscle contractions which may be uncomfortable 
 
Nausea 
Common  
 
Arthralgia 
 
Injection site reactions such as erythema, pruritus, swelling, 
hematoma 
 
Anxiety related to the administration procedure 
Less Common  
 
Severe injection site pain or tenderness 
 
Vasovagal 
reaction/lightheadedness/dizziness 
related 
to 
the 
administration procedure 
 
Temporary bleeding at the injection site 
 
Rash following administration  
Uncommon or 
rare  
 
Injection 
site 
reactions 
such 
as 
laceration, 
induration, 
bruising/ecchymosis, or scab  
 
Infection at the injection site  
 
Muscle damage resulting in transient changes in creatine 
phosphokinase  
 
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  
 
Chills, flu-like syndrome 
 
Autoimmune disease 
 
Electrical injury1 
 
Disruption of function of implanted electronic medical devices (if 
CELLECTRA®  2000 device is not used per User Manual)1 
 
Exacerbation of unstable cardiac disease1 
 
Effects on the fetus and on pregnancy 
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6.4.1.2 RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
In controlled clinical trials for genital warts, the most frequently reported adverse reactions 
were local skin and application site reactions.  Table 10 summarizes local skin reactions 
assessed by the Investigator in the treatment area of females taking imiquimod cream, 
5% cream for external genital warts [30].   
 
Table 10.  Summary of Reported Adverse Events in 114 females taking imiquimod cream, 
5% for external genital warts 
 
 
Imiquimod Cream, 5% 
N =114 
Erythema 
74 (65%) 
Erosion 
35 (31%) 
Excoriation/Flaking 
21 (18% 
Edema 
20 (18%) 
Scabbing 
4 (4%) 
Induration 
6 (5%) 
Ulceration 
9 (8%) 
Vesicles 
3 (3%) 
*All Grades: Mild, Moderate, or Severe 
 
Table 11 summarizes adverse reactions judged to be possibly or probably related to 
Imiquimod Cream, 5% and reported by more than 1% of subjects [30]. 
 
Table 11. Possibly or probably related Adverse Reactions to Imiquimod cream in > 1% of 
subjects 
Location of reaction 
Adverse reaction 
Application Site Disorders 
Burning, hypopigmentation, irritation, itching, pain, 
rash, sensitivity, soreness, stinging, tenderness 
Remote site reactions 
Bleeding, burning, itching, pain, tenderness, tinea 
cruris 
Body as a Whole 
Fatigue, fever, influenza-like symptoms 
Central and Peripheral Nervous 
System Disorders 
Headache 
Gastro-Intestinal System Disorders 
Diarrhea 
Musculo-Skeletal System Disorders 
Myalgia 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 
approximately 1.5 cm diameter amount will be applied with occlusion to the site of injection 
~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who receive 
a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours after 
receiving medication and should have arranged transportation to depart the study site. 
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Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a 
mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.3.6.  
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 minutes 
after each study treatment. Subjects will be advised to record local and systemic AEs for 
7 days after each study treatment on a PD which will be reviewed with study personnel at 
8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject’s CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be 
instructed to use the following grading scale: 
 
Table 12. 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 
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September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
*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 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes (PRO) 
instruments will be provided. The following PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [31]. SF-36v2™ will be administered at the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [32, 33] and will be 
administered with EQ-5D-5L as described below. 
3. WOMAN-PRO (WOMen with vulvAr Neoplasia): for measure of outcomes related to 
vulvar HSIL [18]. 
WOMAN-PRO and EQ-5D-5L will be administered together at the following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 


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 
Week 96  
 
Week 100 
Administration of PRO instruments will be performed according to the validated procedure 
and guidelines of each respective instrument, except for some assessments for 
exploratory analyses. Additional instructions will be provided separately.    
4. Additional Global PRO Questions – regarding quality of life after surgery or biopsy.  
These two questions will be administered at Week 48 only. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity 
may occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-
γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
6.10 
TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses 
have been rendered, then unstained slides and/or the relevant paraffin blocks may be 
collected for immunohistochemistry (IHC).  Assessment of markers may include, but are 
not limited to, CD8+ and FoxP3+ infiltrating cells as well as assessment of cell death via 
Cleaved Caspase 3 assessment. Additional assessments may include visualization of 
Granulysin, Perforin, CD137, CD103 and PD-L1 in cervical tissue as sample allows.  
Markers listed here may change as new relevant information becomes available. 
6.11 
HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 


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6.12 
VULVAR HPV TESTING 
A 4 mm vulvar punch biopsy sample will be obtained at Screening, Weeks 48, 74, and 96, 
and will be sent to a central laboratory for HPV genotyping by PCR.  In the case of 
multifocal disease, a 4 mm vulvar biopsy will be obtained from two regions of most 
advanced and severe disease as judged by the investigator.  The subject will be requested 
to abstain from sexual activity and refrain from use of douching vulvar biopsy samples to 
eliminate potential interference with the results of HPV testing. 
6.13 
COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Screening and at Week 96 for all subjects.  
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep™ test kits at Screening, Weeks 27, 48, 74 
and 96, and read in a central laboratory. HPV PCR will be performed on the ThinPrep™ 
specimen. At each of these visits, menstrual cycle status & recent history will be collected 
via self-report.  If the Pap smear result suggests progression to cancer the investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples to eliminate potential interference with the results of HPV testing. 
6.14 
VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL confirmed 
by the PAC.  Subjects will undergo vulvoscopy to identify the lesion(s). Digital photographs 
of the vulva will be captured after application of acetic acid to document the clinical 
findings.  If a biopsy or surgical excision is performed, images of the vulva should be 
collected before and after the procedure.  Each site will be instructed on 1) the technique 
for capturing the proper images using a standard approach, and 2) the process for 
uploading the images to a secure server.   
In the case of multifocal disease, the two lesions which appears to have the highest 
likelihood according to the investigator of most advanced disease and which is of 
adequate size to ensure that a visible lesion remains after punch biopsy should be chosen 
for vulvar biopsy and documented using photography.     
Interval vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96.  An 
unscheduled biopsy may be performed at the discretion of the investigator if there is 
suspicion of disease progression. Guidelines for managing the findings of unscheduled 
biopsies for suspected disease progression are described in Table 13.  Consult the 
Medical Monitor for any planned departures from these guidelines. 
 


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Table 13:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 
Subject safety is paramount in this study. Therefore, if at any time the investigator may 
suspect disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over the 
default “Schedule of Events”, Table 1. 
6.15 
CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. Medical procedures performed within 8 weeks prior to 
screening biopsy date of eligible subjects that do not affect subject’s eligibility for 
participation and during the study (including over the counter or herbal), will be recorded 
on the CRFs. This information will be obtained from the subject and abstracted from any 
available medical records. The indication for the medication, dose, and dose regimen will 
be documented. Medication that is considered necessary for the subject’s safety and well-
being may be given at the discretion of the investigator and recorded in the appropriate 
sections of the CRF. 
6.16 
RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day 
of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic corticosteroids 
are allowed) 
 
Disease 
modifying 
doses 
of 
anti-rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs 
such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at screening and 
throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
investigator and/or other study personnel. 


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Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1).  Lapses in contraceptive use should be reported to investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples.  
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and unsolicited 
AEs will be monitored and reported on an AE CRF, including the event’s seriousness, 
severity, action taken, and relationship to investigational product(s). AEs should be 
followed until resolution or stable and the outcome will be documented on the appropriate 
CRF. All AEs should be recorded in standard medical terminology rather than the subject’s 
own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.9 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the duration 
of the study, including the follow-up off study drug period will be recorded as an 
AE. 
 
Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit that do not worsen. 
 
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions). 


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 
Overdose without clinical sequelae. 
 
Any medical condition or clinically significant laboratory abnormality with an onset 
date before the informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
 SERIOUS ADVERSE EVENTS 
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; 
 
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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 2) 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, 3) the 
development of drug dependency or drug abuse or 4) the development of a 
malignancy; 
 
Is medically significant or requires intervention to prevent one or other of the outcomes 
listed above. 
 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 that the subject has been formally admitted to a 
hospital for medical reasons, for any length of time. This may or may not be 


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overnight. It does not include presentation and care within an emergency 
department nor does it include full day or overnight stays in observation status. 
 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 9.5. 
 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE.  For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of adenocarcinoma-in-
situ or adenocarcinoma should also be reported as an SAE.  In both instances the 
condition for SAE reporting should be categorized as a medically important event unless 
another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal 
product related to any dose, for which a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility; i.e., there is evidence to suggest 
a causal relationship between the product and the adverse event. An unexpected ADR is 
one, the nature or severity of which is not consistent with the applicable product 
information (investigator’s brochure, protocol, and user manual). Reports that add 
significant information on specificity or severity of a known, already documented SAE 
constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator's Brochure or protocol would be considered "unexpected.” 
Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent 
new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a 
serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the SUSAR 
will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating investigators of information that might materially influence the 
benefit-risk assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. Examples of such information 
include a clinically important increase in the rate of occurrence of a serious expected 
adverse event, the identification of a significant hazard to the subject population, or a 
major safety finding from a study conducted in animals. 


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 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
investigator within 24 hours. Sponsor will assess each device related SAE to determine if 
anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be assessed 
as not related to the IP and/or the investigational device. Because the investigator is 
knowledgeable about the subject (e.g., medical history, concomitant medications), 
administers the IP, and monitors the subject’s response to the IP, the investigator is 
responsible for reporting adverse events and judging the relationship between the 
administration of the IP and device and a subsequent AE. 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 IP delivered by EP 
and determine whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation of 
any potential alternative causes to determine whether or not an adverse event is 
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accordingly. Causality should be assessed by the investigator as “yes, related” or “no, 
unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications known 
to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory 
or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition of an AE (or SAE) as described in Section 7.1. If the laboratory abnormality 
is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory 
result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency from 
the baseline condition and meets one of the following criteria will be recorded as an AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the investigator as clinically significant 
 POST-TRIAL 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 or termination visit and the event is deemed by the investigator to be related 
to the study treatment, he/she should promptly document and report the event to the study 
team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be excluded 


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from participation in the study. Should a subject become pregnant after enrolling in the 
study, she will not be given any further study treatments. A Pregnancy Form will be 
completed by the site personnel and submitted to the sponsor within 24 hours after 
learning of the pregnancy.  Site personnel will submit the Pregnancy Form to the Sponsor 
as described in Section 7.4.2. 
The investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject’s permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results will 
be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be performed. 
Investigators should use clinical judgment regarding subsequent study-related blood 
collection based on the presence or absence of anemia in each subject. Subjects who are 
not withdrawn will continue to be followed for safety assessments to study discharge per 
protocol.  
All pregnancies that occur from the time of first study treatment through the follow up visits 
must be reported. The investigator will monitor the subject and follow the outcome of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the 
outcome will be reported directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when informed 
consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading 
question such as ‘How have you been feeling since your last visit?’ is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator 
to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the 
investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
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 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented  
 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100 delivered with CELLECTRA® 2000 that require expedited communication from the 
site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration recorded 
≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
 
Grade 3 or greater laboratory abnormalities 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and Principal Investigator and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
Treatment;  
 
Three or more subjects in the same treatment arm discontinue due to an AE related 
to the Study Treatment; 
 
Any subject experiences an SAE (or potentially life threatening AE or Grade 4 AE) or 
death assessed as related to Study Treatment; 
 
Two or more subjects within a treatment arm experience the same or similar grade 3 
or 4 adverse event, assessed as related to Study Treatment;  
 
Four or more subjects across all treatment arms experience the same or similar grade 
3 or 4 adverse event, assessed as related to Study Treatment; 
 
Any report of anaphylaxis assessed as related to Study Treatment. 
Upon conclusion, the sponsor or designee will notify all investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 


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7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), whether 
volunteered by the subject, discovered by investigator or study staff questioning, or 
detected through physical examination, laboratory test or other means, will be collected 
and recorded in the subject’s source documents and followed as appropriate. 
TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised of 
the period following the signing of the informed consent form until the end of the study. 
Each AE will be assessed to determine whether it meets seriousness criteria. If the AE is 
considered serious, the investigator should record this event in the EDC system and report 
the event to the Sponsor within 24 hours of becoming aware of the event. The investigator 
may also directly report this event to the Ethics Committee according to its standard 
operating procedures. Expectedness of SAEs will be determined by the Sponsor using 
reference safety information specified in the Investigator’s Brochure and protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.6 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.7 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the Institutional Review Board (IRB)/Ethics Committee (EC) as 
soon as is practical, of serious events in writing where this is required by local regulatory 
authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an investigator becomes aware 
of an SAE that is suspected by the investigator to be related to the study drug, the event 
will be reported to the Sponsor or its designee. If the investigator becomes aware of an 
SAE in a study subject after the last scheduled follow-up visit, and considers the event 
related to prior Study Treatment, the investigator will report it to the Sponsor or the 
appropriate designee. 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
, M.D., Ph.D. 
EMAIL:  safety.inovio@apcerls.com 
  
SAFETY FAX:
 
SAFETY PHONE: 
 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address as 
indicated above.  Any SAE supporting documents provided by facsimile (Fax) are to 


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include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The investigator will supply the Sponsor and the IRB with more information as it becomes 
available and any additional requested information. The original SAE form must be kept 
at the study site. The Sponsor or its representative will be responsible for determining 
and in turn, reporting SAEs to regulatory authorities according to the applicable regulatory 
requirements. SAEs must be followed by the investigator until resolution, even if this 
extends beyond the study-reporting period. Resolution of an SAE is defined as the return 
to baseline status or stabilization of the condition with the expectation that it will remain 
chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the investigator will submit a Pregnancy Form to the Sponsor 
or designee to the safety email address or fax number within 24 hours of learning of the 
pregnancy. 
 NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later than 
10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 15 days for 
all other SUSARS (see Section 7.1.6 and 7.1.7). 
 REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device such as malfunction, misuse or use error 
and inadequate labeling. A malfunction is defined as the failure of a device to meet its 
performance specifications or otherwise perform as intended. The intended performance 
of a device refers to the intended use for which the device is labeled. All product 
complaints that meet this definition must be reported to the sponsor within 10 days of 
discovery.  Any product complaint that involves an AE or SAE must be also be reported 
per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the 
treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  


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Additional instructions on complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple 
sites for safety or administrative reasons at any time. In particular, a site that does not 
recruit at a reasonable rate may be discontinued. Should the study be terminated and/or 
the site closed for whatever reason, all non-source documentation and study product 
pertaining to the study must be returned to Inovio Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research subjects 
are protected. 
8. 
STATISTICAL ANALYSIS PLAN 
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and VGX-
3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and confirmed 
vulvar infection with HPV types 16 and/or 18. The study’s primary endpoint is binary: 
regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from vulvar tissue 
based on tissue collected at Week 48. The primary hypothesis is that each of the treatment 
arms will result in regression of HSIL and clearance. Secondary efficacy analyses pertain 
to regression, clearance of HPV-16 and/or HPV-18 infection, regression to normal, non-
progression, and anatomic extent. Other secondary analyses concern safety and humoral 
and cellular immunological measures. Exploratory efficacy analyses concern extended 
dosing with respect to regression, clearance, and anatomic extent, clearance outside of 
the vulva, and effect of HLA type on efficacy.  Other exploratory analyses pertain to tissue 
immunological measures, effect of needle depth into muscle on efficacy, and patient-
reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 
recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 
2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), 
and (d) age category (<45 years vs. ≥45 years).  There are no requirements for the number 
of subjects in each stratum.  The study is open-label. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each arm superior to historical control, assuming the true proportion 
of subjects who achieve the primary endpoint is 20% and 28% for the respective treatment 
arms and 2% for the historical control, and that 90% are evaluable at Week 48 from 
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8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized.  Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized.  
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy.  Subjects excluded from the PP population 
will be identified and documented prior to unblinding of the study database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects and will 
include the number and percentage randomized, the number and percentage who 
received each dose and the number who completed the trial.  The number and percentage 
of subjects who discontinued will be summarized overall and by reason.  The number in 
each analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the mITT population.  Prior 
and concomitant medications will also be summarized with percentages in this fashion. 
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by 
body system, by treatment arm, for the mITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (within 10 weeks 
prior to Day 0).  Concomitant medications are those used during the course of the trial (on 
or after Day 0).  Partial start dates of prior and concomitant medications will be assumed 
to be the earliest possible date consistent with the partial date.  Partial stop dates of prior 
and concomitant medications will be assumed to be the latest possible date consistent 
with the partial date.  Data for all prior and concomitant medications will be summarized 
with percentages by treatment arm, for the mITT population. 


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8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true population 
probability of the primary endpoint for each arm. The primary hypothesis of superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment arm separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the method of Clopper-Pearson. Superiority will be concluded if the 
one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds 
0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days prior 
to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) will 
be summarized with point estimates and associated Clopper-Pearson 95% confidence 
intervals. 
An exploratory analysis will examine clearance outside of the vulva.  This will be analyzed 
in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and HLA results. As these results are categorical, relationships will be examined 
with contingency tables and logistic regression models which model the primary endpoint 
versus these results and treatment group as regressor variables. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and needle depth into muscle. A logistic regression model which models the 
primary endpoint versus these results and treatment group as regressor variables will be 
used. 
8.10 
IMMUNOGENICITY ANALYSIS 
 
Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 
SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment arm. 
These frequencies will be presented overall and separately by dose, and will depict 


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overall, by system organ class and by preferred term, the percentage of subjects affected. 
Additional frequencies will be presented with respect to maximum severity and to 
strongest relationship to Study Treatment. Multiple occurrences of the same AE will be 
counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of any 
dose.  For this summary, the frequency of preferred term events will be summarized with 
percentages and 95% Clopper-Pearson confidence intervals.  Separate summaries will 
be based on events occurring within 7 days of any dose and regardless of when they 
occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be 
included within specified day-range summaries. AE duration will be calculated as (Stop 
Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment arm. 
Baseline is defined as the last measurement prior to the first treatment administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time point 
will be summarized by treatment arm and by body system, for the mITT population. 
 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or Clopper-
Pearson 95% CIs, for continuous responses and binary responses, respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 


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9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles 
of Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained 
from the applicable IRB/EC and a copy of this approval has been received by the 
sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 During the conduct of the study, submit progress reports to the IRB/EC as 
required.  
 Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 As required, obtain approval from the IRB/EC for protocol amendments and 
for revisions to the consent form or subject recruitment advertisements; 
 Reports on, and reviews of, the trial and its progress will be submitted to the 
IRB by the investigator at intervals stipulated in their guidelines and in 
accordance with pertinent regulations and guidelines. 
 Maintain a file of study-related information that includes all correspondence 
with the IRB; 
 Notify IRB when study is completed (i.e. after the last study visit of the final 
study subject); 
 After study completion provide the IRB with a final report on the study. 
9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., 
NIH Office of Biotechnology Activities) governing research that involves 
recombinant or synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening 
into the study, and/or from the subject’s legally authorized representative.  The 
process for obtaining informed consent must also be documented in the subject’s 
medical record. 


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9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations.  The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating the 
study and re-approval or review at least annually.  Sponsor is to be notified immediately if 
the responsible IRB/EC has been disqualified or if proceedings leading to disqualification 
have begun.  Copies of all IRB/EC correspondence with the investigator must be provided 
to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and for subjects in the imiquimod 
arm a dosing diary during their study participation.  Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation impacting 
Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject’s name will not be disclosed in these documents. 
The subject’s name may be disclosed to the study sponsor, Sponsor, the governing health 
authorities or the Food and Drug Administration (FDA), if they inspect the study records. 
Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information. 


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Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject’s legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA). 
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 the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. Examples 
of these original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subject’s 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 medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be 
present in the source documents. All prescription and nonprescription medications taken 
within l week prior to entry must be recorded on the CRF. Actual or estimated start and 
stop dates must be provided. 
10.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. The sponsor will inform the investigator/institution as to when these documents 
are no longer needed to be retained. 


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10.4 
SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial.  The DSMB will 
meet quarterly or as data are available to review unblinded safety data and 
regression/clearance results.  If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the 
meeting may be cancelled; Ad hoc meetings may be scheduled to review new data as 
applicable. The DSMB will be charged with advising the Sponsor if there appears to be a 
safety issue and with advising the Sponsor if it appears that regression in the VGX-3100 
group is unacceptably low compared to the placebo group. No formal interim analysis will 
be performed. The DSMB Chair, upon consultation with the other voting members of the 
DSMB, has the authority to recommend suspension or stopping the study and to request 
a full DSMB review and ad hoc statistical analyses.  The standard operating procedures 
of the DSMB will be documented in the DSMB charter, including the board’s accountability 
to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of a total of three pathologists. Each specimen will be read by two pathologists 
independently in a masked fashion.  If the two pathologists agree on the diagnosis then 
no further action is required and the clinical disease status for the subject will be 
established. If there is disagreement between the first two pathologists, the third 
pathologist will review and if there is agreement among any two of the three diagnoses, it 
will stand as the clinical disease status for that subject. If there is no agreement after the 
third review, the three reviewers will perform a simultaneous review and come to 
consensus or a majority rule of 2 of 3 if consensus cannot be reached. 
 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant 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 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 


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 
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 
 
Throughout the study, inspect all source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, and accurate 
(ALCOA).  
 
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 investigational drug and device accountability and reconciliation of  
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date of 
receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CMI 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
EC 
ECC 
EDC 
Ethics Committee 
Endocervical Curettage 
Electronic Data Capture 
EP 
DLT 
Electroporation with CELLECTRA® 2000 
Dose Limiting Toxicity 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 


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IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
PCR  
Pathology Adjudication Committee 
Polymerase Chain Reaction 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Participant Diary  
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper Limit of Normal 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
 


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13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Aldea M, Serrano B, Valencia S, Brotons M, Mena M, Cosano R, 
Muñoz J, Bosch FX, de Sanjosé S, Castellsagué X. Human Papillomavirus and Related 
Diseases in United States of America. Summary Report 2016-02-26. . In. Edited by 
Centre). IICoHaCHI; 2016. 
2. 
Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. 
J Natl Cancer Inst 2015,107:djv086. 
3. 
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
Sheets:  Vulvar Cancer. 2016. 
4. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
5. 
Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
6. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
7. 
Sideri M JR, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. Squamous 
vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology 
Subcommittee. J Reprod Med 2005,50:807-810. 
8. 
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: 
background and consensus recommendations from the College of American Pathologists 
and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 
2012,16:205-242. 
9. 
Inovio Pharmaceuticals. Unpublished assessment. 2015. 
10. 
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
natural history and outcome in 405 women. Obstet Gynecol 2005,106:1319-1326. 
11. 
van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
neoplasia III based on enough evidence? A systematic review of 3322 published patients. 
Gynecol Oncol 2005,97:645-651. 
12. 
Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
13. 
ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 
14. 
Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia 
(VIN) usual type after surgical treatment. Med Sci Monit 2011,17:CR532-535. 
15. 
ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
Obstet Gynecol. 2016,128:e178-182. 


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16. 
Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
17. 
Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
Market Research. 2016. 
18. 
Senn B, Eicher M, Mueller MD, Hornung R, Fink D, Baessler K, et al. A patient-reported 
outcome measure to identify occurrence and distress of post-surgery symptoms of 
WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study. Gynecol Oncol 
2013,129:234-240. 
19. 
Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
excision for vulvar intraepithelial neoplasia. J Reprod Med 2007,52:23-27. 
20. 
Petrosky E, Bocchini JA, Jr., Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-
valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations 
of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 
2015,64:300-304. 
21. 
Future II Study Group.  Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
22. 
Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a 
practical approach to diagnosis. J Clin Pathol 2014,67:290-294. 
23. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
24. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
25. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
26. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
27. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
28. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
29. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
30. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
31. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
32. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
33. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA® 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
U.S. BB-IND #13683 
 
 
 
 
Version 1.1 
20 January 2017 
 
 


VGX-3100
HPV-201
lnovio Pharmaceuticals, Inc.
Clinical Protocol
Medical Monitor Approval Page
Drug:
VGX-3100
Sponsor:
Inovio Pharmaceuticals, Inc.
660 W. Germantown Pike, Suite 110
Plymouth Meeting, PA 19462
Medical Monitor:
, M.D., Ph.D.
lnovio Pharmaceuticals, Inc.
Approval Signature:
M.D., Ph.D.
Date
Inovio Pharmaceuticals, Inc.
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 lnovio Pharmaceuticals. Any
supplemental information added to this document is also confidential and proprietary
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner
as the contents of this document.
Version Date: 20Jan2017
CONFIDENTIAL
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PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI’s approval of this 
protocol and provides the necessary assurances that this trial will be conducted in 
accordance with ICH/GCP and ISO guidelines, local legal and regulatory requirements, 
and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
____________________________________  
_________________________ 
<Insert Principal Investigator Printed Name>  
        Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


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SUMMARY OF CHANGES 
 
The following are a list of protocol changes from Version 1.0 dated 13 January 2017 to 
Version 1.1 dated 20 January 2017.  All other changes are administrative and do not 
significantly affect the safety of subjects, trial scope, or scientific quality of the protocol. 
1. An imiquimod dosing log will be implemented to collect imiquimod administration 
dates, instead of an imiquimod dosing diary.  Subjects will be instructed to contact 
their study site to report symptoms.  This change has been made to simplify the 
collection of information from subjects randomized to VGX3100 + imiquimod and 
is reflected in the following sections: 
 Section 6.3.3.10 – Title changed from ‘Imiquimod Dosing Diary’ to 
‘Imiquimod Dosing Log’ and instructions changed to have subjects contact 
study personnel to report symptoms.  
 All references to imiquimod dosing diary have been changed to imiquimod 
dosing log throughout the protocol. 
2. Timing of administration of the global PRO questions have been changed from 
Week 48 to Week 52 to allow the subject time to assess quality of life after the 
Week 48 biopsy.  This change is reflected in the following sections: 
 Section 6.8 – Collection timepoint moved from Week 48 to Week 52 
 Schedule of Events – ‘X’ added to PRO measure at Week 52  
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................................... 5 
CLINICAL PROTOCOL SYNOPSIS ..................................................................................................... 10 
STUDY SCHEDULE OF EVENTS ........................................................................................................ 23 
1. 
INTRODUCTION ......................................................................................................................... 25 
1.1 
Background ..................................................................................................................... 25 
 
Human Papillomavirus and Infection ............................................................. 25 
 
Vulvar Cancer .................................................................................................... 25 
 
Vulvar Intraepithelial Neoplasia (VULVAR HSIL) ......................................... 25 
 
Recurrent Disease with Current Therapeutic Options ................................. 26 
 
Psychological and Physical Impacts of Current Therapeutic Options ...... 27 
 
Impact of Vulvar HSIL Upon Activities of Daily Living ................................. 27 
 
Limitations of Prophylactic HPV Vaccines .................................................... 27 
 
Enhanced Monitoring Plan ............................................................................... 28 
 
VGX-3100 ........................................................................................................... 28 
  Electroporation .................................................................................................. 28 
  Imiquimod Cream, 5% ...................................................................................... 29 
  Study Rationale ................................................................................................. 29 
  Dose and Regimen Rationale for VGX-3100 ................................................ 29 
  Rationale for imiquimod ................................................................................... 29 
  Potential Risks of investigational products .................................................... 30 
  Potential Benefits of Study Participation ....................................................... 30 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ........................................................................... 30 
2.1 
Primary Objective and Endpoint .................................................................................. 31 
2.2 
Secondary Objectives and Associated Endpoints .................................................... 31 
2.3 
Exploratory Objectives and Associated Endpoints ................................................... 33 
3. 
STUDY DESIGN ......................................................................................................................... 34 
3.1 
Treatment Regimens ..................................................................................................... 34 
3.2 
Efficacy Assessment ...................................................................................................... 35 
 
Definition of Responder and Non-Responder ............................................... 36 
3.3 
Safety Assessment ........................................................................................................ 37 
 
Data Safety & Monitoring Board ..................................................................... 37 
3.4 
Immunogenicity Assessment ........................................................................................ 38 
3.5 
Virologic Assessment .................................................................................................... 38 


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4. 
SELECTION OF SUBJECTS .................................................................................................... 38 
4.1 
Inclusion Criteria ............................................................................................................. 38 
4.2 
Exclusion Criteria ........................................................................................................... 39 
4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................... 41 
 
Criteria for Discontinuation of Investigational Product ................................ 41 
 
Criteria for Withdrawal from the Study ........................................................... 42 
 
Sponsor Notification of Discontinuation/Withdrawal .................................... 42 
 
Reason for Discontinuation/Withdrawal ......................................................... 43 
5. 
STUDY TREATMENT ................................................................................................................ 43 
5.1 
Investigational Products ................................................................................................ 43 
5.2 
Packaging and Labeling ................................................................................................ 44 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................... 44 
5.3 
Handling and Storage .................................................................................................... 45 
5.4 
Preparation and Dispensing ......................................................................................... 46 
 
Dispensing of VGX-3100 ................................................................................. 46 
 
Dispensing and Use of Imiquimod .................................................................. 46 
5.5 
Investigational Product Accountability ........................................................................ 46 
5.6 
Return and Destruction of Investigational Product ................................................... 47 
5.7 
Use of Investigational Device ....................................................................................... 47 
5.8 
Packaging and Labeling of Investigational Device ................................................... 48 
5.9 
Investigational Device Accountability .......................................................................... 50 
5.10 
Return of Investigational Devices ................................................................................ 50 
6. 
STUDY PROCEDURES AND TREATMENTS ....................................................................... 51 
6.1 
Before Treatment Procedures ...................................................................................... 51 
 
Screening evaluations ...................................................................................... 51 
 
Ultrasound Measure of Skin-to-Muscle and Related Thicknesses ............ 52 
6.2 
During Treatment Procedures by Visit ........................................................................ 53 
 
Day 0 ................................................................................................................... 53 
 
8-14 Days Post Dose 1 Phone Call ................................................................ 54 
 
Week 4 ................................................................................................................ 54 
 
8-14 Days Post Dose 2 Phone Call ................................................................ 55 
 
Week 12 .............................................................................................................. 55 
 
Week 15 .............................................................................................................. 56 
 
Week 24 .............................................................................................................. 56 
 
Week 27 .............................................................................................................. 57 


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Week 48 .............................................................................................................. 57 
  Week 52 .............................................................................................................. 58 
  Week 74 .............................................................................................................. 58 
  Week 78 .............................................................................................................. 59 
  Week 96 .............................................................................................................. 59 
  Week 100 ........................................................................................................... 60 
6.3 
Evaluations and Procedures ........................................................................................ 61 
 
Informed Consent .............................................................................................. 61 
 
Assignment of Subject Identification Numbers ............................................. 61 
 
Safety Evaluations ............................................................................................ 61 
6.4 
Injection and Electroporation (EP) ............................................................................... 63 
 
Risks of Treatment Procedures ...................................................................... 64 
 
Management of Anxiety and Pain Due to EP Procedure ............................ 65 
6.5 
Assessment of Laboratory Abnormalities ................................................................... 66 
6.6 
Assessment of Clinical Study Adverse Events .......................................................... 66 
6.7 
Assessment of Injection Site Reactions ..................................................................... 66 
6.8 
Assessment of Patient Reported Outcomes .............................................................. 67 
6.9 
Peripheral Blood Immunogenicity Assessments ....................................................... 68 
6.10 
Tissue Immunogenicity Assessment ........................................................................... 68 
6.11 
HLA Typing...................................................................................................................... 68 
6.12 
Vulvar HPV Testing ........................................................................................................ 69 
6.13 
Colposcopy, PAP Smears and HPV Testing ............................................................. 69 
6.14 
Vulvoscopy, Photographs, and Biopsies .................................................................... 69 
6.15 
Concomitant Medications/Treatments ........................................................................ 70 
6.16 
Restrictions...................................................................................................................... 70 
  Other Restrictions ............................................................................................. 70 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY .................................... 71 
7.1 
Safety Parameters ......................................................................................................... 71 
 
Adverse Events ................................................................................................. 71 
 
Serious Adverse Events ................................................................................... 72 
 
Clarification of Serious Adverse Events ........................................................ 72 
 
Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ...................................................................... 73 
 
Unexpected Adverse Drug Reactions and Expedited Reporting ............... 73 
 
Unanticipated (Serious) Adverse Device Effect (UADE) ............................ 74 


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Assessing Severity (Intensity) ......................................................................... 74 
 
Casual Relationship of Clinical Material to Adverse Events ....................... 74 
 
Abnormal Laboratory Value ............................................................................. 75 
  Post-Trial Reporting Requirements ................................................................ 75 
  Procedures for Documenting Pregnancy During Study .............................. 75 
7.2 
Methods and Timing of Collection of Safety Data ..................................................... 76 
7.3 
Safety and Toxicity Management ................................................................................ 76 
 
Adverse Events of Special Interest ................................................................ 77 
 
Stopping Rules (Criteria for Pausing of Study) ............................................. 77 
7.4 
Adverse Experience Reporting .................................................................................... 78 
 
Trial Reporting Period of Adverse Events ..................................................... 78 
 
Trial Reporting Period of Serious Adverse Events ...................................... 78 
 
Notification of Serious Adverse Events ......................................................... 79 
 
Reporting of Device Related Complaints ...................................................... 79 
7.5 
Trial Discontinuation ...................................................................................................... 80 
8. 
STATISTICAL ANALYSIS PLAN ............................................................................................ 80 
8.1 
General Considerations ................................................................................................ 80 
8.2 
Randomization and blinding ......................................................................................... 80 
8.3 
Sample Size/Power ........................................................................................................ 80 
8.4 
Analyses Populations .................................................................................................... 81 
8.5 
Subject Disposition ........................................................................................................ 81 
8.6 
Demographic and Other Baseline Characteristics .................................................... 81 
8.7 
Medical History ............................................................................................................... 81 
8.8 
Prior and Concomitant Medications ............................................................................ 81 
8.9 
Efficacy Analysis ............................................................................................................ 82 
8.10 
Immunogenicity Analysis .............................................................................................. 82 
8.11 
Safety analyses .............................................................................................................. 82 
  Adverse events .................................................................................................. 82 
  Laboratory data ................................................................................................. 83 
  Vital Signs .......................................................................................................... 83 
  Physical Examination ....................................................................................... 83 
  Patient Reported Outcomes ............................................................................ 83 
  Missing Values .................................................................................................. 83 
  Interim Analysis ................................................................................................. 83 
9. 
ETHICS ......................................................................................................................................... 84 


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9.1 
Investigator and Sponsor Responsibilities ................................................................. 84 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ...................................... 84 
9.3 
Office of Biotechnology Activities (OBA) .................................................................... 84 
9.4 
Compliance with Informed Consent Regulations ...................................................... 84 
9.5 
Compliance with IRB/EC Requirements ..................................................................... 85 
9.6 
Compliance with Good Clinical Practice ..................................................................... 85 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 .......................................................................................................................................... 85 
9.8 
Compliance with Protocol ............................................................................................. 85 
9.9 
Changes to the Protocol ................................................................................................ 85 
10. 
DATA COLLECTION, MONITORING AND REPORTING ................................................... 85 
10.1 
Confidentiality and Privacy ........................................................................................... 85 
10.2 
Source Documents ........................................................................................................ 86 
10.3 
Records Retention ......................................................................................................... 86 
10.4 
Safety and Quality Monitoring ...................................................................................... 87 
  Data & Safety Monitoring Board ..................................................................... 87 
  Pathology Adjudication Committee ................................................................ 87 
  Clinical Monitoring ............................................................................................. 87 
11. 
PUBLICATION POLICY ............................................................................................................ 88 
12. 
LIST OF ABBREVIATIONS ...................................................................................................... 89 
13. 
REFERENCES ............................................................................................................................ 91 
 
 
 


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CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA® 2000  Alone or in Combination 
With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 20 sites in the 
United States (US) 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-
16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000  given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA® 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3X) from Day 0 through Week 202 
No. of Subjects 
Approximately 36 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic clearance 
of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar HSIL3 
and no evidence of HPV-16/18 at Week 48 in vulvar tissue 
samples (i.e. collected via biopsy or excisional treatment)4 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3  No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
4  A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive non-study related medication for treatment of 
VIN lesions. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, AIS, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions.   


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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar  HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/186 in vulvar tissue samples at 
Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL and no evidence of 
condyloma on histology (i.e. biopsies or 
excisional treatment) at the Week 48 visit
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion 
of 
subjects 
with 
no 
progression7 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of vulvar 
lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 48, 74 
and 96 compared to baseline8. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
                                                     
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
6 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
7 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
8 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96  
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects who did not have 
complete lesion resolution at Week 48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 74 and/or 
Week 96 compared to baseline9. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior  
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 
infiltrating cells10.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the vulva  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from other 
anatomic locations without surgical 
intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week  48 
                                                     
9 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
10 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Assess 
skin-to-muscle, 
skin-to-bone, 
and 
muscle thicknesses via ultrasound measure of 
deltoid (or quadriceps if applicable) and the 
correlation of needle depth into muscle with 
efficacy. 
7.  Ultrasound-measured skin-to-muscle, 
skin-to-bone, and muscle thicknesses  
8. Describe patient reported outcomes for subjects 
treated with VGX-3100 and VGX-3100 with 
imiquimod 
8.  Patient-reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and 
following each of the first four doses, 
and at Weeks 48, 74, 96, and 100. 
 
 


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Study Design: 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered with 
CELLECTRA® 2000 alone or in combination with imiquimod in adult women with histologically confirmed 
vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled.  
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-3100 
and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass Index 
(BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-5D-5L 
(EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvar Neoplasia) and two additional 
PRO questions assessing quality of life after surgery or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of a 4 mm vulvar 
punch biopsy/biopsies with lesion remaining, and photographs of the acetowhite vulvar lesion(s) at the 
time of screening. In the case of multifocal disease, the two regions of potentially most advanced and 
severe disease, as judged by the investigator, should be chosen for biopsy using vulvoscopy and 
documented using standardized high resolution photography with a digital single-lens reflex (SLR) 
camera, on the case report form. Biopsy slides or tissue will be sent to a Pathology Adjudication 
Committee (PAC) for evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must 
assign the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar 
tissue specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study.
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of VGX-
3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject’s biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of VGX-
3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic and 
lesion area changes.  The first dose will be administered on Day 0, the second at Week 4, the third at 
Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 48 
(Subgroups A and B) will receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator.  Subjects in Subgroup E may receive surgical treatment per the 
judgement of the Investigator.  All subjects are scheduled to be followed to Week 100.  
 
 
 


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Figure 1: Study Visit Schedule 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will apply imiquimod 
5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to apply imiquimod 
cream three times per week for 20 weeks (inclusive of administration in the evening of VGX-3100 
dosing).  Subjects unable to tolerate imiquimod treatment may reduce their dosing frequency, and will 
document their use on the imiquimod dosing log provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by visual inspection with vulvoscopy is insufficient evidence 
to confirm disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74, and 96. Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), 
defined as areas that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0, and 
Weeks 4, 12, 27, 48, 74 and 96. Using standardized high resolution digital imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 3 
for Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC there is no 
evidence of HSIL (Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and biopsy 
adjacent to the site of the initial biopsy. Repeat biopsies that are indicated beyond Week 48 must be 
taken from the same lesion, adjacent to the prior biopsy site(s) within the boundaries of the original 
lesion.  
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size or no change 
in lesion size from baseline (Subgroups C or D), the Investigator has the option to give the subject a 5th 
dose of VGX-3100 at Week 52, and the subject will continue on study with vulvoscopy and biopsy at 


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Week 74.  Alternatively, the Investigator may choose to treat the subject with surgical or standard 
treatment, and the subject will continue on study without further biopsy.   
 
Figure 2: Decision process at Week 52  
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as follows: 
At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion as study 
start, but adjacent to the original site within the boundaries of the original lesion (see Table 3). If after 
evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject 
will continue to Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at Week 
78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, the 
Investigator may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy.   
 
 
 
 
 
 
 


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Figure 3: Decision Process at Week 78 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 3). 
If there is no vulvar HSIL (Subgroups A or B), no further procedures are required. If after evaluation of 
biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), 
the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 


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In the event of worsening disease at any time (ie, Subgroup E – any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per the 
Investigator’s judgement and will continue on study through Week 100 with vulvoscopy, but without 
further biopsy.  For a finding of carcinoma, subjects will receive surgical treatment, and be discontinued 
from study treatment.  The event will be reported as an SAE per section 7.1.4.  If wide excision is 
required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder: 
Responder and non-responder definitions (Table 4) take into account both histopathologic regression 
of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since HPV persistence is an 
important factor in the clinical progression of HSIL. A treatment responder is defined as a subject with 
no histologic evidence of vulvar HSIL and no evidence of HPV-16 or HPV-18 in vulvar tissue at 
evaluation and who did not receive non-study related medication for treatment of VIN lesions.  A 
treatment non-responder is a subject with histologic evidence of vulvar HSIL, adenocarcinoma-in-situ, 
or vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions. Any case of 
histologically confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. No formal interim 
analysis is planned. The following stopping rules will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, assessed 
as related to study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal Investigator 
for the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding the outcome of 
any investigation stemming from a Study Pause.  


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Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (both Screening as well 
as Day 0 prior to dosing) and at Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and at Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize HPV infection at Screening, 
Week 48, 74 and 96. Cervical samples, oropharyngeal rinse samples, vaginal, and intra-anal tissue 
swab samples will be obtained to characterize HPV infection in samples from study subjects taken at 
Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and intra-anal only) and at Weeks 
27, 48, 74, and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks will be collected for immunohistochemistry (IHC) 
and in situ hybridization (ISH) for the presence of HPV-16/18. Whenever possible, these studies will be 
performed on tissue sections from the diagnostic biopsy (pre-dose) and from tissue obtained post-dose 
(Week 48, 74 and 96). 
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
relationship between subject HLA haplotypes and regression.  


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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above; 
3. 
Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. 
Vulvar tissue specimen/slides provided to the Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
5. 
Histologic evidence of vulvar HSIL as confirmed by the PAC at screening; 
6. 
Must be judged by investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
7. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system; 
iv) Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject. 
10. Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 


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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing treatment for CIN;
5) Biopsy-proven differentiated VIN; 
6) More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day of first 
dose (i.e. Day 0); 
7) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
8) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
9) Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into cervical 
canal at screening; 
10) History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, or insufficient 
for diagnosis (ECC is not performed as part of study screening) and did not receive definitive 
treatment; 
11) Treatment for genital warts within 4 weeks prior to screening; 
12) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
13) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last dose 
of investigational product; 
15) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the investigator; 
16) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying drugs such as 
TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
17) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
18) Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
20) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the investigator; 
21) Current or history of clinically significant, medically unstable disease which, in the judgement of the 
investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results (e.g. chronic renal failure, angina, 
myocardial ischemia or infarction, class 3 or higher congestive heart failure, cardiomyopathy, or 
clinically significant arrhythmias); 
22) Malignancy or treatment for malignancy within 2 years of screening, with the exception of superficial 


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skin cancers that only require local excision; 
23) Acute or chronic bleeding or clotting disorder that would contraindicate IM injections or use of blood 
thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 
24) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic agents; 
25) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at Screening or 
Day 0; 
27) Prior major surgery within 4 weeks of Day 0; 
28) Participated in an interventional study with an investigational compound or device within 4 weeks of 
signing informed consent (participation in an observational study is permitted); 
29) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
30) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
31) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in 
ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
32) Metal implants or implantable medical device within the intended treatment site (i.e. electroporation 
area);  
33) Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with 
adherence to study requirements; 
34) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (i.e. infectious disease) illness; 
35) Active military service personnel; 
36) Study-related staff or family members of study-related staff; 
37) 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.  


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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X
Inclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X---------------------------------------------------------------------------------------------------X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Vital signs 
Xb 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xe 
 
Xf
 
Xe 
 
Xe
 
Xe 
 
HLA testing g 
 
X 
Cervical cytology, ThinPrep™ h 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject  VGX-3100 +EP m 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Review PD o 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X-----------------------------------------------------------------------------------------------------------X 
Ultrasound Measure of skin-to-
muscle and related thicknesses 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X
Abbreviations: OP; oropharynx 


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a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE. 
b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared).  Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 30 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27. 
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrepTM cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected.  Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j Standardized high resolution digital imaging of the vulva and the associated acetowhite stained lesion(s) 
must be performed prior to and after biopsy, and at all vulvoscopy examinations. Additionally, 
standardized high resolution digital imaging should be obtained during examinations of the vagina if 
lesions are identified, for documentation. 
k Tissue specimen and slides from all excised tissue must be reviewed by the PAC and residual vulvar 
tissue from entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) should be 
sent to the central pathology laboratory for immunohistochemistry (IHC) and HPV testing.   
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod.  
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36, EQ-5D-5L, WOMAN-PRO) plus two additional questions will be assessed as 
described in Section 6.8.     
 
 
 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, 
and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the most 
significant amongst high-risk types since they are responsible for most HPV-caused 
cancers [1].   
HPV-16 is involved in more than 85% of HPV-associated vulvar HSIL cases in the U.S.[1]. 
Persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions 
(HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oro-pharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS)[2].  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 5,950 new cases and 1,110 
attributable deaths annually for year 2016 in the United States [3]. Vulvar cancers consist 
largely of squamous cell carcinomas and accounts for approximately 5% of all female 
genital malignancies [4]. Differentiated VIN, which is typically not caused by HPV infection 
and is more typically found in older women, is more likely to progress to cancer more 
rapidly than HPV-associated-VIN. The five year overall relative survival for vulvar cancer 
in the U.S. is 70.7% [3].  Recurrent vulvar cancer occurs in an average of 24% of cases 
after primary treatment, after surgery with or without radiation [5].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia.  The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance of 
pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [6]    
In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) replaced 
the three grade classification system with the current single grade classification for which 


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only high grade VIN (2/3) is classified as VIN [7]. In 2012, the Lower Anogenital Squamous 
Terminology (LAST) Standardization Project for HPV-associated lesions applied the term 
high grade squamous intraepithelial lesion (HSIL) to encompass high grade dysplasia [8].  
Therefore, for the purpose of this study, the term vulvar HSIL will be used, which 
encompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to encompass what 
was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [9]. Over time, typically years, vulvar HSIL can progress to invasive 
cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group and median 
13.8 years in another group [10], and from VIN3 patients, mean = 2.5 years, range: 4 – 
216 months [11].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity against 
vulvar HSIL and have not achieved universal uptake, leaving a population of susceptible 
and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to visual 
inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for vulvar 
HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, often 
requiring multiple, repeat treatments. Progression to vulvar cancer following current vulvar 
HSIL treatments can also occur within 1 year of treatment and for up to 20 years post 
treatment. The current treatment options for vulvar HSIL are surgical excision, laser 
ablation, and off-label medical therapy. The rate of HPV-associated vulvar HSIL 
recurrence after surgical treatment is high; post-treatment recurrence rates exceed 30-
50% with all currently available treatment regimens [12, 13].   
Wide local excision is the ‘preferred initial intervention’ by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation.  Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues with 
body image and sexual dysfunction.  Medical therapies have been investigated as a 
means to avoid these negative outcomes.  Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food and 
Drug Administration for this indication.  Inconsistent treatment efficacy results have been 
shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 
of recurrence is slightly higher compared to wide local excision. Laser treatment of vulvar 
HSIL requires destruction of cells through the entire thickness of the epithelium including 
hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation should 


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extend through the dermis. Post-treatment recurrence rates exceed 30% (for all treatment 
regimens), and is higher with positive excision margins [14]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low rate 
of spontaneous resolution.  According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is suspected 
(even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is wide local 
excision (i.e. surgery) [15].  When occult invasion is not a concern, vulvar HSIL can be 
treated with excision, laser ablation, or topical imiquimod as an off-label medical therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [14].  Therefore, many patients have a fear 
of recurrence and progression to cancer [16].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks.  
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid use of toilet paper and to rather rinse with warm water.  
During recovery, common effects include pain in urinating and wiping, soreness, difficulty 
sitting, and feeling tired [17]. In the first week after hospital discharge, common patient-
reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [18].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-being 
[17].  The symptoms and signs of vulvar HSIL can be moderate to severe and include 
painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating [18]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than age-
matched healthy women [19]. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor’s office all the time [17]. 
 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid HPV-associated vulvar HSIL 
and subsequent vulvar cancer. The US-licensed prophylactic HPV vaccines are indicated 
for girls and women ages 9 through 26 years for Gardasil® and Gardasil®9 (Merck & Co. 
Inc.), and ages 9 through 25 years for Cervarix® (GlaxoSmithKline). The early portions of 


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these age ranges are generally before sexual debut and thus can allow immunologic 
protection against the anticipated earliest normal exposures to HPV infection. HPV 
prophylactic vaccination is highly effective and safe, and routine vaccination is 
recommended for females in the United States starting at age 11 or 12 years [20]. 
However, the prophylactic vaccines have no therapeutic effect upon existing HPV infection 
or existing HPV-related intraepithelial neoplasia [21]). 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan is used in this study to address the risk of a potential delay 
in treatment of vulvar HSIL.  The feasibility of this approach was demonstrated in the 
Phase 2b study of cervical HSIL.  Given that vulvar disease progresses slowly to vulvar 
cancer if untreated, the proposed enhanced monitoring plan is expected to maintain the 
safety of trial subjects for this study.  First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study investigators.  Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, by 
two independent expert pathologists (pathology adjudication committee). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
[22], is specifically excluded from study entry.  By contrast, HPV-associated vulvar HSIL 
does not progress rapidly, typically taking years to manifest and progress, making 
enhanced monitoring feasible.   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.14).  Colposcopy will also be 
done at baseline and during the study given that concurrent disease in the lower genital 
tract can occur.   A Data Safety Monitoring Board will be utilized to review subject safety 
data and advise on any study-level safety concerns. Investigators always have the option 
of performing ad hoc vulvar biopsies to rule out disease progression.  Additional treatment 
(e.g., additional excision, ablation, or medical therapy) may be carried out, if deemed 
necessary according to Investigator judgement. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA® device represent an integrated investigational 
product designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, 
CIN3) via an immune response directed against HPV-16/18.  Further information about 
VGX-3100 is provided in the Investigator’s Brochure. 
 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA® in vivo electroporation (EP) device. EP is 
a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [23, 24]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 


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10 to 100 fold [25, 26]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as shown 
by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [27].  
This study will use the CELLECTRA® 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no significant 
safety issues identified.  Further information about the CELLECTRA® 2000 device can be 
found in the Investigator’s Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device.  Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 250 
mg of the cream, equivalent to 12.5 mg of imiquimod.  The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod.  The overall aim is to determine if treatment with VGX-3100 could allow women 
with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of concept that 
VGX-3100 can induce resolution of both HPV-associated dysplastic lesions and the 
underlying HPV 16/18 infection was shown in a Phase 2b study of cervical intraepithelial 
neoplasia (CIN).  The similar underlying pathogenic mechanisms between cervical and 
vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could be a non-
surgical therapeutic option for the treatment of vulvar HSIL, which is a significantly under 
met medical condition.  A VGX-3100 with imiquimod-administration arm is also included, 
given the prevalent use of imiquimod as a topical medical treatment of vulvar lesions, to 
investigate if a more robust immune response is achieved with VGX-3100, to potentially 
increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 
responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [28].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Imiquimod may be able to be used synergistically with 
VGX-3100. 


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Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG).  Published regimens include three times weekly 
application to affected areas for 12 – 20 weeks, with colposcopic assessment at 4-6 week 
intervals during treatment [15].  
The current study will include an imiquimod arm with VGX-3100, to evaluate 
histopathologic regression of vulvar HSIL and virologic clearance of HPV-16/18, compared 
to the current body of knowledge in imiquimod alone.     
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 
reported at the application site [29].  The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity.  In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure including 
anesthesia, post-operative bleeding, infection, or damage to surrounding structures such 
as the clitoris, urethra, or anus. The other potential benefit is that the response to VGX-
3100 is systemic and may clear the underlying HPV infection, which is the root cause of 
vulvar HSIL.  Consequently, there is the potential to reduce the risk of recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL  associated with HPV-16 and/or HPV-18 (HPV-16/18), 
will result in a higher percentage of women with regression of HSIL of the vulva based on 
histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from 
vulvar tissue compared with historical control. 
 
 
 


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2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional treatment).  
2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL11 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/1812 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression13 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
                                                     
11 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
12 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
13 Progression is defined as advancement to carcinoma according to the Pathology Adjudication Committee by 
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6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
48, 74 and 96 compared to baseline14. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion size of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).  
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone 
or in combination with imiquimod,  post dose 
3, post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes 
at baseline and Weeks 15, 27, 48, 74 and 
96 visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 
                                                     
14 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe 
the 
efficacy 
of 
VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects without a 
complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
74 and/or Week 96 compared to baseline15. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in lesion 
area of 0-25%), partial lesion area resolution 
(>25% and <100% reduction), and complete 
lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6  doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, 
as 
measured 
by 
virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 infiltrating 
cells16.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the 
vulva   
5. Proportion of subjects who have cleared HPV-
16/18 on specimens from other anatomic 
locations 
without 
surgical 
intervention 
(inclusive of cervix, oropharynx, vagina and 
intra-anus) at Week  48 
6. Characterize 
HLA 
haplotypes 
and 
the 
correlation with efficacy 
6.  Proportion of subjects with regression of HSIL 
on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Assess skin-to-muscle, skin-to-bone, and 
muscle thicknesses via ultrasound measure 
of deltoid (or quadriceps if applicable) and the 
correlation of needle depth into muscle with 
efficacy. 
7. Ultrasound-measured skin-to-muscle, skin-
to-bone, and muscle thicknesses.  
8. Describe patient reported outcomes for 
subjects treated with VGX-3100 and VGX-
3100 with imiquimod 
8. A patient-reported outcome (PRO) endpoint 
may be obtained prior to first dose (Day 0), 
following each of the first doses, and at 
Weeks 74, and 96. 
                                                     
15 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
16 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA® 2000 alone or in combination with 
imiquimod in adult women with histologically confirmed vulvar HSIL associated with HPV-
16/18. Approximately 36 subjects will be enrolled.  Twenty-four subjects will receive VGX-
3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at 
screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category 
(<45 years vs. ≥45 years). 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be provided and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with 
vulvar Neoplasia) and two additional PRO questions assessing quality of life after surgery 
or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of 
a 4 mm vulvar punch biopsy/biopsies with lesion remaining, and photographs of the 
acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, the 
two regions of most advanced and severe disease, as judged by the investigator, should 
be chosen for biopsy using vulvoscopy and documented using standardized high 
resolution photography with a digital single-lens reflex (SLR) camera on the case report 
form. Biopsy slides or tissue will be sent to a Pathology Adjudication Committee (PAC) for 
evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must assign 
the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a 
vulvar specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation 
in the study. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 mg 
of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-16/18 
status and all other eligibility criteria but no more than 10 weeks following collection of the 
subject’s biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid, preferred site, 
or anterolateral quadriceps, alternate site) followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes.  The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  


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Subjects with HSIL at Week 74, who have a reduction in lesion size or no increase in 
lesion size from baseline (Subgroups C or D), may receive a sixth dose of VGX-3100 
administered IM with EP at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgement of the Investigator.  All 
subjects will complete the study at Week 100. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will 
apply imiquimod 5% cream to the vulvar lesion beginning in the evening on Day 0, and 
will continue to apply treatment three times per week for 20 weeks (inclusive of 
administration in the evening of VGX-3100 dosing).  Subjects unable to tolerate imiquimod 
treatment may reduce their dosing frequency, and will document their use on the 
imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital imaging, vulvar lesion(s) will also be quantitatively 
measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 
mm in length. Visible lesion must remain after screening biopsy to ensure measurement 
on study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3 for Minimally Required Biopsy 
Procedures). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Figure 2, Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and 
biopsy adjacent to the site of initial biopsy.     
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size 
or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the Investigator 
has the option to give the subject a 5th dose of VGX-3100 at Week 52, and the subject will 
continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator 
may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3). If after evaluation of biopsy tissue by 
the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to 
Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no increase in lesion size from 
baseline (Subgroups C or D), the Investigator has the option to give the subject a 6th dose 


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of VGX-3100 at Week 78, and the subject will continue on study with vulvoscopy and 
biopsy at Week 96. Alternatively, the Investigator may choose to treat the subject with 
surgical or standard treatment, and the subject will continue on study without further 
biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3). If there is no vulvar HSIL (Subgroups 
A or B), no further procedures are required. If after evaluation of biopsy tissue by the PAC 
there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), the subject 
will receive surgical or other standard treatment. 
In the event of worsening disease (ie, Subgroup E - any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per 
the Investigator’s judgement and will continue on study through Week 100 with 
vulvoscopy, but without further biopsy.  For a finding of carcinoma, subjects will receive 
surgical treatment, and be discontinued from study treatment.  The event will be reported 
as an SAE per section 7.1.4. If wide excision is required, the sample obtained will be sent 
to the PAC for evaluation.  
 
Table 3:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original biopsy site within the boundaries of the original 
lesion; 
Acetowhite Lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original site within the boundaries of the original lesion; 
biopsy of lesion must include suspected area of most 
advanced disease  
Multiple acetowhite lesions 
Vulvar punch biopsies and imaging; biopsy should be 
conducted of the same two lesions as study entry but 
adjacent to the original site within the boundaries of the 
original lesion; biopsies must include area of most advanced 
and severe disease as determined at screening  
 
  
 DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 4) take into account both histopathologic 
regression of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since 
HPV persistence is an important factor in the clinical progression of HSIL.  
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive non-study related medication for treatment of VIN lesions.  A treatment non-
responder is a subject with histologic evidence of vulvar HSIL, adenocarcinoma-in-situ, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, 


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or a subject who received non-study related medications for treatment of VIN lesions. Any 
case of histologically confirmed progression is considered a non-responder. Progression 
is defined as advancement to carcinoma by histology. 
Table 4: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSILa  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive non-study 
related medication for treatment of VIN 
lesions. 
 
Subject with histologic evidence of vulvar HSIL, 
Adenocarcinoma-in-situ (AIS), vulvar carcinoma at 
evaluation 
  
AND/OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related 
medication for treatment of VIN lesions 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight.  
The DSMB will meet quarterly to review safety data. The DSMB will be charged with 
advising the Sponsor if there appears to be a safety issue. No formal interim analysis is 
planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, Principal Investigator for the trial, and the DSMB. 


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 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately until 
a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) and at 
Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and at Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize HPV infection at Screening, Week 48, 74 
and 96. Cervical samples, oropharyngeal (OP) rinse samples, vaginal, and intra-anal 
tissue swab samples will be obtained to characterize HPV infection in samples from study 
subjects taken at Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and 
intra-anal only) and at Weeks 27, 48, 74 and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then unstained slides and/or the relevant paraffin blocks will be collected for 
immunohistochemistry (IHC) and in situ hybridization (ISH) for the presence of  
HPV-16/18. Whenever possible, these studies will be performed on tissue sections from 
the diagnostic biopsy (pre-dose) and from tissue obtained post-dose (Week 48, 74 and 
96).  
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. Vulvar tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
5. Histologic evidence of vulvar HSIL as confirmed by PAC at screening; 
6. Must be judged by investigator to be an appropriate candidate for the protocol-specified 


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procedure (i.e. excision or biopsy) required at Week 48; 
7. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 
adequate size to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months 
or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 12 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method 
with failure rate of less than 1% per year when used consistently and correctly from 
screening until 6 months following the last dose of investigational product. Acceptable 
methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into 
the study, and this male is the sole partner for that subject. 
10. Normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment 
for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. More than 10 weeks have elapsed between date of initial tissue biopsy for screening 
and day of first dose (i.e. Day 0); 
7. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
8. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after 
biopsy; 


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9. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension 
high into cervical canal at screening; 
10. History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, 
or insufficient for diagnosis (ECC is not performed as part of study screening) and 
did not receive definitive treatment; 
11. Treatment for genital warts within 4 weeks prior to screening; 
12. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 
4 weeks prior to screening; 
13. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
15. Presence of any abnormal clinical laboratory values greater than Grade 1 per Common 
Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or 
less than Grade 1 but deemed clinically significant by the investigator; 
16. Immunosuppression as a result of underlying illness or treatment including: 
a. History of or positive serologic test for HIV at screening;  
b. Primary immunodeficiencies; 
c. Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d. Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e.  History of solid organ or bone marrow transplantation; 
f. 
 Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
17. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
18. Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of 
Day 0; 
20. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the investigator; 
21. Current or history of clinically significant, medically unstable disease which, in the 
judgement of the investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the study 
results (e.g. chronic renal failure, angina, myocardial ischemia or infarction, class 3 or 
higher congestive heart failure, cardiomyopathy, or clinically significant arrhythmias); 
22. Malignancy or treatment for malignancy within 2 years of screening, with the exception 
of superficial skin cancers that only require local excision; 


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23. Acute or chronic bleeding or clotting disorder that would contraindicate IM injections 
or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
24. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
25. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 
mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
27. Prior major surgery within 4 weeks of Day 0; 
28. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
29. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
30. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment 
site; 
31. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) 
that is located in ipsilateral deltoid injection site (unless deemed acceptable by a 
cardiologist); 
32. Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
33. Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
34. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
35. Active military service personnel; 
36. Study-related staff or family members of study-related staff; 
37. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study treatment/EP 
but will be encouraged to continue follow-up safety assessment through study discharge 
and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that subject. 


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 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw from 
study participation at any time. A subject may be withdrawn at any time at the discretion 
of the investigator for any maternal obstetrical or medical complications after consultation 
with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report form 
(eCRF) and the subject’s source document 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule for 
follow-up and treatment of VIN, and ascertain whether or not the subject wishes to and/or 
should continue in the study based on previous noncompliance. In cases where the 
subject does not return for the rescheduled visit or cannot be reached to reschedule the 
missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls to the subject should be made and if that fails, then a certified letter is sent 
to the subject’s last known mailing address) so that they can be considered withdrawn 
from the study for disposition purposes. These contact attempts should be documented in 
the subject’s medical record. Should the subject continue to be unreachable, then and 
only then will she be considered to have withdrawn from the study with a primary reason 
of “Lost to Follow-up.” For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). At 
a minimum, the investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100).  A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The investigator or study coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the study 
or is withdrawn from the study prior to study completion, all applicable activities scheduled 
for the final study visit should be performed at the time of discontinuation. The investigator 
will make every effort to have all scheduled immune assessment blood samples collected 
as indicated in the Schedule of Events in the synopsis, Table 1. Any AEs and/or SAEs 
present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in section 7.1 – Safety Parameters. 


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 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 
 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs regardless 
of relation to study drug. 
 
 Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical 
need to withdraw. If the subject gave a reason for withdrawal, it must be recorded 
on the eCRF. This reason does not allow for further data collection and should not 
be selected if follow-up data collection of this subject is anticipated by the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation should 
be discussed with the Sponsor’s Medical Monitor prior to discontinuation of study 
treatments or study withdrawal. 
 
 Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter sent 
by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon®) technology.  The VGX-
3100 formulation to be used in this study is described in Table 5 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum.  There are 24 single-use packets of imiquimod in one box.  The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older.  Although it is not approved by the US Food 
and Drug Administration for the treatment of vulvar HSIL, imiquimod is currently 


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recommended as a non-surgical, off-label treatment option for vulvar dysplasia by the 
American College of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 5. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  Imiquimod Cream, 5% will have both the original 
manufacturer's label on individual packets and the back of the carton, and an 
investigational label on the front of the carton.  The labels will contain, at minimum, the 
information shown in Figure 6.   


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Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  
 
Figure 6. Example labels for imiquimod 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Opthalmic Use. 
Keep out of reach of children.  This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer’s instructions. Avoid freezing.    


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5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. The 
product must be used within 4 hours of removal from the refrigerator. All material removed 
from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 
 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations.  Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks.  Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water.  Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period.  The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 


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5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to 
be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 IP can only 
be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer.  The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, adverse effects, interfering substances 
or devices, warnings, and precautions.  Each CELLECTRA® 2000 Pulse Generator has a 
unique serial number, and each CELLECTRA® 2000 Applicator has a unique serial 
number. Each CELLECTRA® 2000 Array has a Lot Number, Manufacture Date, and 
Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local authorities 
to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to successfully 
completing device training from sponsor personnel. Individuals whose credentials do not 
meet the relevant local requirements may perform the treatment procedure under both of 
the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or 
an approved Sub-Investigator who has already been trained by the sponsor’s 
personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and 
approved by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its 
designee. 


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5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 7 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers (as 
applicable) is included at the time of manufacture and may vary from these examples. The 
information found on the actual device labels should always be used to manage, track and 
record investigational product accountability during study conduct. 
 
 
 
 
 
 
 
 


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Table 7. Example Labels for the CELLECTRA® 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA® 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA® 
2000 5P  
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA® IM 
Array 
 
REF: M01-
002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. This 
includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA® 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA® 2000 IM Applicator is intended to be used multiple times on the same 
subject and then disposed after final use in accordance with accepted medical practice 
and any applicable local, state, and federal laws and regulations. Once the IM applicator 
is assigned to a subject, it may NOT be used on another subject. The used sterile 
disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.10 
RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the responsible Study 
Monitor. 
If product is to be destroyed on site, it is the Investigator’s responsibility to ensure that 
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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected 
prior to consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the samples 
sent to the central pathology lab for review by the PAC to assess eligibility.  There will be 
a maximum allowable window of 10 weeks from the date of collection of the qualifying 
biopsy sample(s) (i.e. slides/samples(s) reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be obtained 
within a reasonable timeframe, an additional biopsy sample should be collected during 
screening following the consent of the subject. The 10 week screening window begins 
upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets other 
eligibility criteria). Subjects whose vulvar specimens also test positive for other HPV 
genotypes are not excluded as long as they have a positive result for HPV-16 and/or HPV-
18.  
The assessments during the screening period will determine the subjects’ eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, which 
must be performed within 30 days prior to Day 0. All screening assessment values must 
be reviewed prior to study treatment. 
 
Signed informed consent 
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG (within 30 days prior to Day 0) 
 
Baseline laboratory evaluations (includes complete blood count [CBC), serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine aminotransferase 
[ALT], creatine phosphokinase [CPK], and urinalysis) to be performed within 30 days 
prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be performed 
once) 
 
Cervical cytology and ThinPrep™ for cervical HPV type 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical areas 
should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photographs of the vulva and the associated lesion must be collected prior to 
and after biopsy at screening.  
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC. If residual vulvar 
tissue is available from entry either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 ULTRASOUND MEASURE OF SKIN-TO-MUSCLE AND RELATED 
THICKNESSES 
Subjects who consent to participate in the ultrasound sub-study will have both right and 
left deltoids and one (either) quadriceps measured. The precise site of the ultrasound 


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within the deltoid and quadriceps will align with where EP is administered. The ultrasound 
measure will be performed at each of those three body sites in two manners: with no 
pressure applied by the technician through the probe to the tissue and separately, and 
with EP-like pressure applied by the technician through the probe to the tissue and 
separately. The “EP-like pressure” is defined as a firm push against the skin resulting in 
puckering of the skin by the ultrasound probe. The rationale for the differing pressures is 
to determine if and how much the thickness being measured will change. For each body 
site and pressure, three triplicate measures will be performed.  The type and number of 
ultrasound images and replicates taken for each body site for each patient would be as 
follows: 
 
   Table 8. Type and Number of Ultrasound Images, by Muscle and Probe Pressure 
 
Right 
Deltoid
Left 
Deltoid
Either 
Quadricep
s 
Total 
No pressure of the ultrasound probe on tissue 
site 
 
3 
 
3 
 
3 
 
9 
EP-like pressure of the ultrasound probe on 
tissue site 
 
3 
 
3 
 
3 
 
9 
Total number of replicate measures 
6 
6 
6 
18 
 
Ultrasound measures will be performed during the screening period, i.e. before enrollment 
and hence before any administrations of VGX-3100, and will thus include both enrolled 
and screen-failed subjects.   
Locally stored images of each ultrasound measure will be measured via digitizer or simple 
scale to obtain the following cross-sectional distances, for each replicate image: 
- 
Skin to muscle distance (i.e. depth of the beginning of the muscle) = “S-M” 
- 
Skin to bone distance (i.e. depth of the beginning of the bone) = “S-B” 
- 
Muscle thickness (i.e. distance of the beginning to end of the muscle) = “MT”, a 
calculated field with the following equation: 
 
  
MT = “S-B” - “S-M” 
The ultrasound measures will be performed on all screened patients in this trial, thus 
including both enrolled patients and ultimately screen-failed patients in these sub-
analyses.    
 
Last, each patient would be asked for their handedness, i.e. whether they are they right-
handed, left-handed, or ambidextrous.   
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment.  Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 


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 
Review of concomitant medications and adverse events 
 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP rinse, vaginal and intra-anal swabs 
 
Baseline vulvoscopy  
 
Vulvar lesion photography 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 4 
The following study evaluations will be performed at Week 4 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 


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 
Vulvoscopy  
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression. 
 
Vulvar lesion photography  
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after study 
treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 
The following study evaluations will be performed at Week 12 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 and Week 94 unless PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression 


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 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 
The following study evaluations will be performed at Week 15 (± 7 days): 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay 
 WEEK 24 
The following study evaluations will be performed at Week 24 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 


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 WEEK 27 
The following study evaluations will be performed at Week 27 (± 7 days): 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 or Week 96 unless the PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression.  
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 WEEK 48 
The following study evaluations will be performed at Week 48 (± 7 days): 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 


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 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected. 
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
 If residual vulvar tissue is available from entry and/or Week 48 
specimen(s) either paraffin blocks or unstained slides should be sent to 
the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 
Patient Reported Outcomes 
 WEEK 52  
Subjects will have a Week 52 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 74 
The following study evaluations will be performed at Week 74 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 


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 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 78 
Subjects will have a Week 78 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 
 WEEK 96 
The following study evaluations will be performed at Week 96 (± 14 days): 
 
Review of concomitant medications and adverse events 


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 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical 
areas should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 100 
The following study evaluations will be performed at Week 100 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 


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6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, study 
objectives, potential benefits and risks, discomforts/inconveniences, and the subject’s 
rights and responsibilities. The subject is then requested to sign and date the ICF. A copy 
of the signed informed consent documentation must be provided to the subject. The 
qualified study personnel will document the process of obtaining informed consent within 
the source record. Signed ICFs are maintained in the subject’s source records and must 
be accessible for verification at any time. 
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all study-related procedures. SIDs are a combination of a 
up to two alpha letters study code, two alpha letter Country code, two digit site number, 
plus 3-digit subject number starting with 001 (e.g., VNUS01001). Once assigned, SIDs 
cannot be reused for any reason. Information regarding the SID and screen date must be 
documented on a Screening log/system and in the Interactive Response Technology 
(IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated allocation 
schedule.  
 SAFETY EVALUATIONS 
6.3.3.1 PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100).  It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems.   
A targeted physical assessment will be performed at other visits as determined by 
the investigator or directed per subject complaints. 
6.3.3.2 VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 


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 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.3.3 WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.3.4 MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be obtained 
at screening. All relevant (as judged by the investigator) past and present 
conditions, as well as prior surgical procedures will be recorded for the main body 
systems.  
6.3.3.5 SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, history 
of prior cervical dysplasia, and pregnancy history will be obtained at Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to document 
any change from screening. 
6.3.3.6 LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 


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6.3.3.7 PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.3.8 ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has been 
in a supine position for 10 to 15 minutes. The ECG should include measurements 
of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, Twave as 
well as an investigator assessment of whether the ECG is normal or abnormal 
(automated interpretations of ECG should not be used). Abnormal ECGs should 
be interpreted as “clinically significant (CS)” or “not clinically significant (NCS)” by 
the investigator. 
6.3.3.9 POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after the 
study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.3.10 
IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA® 2000. Study treatment plus EP must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is implanted 


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metal within the same limb. Any device implanted in the chest (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal) excludes the use of the deltoid 
muscle on the same side of the body. The timing of the initial dose will be designated Day 
0 with the subsequent doses scheduled for administration at Weeks 4, 12, 24, and at 
Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 RISKS OF TREATMENT PROCEDURES TO VGX-3100 
Table 9 summarizes reported AEs and potential risks of VGX-3100. 
Table 9. Summary of Reported Adverse Events and Potential Risks of VGX-3100 Delivered 
IM EP with CELLECTRA® 2000 
Very Common  
 
Mild to moderate injection site pain or tenderness 
 
Malaise/fatigue, myalgia, or headache in the first few days following 
injection 
 
Upper respiratory tract infection 
 
Brief muscle contractions which may be uncomfortable 
 
Nausea 
Common  
 
Arthralgia 
 
Injection site reactions such as erythema, pruritus, swelling, 
hematoma 
 
Anxiety related to the administration procedure 
Less Common  
 
Severe injection site pain or tenderness 
 
Vasovagal 
reaction/lightheadedness/dizziness 
related 
to 
the 
administration procedure 
 
Temporary bleeding at the injection site 
 
Rash following administration  
Uncommon or 
rare  
 
Injection 
site 
reactions 
such 
as 
laceration, 
induration, 
bruising/ecchymosis, or scab  
 
Infection at the injection site  
 
Muscle damage resulting in transient changes in creatine 
phosphokinase  
 
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  
 
Chills, flu-like syndrome 
 
Autoimmune disease 
 
Electrical injury1 
 
Disruption of function of implanted electronic medical devices (if 
CELLECTRA®  2000 device is not used per User Manual)1 
 
Exacerbation of unstable cardiac disease1 
 
Effects on the fetus and on pregnancy 
1device only 


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6.4.1.2 RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
In controlled clinical trials for genital warts, the most frequently reported adverse reactions 
were local skin and application site reactions.  Table 10 summarizes local skin reactions 
assessed by the Investigator in the treatment area of females taking imiquimod cream, 
5% cream for external genital warts [30].   
 
Table 10.  Summary of Reported Adverse Events in 114 females taking imiquimod cream, 
5% for external genital warts 
 
 
Imiquimod Cream, 5% 
N =114 
Erythema 
74 (65%) 
Erosion 
35 (31%) 
Excoriation/Flaking 
21 (18% 
Edema 
20 (18%) 
Scabbing 
4 (4%) 
Induration 
6 (5%) 
Ulceration 
9 (8%) 
Vesicles 
3 (3%) 
*All Grades: Mild, Moderate, or Severe 
 
Table 11 summarizes adverse reactions judged to be possibly or probably related to 
Imiquimod Cream, 5% and reported by more than 1% of subjects [30]. 
 
Table 11. Possibly or probably related Adverse Reactions to Imiquimod cream in > 1% of 
subjects 
Location of reaction 
Adverse reaction 
Application Site Disorders 
Burning, hypopigmentation, irritation, itching, pain, 
rash, sensitivity, soreness, stinging, tenderness 
Remote site reactions 
Bleeding, burning, itching, pain, tenderness, tinea 
cruris 
Body as a Whole 
Fatigue, fever, influenza-like symptoms 
Central and Peripheral Nervous 
System Disorders 
Headache 
Gastro-Intestinal System Disorders 
Diarrhea 
Musculo-Skeletal System Disorders 
Myalgia 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 
approximately 1.5 cm diameter amount will be applied with occlusion to the site of injection 
~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who receive 
a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours after 
receiving medication and should have arranged transportation to depart the study site. 
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Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a 
mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.3.6.  
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 minutes 
after each study treatment. Subjects will be advised to record local and systemic AEs for 
7 days after each study treatment on a PD which will be reviewed with study personnel at 
8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject’s CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be 
instructed to use the following grading scale: 
 
Table 12. 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 


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September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
*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 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes (PRO) 
instruments will be provided. The following PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [31]. SF-36v2™ will be administered at the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [32, 33] and will be 
administered with EQ-5D-5L as described below. 
3. WOMAN-PRO (WOMen with vulvAr Neoplasia): for measure of outcomes related to 
vulvar HSIL [18]. 
WOMAN-PRO and EQ-5D-5L will be administered together at the following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 


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 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
Administration of PRO instruments will be performed according to the validated procedure 
and guidelines of each respective instrument, except for some assessments for 
exploratory analyses. Additional instructions will be provided separately.    
4. Additional Global PRO Questions – regarding quality of life after surgery or biopsy.  
These two questions will be administered at Week 52 only. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity 
may occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-
γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
6.10 
TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses 
have been rendered, then unstained slides and/or the relevant paraffin blocks may be 
collected for immunohistochemistry (IHC).  Assessment of markers may include, but are 
not limited to, CD8+ and FoxP3+ infiltrating cells as well as assessment of cell death via 
Cleaved Caspase 3 assessment. Additional assessments may include visualization of 
Granulysin, Perforin, CD137, CD103 and PD-L1 in cervical tissue as sample allows.  
Markers listed here may change as new relevant information becomes available. 
6.11 
HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 


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6.12 
VULVAR HPV TESTING 
A 4 mm vulvar punch biopsy sample will be obtained at Screening, Weeks 48, 74, and 96, 
and will be sent to a central laboratory for HPV genotyping by PCR.  In the case of 
multifocal disease, a 4 mm vulvar biopsy will be obtained from two regions of most 
advanced and severe disease as judged by the investigator.  The subject will be requested 
to abstain from sexual activity and refrain from use of douching vulvar biopsy samples to 
eliminate potential interference with the results of HPV testing. 
6.13 
COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Screening and at Week 96 for all subjects.  
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep™ test kits at Screening, Weeks 27, 48, 74 
and 96, and read in a central laboratory. HPV PCR will be performed on the ThinPrep™ 
specimen. At each of these visits, menstrual cycle status & recent history will be collected 
via self-report.  If the Pap smear result suggests progression to cancer the investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples to eliminate potential interference with the results of HPV testing. 
6.14 
VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL confirmed 
by the PAC.  Subjects will undergo vulvoscopy to identify the lesion(s). Digital photographs 
of the vulva will be captured after application of acetic acid to document the clinical 
findings.  If a biopsy or surgical excision is performed, images of the vulva should be 
collected before and after the procedure.  Each site will be instructed on 1) the technique 
for capturing the proper images using a standard approach, and 2) the process for 
uploading the images to a secure server.   
In the case of multifocal disease, the two lesions which appears to have the highest 
likelihood according to the investigator of most advanced disease and which is of 
adequate size to ensure that a visible lesion remains after punch biopsy should be chosen 
for vulvar biopsy and documented using photography.     
Interval vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96.  An 
unscheduled biopsy may be performed at the discretion of the investigator if there is 
suspicion of disease progression. Guidelines for managing the findings of unscheduled 
biopsies for suspected disease progression are described in Table 13.  Consult the 
Medical Monitor for any planned departures from these guidelines. 
 


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Table 13:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 
Subject safety is paramount in this study. Therefore, if at any time the investigator may 
suspect disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over the 
default “Schedule of Events”, Table 1. 
6.15 
CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. Medical procedures performed within 8 weeks prior to 
screening biopsy date of eligible subjects that do not affect subject’s eligibility for 
participation and during the study (including over the counter or herbal), will be recorded 
on the CRFs. This information will be obtained from the subject and abstracted from any 
available medical records. The indication for the medication, dose, and dose regimen will 
be documented. Medication that is considered necessary for the subject’s safety and well-
being may be given at the discretion of the investigator and recorded in the appropriate 
sections of the CRF. 
6.16 
RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day 
of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic corticosteroids 
are allowed) 
 
Disease 
modifying 
doses 
of 
anti-rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs 
such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at screening and 
throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
investigator and/or other study personnel. 


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Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1).  Lapses in contraceptive use should be reported to investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples.  
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and unsolicited 
AEs will be monitored and reported on an AE CRF, including the event’s seriousness, 
severity, action taken, and relationship to investigational product(s). AEs should be 
followed until resolution or stable and the outcome will be documented on the appropriate 
CRF. All AEs should be recorded in standard medical terminology rather than the subject’s 
own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.9 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the duration 
of the study, including the follow-up off study drug period will be recorded as an 
AE. 
 
Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit that do not worsen. 
 
Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions). 


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 
Overdose without clinical sequelae. 
 
Any medical condition or clinically significant laboratory abnormality with an onset 
date before the informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
 SERIOUS ADVERSE EVENTS 
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; 
 
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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 2) 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, 3) the 
development of drug dependency or drug abuse or 4) the development of a 
malignancy; 
 
Is medically significant or requires intervention to prevent one or other of the outcomes 
listed above. 
 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 that the subject has been formally admitted to a 
hospital for medical reasons, for any length of time. This may or may not be 


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overnight. It does not include presentation and care within an emergency 
department nor does it include full day or overnight stays in observation status. 
 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 9.5. 
 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE.  For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of adenocarcinoma-in-
situ or adenocarcinoma should also be reported as an SAE.  In both instances the 
condition for SAE reporting should be categorized as a medically important event unless 
another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal 
product related to any dose, for which a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility; i.e., there is evidence to suggest 
a causal relationship between the product and the adverse event. An unexpected ADR is 
one, the nature or severity of which is not consistent with the applicable product 
information (investigator’s brochure, protocol, and user manual). Reports that add 
significant information on specificity or severity of a known, already documented SAE 
constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator's Brochure or protocol would be considered "unexpected.” 
Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent 
new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a 
serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the SUSAR 
will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating investigators of information that might materially influence the 
benefit-risk assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. Examples of such information 
include a clinically important increase in the rate of occurrence of a serious expected 
adverse event, the identification of a significant hazard to the subject population, or a 
major safety finding from a study conducted in animals. 


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 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
investigator within 24 hours. Sponsor will assess each device related SAE to determine if 
anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be assessed 
as not related to the IP and/or the investigational device. Because the investigator is 
knowledgeable about the subject (e.g., medical history, concomitant medications), 
administers the IP, and monitors the subject’s response to the IP, the investigator is 
responsible for reporting adverse events and judging the relationship between the 
administration of the IP and device and a subsequent AE. 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 IP delivered by EP 
and determine whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation of 
any potential alternative causes to determine whether or not an adverse event is 
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accordingly. Causality should be assessed by the investigator as “yes, related” or “no, 
unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications known 
to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory 
or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition of an AE (or SAE) as described in Section 7.1. If the laboratory abnormality 
is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory 
result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency from 
the baseline condition and meets one of the following criteria will be recorded as an AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the investigator as clinically significant 
 POST-TRIAL 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 or termination visit and the event is deemed by the investigator to be related 
to the study treatment, he/she should promptly document and report the event to the study 
team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be excluded 


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from participation in the study. Should a subject become pregnant after enrolling in the 
study, she will not be given any further study treatments. A Pregnancy Form will be 
completed by the site personnel and submitted to the sponsor within 24 hours after 
learning of the pregnancy.  Site personnel will submit the Pregnancy Form to the Sponsor 
as described in Section 7.4.2. 
The investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject’s permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results will 
be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be performed. 
Investigators should use clinical judgment regarding subsequent study-related blood 
collection based on the presence or absence of anemia in each subject. Subjects who are 
not withdrawn will continue to be followed for safety assessments to study discharge per 
protocol.  
All pregnancies that occur from the time of first study treatment through the follow up visits 
must be reported. The investigator will monitor the subject and follow the outcome of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the 
outcome will be reported directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when informed 
consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading 
question such as ‘How have you been feeling since your last visit?’ is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator 
to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the 
investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
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 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented  
 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100 delivered with CELLECTRA® 2000 that require expedited communication from the 
site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration recorded 
≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
 
Grade 3 or greater laboratory abnormalities 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and Principal Investigator and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
Treatment;  
 
Three or more subjects in the same treatment arm discontinue due to an AE related 
to the Study Treatment; 
 
Any subject experiences an SAE (or potentially life threatening AE or Grade 4 AE) or 
death assessed as related to Study Treatment; 
 
Two or more subjects within a treatment arm experience the same or similar grade 3 
or 4 adverse event, assessed as related to Study Treatment;  
 
Four or more subjects across all treatment arms experience the same or similar grade 
3 or 4 adverse event, assessed as related to Study Treatment; 
 
Any report of anaphylaxis assessed as related to Study Treatment. 
Upon conclusion, the sponsor or designee will notify all investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 


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7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), whether 
volunteered by the subject, discovered by investigator or study staff questioning, or 
detected through physical examination, laboratory test or other means, will be collected 
and recorded in the subject’s source documents and followed as appropriate. 
TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised of 
the period following the signing of the informed consent form until the end of the study. 
Each AE will be assessed to determine whether it meets seriousness criteria. If the AE is 
considered serious, the investigator should record this event in the EDC system and report 
the event to the Sponsor within 24 hours of becoming aware of the event. The investigator 
may also directly report this event to the Ethics Committee according to its standard 
operating procedures. Expectedness of SAEs will be determined by the Sponsor using 
reference safety information specified in the Investigator’s Brochure and protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.6 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.7 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the Institutional Review Board (IRB)/Ethics Committee (EC) as 
soon as is practical, of serious events in writing where this is required by local regulatory 
authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an investigator becomes aware 
of an SAE that is suspected by the investigator to be related to the study drug, the event 
will be reported to the Sponsor or its designee. If the investigator becomes aware of an 
SAE in a study subject after the last scheduled follow-up visit, and considers the event 
related to prior Study Treatment, the investigator will report it to the Sponsor or the 
appropriate designee. 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
, M.D., Ph.D. 
EMAIL:  safety.inovio@apcerls.com 
  
SAFETY FAX: 
 
SAFETY PHONE:
 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address as 
indicated above.  Any SAE supporting documents provided by facsimile (Fax) are to 


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include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The investigator will supply the Sponsor and the IRB with more information as it becomes 
available and any additional requested information. The original SAE form must be kept 
at the study site. The Sponsor or its representative will be responsible for determining 
and in turn, reporting SAEs to regulatory authorities according to the applicable regulatory 
requirements. SAEs must be followed by the investigator until resolution, even if this 
extends beyond the study-reporting period. Resolution of an SAE is defined as the return 
to baseline status or stabilization of the condition with the expectation that it will remain 
chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the investigator will submit a Pregnancy Form to the Sponsor 
or designee to the safety email address or fax number within 24 hours of learning of the 
pregnancy. 
 NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later than 
10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 15 days for 
all other SUSARS (see Section 7.1.6 and 7.1.7). 
 REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device such as malfunction, misuse or use error 
and inadequate labeling. A malfunction is defined as the failure of a device to meet its 
performance specifications or otherwise perform as intended. The intended performance 
of a device refers to the intended use for which the device is labeled. All product 
complaints that meet this definition must be reported to the sponsor within 10 days of 
discovery.  Any product complaint that involves an AE or SAE must be also be reported 
per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the 
treatment procedure must be reported to the Sponsor or designee immediately for 
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Additional instructions on complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple 
sites for safety or administrative reasons at any time. In particular, a site that does not 
recruit at a reasonable rate may be discontinued. Should the study be terminated and/or 
the site closed for whatever reason, all non-source documentation and study product 
pertaining to the study must be returned to Inovio Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research subjects 
are protected. 
8. 
STATISTICAL ANALYSIS PLAN 
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and VGX-
3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and confirmed 
vulvar infection with HPV types 16 and/or 18. The study’s primary endpoint is binary: 
regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from vulvar tissue 
based on tissue collected at Week 48. The primary hypothesis is that each of the treatment 
arms will result in regression of HSIL and clearance. Secondary efficacy analyses pertain 
to regression, clearance of HPV-16 and/or HPV-18 infection, regression to normal, non-
progression, and anatomic extent. Other secondary analyses concern safety and humoral 
and cellular immunological measures. Exploratory efficacy analyses concern extended 
dosing with respect to regression, clearance, and anatomic extent, clearance outside of 
the vulva, and effect of HLA type on efficacy.  Other exploratory analyses pertain to tissue 
immunological measures, effect of needle depth into muscle on efficacy, and patient-
reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 
recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 
2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), 
and (d) age category (<45 years vs. ≥45 years).  There are no requirements for the number 
of subjects in each stratum.  The study is open-label. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each arm superior to historical control, assuming the true proportion 
of subjects who achieve the primary endpoint is 20% and 28% for the respective treatment 
arms and 2% for the historical control, and that 90% are evaluable at Week 48 from 
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8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized.  Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized.  
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy.  Subjects excluded from the PP population 
will be identified and documented prior to unblinding of the study database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects and will 
include the number and percentage randomized, the number and percentage who 
received each dose and the number who completed the trial.  The number and percentage 
of subjects who discontinued will be summarized overall and by reason.  The number in 
each analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the mITT population.  Prior 
and concomitant medications will also be summarized with percentages in this fashion. 
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by 
body system, by treatment arm, for the mITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (within 10 weeks 
prior to Day 0).  Concomitant medications are those used during the course of the trial (on 
or after Day 0).  Partial start dates of prior and concomitant medications will be assumed 
to be the earliest possible date consistent with the partial date.  Partial stop dates of prior 
and concomitant medications will be assumed to be the latest possible date consistent 
with the partial date.  Data for all prior and concomitant medications will be summarized 
with percentages by treatment arm, for the mITT population. 


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8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true population 
probability of the primary endpoint for each arm. The primary hypothesis of superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment arm separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the method of Clopper-Pearson. Superiority will be concluded if the 
one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds 
0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days prior 
to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) will 
be summarized with point estimates and associated Clopper-Pearson 95% confidence 
intervals. 
An exploratory analysis will examine clearance outside of the vulva.  This will be analyzed 
in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and HLA results. As these results are categorical, relationships will be examined 
with contingency tables and logistic regression models which model the primary endpoint 
versus these results and treatment group as regressor variables. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and needle depth into muscle. A logistic regression model which models the 
primary endpoint versus these results and treatment group as regressor variables will be 
used. 
8.10 
IMMUNOGENICITY ANALYSIS 
 
Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 
SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment arm. 
These frequencies will be presented overall and separately by dose, and will depict 


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overall, by system organ class and by preferred term, the percentage of subjects affected. 
Additional frequencies will be presented with respect to maximum severity and to 
strongest relationship to Study Treatment. Multiple occurrences of the same AE will be 
counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of any 
dose.  For this summary, the frequency of preferred term events will be summarized with 
percentages and 95% Clopper-Pearson confidence intervals.  Separate summaries will 
be based on events occurring within 7 days of any dose and regardless of when they 
occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be 
included within specified day-range summaries. AE duration will be calculated as (Stop 
Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment arm. 
Baseline is defined as the last measurement prior to the first treatment administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time point 
will be summarized by treatment arm and by body system, for the mITT population. 
 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or Clopper-
Pearson 95% CIs, for continuous responses and binary responses, respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 


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9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles 
of Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained 
from the applicable IRB/EC and a copy of this approval has been received by the 
sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 During the conduct of the study, submit progress reports to the IRB/EC as 
required.  
 Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 As required, obtain approval from the IRB/EC for protocol amendments and 
for revisions to the consent form or subject recruitment advertisements; 
 Reports on, and reviews of, the trial and its progress will be submitted to the 
IRB by the investigator at intervals stipulated in their guidelines and in 
accordance with pertinent regulations and guidelines. 
 Maintain a file of study-related information that includes all correspondence 
with the IRB; 
 Notify IRB when study is completed (i.e. after the last study visit of the final 
study subject); 
 After study completion provide the IRB with a final report on the study. 
9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., 
NIH Office of Biotechnology Activities) governing research that involves 
recombinant or synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening 
into the study, and/or from the subject’s legally authorized representative.  The 
process for obtaining informed consent must also be documented in the subject’s 
medical record. 


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9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating the 
study and re-approval or review at least annually.  Sponsor is to be notified immediately if 
the responsible IRB/EC has been disqualified or if proceedings leading to disqualification 
have begun.  Copies of all IRB/EC correspondence with the investigator must be provided 
to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and for subjects in the imiquimod 
arm a dosing log during their study participation.  Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation impacting 
Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject’s name will not be disclosed in these documents. 
The subject’s name may be disclosed to the study sponsor, Sponsor, the governing health 
authorities or the Food and Drug Administration (FDA), if they inspect the study records. 
Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information. 


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Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject’s legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA). 
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 the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. Examples 
of these original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subject’s 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 medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be 
present in the source documents. All prescription and nonprescription medications taken 
within l week prior to entry must be recorded on the CRF. Actual or estimated start and 
stop dates must be provided. 
10.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. The sponsor will inform the investigator/institution as to when these documents 
are no longer needed to be retained. 


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10.4 
SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial.  The DSMB will 
meet quarterly or as data are available to review unblinded safety data and 
regression/clearance results.  If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the 
meeting may be cancelled; Ad hoc meetings may be scheduled to review new data as 
applicable. The DSMB will be charged with advising the Sponsor if there appears to be a 
safety issue and with advising the Sponsor if it appears that regression in the VGX-3100 
group is unacceptably low compared to the placebo group. No formal interim analysis will 
be performed. The DSMB Chair, upon consultation with the other voting members of the 
DSMB, has the authority to recommend suspension or stopping the study and to request 
a full DSMB review and ad hoc statistical analyses.  The standard operating procedures 
of the DSMB will be documented in the DSMB charter, including the board’s accountability 
to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of a total of three pathologists. Each specimen will be read by two pathologists 
independently in a masked fashion.  If the two pathologists agree on the diagnosis then 
no further action is required and the clinical disease status for the subject will be 
established. If there is disagreement between the first two pathologists, the third 
pathologist will review and if there is agreement among any two of the three diagnoses, it 
will stand as the clinical disease status for that subject. If there is no agreement after the 
third review, the three reviewers will perform a simultaneous review and come to 
consensus or a majority rule of 2 of 3 if consensus cannot be reached. 
 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant 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 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 


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 
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 
 
Throughout the study, inspect all source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, and accurate 
(ALCOA).  
 
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 investigational drug and device accountability and reconciliation of  
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date of 
receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CMI 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
EC 
ECC 
EDC 
Ethics Committee 
Endocervical Curettage 
Electronic Data Capture 
EP 
DLT 
Electroporation with CELLECTRA® 2000 
Dose Limiting Toxicity 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 


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IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
PCR  
Pathology Adjudication Committee 
Polymerase Chain Reaction 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Participant Diary  
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper Limit of Normal 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
 


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13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Aldea M, Serrano B, Valencia S, Brotons M, Mena M, Cosano R, 
Muñoz J, Bosch FX, de Sanjosé S, Castellsagué X. Human Papillomavirus and Related 
Diseases in United States of America. Summary Report 2016-02-26. . In. Edited by 
Centre). IICoHaCHI; 2016. 
2. 
Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. 
J Natl Cancer Inst 2015,107:djv086. 
3. 
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
Sheets:  Vulvar Cancer. 2016. 
4. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
5. 
Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
6. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
7. 
Sideri M JR, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. Squamous 
vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology 
Subcommittee. J Reprod Med 2005,50:807-810. 
8. 
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: 
background and consensus recommendations from the College of American Pathologists 
and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 
2012,16:205-242. 
9. 
Inovio Pharmaceuticals. Unpublished assessment. 2015. 
10. 
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
natural history and outcome in 405 women. Obstet Gynecol 2005,106:1319-1326. 
11. 
van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
neoplasia III based on enough evidence? A systematic review of 3322 published patients. 
Gynecol Oncol 2005,97:645-651. 
12. 
Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
13. 
ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 
14. 
Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia 
(VIN) usual type after surgical treatment. Med Sci Monit 2011,17:CR532-535. 
15. 
ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
Obstet Gynecol. 2016,128:e178-182. 


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Clinical Protocol 
 
 
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16. 
Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
17. 
Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
Market Research. 2016. 
18. 
Senn B, Eicher M, Mueller MD, Hornung R, Fink D, Baessler K, et al. A patient-reported 
outcome measure to identify occurrence and distress of post-surgery symptoms of 
WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study. Gynecol Oncol 
2013,129:234-240. 
19. 
Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
excision for vulvar intraepithelial neoplasia. J Reprod Med 2007,52:23-27. 
20. 
Petrosky E, Bocchini JA, Jr., Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-
valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations 
of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 
2015,64:300-304. 
21. 
Future II Study Group.  Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
22. 
Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a 
practical approach to diagnosis. J Clin Pathol 2014,67:290-294. 
23. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
24. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
25. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
26. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
27. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
28. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
29. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
30. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
31. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
32. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
33. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA® 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
U.S. BB-IND #13683 
 
 
 
 
Version 1.2 
24 January 2017 
 
 


VGX-3100
HPV-201
Inovio Pharmaceuticals, Inc.
Clinical Protocol
Medical Monitor Approval Page
Drug:
VGX-3100
Sponsor:
lnovio Pharmaceuticals, Inc.
660W. Germantown Pike, Suite 110
Plymouth Meeting, PA 19462
Medical Monitor:
M.D., Ph.D.
lnovio Pharmaceuticals, Inc.
Approval Signature:
M.D., Ph.D.
Date
Inovio Pharmaceuticals, Inc.
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 lnovio Pharmaceuticals. Any
supplemental information added to this document is also confidential and proprietary
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner
as the contents of this document.
Version Date: 24]an2017
CONFIDENTIAL
v 1.2
Page 2 of 93


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Clinical Protocol 
 
 
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PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI’s approval of this 
protocol and provides the necessary assurances that this trial will be conducted in 
accordance with ICH/GCP and ISO guidelines, local legal and regulatory requirements, 
and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
____________________________________  
_________________________ 
<Insert Principal Investigator Printed Name>  
        Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


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Clinical Protocol 
 
 
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SUMMARY OF CHANGES 
 
The following are a list of protocol changes from Version 1.1 dated 20 January 2017 to 
Version 1.2 dated 24 January 2017.  All other changes are administrative and do not 
significantly affect the safety of subjects, trial scope, or scientific quality of the protocol. 
1. The WOMAN-PRO instrument has been removed from the list of Patient Reported 
Outcomes administered in Section 6.8 since the instrument is still under 
development.   
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................................... 5 
CLINICAL PROTOCOL SYNOPSIS ..................................................................................................... 10 
STUDY SCHEDULE OF EVENTS ........................................................................................................ 23 
1. 
INTRODUCTION ......................................................................................................................... 25 
1.1 
Background ..................................................................................................................... 25 
 
Human Papillomavirus and Infection ............................................................. 25 
 
Vulvar Cancer .................................................................................................... 25 
 
Vulvar Intraepithelial Neoplasia (VULVAR HSIL) ......................................... 25 
 
Recurrent Disease with Current Therapeutic Options ................................. 26 
 
Psychological and Physical Impacts of Current Therapeutic Options ...... 27 
 
Impact of Vulvar HSIL Upon Activities of Daily Living ................................. 27 
 
Limitations of Prophylactic HPV Vaccines .................................................... 27 
 
Enhanced Monitoring Plan ............................................................................... 28 
 
VGX-3100 ........................................................................................................... 28 
  Electroporation .................................................................................................. 28 
  Imiquimod Cream, 5% ...................................................................................... 29 
  Study Rationale ................................................................................................. 29 
  Dose and Regimen Rationale for VGX-3100 ................................................ 29 
  Rationale for imiquimod ................................................................................... 29 
  Potential Risks of investigational products .................................................... 30 
  Potential Benefits of Study Participation ....................................................... 30 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ........................................................................... 30 
2.1 
Primary Objective and Endpoint .................................................................................. 31 
2.2 
Secondary Objectives and Associated Endpoints .................................................... 31 
2.3 
Exploratory Objectives and Associated Endpoints ................................................... 33 
3. 
STUDY DESIGN ......................................................................................................................... 34 
3.1 
Treatment Regimens ..................................................................................................... 34 
3.2 
Efficacy Assessment ...................................................................................................... 35 
 
Definition of Responder and Non-Responder ............................................... 36 
3.3 
Safety Assessment ........................................................................................................ 37 
 
Data Safety & Monitoring Board ..................................................................... 37 
3.4 
Immunogenicity Assessment ........................................................................................ 38 
3.5 
Virologic Assessment .................................................................................................... 38 


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4. 
SELECTION OF SUBJECTS .................................................................................................... 38 
4.1 
Inclusion Criteria ............................................................................................................. 38 
4.2 
Exclusion Criteria ........................................................................................................... 39 
4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................... 41 
 
Criteria for Discontinuation of Investigational Product ................................ 41 
 
Criteria for Withdrawal from the Study ........................................................... 42 
 
Sponsor Notification of Discontinuation/Withdrawal .................................... 42 
 
Reason for Discontinuation/Withdrawal ......................................................... 43 
5. 
STUDY TREATMENT ................................................................................................................ 43 
5.1 
Investigational Products ................................................................................................ 43 
5.2 
Packaging and Labeling ................................................................................................ 44 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................... 44 
5.3 
Handling and Storage .................................................................................................... 45 
5.4 
Preparation and Dispensing ......................................................................................... 46 
 
Dispensing of VGX-3100 ................................................................................. 46 
 
Dispensing and Use of Imiquimod .................................................................. 46 
5.5 
Investigational Product Accountability ........................................................................ 46 
5.6 
Return and Destruction of Investigational Product ................................................... 47 
5.7 
Use of Investigational Device ....................................................................................... 47 
5.8 
Packaging and Labeling of Investigational Device ................................................... 48 
5.9 
Investigational Device Accountability .......................................................................... 50 
5.10 
Return of Investigational Devices ................................................................................ 50 
6. 
STUDY PROCEDURES AND TREATMENTS ....................................................................... 51 
6.1 
Before Treatment Procedures ...................................................................................... 51 
 
Screening evaluations ...................................................................................... 51 
 
Ultrasound Measure of Skin-to-Muscle and Related Thicknesses ............ 52 
6.2 
During Treatment Procedures by Visit ........................................................................ 53 
 
Day 0 ................................................................................................................... 53 
 
8-14 Days Post Dose 1 Phone Call ................................................................ 54 
 
Week 4 ................................................................................................................ 54 
 
8-14 Days Post Dose 2 Phone Call ................................................................ 55 
 
Week 12 .............................................................................................................. 55 
 
Week 15 .............................................................................................................. 56 
 
Week 24 .............................................................................................................. 56 
 
Week 27 .............................................................................................................. 57 


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Week 38 Phone Call ......................................................................................... 57 
  Week 48 .............................................................................................................. 57 
  Week 52 .............................................................................................................. 58 
  Week 74 .............................................................................................................. 58 
  Week 78 .............................................................................................................. 59 
  Week 96 .............................................................................................................. 60 
  Week 100 ........................................................................................................... 60 
6.3 
Evaluations and Procedures ........................................................................................ 61 
 
Informed Consent .............................................................................................. 61 
 
Assignment of Subject Identification Numbers ............................................. 61 
 
Safety Evaluations ............................................................................................ 61 
6.4 
Injection and Electroporation (EP) ............................................................................... 64 
 
Risks of Treatment Procedures ...................................................................... 64 
 
Management of Anxiety and Pain Due to EP Procedure ............................ 66 
6.5 
Assessment of Laboratory Abnormalities ................................................................... 67 
6.6 
Assessment of Clinical Study Adverse Events .......................................................... 67 
6.7 
Assessment of Injection Site Reactions ..................................................................... 67 
6.8 
Assessment of Patient Reported Outcomes .............................................................. 68 
6.9 
Peripheral Blood Immunogenicity Assessments ....................................................... 69 
6.10 
Tissue Immunogenicity Assessment ........................................................................... 69 
6.11 
HLA Typing...................................................................................................................... 69 
6.12 
Vulvar HPV Testing ........................................................................................................ 69 
6.13 
Colposcopy, PAP Smears and HPV Testing ............................................................. 70 
6.14 
Vulvoscopy, Photographs, and Biopsies .................................................................... 70 
6.15 
Concomitant Medications/Treatments ........................................................................ 71 
6.16 
Restrictions...................................................................................................................... 71 
  Other Restrictions ............................................................................................. 71 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY .................................... 72 
7.1 
Safety Parameters ......................................................................................................... 72 
 
Adverse Events ................................................................................................. 72 
 
Serious Adverse Events ................................................................................... 73 
 
Clarification of Serious Adverse Events ........................................................ 73 
 
Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ...................................................................... 74 
 
Unexpected Adverse Drug Reactions and Expedited Reporting ............... 74 


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Unanticipated (Serious) Adverse Device Effect (UADE) ............................ 74 
 
Assessing Severity (Intensity) ......................................................................... 75 
 
Casual Relationship of Clinical Material to Adverse Events ....................... 75 
 
Abnormal Laboratory Value ............................................................................. 76 
  Post-Trial Reporting Requirements ................................................................ 76 
  Procedures for Documenting Pregnancy During Study .............................. 76 
7.2 
Methods and Timing of Collection of Safety Data ..................................................... 77 
7.3 
Safety and Toxicity Management ................................................................................ 77 
 
Adverse Events of Special Interest ................................................................ 78 
 
Stopping Rules (Criteria for Pausing of Study) ............................................. 78 
7.4 
Adverse Experience Reporting .................................................................................... 78 
 
Trial Reporting Period of Adverse Events ..................................................... 79 
 
Trial Reporting Period of Serious Adverse Events ...................................... 79 
 
Notification of Serious Adverse Events ......................................................... 80 
 
Reporting of Device Related Complaints ...................................................... 80 
7.5 
Trial Discontinuation ...................................................................................................... 80 
8. 
STATISTICAL ANALYSIS PLAN ............................................................................................ 81 
8.1 
General Considerations ................................................................................................ 81 
8.2 
Randomization and blinding ......................................................................................... 81 
8.3 
Sample Size/Power ........................................................................................................ 81 
8.4 
Analyses Populations .................................................................................................... 81 
8.5 
Subject Disposition ........................................................................................................ 82 
8.6 
Demographic and Other Baseline Characteristics .................................................... 82 
8.7 
Medical History ............................................................................................................... 82 
8.8 
Prior and Concomitant Medications ............................................................................ 82 
8.9 
Efficacy Analysis ............................................................................................................ 82 
8.10 
Immunogenicity Analysis .............................................................................................. 83 
8.11 
Safety analyses .............................................................................................................. 83 
  Adverse events .................................................................................................. 83 
  Laboratory data ................................................................................................. 84 
  Vital Signs .......................................................................................................... 84 
  Physical Examination ....................................................................................... 84 
  Patient Reported Outcomes ............................................................................ 84 
  Missing Values .................................................................................................. 84 
  Interim Analysis ................................................................................................. 84 


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9. 
ETHICS ......................................................................................................................................... 84 
9.1 
Investigator and Sponsor Responsibilities ................................................................. 84 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ...................................... 85 
9.3 
Office of Biotechnology Activities (OBA) .................................................................... 85 
9.4 
Compliance with Informed Consent Regulations ...................................................... 85 
9.5 
Compliance with IRB/EC Requirements ..................................................................... 85 
9.6 
Compliance with Good Clinical Practice ..................................................................... 86 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 .......................................................................................................................................... 86 
9.8 
Compliance with Protocol ............................................................................................. 86 
9.9 
Changes to the Protocol ................................................................................................ 86 
10. 
DATA COLLECTION, MONITORING AND REPORTING ................................................... 86 
10.1 
Confidentiality and Privacy ........................................................................................... 86 
10.2 
Source Documents ........................................................................................................ 87 
10.3 
Records Retention ......................................................................................................... 87 
10.4 
Safety and Quality Monitoring ...................................................................................... 87 
  Data & Safety Monitoring Board ..................................................................... 87 
  Pathology Adjudication Committee ................................................................ 88 
  Clinical Monitoring ............................................................................................. 88 
11. 
PUBLICATION POLICY ............................................................................................................ 89 
12. 
LIST OF ABBREVIATIONS ...................................................................................................... 90 
13. 
REFERENCES ............................................................................................................................ 92 
 
 
 


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CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA® 2000  Alone or in Combination 
With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 20 sites in the 
United States (US) 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-
16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000  given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA® 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3X) from Day 0 through Week 202 
No. of Subjects 
Approximately 36 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic clearance 
of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar HSIL3 
and no evidence of HPV-16/18 at Week 48 in vulvar tissue 
samples (i.e. collected via biopsy or excisional treatment)4 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3  No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
4  A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive non-study related medication for treatment of 
VIN lesions. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, AIS, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions.   


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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar  HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/186 in vulvar tissue samples at 
Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL and no evidence of 
condyloma on histology (i.e. biopsies or 
excisional treatment) at the Week 48 visit
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion 
of 
subjects 
with 
no 
progression7 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of vulvar 
lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 48, 74 
and 96 compared to baseline8. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
                                                     
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
6 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
7 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
8 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96  
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects who did not have 
complete lesion resolution at Week 48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 74 and/or 
Week 96 compared to baseline9. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior  
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 
infiltrating cells10.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the vulva  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from other 
anatomic locations without surgical 
intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week  48 
                                                     
9 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
10 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Assess 
skin-to-muscle, 
skin-to-bone, 
and 
muscle thicknesses via ultrasound measure of 
deltoid (or quadriceps if applicable) and the 
correlation of needle depth into muscle with 
efficacy. 
7.  Ultrasound-measured skin-to-muscle, 
skin-to-bone, and muscle thicknesses  
8. Describe patient reported outcomes for subjects 
treated with VGX-3100 and VGX-3100 with 
imiquimod 
8.  Patient-reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and 
following each of the first four doses, 
and at Weeks 48, 52, 74, 96, and 100. 
 
 


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Study Design: 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered with 
CELLECTRA® 2000 alone or in combination with imiquimod in adult women with histologically confirmed 
vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled.  
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-3100 
and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass Index 
(BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-5D-5L 
(EuroQol Research Foundation), and two additional PRO questions assessing quality of life after 
surgery or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of a 4 mm vulvar 
punch biopsy/biopsies with lesion remaining, and photographs of the acetowhite vulvar lesion(s) at the 
time of screening. In the case of multifocal disease, the two regions of potentially most advanced and 
severe disease, as judged by the investigator, should be chosen for biopsy using vulvoscopy and 
documented using standardized high resolution photography with a digital single-lens reflex (SLR) 
camera, on the case report form. Biopsy slides or tissue will be sent to a Pathology Adjudication 
Committee (PAC) for evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must 
assign the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar 
tissue specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study.
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of VGX-
3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject’s biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of VGX-
3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic and 
lesion area changes.  The first dose will be administered on Day 0, the second at Week 4, the third at 
Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 48 
(Subgroups A and B) will receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator.  Subjects in Subgroup E may receive surgical treatment per the 
judgement of the Investigator.  All subjects are scheduled to be followed to Week 100.  
 
 
 


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Figure 1: Study Visit Schedule 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will apply imiquimod 
5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to apply imiquimod 
cream three times per week for 20 weeks (inclusive of administration in the evening of VGX-3100 
dosing).  Subjects unable to tolerate imiquimod treatment may reduce their dosing frequency, and will 
document their use on the imiquimod dosing log provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by visual inspection with vulvoscopy is insufficient evidence 
to confirm disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74, and 96. Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), 
defined as areas that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0, and 
Weeks 4, 12, 27, 48, 74 and 96. Using standardized high resolution digital imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 3 
for Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC there is no 
evidence of HSIL (Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and biopsy 
adjacent to the site of the initial biopsy. Repeat biopsies that are indicated beyond Week 48 must be 
taken from the same lesion, adjacent to the prior biopsy site(s) within the boundaries of the original 
lesion.  
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size or no change 
in lesion size from baseline (Subgroups C or D), the Investigator has the option to give the subject a 5th 
dose of VGX-3100 at Week 52, and the subject will continue on study with vulvoscopy and biopsy at 


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Week 74.  Alternatively, the Investigator may choose to treat the subject with surgical or standard 
treatment, and the subject will continue on study without further biopsy.   
 
Figure 2: Decision process at Week 52  
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as follows: 
At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion as study 
start, but adjacent to the original site within the boundaries of the original lesion (see Table 3). If after 
evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject 
will continue to Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at Week 
78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, the 
Investigator may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy.   
 
 
 
 
 
 
 


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Figure 3: Decision Process at Week 78 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 3). 
If there is no vulvar HSIL (Subgroups A or B), no further procedures are required. If after evaluation of 
biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), 
the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 


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In the event of worsening disease at any time (ie, Subgroup E – any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per the 
Investigator’s judgement and will continue on study through Week 100 with vulvoscopy, but without 
further biopsy.  For a finding of carcinoma, subjects will receive surgical treatment, and be discontinued 
from study treatment.  The event will be reported as an SAE per section 7.1.4.  If wide excision is 
required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder: 
Responder and non-responder definitions (Table 4) take into account both histopathologic regression 
of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since HPV persistence is an 
important factor in the clinical progression of HSIL. A treatment responder is defined as a subject with 
no histologic evidence of vulvar HSIL and no evidence of HPV-16 or HPV-18 in vulvar tissue at 
evaluation and who did not receive non-study related medication for treatment of VIN lesions.  A 
treatment non-responder is a subject with histologic evidence of vulvar HSIL, adenocarcinoma-in-situ, 
or vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions. Any case of 
histologically confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. No formal interim 
analysis is planned. The following stopping rules will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, assessed 
as related to study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal Investigator 
for the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding the outcome of 
any investigation stemming from a Study Pause.  


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Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (both Screening as well 
as Day 0 prior to dosing) and at Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and at Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize HPV infection at Screening, 
Week 48, 74 and 96. Cervical samples, oropharyngeal rinse samples, vaginal, and intra-anal tissue 
swab samples will be obtained to characterize HPV infection in samples from study subjects taken at 
Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and intra-anal only) and at Weeks 
27, 48, 74, and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks will be collected for immunohistochemistry (IHC) 
and in situ hybridization (ISH) for the presence of HPV-16/18. Whenever possible, these studies will be 
performed on tissue sections from the diagnostic biopsy (pre-dose) and from tissue obtained post-dose 
(Week 48, 74 and 96). 
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
relationship between subject HLA haplotypes and regression.  


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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above; 
3. 
Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. 
Vulvar tissue specimen/slides provided to the Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
5. 
Histologic evidence of vulvar HSIL as confirmed by the PAC at screening; 
6. 
Must be judged by investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
7. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system; 
iv) Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject. 
10. Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 


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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing treatment for CIN;
5) Biopsy-proven differentiated VIN; 
6) More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day of first 
dose (i.e. Day 0); 
7) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
8) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
9) Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into cervical 
canal at screening; 
10) History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, or insufficient 
for diagnosis (ECC is not performed as part of study screening) and did not receive definitive 
treatment; 
11) Treatment for genital warts within 4 weeks prior to screening; 
12) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
13) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last dose 
of investigational product; 
15) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the investigator; 
16) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying drugs such as 
TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
17) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
18) Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
20) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the investigator; 
21) Current or history of clinically significant, medically unstable disease which, in the judgement of the 
investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results (e.g. chronic renal failure, angina, 
myocardial ischemia or infarction, class 3 or higher congestive heart failure, cardiomyopathy, or 
clinically significant arrhythmias); 
22) Malignancy or treatment for malignancy within 2 years of screening, with the exception of superficial 


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skin cancers that only require local excision; 
23) Acute or chronic bleeding or clotting disorder that would contraindicate IM injections or use of blood 
thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 
24) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic agents; 
25) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at Screening or 
Day 0; 
27) Prior major surgery within 4 weeks of Day 0; 
28) Participated in an interventional study with an investigational compound or device within 4 weeks of 
signing informed consent (participation in an observational study is permitted); 
29) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
30) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
31) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in 
ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
32) Metal implants or implantable medical device within the intended treatment site (i.e. electroporation 
area);  
33) Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with 
adherence to study requirements; 
34) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (i.e. infectious disease) illness; 
35) Active military service personnel; 
36) Study-related staff or family members of study-related staff; 
37) 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.  


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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Vital signs 
Xb 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xe 
 
Xf
 
Xe 
 
Xe
 
Xe 
 
HLA testing g 
 
X 
Cervical cytology, ThinPrep™ h 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject  VGX-3100 +EP m 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Review PD o 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X-----------------------------------------------------------------------------------------------------------X 
Ultrasound Measure of skin-to-
muscle and related thicknesses 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X
Abbreviations: OP; oropharynx 


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a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE. 
b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared).  Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 30 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27. 
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrepTM cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected.  Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j Standardized high resolution digital imaging of the vulva and the associated acetowhite stained lesion(s) 
must be performed prior to and after biopsy, and at all vulvoscopy examinations. Additionally, 
standardized high resolution digital imaging should be obtained during examinations of the vagina if 
lesions are identified, for documentation. 
k Tissue specimen and slides from all excised tissue must be reviewed by the PAC and residual vulvar 
tissue from entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) should be 
sent to the central pathology laboratory for immunohistochemistry (IHC) and HPV testing.   
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod.  
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36, EQ-5D-5L) plus two additional questions will be assessed as described in Section 
6.8.     
 
 
 


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1. 
INTRODUCTION 
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, 
and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the most 
significant amongst high-risk types since they are responsible for most HPV-caused 
cancers [1].   
HPV-16 is involved in more than 85% of HPV-associated vulvar HSIL cases in the U.S.[1]. 
Persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions 
(HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oro-pharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS)[2].  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 5,950 new cases and 1,110 
attributable deaths annually for year 2016 in the United States [3]. Vulvar cancers consist 
largely of squamous cell carcinomas and accounts for approximately 5% of all female 
genital malignancies [4]. Differentiated VIN, which is typically not caused by HPV infection 
and is more typically found in older women, is more likely to progress to cancer more 
rapidly than HPV-associated-VIN. The five year overall relative survival for vulvar cancer 
in the U.S. is 70.7% [3].  Recurrent vulvar cancer occurs in an average of 24% of cases 
after primary treatment, after surgery with or without radiation [5].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia.  The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance of 
pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [6]    
In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) replaced 
the three grade classification system with the current single grade classification for which 


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only high grade VIN (2/3) is classified as VIN [7]. In 2012, the Lower Anogenital Squamous 
Terminology (LAST) Standardization Project for HPV-associated lesions applied the term 
high grade squamous intraepithelial lesion (HSIL) to encompass high grade dysplasia [8].  
Therefore, for the purpose of this study, the term vulvar HSIL will be used, which 
encompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to encompass what 
was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [9]. Over time, typically years, vulvar HSIL can progress to invasive 
cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group and median 
13.8 years in another group [10], and from VIN3 patients, mean = 2.5 years, range: 4 – 
216 months [11].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity against 
vulvar HSIL and have not achieved universal uptake, leaving a population of susceptible 
and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to visual 
inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for vulvar 
HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, often 
requiring multiple, repeat treatments. Progression to vulvar cancer following current vulvar 
HSIL treatments can also occur within 1 year of treatment and for up to 20 years post 
treatment. The current treatment options for vulvar HSIL are surgical excision, laser 
ablation, and off-label medical therapy. The rate of HPV-associated vulvar HSIL 
recurrence after surgical treatment is high; post-treatment recurrence rates exceed 30-
50% with all currently available treatment regimens [12, 13].   
Wide local excision is the ‘preferred initial intervention’ by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation.  Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues with 
body image and sexual dysfunction.  Medical therapies have been investigated as a 
means to avoid these negative outcomes.  Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food and 
Drug Administration for this indication.  Inconsistent treatment efficacy results have been 
shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 
of recurrence is slightly higher compared to wide local excision. Laser treatment of vulvar 
HSIL requires destruction of cells through the entire thickness of the epithelium including 
hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation should 


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extend through the dermis. Post-treatment recurrence rates exceed 30% (for all treatment 
regimens), and is higher with positive excision margins [14]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low rate 
of spontaneous resolution.  According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is suspected 
(even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is wide local 
excision (i.e. surgery) [15].  When occult invasion is not a concern, vulvar HSIL can be 
treated with excision, laser ablation, or topical imiquimod as an off-label medical therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [14].  Therefore, many patients have a fear 
of recurrence and progression to cancer [16].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks.  
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid use of toilet paper and to rather rinse with warm water.  
During recovery, common effects include pain in urinating and wiping, soreness, difficulty 
sitting, and feeling tired [17]. In the first week after hospital discharge, common patient-
reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [18].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-being 
[17].  The symptoms and signs of vulvar HSIL can be moderate to severe and include 
painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating [18]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than age-
matched healthy women [19]. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor’s office all the time [17]. 
 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid HPV-associated vulvar HSIL 
and subsequent vulvar cancer. The US-licensed prophylactic HPV vaccines are indicated 
for girls and women ages 9 through 26 years for Gardasil® and Gardasil®9 (Merck & Co. 
Inc.), and ages 9 through 25 years for Cervarix® (GlaxoSmithKline). The early portions of 


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these age ranges are generally before sexual debut and thus can allow immunologic 
protection against the anticipated earliest normal exposures to HPV infection. HPV 
prophylactic vaccination is highly effective and safe, and routine vaccination is 
recommended for females in the United States starting at age 11 or 12 years [20]. 
However, the prophylactic vaccines have no therapeutic effect upon existing HPV infection 
or existing HPV-related intraepithelial neoplasia [21]). 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan is used in this study to address the risk of a potential delay 
in treatment of vulvar HSIL.  The feasibility of this approach was demonstrated in the 
Phase 2b study of cervical HSIL.  Given that vulvar disease progresses slowly to vulvar 
cancer if untreated, the proposed enhanced monitoring plan is expected to maintain the 
safety of trial subjects for this study.  First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study investigators.  Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, by 
two independent expert pathologists (pathology adjudication committee). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
[22], is specifically excluded from study entry.  By contrast, HPV-associated vulvar HSIL 
does not progress rapidly, typically taking years to manifest and progress, making 
enhanced monitoring feasible.   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.14).  Colposcopy will also be 
done at baseline and during the study given that concurrent disease in the lower genital 
tract can occur.   A Data Safety Monitoring Board will be utilized to review subject safety 
data and advise on any study-level safety concerns. Investigators always have the option 
of performing ad hoc vulvar biopsies to rule out disease progression.  Additional treatment 
(e.g., additional excision, ablation, or medical therapy) may be carried out, if deemed 
necessary according to Investigator judgement. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA® device represent an integrated investigational 
product designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, 
CIN3) via an immune response directed against HPV-16/18.  Further information about 
VGX-3100 is provided in the Investigator’s Brochure. 
 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA® in vivo electroporation (EP) device. EP is 
a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [23, 24]. Electroporation increases the uptake of plasmid 
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10 to 100 fold [25, 26]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as shown 
by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [27].  
This study will use the CELLECTRA® 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no significant 
safety issues identified.  Further information about the CELLECTRA® 2000 device can be 
found in the Investigator’s Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device.  Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 250 
mg of the cream, equivalent to 12.5 mg of imiquimod.  The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod.  The overall aim is to determine if treatment with VGX-3100 could allow women 
with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of concept that 
VGX-3100 can induce resolution of both HPV-associated dysplastic lesions and the 
underlying HPV 16/18 infection was shown in a Phase 2b study of cervical intraepithelial 
neoplasia (CIN).  The similar underlying pathogenic mechanisms between cervical and 
vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could be a non-
surgical therapeutic option for the treatment of vulvar HSIL, which is a significantly under 
met medical condition.  A VGX-3100 with imiquimod-administration arm is also included, 
given the prevalent use of imiquimod as a topical medical treatment of vulvar lesions, to 
investigate if a more robust immune response is achieved with VGX-3100, to potentially 
increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 
responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [28].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Imiquimod may be able to be used synergistically with 
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Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG).  Published regimens include three times weekly 
application to affected areas for 12 – 20 weeks, with colposcopic assessment at 4-6 week 
intervals during treatment [15].  
The current study will include an imiquimod arm with VGX-3100, to evaluate 
histopathologic regression of vulvar HSIL and virologic clearance of HPV-16/18, compared 
to the current body of knowledge in imiquimod alone.     
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 
reported at the application site [29].  The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity.  In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure including 
anesthesia, post-operative bleeding, infection, or damage to surrounding structures such 
as the clitoris, urethra, or anus. The other potential benefit is that the response to VGX-
3100 is systemic and may clear the underlying HPV infection, which is the root cause of 
vulvar HSIL.  Consequently, there is the potential to reduce the risk of recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL  associated with HPV-16 and/or HPV-18 (HPV-16/18), 
will result in a higher percentage of women with regression of HSIL of the vulva based on 
histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from 
vulvar tissue compared with historical control. 
 
 
 


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2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional treatment).  
2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL11 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/1812 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression13 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
                                                     
11 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
12 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
13 Progression is defined as advancement to carcinoma according to the Pathology Adjudication Committee by 
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6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
48, 74 and 96 compared to baseline14. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion size of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).  
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone 
or in combination with imiquimod,  post dose 
3, post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes 
at baseline and Weeks 15, 27, 48, 74 and 
96 visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 
                                                     
14 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe 
the 
efficacy 
of 
VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects without a 
complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
74 and/or Week 96 compared to baseline15. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in lesion 
area of 0-25%), partial lesion area resolution 
(>25% and <100% reduction), and complete 
lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6  doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, 
as 
measured 
by 
virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 infiltrating 
cells16.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the 
vulva   
5. Proportion of subjects who have cleared HPV-
16/18 on specimens from other anatomic 
locations 
without 
surgical 
intervention 
(inclusive of cervix, oropharynx, vagina and 
intra-anus) at Week  48 
6. Characterize 
HLA 
haplotypes 
and 
the 
correlation with efficacy 
6.  Proportion of subjects with regression of HSIL 
on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Assess skin-to-muscle, skin-to-bone, and 
muscle thicknesses via ultrasound measure 
of deltoid (or quadriceps if applicable) and the 
correlation of needle depth into muscle with 
efficacy. 
7. Ultrasound-measured skin-to-muscle, skin-
to-bone, and muscle thicknesses.  
8. Describe patient reported outcomes for 
subjects treated with VGX-3100 and VGX-
3100 with imiquimod 
8. Patient-reported outcome (PRO) endpoints 
will be obtained prior to first dose (Day 0), on 
the day of and following each of the first four 
doses, and at Weeks 48, 52, 74, 96 and 100.
                                                     
15 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
16 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA® 2000 alone or in combination with 
imiquimod in adult women with histologically confirmed vulvar HSIL associated with HPV-
16/18. Approximately 36 subjects will be enrolled.  Twenty-four subjects will receive VGX-
3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at 
screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category 
(<45 years vs. ≥45 years). 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be provided and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), and two additional PRO 
questions assessing quality of life after surgery or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of 
a 4 mm vulvar punch biopsy/biopsies with lesion remaining, and photographs of the 
acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, the 
two regions of most advanced and severe disease, as judged by the investigator, should 
be chosen for biopsy using vulvoscopy and documented using standardized high 
resolution photography with a digital single-lens reflex (SLR) camera on the case report 
form. Biopsy slides or tissue will be sent to a Pathology Adjudication Committee (PAC) for 
evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must assign 
the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a 
vulvar specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation 
in the study. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 mg 
of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-16/18 
status and all other eligibility criteria but no more than 10 weeks following collection of the 
subject’s biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid, preferred site, 
or anterolateral quadriceps, alternate site) followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes.  The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  
Subjects with HSIL at Week 74, who have a reduction in lesion size or no increase in 


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lesion size from baseline (Subgroups C or D), may receive a sixth dose of VGX-3100 
administered IM with EP at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgement of the Investigator.  All 
subjects will complete the study at Week 100. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will 
apply imiquimod 5% cream to the vulvar lesion beginning in the evening on Day 0, and 
will continue to apply treatment three times per week for 20 weeks (inclusive of 
administration in the evening of VGX-3100 dosing).  Subjects unable to tolerate imiquimod 
treatment may reduce their dosing frequency, and will document their use on the 
imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital imaging, vulvar lesion(s) will also be quantitatively 
measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 
mm in length. Visible lesion must remain after screening biopsy to ensure measurement 
on study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3 for Minimally Required Biopsy 
Procedures). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Figure 2, Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and 
biopsy adjacent to the site of initial biopsy.     
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size 
or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the Investigator 
has the option to give the subject a 5th dose of VGX-3100 at Week 52, and the subject will 
continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator 
may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3). If after evaluation of biopsy tissue by 
the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to 
Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no increase in lesion size from 
baseline (Subgroups C or D), the Investigator has the option to give the subject a 6th dose 
of VGX-3100 at Week 78, and the subject will continue on study with vulvoscopy and 


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biopsy at Week 96. Alternatively, the Investigator may choose to treat the subject with 
surgical or standard treatment, and the subject will continue on study without further 
biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 3). If there is no vulvar HSIL (Subgroups 
A or B), no further procedures are required. If after evaluation of biopsy tissue by the PAC 
there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), the subject 
will receive surgical or other standard treatment. 
In the event of worsening disease (ie, Subgroup E - any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per 
the Investigator’s judgement and will continue on study through Week 100 with 
vulvoscopy, but without further biopsy.  For a finding of carcinoma, subjects will receive 
surgical treatment, and be discontinued from study treatment.  The event will be reported 
as an SAE per section 7.1.4. If wide excision is required, the sample obtained will be sent 
to the PAC for evaluation.  
 
Table 3:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original biopsy site within the boundaries of the original 
lesion; 
Acetowhite Lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original site within the boundaries of the original lesion; 
biopsy of lesion must include suspected area of most 
advanced disease  
Multiple acetowhite lesions 
Vulvar punch biopsies and imaging; biopsy should be 
conducted of the same two lesions as study entry but 
adjacent to the original site within the boundaries of the 
original lesion; biopsies must include area of most advanced 
and severe disease as determined at screening  
 
  
 DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 4) take into account both histopathologic 
regression of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since 
HPV persistence is an important factor in the clinical progression of HSIL.  
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive non-study related medication for treatment of VIN lesions.  A treatment non-
responder is a subject with histologic evidence of vulvar HSIL, adenocarcinoma-in-situ, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, 
or a subject who received non-study related medications for treatment of VIN lesions. Any 


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case of histologically confirmed progression is considered a non-responder. Progression 
is defined as advancement to carcinoma by histology. 
Table 4: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSILa  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive non-study 
related medication for treatment of VIN 
lesions. 
 
Subject with histologic evidence of vulvar HSIL, 
Adenocarcinoma-in-situ (AIS), vulvar carcinoma at 
evaluation 
  
AND/OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related 
medication for treatment of VIN lesions 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight.  
The DSMB will meet quarterly to review safety data. The DSMB will be charged with 
advising the Sponsor if there appears to be a safety issue. No formal interim analysis is 
planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, Principal Investigator for the trial, and the DSMB. 


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 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately until 
a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) and at 
Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and at Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize HPV infection at Screening, Week 48, 74 
and 96. Cervical samples, oropharyngeal (OP) rinse samples, vaginal, and intra-anal 
tissue swab samples will be obtained to characterize HPV infection in samples from study 
subjects taken at Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and 
intra-anal only) and at Weeks 27, 48, 74 and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then unstained slides and/or the relevant paraffin blocks will be collected for 
immunohistochemistry (IHC) and in situ hybridization (ISH) for the presence of  
HPV-16/18. Whenever possible, these studies will be performed on tissue sections from 
the diagnostic biopsy (pre-dose) and from tissue obtained post-dose (Week 48, 74 and 
96).  
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. Vulvar tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
5. Histologic evidence of vulvar HSIL as confirmed by PAC at screening; 
6. Must be judged by investigator to be an appropriate candidate for the protocol-specified 


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procedure (i.e. excision or biopsy) required at Week 48; 
7. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 
adequate size to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months 
or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 12 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method 
with failure rate of less than 1% per year when used consistently and correctly from 
screening until 6 months following the last dose of investigational product. Acceptable 
methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into 
the study, and this male is the sole partner for that subject. 
10. Normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment 
for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. More than 10 weeks have elapsed between date of initial tissue biopsy for screening 
and day of first dose (i.e. Day 0); 
7. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
8. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after 
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9. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension 
high into cervical canal at screening; 
10. History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, 
or insufficient for diagnosis (ECC is not performed as part of study screening) and 
did not receive definitive treatment; 
11. Treatment for genital warts within 4 weeks prior to screening; 
12. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 
4 weeks prior to screening; 
13. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
15. Presence of any abnormal clinical laboratory values greater than Grade 1 per Common 
Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or 
less than Grade 1 but deemed clinically significant by the investigator; 
16. Immunosuppression as a result of underlying illness or treatment including: 
a. History of or positive serologic test for HIV at screening;  
b. Primary immunodeficiencies; 
c. Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d. Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e.  History of solid organ or bone marrow transplantation; 
f. 
 Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
17. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
18. Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of 
Day 0; 
20. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the investigator; 
21. Current or history of clinically significant, medically unstable disease which, in the 
judgement of the investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the study 
results (e.g. chronic renal failure, angina, myocardial ischemia or infarction, class 3 or 
higher congestive heart failure, cardiomyopathy, or clinically significant arrhythmias); 
22. Malignancy or treatment for malignancy within 2 years of screening, with the exception 
of superficial skin cancers that only require local excision; 


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23. Acute or chronic bleeding or clotting disorder that would contraindicate IM injections 
or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
24. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
25. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 
mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
27. Prior major surgery within 4 weeks of Day 0; 
28. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
29. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
30. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment 
site; 
31. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) 
that is located in ipsilateral deltoid injection site (unless deemed acceptable by a 
cardiologist); 
32. Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
33. Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
34. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
35. Active military service personnel; 
36. Study-related staff or family members of study-related staff; 
37. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study treatment/EP 
but will be encouraged to continue follow-up safety assessment through study discharge 
and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that subject. 


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 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw from 
study participation at any time. A subject may be withdrawn at any time at the discretion 
of the investigator for any maternal obstetrical or medical complications after consultation 
with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report form 
(eCRF) and the subject’s source document 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule for 
follow-up and treatment of VIN, and ascertain whether or not the subject wishes to and/or 
should continue in the study based on previous noncompliance. In cases where the 
subject does not return for the rescheduled visit or cannot be reached to reschedule the 
missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls to the subject should be made and if that fails, then a certified letter is sent 
to the subject’s last known mailing address) so that they can be considered withdrawn 
from the study for disposition purposes. These contact attempts should be documented in 
the subject’s medical record. Should the subject continue to be unreachable, then and 
only then will she be considered to have withdrawn from the study with a primary reason 
of “Lost to Follow-up.” For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). At 
a minimum, the investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100).  A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The investigator or study coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the study 
or is withdrawn from the study prior to study completion, all applicable activities scheduled 
for the final study visit should be performed at the time of discontinuation. The investigator 
will make every effort to have all scheduled immune assessment blood samples collected 
as indicated in the Schedule of Events in the synopsis, Table 1. Any AEs and/or SAEs 
present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in section 7.1 – Safety Parameters. 


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 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 
 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs regardless 
of relation to study drug. 
 
 Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical 
need to withdraw. If the subject gave a reason for withdrawal, it must be recorded 
on the eCRF. This reason does not allow for further data collection and should not 
be selected if follow-up data collection of this subject is anticipated by the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation should 
be discussed with the Sponsor’s Medical Monitor prior to discontinuation of study 
treatments or study withdrawal. 
 
 Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter sent 
by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon®) technology.  The VGX-
3100 formulation to be used in this study is described in Table 5 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum.  There are 24 single-use packets of imiquimod in one box.  The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older.  Although it is not approved by the US Food 
and Drug Administration for the treatment of vulvar HSIL, imiquimod is currently 


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recommended as a non-surgical, off-label treatment option for vulvar dysplasia by the 
American College of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 5. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  Imiquimod Cream, 5% will have both the original 
manufacturer's label on individual packets and the back of the carton, and an 
investigational label on the front of the carton.  The labels will contain, at minimum, the 
information shown in Figure 6.   


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Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  
 
Figure 6. Example labels for imiquimod 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Opthalmic Use. 
Keep out of reach of children.  This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer’s instructions. Avoid freezing.    


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5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. The 
product must be used within 4 hours of removal from the refrigerator. All material removed 
from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 
 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations.  Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks.  Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water.  Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period.  The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 


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5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to 
be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 IP can only 
be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer.  The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, adverse effects, interfering substances 
or devices, warnings, and precautions.  Each CELLECTRA® 2000 Pulse Generator has a 
unique serial number, and each CELLECTRA® 2000 Applicator has a unique serial 
number. Each CELLECTRA® 2000 Array has a Lot Number, Manufacture Date, and 
Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local authorities 
to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to successfully 
completing device training from sponsor personnel. Individuals whose credentials do not 
meet the relevant local requirements may perform the treatment procedure under both of 
the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or 
an approved Sub-Investigator who has already been trained by the sponsor’s 
personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and 
approved by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its 
designee. 


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5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 7 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers (as 
applicable) is included at the time of manufacture and may vary from these examples. The 
information found on the actual device labels should always be used to manage, track and 
record investigational product accountability during study conduct. 
 


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Table 7. Example Labels for the CELLECTRA® 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA® 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA® 
2000 5P  
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA® IM 
Array 
 
REF: M01-
002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. This 
includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA® 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA® 2000 IM Applicator is intended to be used multiple times on the same 
subject and then disposed after final use in accordance with accepted medical practice 
and any applicable local, state, and federal laws and regulations. Once the IM applicator 
is assigned to a subject, it may NOT be used on another subject. The used sterile 
disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.10 
RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the responsible Study 
Monitor. 
If product is to be destroyed on site, it is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted 


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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected 
prior to consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the samples 
sent to the central pathology lab for review by the PAC to assess eligibility.  There will be 
a maximum allowable window of 10 weeks from the date of collection of the qualifying 
biopsy sample(s) (i.e. slides/samples(s) reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be obtained 
within a reasonable timeframe, an additional biopsy sample should be collected during 
screening following the consent of the subject. The 10 week screening window begins 
upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets other 
eligibility criteria). Subjects whose vulvar specimens also test positive for other HPV 
genotypes are not excluded as long as they have a positive result for HPV-16 and/or HPV-
18.  
The assessments during the screening period will determine the subjects’ eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, which 
must be performed within 30 days prior to Day 0. All screening assessment values must 
be reviewed prior to study treatment. 
 
Signed informed consent 
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG (within 30 days prior to Day 0) 
 
Baseline laboratory evaluations (includes complete blood count [CBC), serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine aminotransferase 
[ALT], creatine phosphokinase [CPK], and urinalysis) to be performed within 30 days 
prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be performed 
once) 
 
Cervical cytology and ThinPrep™ for cervical HPV type 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical areas 
should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photographs of the vulva and the associated lesion must be collected prior to 
and after biopsy at screening.  
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC. If residual vulvar 
tissue is available from entry either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 ULTRASOUND MEASURE OF SKIN-TO-MUSCLE AND RELATED 
THICKNESSES 
Subjects who consent to participate in the ultrasound sub-study will have both right and 
left deltoids and one (either) quadriceps measured. The precise site of the ultrasound 


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within the deltoid and quadriceps will align with where EP is administered. The ultrasound 
measure will be performed at each of those three body sites in two manners: with no 
pressure applied by the technician through the probe to the tissue and separately, and 
with EP-like pressure applied by the technician through the probe to the tissue and 
separately. The “EP-like pressure” is defined as a firm push against the skin resulting in 
puckering of the skin by the ultrasound probe. The rationale for the differing pressures is 
to determine if and how much the thickness being measured will change. For each body 
site and pressure, three triplicate measures will be performed.  The type and number of 
ultrasound images and replicates taken for each body site for each patient would be as 
follows: 
 
   Table 8. Type and Number of Ultrasound Images, by Muscle and Probe Pressure 
 
Right 
Deltoid
Left 
Deltoid
Either 
Quadricep
s 
Total 
No pressure of the ultrasound probe on tissue 
site 
 
3 
 
3 
 
3 
 
9 
EP-like pressure of the ultrasound probe on 
tissue site 
 
3 
 
3 
 
3 
 
9 
Total number of replicate measures 
6 
6 
6 
18 
 
Ultrasound measures will be performed during the screening period, i.e. before enrollment 
and hence before any administrations of VGX-3100, and will thus include both enrolled 
and screen-failed subjects.   
Locally stored images of each ultrasound measure will be measured via digitizer or simple 
scale to obtain the following cross-sectional distances, for each replicate image: 
- 
Skin to muscle distance (i.e. depth of the beginning of the muscle) = “S-M” 
- 
Skin to bone distance (i.e. depth of the beginning of the bone) = “S-B” 
- 
Muscle thickness (i.e. distance of the beginning to end of the muscle) = “MT”, a 
calculated field with the following equation: 
 
  
MT = “S-B” - “S-M” 
The ultrasound measures will be performed on all screened patients in this trial, thus 
including both enrolled patients and ultimately screen-failed patients in these sub-
analyses.    
 
Last, each patient would be asked for their handedness, i.e. whether they are they right-
handed, left-handed, or ambidextrous.   
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment.  Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 


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 
Review of concomitant medications and adverse events 
 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP rinse, vaginal and intra-anal swabs 
 
Baseline vulvoscopy  
 
Vulvar lesion photography 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 4 
The following study evaluations will be performed at Week 4 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 


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 
Vulvoscopy  
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression. 
 
Vulvar lesion photography  
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after study 
treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 
The following study evaluations will be performed at Week 12 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 and Week 94 unless PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression 


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 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 
The following study evaluations will be performed at Week 15 (± 7 days): 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay 
 WEEK 24 
The following study evaluations will be performed at Week 24 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 


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 WEEK 27 
The following study evaluations will be performed at Week 27 (± 7 days): 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 or Week 96 unless the PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression.  
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 WEEK 38 PHONE CALL 
 
Review concomitant medications and adverse events 
 WEEK 48 
The following study evaluations will be performed at Week 48 (± 7 days): 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 


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 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected. 
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
 If residual vulvar tissue is available from entry and/or Week 48 
specimen(s) either paraffin blocks or unstained slides should be sent to 
the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 
Patient Reported Outcomes 
 WEEK 52  
Subjects will have a Week 52 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 74 
The following study evaluations will be performed at Week 74 (± 14 days): 
 
Review of concomitant medications and adverse events 


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 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 78 
Subjects will have a Week 78 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 


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 WEEK 96 
The following study evaluations will be performed at Week 96 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical 
areas should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 100 
The following study evaluations will be performed at Week 100 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 


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 
Vital signs 
 
Urine pregnancy test 
6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, study 
objectives, potential benefits and risks, discomforts/inconveniences, and the subject’s 
rights and responsibilities. The subject is then requested to sign and date the ICF. A copy 
of the signed informed consent documentation must be provided to the subject. The 
qualified study personnel will document the process of obtaining informed consent within 
the source record. Signed ICFs are maintained in the subject’s source records and must 
be accessible for verification at any time. 
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all study-related procedures. SIDs are a combination of a 
up to two alpha letters study code, two alpha letter Country code, two digit site number, 
plus 3-digit subject number starting with 001 (e.g., VNUS01001). Once assigned, SIDs 
cannot be reused for any reason. Information regarding the SID and screen date must be 
documented on a Screening log/system and in the Interactive Response Technology 
(IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated allocation 
schedule.  
 SAFETY EVALUATIONS 
6.3.3.1 PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100).  It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems.   
A targeted physical assessment will be performed at other visits as determined by 
the investigator or directed per subject complaints. 
6.3.3.2 VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 


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 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 
 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.3.3 WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.3.4 MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be obtained 
at screening. All relevant (as judged by the investigator) past and present 
conditions, as well as prior surgical procedures will be recorded for the main body 
systems.  
6.3.3.5 SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, history 
of prior cervical dysplasia, and pregnancy history will be obtained at Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to document 
any change from screening. 
6.3.3.6 LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
 


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Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 
6.3.3.7 PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.3.8 ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has been 
in a supine position for 10 to 15 minutes. The ECG should include measurements 
of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, Twave as 
well as an investigator assessment of whether the ECG is normal or abnormal 
(automated interpretations of ECG should not be used). Abnormal ECGs should 
be interpreted as “clinically significant (CS)” or “not clinically significant (NCS)” by 
the investigator. 
6.3.3.9 POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after the 
study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.3.10 
IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  


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6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA® 2000. Study treatment plus EP must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is implanted 
metal within the same limb. Any device implanted in the chest (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal) excludes the use of the deltoid 
muscle on the same side of the body. The timing of the initial dose will be designated Day 
0 with the subsequent doses scheduled for administration at Weeks 4, 12, 24, and at 
Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 RISKS OF TREATMENT PROCEDURES TO VGX-3100 
Table 9 summarizes reported AEs and potential risks of VGX-3100. 


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Table 9. Summary of Reported Adverse Events and Potential Risks of VGX-3100 Delivered 
IM EP with CELLECTRA® 2000 
Very Common  
 
Mild to moderate injection site pain or tenderness 
 
Malaise/fatigue, myalgia, or headache in the first few days following 
injection 
 
Upper respiratory tract infection 
 
Brief muscle contractions which may be uncomfortable 
 
Nausea 
Common  
 
Arthralgia 
 
Injection site reactions such as erythema, pruritus, swelling, 
hematoma 
 
Anxiety related to the administration procedure 
Less Common  
 
Severe injection site pain or tenderness 
 
Vasovagal 
reaction/lightheadedness/dizziness 
related 
to 
the 
administration procedure 
 
Temporary bleeding at the injection site 
 
Rash following administration  
Uncommon or 
rare  
 
Injection 
site 
reactions 
such 
as 
laceration, 
induration, 
bruising/ecchymosis, or scab  
 
Infection at the injection site  
 
Muscle damage resulting in transient changes in creatine 
phosphokinase  
 
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  
 
Chills, flu-like syndrome 
 
Autoimmune disease 
 
Electrical injury1 
 
Disruption of function of implanted electronic medical devices (if 
CELLECTRA®  2000 device is not used per User Manual)1 
 
Exacerbation of unstable cardiac disease1 
 
Effects on the fetus and on pregnancy 
1device only 
6.4.1.2 RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
In controlled clinical trials for genital warts, the most frequently reported adverse reactions 
were local skin and application site reactions.  Table 10 summarizes local skin reactions 
assessed by the Investigator in the treatment area of females taking imiquimod cream, 
5% cream for external genital warts [30].   
 


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Table 10.  Summary of Reported Adverse Events in 114 females taking imiquimod cream, 
5% for external genital warts 
 
 
Imiquimod Cream, 5% 
N =114 
Erythema 
74 (65%) 
Erosion 
35 (31%) 
Excoriation/Flaking 
21 (18% 
Edema 
20 (18%) 
Scabbing 
4 (4%) 
Induration 
6 (5%) 
Ulceration 
9 (8%) 
Vesicles 
3 (3%) 
*All Grades: Mild, Moderate, or Severe 
 
Table 11 summarizes adverse reactions judged to be possibly or probably related to 
Imiquimod Cream, 5% and reported by more than 1% of subjects [30]. 
 
Table 11. Possibly or probably related Adverse Reactions to Imiquimod cream in > 1% of 
subjects 
Location of reaction 
Adverse reaction 
Application Site Disorders 
Burning, hypopigmentation, irritation, itching, pain, 
rash, sensitivity, soreness, stinging, tenderness 
Remote site reactions 
Bleeding, burning, itching, pain, tenderness, tinea 
cruris 
Body as a Whole 
Fatigue, fever, influenza-like symptoms 
Central and Peripheral Nervous 
System Disorders 
Headache 
Gastro-Intestinal System Disorders 
Diarrhea 
Musculo-Skeletal System Disorders 
Myalgia 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 
approximately 1.5 cm diameter amount will be applied with occlusion to the site of injection 
~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who receive 
a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours after 
receiving medication and should have arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a 
mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
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6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.3.6.  
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 minutes 
after each study treatment. Subjects will be advised to record local and systemic AEs for 
7 days after each study treatment on a PD which will be reviewed with study personnel at 
8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject’s CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be 
instructed to use the following grading scale: 
 
Table 12. 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” 
*In addition to grading the measured local reaction at the greatest single diameter, the 
measurement should be recorded as a continuous variable 


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**Induration/Swelling should be evaluated and graded using the functional scale as well as the 
actual measurement 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes (PRO) 
instruments will be provided. The following PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [31]. SF-36v2™ will be administered at the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [32, 33] and will be 
administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
Administration of PRO instruments will be performed according to the validated procedure 
and guidelines of each respective instrument, except for some assessments for 
exploratory analyses. Additional instructions will be provided separately.    
 


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3. Additional Global PRO Questions – regarding quality of life after surgery or biopsy.  
These two questions will be administered at Week 52 only. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity 
may occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-
γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
6.10 
TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses 
have been rendered, then unstained slides and/or the relevant paraffin blocks may be 
collected for immunohistochemistry (IHC).  Assessment of markers may include, but are 
not limited to, CD8+ and FoxP3+ infiltrating cells as well as assessment of cell death via 
Cleaved Caspase 3 assessment. Additional assessments may include visualization of 
Granulysin, Perforin, CD137, CD103 and PD-L1 in cervical tissue as sample allows.  
Markers listed here may change as new relevant information becomes available. 
6.11 
HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 
6.12 
VULVAR HPV TESTING 
A 4 mm vulvar punch biopsy sample will be obtained at Screening, Weeks 48, 74, and 96, 
and will be sent to a central laboratory for HPV genotyping by PCR.  In the case of 
multifocal disease, a 4 mm vulvar biopsy will be obtained from two regions of most 
advanced and severe disease as judged by the investigator.  The subject will be requested 


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to abstain from sexual activity and refrain from use of douching vulvar biopsy samples to 
eliminate potential interference with the results of HPV testing. 
6.13 
COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Screening and at Week 96 for all subjects.  
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep™ test kits at Screening, Weeks 27, 48, 74 
and 96, and read in a central laboratory. HPV PCR will be performed on the ThinPrep™ 
specimen. At each of these visits, menstrual cycle status & recent history will be collected 
via self-report.  If the Pap smear result suggests progression to cancer the investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples to eliminate potential interference with the results of HPV testing. 
6.14 
VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL confirmed 
by the PAC.  Subjects will undergo vulvoscopy to identify the lesion(s). Digital photographs 
of the vulva will be captured after application of acetic acid to document the clinical 
findings.  If a biopsy or surgical excision is performed, images of the vulva should be 
collected before and after the procedure.  Each site will be instructed on 1) the technique 
for capturing the proper images using a standard approach, and 2) the process for 
uploading the images to a secure server.   
In the case of multifocal disease, the two lesions which appears to have the highest 
likelihood according to the investigator of most advanced disease and which is of 
adequate size to ensure that a visible lesion remains after punch biopsy should be chosen 
for vulvar biopsy and documented using photography.     
Interval vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96.  An 
unscheduled biopsy may be performed at the discretion of the investigator if there is 
suspicion of disease progression. Guidelines for managing the findings of unscheduled 
biopsies for suspected disease progression are described in Table 13.  Consult the 
Medical Monitor for any planned departures from these guidelines. 
 
Table 13:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 


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Subject safety is paramount in this study. Therefore, if at any time the investigator may 
suspect disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over the 
default “Schedule of Events”, Table 1. 
6.15 
CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. Medical procedures performed within 8 weeks prior to 
screening biopsy date of eligible subjects that do not affect subject’s eligibility for 
participation and during the study (including over the counter or herbal), will be recorded 
on the CRFs. This information will be obtained from the subject and abstracted from any 
available medical records. The indication for the medication, dose, and dose regimen will 
be documented. Medication that is considered necessary for the subject’s safety and well-
being may be given at the discretion of the investigator and recorded in the appropriate 
sections of the CRF. 
6.16 
RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day 
of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic corticosteroids 
are allowed) 
 
Disease 
modifying 
doses 
of 
anti-rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs 
such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at screening and 
throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1).  Lapses in contraceptive use should be reported to investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples.  


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7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and unsolicited 
AEs will be monitored and reported on an AE CRF, including the event’s seriousness, 
severity, action taken, and relationship to investigational product(s). AEs should be 
followed until resolution or stable and the outcome will be documented on the appropriate 
CRF. All AEs should be recorded in standard medical terminology rather than the subject’s 
own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.9 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the duration 
of the study, including the follow-up off study drug period will be recorded as an 
AE. 
 
Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit 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 informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 


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 SERIOUS ADVERSE EVENTS 
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; 
 
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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 2) 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, 3) the 
development of drug dependency or drug abuse or 4) the development of a 
malignancy; 
 
Is medically significant or requires intervention to prevent one or other of the outcomes 
listed above. 
 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 that 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 nor does it include full day or overnight stays in observation status. 
 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 


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Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 9.5. 
 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE.  For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of adenocarcinoma-in-
situ or adenocarcinoma should also be reported as an SAE.  In both instances the 
condition for SAE reporting should be categorized as a medically important event unless 
another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal 
product related to any dose, for which a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility; i.e., there is evidence to suggest 
a causal relationship between the product and the adverse event. An unexpected ADR is 
one, the nature or severity of which is not consistent with the applicable product 
information (investigator’s brochure, protocol, and user manual). Reports that add 
significant information on specificity or severity of a known, already documented SAE 
constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator's Brochure or protocol would be considered "unexpected.” 
Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent 
new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a 
serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the SUSAR 
will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating investigators of information that might materially influence the 
benefit-risk assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. Examples of such information 
include a clinically important increase in the rate of occurrence of a serious expected 
adverse event, the identification of a significant hazard to the subject population, or a 
major safety finding from a study conducted in animals. 
 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 


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application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
investigator within 24 hours. Sponsor will assess each device related SAE to determine if 
anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be assessed 
as not related to the IP and/or the investigational device. Because the investigator is 
knowledgeable about the subject (e.g., medical history, concomitant medications), 
administers the IP, and monitors the subject’s response to the IP, the investigator is 
responsible for reporting adverse events and judging the relationship between the 
administration of the IP and device and a subsequent AE. 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 IP delivered by EP 
and determine whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation of 
any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the IP and/or the investigational device indicating "yes" or "no" 
accordingly. Causality should be assessed by the investigator as “yes, related” or “no, 
unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 


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The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications known 
to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory 
or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition of an AE (or SAE) as described in Section 7.1. If the laboratory abnormality 
is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory 
result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency from 
the baseline condition and meets one of the following criteria will be recorded as an AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the investigator as clinically significant 
 POST-TRIAL 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 or termination visit and the event is deemed by the investigator to be related 
to the study treatment, he/she should promptly document and report the event to the study 
team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be excluded 
from participation in the study. Should a subject become pregnant after enrolling in the 
study, she will not be given any further study treatments. A Pregnancy Form will be 
completed by the site personnel and submitted to the sponsor within 24 hours after 
learning of the pregnancy.  Site personnel will submit the Pregnancy Form to the Sponsor 
as described in Section 7.4.2. 


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The investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject’s permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results will 
be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be performed. 
Investigators should use clinical judgment regarding subsequent study-related blood 
collection based on the presence or absence of anemia in each subject. Subjects who are 
not withdrawn will continue to be followed for safety assessments to study discharge per 
protocol.  
All pregnancies that occur from the time of first study treatment through the follow up visits 
must be reported. The investigator will monitor the subject and follow the outcome of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the 
outcome will be reported directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when informed 
consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading 
question such as ‘How have you been feeling since your last visit?’ is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator 
to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the 
investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
urinalysis) 
 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
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 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100 delivered with CELLECTRA® 2000 that require expedited communication from the 
site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration recorded 
≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
 
Grade 3 or greater laboratory abnormalities 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and Principal Investigator and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
Treatment;  
 
Three or more subjects in the same treatment arm discontinue due to an AE related 
to the Study Treatment; 
 
Any subject experiences an SAE (or potentially life threatening AE or Grade 4 AE) or 
death assessed as related to Study Treatment; 
 
Two or more subjects within a treatment arm experience the same or similar grade 3 
or 4 adverse event, assessed as related to Study Treatment;  
 
Four or more subjects across all treatment arms experience the same or similar grade 
3 or 4 adverse event, assessed as related to Study Treatment; 
 
Any report of anaphylaxis assessed as related to Study Treatment. 
Upon conclusion, the sponsor or designee will notify all investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 
7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), whether 
volunteered by the subject, discovered by investigator or study staff questioning, or 
detected through physical examination, laboratory test or other means, will be collected 
and recorded in the subject’s source documents and followed as appropriate. 


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TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised of 
the period following the signing of the informed consent form until the end of the study. 
Each AE will be assessed to determine whether it meets seriousness criteria. If the AE is 
considered serious, the investigator should record this event in the EDC system and report 
the event to the Sponsor within 24 hours of becoming aware of the event. The investigator 
may also directly report this event to the Ethics Committee according to its standard 
operating procedures. Expectedness of SAEs will be determined by the Sponsor using 
reference safety information specified in the Investigator’s Brochure and protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.6 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.7 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the Institutional Review Board (IRB)/Ethics Committee (EC) as 
soon as is practical, of serious events in writing where this is required by local regulatory 
authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an investigator becomes aware 
of an SAE that is suspected by the investigator to be related to the study drug, the event 
will be reported to the Sponsor or its designee. If the investigator becomes aware of an 
SAE in a study subject after the last scheduled follow-up visit, and considers the event 
related to prior Study Treatment, the investigator will report it to the Sponsor or the 
appropriate designee. 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
, M.D., Ph.D. 
EMAIL:  safety.inovio@apcerls.com 
  
SAFETY FAX: 
 
SAFETY PHONE: 
 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address as 
indicated above.  Any SAE supporting documents provided by facsimile (Fax) are to 
include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
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The investigator will supply the Sponsor and the IRB with more information as it becomes 
available and any additional requested information. The original SAE form must be kept 
at the study site. The Sponsor or its representative will be responsible for determining 
and in turn, reporting SAEs to regulatory authorities according to the applicable regulatory 
requirements. SAEs must be followed by the investigator until resolution, even if this 
extends beyond the study-reporting period. Resolution of an SAE is defined as the return 
to baseline status or stabilization of the condition with the expectation that it will remain 
chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the investigator will submit a Pregnancy Form to the Sponsor 
or designee to the safety email address or fax number within 24 hours of learning of the 
pregnancy. 
 NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later than 
10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 15 days for 
all other SUSARS (see Section 7.1.6 and 7.1.7). 
 REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device such as malfunction, misuse or use error 
and inadequate labeling. A malfunction is defined as the failure of a device to meet its 
performance specifications or otherwise perform as intended. The intended performance 
of a device refers to the intended use for which the device is labeled. All product 
complaints that meet this definition must be reported to the sponsor within 10 days of 
discovery.  Any product complaint that involves an AE or SAE must be also be reported 
per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the 
treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  
Additional instructions on complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple 
sites for safety or administrative reasons at any time. In particular, a site that does not 
recruit at a reasonable rate may be discontinued. Should the study be terminated and/or 


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the site closed for whatever reason, all non-source documentation and study product 
pertaining to the study must be returned to Inovio Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research subjects 
are protected. 
8. 
STATISTICAL ANALYSIS PLAN 
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and VGX-
3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and confirmed 
vulvar infection with HPV types 16 and/or 18. The study’s primary endpoint is binary: 
regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from vulvar tissue 
based on tissue collected at Week 48. The primary hypothesis is that each of the treatment 
arms will result in regression of HSIL and clearance. Secondary efficacy analyses pertain 
to regression, clearance of HPV-16 and/or HPV-18 infection, regression to normal, non-
progression, and anatomic extent. Other secondary analyses concern safety and humoral 
and cellular immunological measures. Exploratory efficacy analyses concern extended 
dosing with respect to regression, clearance, and anatomic extent, clearance outside of 
the vulva, and effect of HLA type on efficacy.  Other exploratory analyses pertain to tissue 
immunological measures, effect of needle depth into muscle on efficacy, and patient-
reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 
recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 
2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), 
and (d) age category (<45 years vs. ≥45 years).  There are no requirements for the number 
of subjects in each stratum.  The study is open-label. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each arm superior to historical control, assuming the true proportion 
of subjects who achieve the primary endpoint is 20% and 28% for the respective treatment 
arms and 2% for the historical control, and that 90% are evaluable at Week 48 from 
randomization. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 


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Subjects in this sample will be grouped to treatment arms as randomized.  Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized.  
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy.  Subjects excluded from the PP population 
will be identified and documented prior to unblinding of the study database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects and will 
include the number and percentage randomized, the number and percentage who 
received each dose and the number who completed the trial.  The number and percentage 
of subjects who discontinued will be summarized overall and by reason.  The number in 
each analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the mITT population.  Prior 
and concomitant medications will also be summarized with percentages in this fashion. 
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by 
body system, by treatment arm, for the mITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (within 10 weeks 
prior to Day 0).  Concomitant medications are those used during the course of the trial (on 
or after Day 0).  Partial start dates of prior and concomitant medications will be assumed 
to be the earliest possible date consistent with the partial date.  Partial stop dates of prior 
and concomitant medications will be assumed to be the latest possible date consistent 
with the partial date.  Data for all prior and concomitant medications will be summarized 
with percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true population 
probability of the primary endpoint for each arm. The primary hypothesis of superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment arm separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
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one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds 
0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days prior 
to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) will 
be summarized with point estimates and associated Clopper-Pearson 95% confidence 
intervals. 
An exploratory analysis will examine clearance outside of the vulva.  This will be analyzed 
in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and HLA results. As these results are categorical, relationships will be examined 
with contingency tables and logistic regression models which model the primary endpoint 
versus these results and treatment group as regressor variables. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and needle depth into muscle. A logistic regression model which models the 
primary endpoint versus these results and treatment group as regressor variables will be 
used. 
8.10 
IMMUNOGENICITY ANALYSIS 
 
Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 
SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment arm. 
These frequencies will be presented overall and separately by dose, and will depict 
overall, by system organ class and by preferred term, the percentage of subjects affected. 
Additional frequencies will be presented with respect to maximum severity and to 
strongest relationship to Study Treatment. Multiple occurrences of the same AE will be 
counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of any 
dose.  For this summary, the frequency of preferred term events will be summarized with 
percentages and 95% Clopper-Pearson confidence intervals.  Separate summaries will 


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be based on events occurring within 7 days of any dose and regardless of when they 
occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be 
included within specified day-range summaries. AE duration will be calculated as (Stop 
Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment arm. 
Baseline is defined as the last measurement prior to the first treatment administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time point 
will be summarized by treatment arm and by body system, for the mITT population. 
 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or Clopper-
Pearson 95% CIs, for continuous responses and binary responses, respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 
9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles 
of Good Clinical Practice (GCP), and applicable regulatory requirements. 


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9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained 
from the applicable IRB/EC and a copy of this approval has been received by the 
sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 During the conduct of the study, submit progress reports to the IRB/EC as 
required.  
 Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 As required, obtain approval from the IRB/EC for protocol amendments and 
for revisions to the consent form or subject recruitment advertisements; 
 Reports on, and reviews of, the trial and its progress will be submitted to the 
IRB by the investigator at intervals stipulated in their guidelines and in 
accordance with pertinent regulations and guidelines. 
 Maintain a file of study-related information that includes all correspondence 
with the IRB; 
 Notify IRB when study is completed (i.e. after the last study visit of the final 
study subject); 
 After study completion provide the IRB with a final report on the study. 
9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., 
NIH Office of Biotechnology Activities) governing research that involves 
recombinant or synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening 
into the study, and/or from the subject’s legally authorized representative.  The 
process for obtaining informed consent must also be documented in the subject’s 
medical record. 
9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating the 
study and re-approval or review at least annually.  Sponsor is to be notified immediately if 
the responsible IRB/EC has been disqualified or if proceedings leading to disqualification 
have begun.  Copies of all IRB/EC correspondence with the investigator must be provided 
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9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and for subjects in the imiquimod 
arm a dosing log during their study participation.  Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation impacting 
Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject’s name will not be disclosed in these documents. 
The subject’s name may be disclosed to the study sponsor, Sponsor, the governing health 
authorities or the Food and Drug Administration (FDA), if they inspect the study records. 
Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information. 
Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject’s legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA). 
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: 


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 
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 the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. Examples 
of these original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subject’s 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 medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be 
present in the source documents. All prescription and nonprescription medications taken 
within l week prior to entry must be recorded on the CRF. Actual or estimated start and 
stop dates must be provided. 
10.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. The sponsor will inform the investigator/institution as to when these documents 
are no longer needed to be retained. 
10.4 
SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial.  The DSMB will 
meet quarterly or as data are available to review unblinded safety data and 
regression/clearance results.  If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the 
meeting may be cancelled; Ad hoc meetings may be scheduled to review new data as 
applicable. The DSMB will be charged with advising the Sponsor if there appears to be a 


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safety issue and with advising the Sponsor if it appears that regression in the VGX-3100 
group is unacceptably low compared to the placebo group. No formal interim analysis will 
be performed. The DSMB Chair, upon consultation with the other voting members of the 
DSMB, has the authority to recommend suspension or stopping the study and to request 
a full DSMB review and ad hoc statistical analyses.  The standard operating procedures 
of the DSMB will be documented in the DSMB charter, including the board’s accountability 
to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of a total of three pathologists. Each specimen will be read by two pathologists 
independently in a masked fashion.  If the two pathologists agree on the diagnosis then 
no further action is required and the clinical disease status for the subject will be 
established. If there is disagreement between the first two pathologists, the third 
pathologist will review and if there is agreement among any two of the three diagnoses, it 
will stand as the clinical disease status for that subject. If there is no agreement after the 
third review, the three reviewers will perform a simultaneous review and come to 
consensus or a majority rule of 2 of 3 if consensus cannot be reached. 
 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant 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 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 
 
Throughout the study, inspect all source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, and accurate 
(ALCOA).  
 
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 investigational drug and device accountability and reconciliation of  
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 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date of 
receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CMI 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
EC 
ECC 
EDC 
Ethics Committee 
Endocervical Curettage 
Electronic Data Capture 
EP 
DLT 
Electroporation with CELLECTRA® 2000 
Dose Limiting Toxicity 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 


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IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
PCR  
Pathology Adjudication Committee 
Polymerase Chain Reaction 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Participant Diary  
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper Limit of Normal 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
 


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13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Aldea M, Serrano B, Valencia S, Brotons M, Mena M, Cosano R, 
Muñoz J, Bosch FX, de Sanjosé S, Castellsagué X. Human Papillomavirus and Related 
Diseases in United States of America. Summary Report 2016-02-26. . In. Edited by 
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2. 
Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. 
J Natl Cancer Inst 2015,107:djv086. 
3. 
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
Sheets:  Vulvar Cancer. 2016. 
4. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
5. 
Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
6. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
7. 
Sideri M JR, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. Squamous 
vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology 
Subcommittee. J Reprod Med 2005,50:807-810. 
8. 
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: 
background and consensus recommendations from the College of American Pathologists 
and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 
2012,16:205-242. 
9. 
Inovio Pharmaceuticals. Unpublished assessment. 2015. 
10. 
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
natural history and outcome in 405 women. Obstet Gynecol 2005,106:1319-1326. 
11. 
van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
neoplasia III based on enough evidence? A systematic review of 3322 published patients. 
Gynecol Oncol 2005,97:645-651. 
12. 
Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
13. 
ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 
14. 
Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia 
(VIN) usual type after surgical treatment. Med Sci Monit 2011,17:CR532-535. 
15. 
ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
Obstet Gynecol. 2016,128:e178-182. 


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16. 
Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
17. 
Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
Market Research. 2016. 
18. 
Senn B, Eicher M, Mueller MD, Hornung R, Fink D, Baessler K, et al. A patient-reported 
outcome measure to identify occurrence and distress of post-surgery symptoms of 
WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study. Gynecol Oncol 
2013,129:234-240. 
19. 
Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
excision for vulvar intraepithelial neoplasia. J Reprod Med 2007,52:23-27. 
20. 
Petrosky E, Bocchini JA, Jr., Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-
valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations 
of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 
2015,64:300-304. 
21. 
Future II Study Group.  Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
22. 
Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a 
practical approach to diagnosis. J Clin Pathol 2014,67:290-294. 
23. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
24. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
25. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
26. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
27. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
28. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
29. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
30. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
31. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
32. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
33. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA® 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
U.S. BB-IND #13683 
 
 
 
 
Version 1.3 
21 April 2017 
 
 


VGX-3100
HPV-201
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Clinical Protocol
Medical Monitor Approval Page
Drug:
VGX-3100
Sponsor:
lnovio Pharmaceuticals, Inc.
660 W. Germantown Pike, Suite 110
Plymouth Meeting, PA 19462
Medical Monitor:
M.D., Ph.D.
lnovio Pharmaceuticals, Inc.
Approval Signature:
M.D., Ph.D.
Date
lnovio Pharmaceuticals, Inc.
CONFIDENTIAL
The information in this document is considered privileged and confidential by lnovio
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.
Protocol Version Date: 21Apr2017
CONFIDENTIAL
Protocol Version: 1.3
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PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI’s approval of this 
protocol and provides the necessary assurances that this trial will be conducted in 
accordance with ICH/GCP and ISO guidelines, local legal and regulatory requirements, 
and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
____________________________________  
_________________________ 
<Insert Principal Investigator Printed Name>  
        Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


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SUMMARY OF CHANGES 
 
The following are a list of protocol changes from Version 1.2 dated 24 January 2017 to 
Version 1.3 dated 21 April 2017.  All other changes are administrative and do not 
significantly affect the safety of subjects, trial scope, or scientific quality of the protocol. 
1. The Ultra-sound sub-study (Section 6.1.2) has been removed from the study and 
will be conducted under a separate cover.  Exploratory Objective # 7, Assess skin-
to-muscle, skin-to-bone, and muscle thicknesses via ultrasound measure of deltoid 
(or quadriceps if applicable) and the correlation of needle depth into muscle with 
efficacy, and the corresponding time point in Table 1, Schedule of Events has 
consequently been removed. 
2. A microRNA endpoint has been added to the exploratory objectives, to assess 
biomarkers that may be predictive of response.  This endpoint will be assessed at 
Day 0, Week 15 and Week 48.  Sections 6.2, 6.9 and 8.9 have been updated to 
reflect this addition. 
3. References to adenocarcinoma or adenocarcinoma-in-situ have been removed 
since they are not an applicable risk for vulvar HSIL. 
4. Section 5.2.1 was updated to provide details about the VGX-3100 product label. 
5. CELLECTRA® 2000 specifications were added to Section 5.7 of the protocol. 
6. The risk of treatment procedures to VGX-3100 and Imiquimod have been removed 
from Section 6.4.1 and reference made to the VGX-3100 + Imiquimod 
Investigator’s Brochure and the Imiquimod product label, where they can be found.  
7. Section 7.3.2 Stopping Rules have been updated to be consistent with the stopping 
rules outlined in Section 3.3.1. 
8. The Sponsor Contact Information and SAE Reporting Information have been 
separated in Section 7.4.2. 
9. DSMB review in Section 10.4.1 has been updated to remove language around 
unblinded data and placebo groups, which were carried over from a previous 
protocol and are not applicable to this study.  Section 3.3.1 was updated to include 
histopathologic regression results to the DSMB review, to be consistent with 
Section 10.4.1. 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................... 5 
CLINICAL PROTOCOL SYNOPSIS .......................................................................................... 10 
STUDY SCHEDULE OF EVENTS .............................................................................................. 23 
1. 
INTRODUCTION ............................................................................................................. 25 
1.1 
Background ......................................................................................................... 25 
 
Human Papillomavirus and Infection ....................................................... 25 
 
Vulvar Cancer .......................................................................................... 25 
 
Vulvar Intraepithelial Neoplasia (VULVAR HSIL) .................................... 25 
 
Recurrent Disease with Current Therapeutic Options ............................. 26 
 
Psychological and Physical Impacts of Current Therapeutic Options ..... 27 
 
Impact of Vulvar HSIL Upon Activities of Daily Living .............................. 27 
 
Limitations of Prophylactic HPV Vaccines ............................................... 27 
 
Enhanced Monitoring Plan....................................................................... 28 
 
VGX-3100 ................................................................................................ 28 
  Electroporation......................................................................................... 28 
  Imiquimod Cream, 5% ............................................................................. 29 
  Study Rationale ....................................................................................... 29 
  Dose and Regimen Rationale for VGX-3100 ........................................... 29 
  Rationale for imiquimod ........................................................................... 29 
  Potential Risks of investigational products .............................................. 30 
  Potential Benefits of Study Participation .................................................. 30 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 30 
2.1 
Primary Objective and Endpoint .......................................................................... 31 
2.2 
Secondary Objectives and Associated Endpoints ............................................... 31 
2.3 
Exploratory Objectives and Associated Endpoints .............................................. 33 
3. 
STUDY DESIGN ............................................................................................................. 34 
3.1 
Treatment Regimens ........................................................................................... 34 
3.2 
Efficacy Assessment ........................................................................................... 35 
 
Definition of Responder and Non-Responder .......................................... 36 
3.3 
Safety Assessment .............................................................................................. 37 
 
Data Safety & Monitoring Board .............................................................. 37 
3.4 
Immunogenicity Assessment ............................................................................... 38 
3.5 
Virologic Assessment .......................................................................................... 38 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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4. 
SELECTION OF SUBJECTS ......................................................................................... 38 
4.1 
Inclusion Criteria .................................................................................................. 38 
4.2 
Exclusion Criteria ................................................................................................ 39 
4.3 
Discontinuation/Withdrawal of Study Subjects .................................................... 41 
 
Criteria for Discontinuation of Investigational Product ............................. 41 
 
Criteria for Withdrawal from the Study ..................................................... 42 
 
Sponsor Notification of Discontinuation/Withdrawal ................................ 42 
 
Reason for Discontinuation/Withdrawal ................................................... 43 
5. 
STUDY TREATMENT ..................................................................................................... 43 
5.1 
Investigational Products ...................................................................................... 43 
5.2 
Packaging and Labeling ...................................................................................... 44 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................ 44 
5.3 
Handling and Storage .......................................................................................... 45 
5.4 
Preparation and Dispensing ................................................................................ 46 
 
Dispensing of VGX-3100 ......................................................................... 46 
 
Dispensing and Use of Imiquimod ........................................................... 46 
5.5 
Investigational Product Accountability ................................................................. 46 
5.6 
Return and Destruction of Investigational Product .............................................. 47 
5.7 
Use of Investigational Device .............................................................................. 47 
5.8 
Packaging and Labeling of Investigational Device .............................................. 48 
5.9 
Investigational Device Accountability .................................................................. 50 
5.10 
Return of Investigational Devices ........................................................................ 50 
6. 
STUDY PROCEDURES AND TREATMENTS ............................................................... 51 
6.1 
Before Treatment Procedures ............................................................................. 51 
 
Screening evaluations ............................................................................. 51 
6.2 
During Treatment Procedures by Visit................................................................. 52 
 
Day 0 ....................................................................................................... 53 
 
8-14 Days Post Dose 1 Phone Call ......................................................... 53 
 
Week 4 .................................................................................................... 53 
 
8-14 Days Post Dose 2 Phone Call ......................................................... 54 
 
Week 12................................................................................................... 54 
 
Week 15................................................................................................... 55 
 
Week 24................................................................................................... 55 
 
Week 27................................................................................................... 56 
 
Week 38 Phone Call ................................................................................ 56 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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  Week 48................................................................................................... 56 
  Week 52................................................................................................... 57 
  Week 74................................................................................................... 58 
  Week 78................................................................................................... 58 
  Week 96................................................................................................... 59 
  Week 100................................................................................................. 60 
6.3 
Evaluations and Procedures ............................................................................... 60 
 
Informed Consent .................................................................................... 60 
 
Assignment of Subject Identification Numbers ........................................ 60 
 
Safety Evaluations ................................................................................... 61 
6.4 
Injection and Electroporation (EP) ....................................................................... 63 
 
Risks of Treatment Procedures ............................................................... 63 
 
Management of Anxiety and Pain Due to EP Procedure ......................... 63 
6.5 
Assessment of Laboratory Abnormalities ............................................................ 64 
6.6 
Assessment of Clinical Study Adverse Events .................................................... 64 
6.7 
Assessment of Injection Site Reactions .............................................................. 64 
6.8 
Assessment of Patient Reported Outcomes ........................................................ 65 
6.9 
Peripheral Blood Immunogenicity Assessments ................................................. 66 
6.10 
Tissue Immunogenicity Assessment ................................................................... 67 
6.11 
HLA Typing .......................................................................................................... 67 
6.12 
Vulvar HPV Testing ............................................................................................. 67 
6.13 
Colposcopy, PAP Smears and HPV Testing ....................................................... 67 
6.14 
Vulvoscopy, Photographs, and Biopsies ............................................................. 67 
6.15 
Concomitant Medications/Treatments ................................................................. 68 
6.16 
Restrictions .......................................................................................................... 68 
  Other Restrictions .................................................................................... 69 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ................................ 69 
7.1 
Safety Parameters ............................................................................................... 69 
 
Adverse Events........................................................................................ 69 
 
Serious Adverse Events .......................................................................... 70 
 
Clarification of Serious Adverse Events ................................................... 71 
 
Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ............................................................... 71 
 
Unexpected Adverse Drug Reactions and Expedited Reporting ............. 71 
 
Unanticipated (Serious) Adverse Device Effect (UADE) ......................... 72 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Assessing Severity (Intensity) .................................................................. 72 
 
Casual Relationship of Clinical Material to Adverse Events .................... 73 
 
Abnormal Laboratory Value ..................................................................... 73 
  Post-Trial Reporting Requirements ......................................................... 74 
  Procedures for Documenting Pregnancy During Study ........................... 74 
7.2 
Methods and Timing of Collection of Safety Data ............................................... 74 
7.3 
Safety and Toxicity Management ........................................................................ 75 
 
Adverse Events of Special Interest .......................................................... 75 
 
Stopping Rules (Criteria for Pausing of Study) ........................................ 75 
7.4 
Adverse Experience Reporting ............................................................................ 76 
 
Trial Reporting Period of Adverse Events ................................................ 76 
 
Trial Reporting Period of Serious Adverse Events .................................. 76 
 
Notification of Serious Adverse Events .................................................... 77 
 
Reporting of Device Related Complaints ................................................. 78 
7.5 
Trial Discontinuation ............................................................................................ 78 
8. 
STATISTICAL ANALYSIS PLAN ................................................................................... 78 
8.1 
General Considerations ....................................................................................... 78 
8.2 
Randomization and blinding ................................................................................ 79 
8.3 
Sample Size/Power ............................................................................................. 79 
8.4 
Analyses Populations .......................................................................................... 79 
8.5 
Subject Disposition .............................................................................................. 79 
8.6 
Demographic and Other Baseline Characteristics............................................... 79 
8.7 
Medical History .................................................................................................... 80 
8.8 
Prior and Concomitant Medications..................................................................... 80 
8.9 
Efficacy Analysis ................................................................................................. 80 
8.10 
Immunogenicity Analysis ..................................................................................... 81 
8.11 
Safety analyses ................................................................................................... 81 
  Adverse events ........................................................................................ 81 
  Laboratory data........................................................................................ 81 
  Vital Signs ................................................................................................ 81 
  Physical Examination............................................................................... 81 
  Patient Reported Outcomes .................................................................... 82 
  Missing Values......................................................................................... 82 
  Interim Analysis ....................................................................................... 82 
9. 
ETHICS ........................................................................................................................... 82 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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9.1 
Investigator and Sponsor Responsibilities .......................................................... 82 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) .................................. 82 
9.3 
Office of Biotechnology Activities (OBA) ............................................................. 83 
9.4 
Compliance with Informed Consent Regulations ................................................. 83 
9.5 
Compliance with IRB/EC Requirements .............................................................. 83 
9.6 
Compliance with Good Clinical Practice .............................................................. 83 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 ............................................................................................................................ 83 
9.8 
Compliance with Protocol .................................................................................... 83 
9.9 
Changes to the Protocol ...................................................................................... 83 
10. 
DATA COLLECTION, MONITORING AND REPORTING ............................................. 84 
10.1 
Confidentiality and Privacy .................................................................................. 84 
10.2 
Source Documents .............................................................................................. 84 
10.3 
Records Retention ............................................................................................... 85 
10.4 
Safety and Quality Monitoring ............................................................................. 85 
  Data & Safety Monitoring Board .............................................................. 85 
  Pathology Adjudication Committee .......................................................... 85 
  Clinical Monitoring ................................................................................... 85 
11. 
PUBLICATION POLICY ................................................................................................. 86 
12. 
LIST OF ABBREVIATIONS ............................................................................................ 87 
13. 
REFERENCES ................................................................................................................ 89 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
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CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA® 2000  Alone or in Combination 
With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 20 sites in the 
United States (US) 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-
16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000  given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA® 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3X) from Day 0 through Week 202 
No. of Subjects 
Approximately 36 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic clearance 
of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar HSIL3 
and no evidence of HPV-16/18 at Week 48 in vulvar tissue 
samples (i.e. collected via biopsy or excisional treatment)4 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3  No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
4  A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive non-study related medication for treatment of 
VIN lesions. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, AIS, or 
vulvar carcinoma at evaluation, and/or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a 
subject who received non-study related medication for treatment of VIN lesions.   


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 1.3 
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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar  HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/186 in vulvar tissue samples at 
Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL and no evidence of 
condyloma on histology (i.e. biopsies or 
excisional treatment) at the Week 48 visit
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion 
of 
subjects 
with 
no 
progression7 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of vulvar 
lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 48, 74 
and 96 compared to baseline8. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
                                                     
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
6 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
7 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
8 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96  
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects who did not have 
complete lesion resolution at Week 48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
photographic imaging at Week 74 and/or 
Week 96 compared to baseline9. Results 
will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction) 
and complete lesion resolution (no 
visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior  
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 
infiltrating cells10.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the vulva  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from other 
anatomic locations without surgical 
intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week  48 
                                                     
9 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
10 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
7. Vulvoscopy, HPV test results and 
miRNA profile (Day 0, Week 15 and 48) 
in conjunction with histologic regression 
of vulvar HSIL at Week 48 visit 
8. Describe patient reported outcomes for subjects 
treated with VGX-3100 and VGX-3100 with 
imiquimod 
8.  Patient-reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and 
following each of the first four doses, 
and at Weeks 48, 52, 74, 96, and 100. 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
Page 14 of 90 
 
Study Design: 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered with 
CELLECTRA® 2000 alone or in combination with imiquimod in adult women with histologically confirmed 
vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled.  
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-3100 
and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass Index 
(BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-5D-5L 
(EuroQol Research Foundation), and two additional PRO questions assessing quality of life after 
surgery or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of a 4 mm vulvar 
punch biopsy/biopsies with lesion remaining, and photographs of the acetowhite vulvar lesion(s) at the 
time of screening. In the case of multifocal disease, the two regions of potentially most advanced and 
severe disease, as judged by the investigator, should be chosen for biopsy using vulvoscopy and 
documented using standardized high resolution photography with a digital single-lens reflex (SLR) 
camera, on the case report form. Biopsy slides or tissue will be sent to a Pathology Adjudication 
Committee (PAC) for evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must 
assign the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar 
tissue specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study.
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of VGX-
3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject’s biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of VGX-
3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic and 
lesion area changes.  The first dose will be administered on Day 0, the second at Week 4, the third at 
Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 48 
(Subgroups A and B) will receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator.  Subjects in Subgroup E may receive surgical treatment per the 
judgement of the Investigator.  All subjects are scheduled to be followed to Week 100.  
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
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Figure 1: Study Visit Schedule 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will apply imiquimod 
5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to apply imiquimod 
cream three times per week for 20 weeks (inclusive of administration in the evening of VGX-3100 
dosing).  Subjects unable to tolerate imiquimod treatment may reduce their dosing frequency, and will 
document their use on the imiquimod dosing log provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by visual inspection with vulvoscopy is insufficient evidence 
to confirm disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74, and 96. Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), 
defined as areas that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0, and 
Weeks 4, 12, 27, 48, 74 and 96. Using standardized high resolution digital imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 2 
for Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC there is no 
evidence of HSIL (Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and biopsy 
adjacent to the site of the initial biopsy. Repeat biopsies that are indicated beyond Week 48 must be 
taken from the same lesion, adjacent to the prior biopsy site(s) within the boundaries of the original 
lesion.  
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size or no change 
in lesion size from baseline (Subgroups C or D), the Investigator has the option to give the subject a 5th 
dose of VGX-3100 at Week 52, and the subject will continue on study with vulvoscopy and biopsy at 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
Page 16 of 90 
 
Week 74.  Alternatively, the Investigator may choose to treat the subject with surgical or standard 
treatment, and the subject will continue on study without further biopsy.   
 
Figure 2: Decision process at Week 52  
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as follows: 
At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion as study 
start, but adjacent to the original site within the boundaries of the original lesion (see Table 2). If after 
evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject 
will continue to Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at Week 
78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, the 
Investigator may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy.   
 
 
 
 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
Page 17 of 90 
 
Figure 3: Decision Process at Week 78 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but adjacent to the original site within the boundaries of the original lesion (see Table 2). 
If there is no vulvar HSIL (Subgroups A or B), no further procedures are required. If after evaluation of 
biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), 
the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
Page 18 of 90 
 
In the event of worsening disease at any time (ie, Subgroup E – any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per the 
Investigator’s judgement and will continue on study through Week 100 with vulvoscopy, but without 
further study treatment or biopsy.  For a finding of carcinoma, subjects will receive surgical treatment, 
and be discontinued from study treatment.  The event will be reported as an SAE per section 7.1.4.  If 
wide excision is required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder: 
Responder and non-responder definitions (Table 3) take into account both histopathologic regression 
of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since HPV persistence is an 
important factor in the clinical progression of HSIL. A treatment responder is defined as a subject with 
no histologic evidence of vulvar HSIL and no evidence of HPV-16 or HPV-18 in vulvar tissue at 
evaluation and who did not receive non-study related medication for treatment of VIN lesions.  A 
treatment non-responder is a subject with histologic evidence of vulvar HSIL or vulvar carcinoma at 
evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, or a subject who received non-
study related medication for treatment of VIN lesions. Any case of histologically confirmed progression 
from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data and tissue 
regression and viral clearance results. The DSMB will be charged with advising the Sponsor if there 
appears to be a safety issue. No formal interim analysis is planned. The following stopping rules will be 
applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, assessed 
as related to study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal Investigator 
for the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, IRB 
(if applicable) and the DSMB.  


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The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding the outcome of 
any investigation stemming from a Study Pause.  
Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (both Screening as well 
as Day 0 prior to dosing) and at Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and at Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize HPV infection at Screening, 
Week 48, 74 and 96. Cervical samples, oropharyngeal rinse samples, vaginal, and intra-anal tissue 
swab samples will be obtained to characterize HPV infection in samples from study subjects taken at 
Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and intra-anal only) and at Weeks 
27, 48, 74, and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks will be collected for immunohistochemistry (IHC) 
and in situ hybridization (ISH) for the presence of HPV-16/18. Whenever possible, these studies will be 
performed on tissue sections from the diagnostic biopsy (pre-dose) and from tissue obtained post-dose 
(Week 48, 74 and 96). 
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
relationship between subject HLA haplotypes and regression.  


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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above; 
3. 
Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. 
Vulvar tissue specimen/slides provided to the Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
5. 
Histologic evidence of vulvar HSIL as confirmed by the PAC at screening; 
6. 
Must be judged by investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
7. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system; 
iv) Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject. 
10. Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 


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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing treatment for CIN;
5) Biopsy-proven differentiated VIN; 
6) More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day of first 
dose (i.e. Day 0); 
7) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
8) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
9) Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into cervical 
canal at screening; 
10) History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, or insufficient 
for diagnosis (ECC is not performed as part of study screening) and did not receive definitive 
treatment; 
11) Treatment for genital warts within 4 weeks prior to screening; 
12) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
13) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last dose 
of investigational product; 
15) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the investigator; 
16) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying drugs such as 
TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
17) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
18) Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
20) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the investigator; 
21) Current or history of clinically significant, medically unstable disease which, in the judgement of the 
investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results (e.g. chronic renal failure, angina, 
myocardial ischemia or infarction, class 3 or higher congestive heart failure, cardiomyopathy, or 
clinically significant arrhythmias); 
22) Malignancy or treatment for malignancy within 2 years of screening, with the exception of superficial 


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skin cancers that only require local excision; 
23) Acute or chronic bleeding or clotting disorder that would contraindicate IM injections or use of blood 
thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 
24) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic agents; 
25) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at Screening or 
Day 0; 
27) Prior major surgery within 4 weeks of Day 0; 
28) Participated in an interventional study with an investigational compound or device within 4 weeks of 
signing informed consent (participation in an observational study is permitted); 
29) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
30) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
31) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in 
ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
32) Metal implants or implantable medical device within the intended treatment site (i.e. electroporation 
area);  
33) Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with 
adherence to study requirements; 
34) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of either a 
psychiatric or physical (i.e. infectious disease) illness; 
35) Active military service personnel; 
36) Study-related staff or family members of study-related staff; 
37) 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.  


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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Vital signs 
Xb 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xe 
 
Xf
 
Xe 
 
Xe
 
Xe 
 
HLA testing g 
 
X 
Cervical cytology, ThinPrep™ h 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject  VGX-3100 +EP m 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Review PD o 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X-----------------------------------------------------------------------------------------------------------X 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X
Abbreviations: OP; oropharynx 
a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE. 


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b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared).  Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 30 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. One additional 8.5 mL yellow 
(ACD) tube to be collected at Day 0, Week 15 and 48 for microRNA analysis. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27.   
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrepTM cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected.  Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j Standardized high resolution digital imaging of the vulva and the associated acetowhite stained lesion(s) 
must be performed prior to and after biopsy, and at all vulvoscopy examinations. Additionally, 
standardized high resolution digital imaging should be obtained during examinations of the vagina if 
lesions are identified, for documentation. 
k Tissue specimen from all excised tissue must be reviewed by the PAC and residual vulvar tissue from 
entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) should be sent to the 
central pathology laboratory for immunohistochemistry (IHC) and HPV testing.   
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod.  
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36, EQ-5D-5L) plus two additional questions will be assessed as described in Section 
6.8.     
 
 
 


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1. 
INTRODUCTION  
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, 
and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the most 
significant amongst high-risk types since they are responsible for most HPV-caused 
cancers [1].   
HPV-16 is involved in more than 85% of HPV-associated vulvar HSIL cases in the U.S.[1]. 
Persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions 
(HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oro-pharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS)[2].  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 5,950 new cases and 1,110 
attributable deaths annually for year 2016 in the United States [3]. Vulvar cancers consist 
largely of squamous cell carcinomas and accounts for approximately 5% of all female 
genital malignancies [4]. Differentiated VIN, which is typically not caused by HPV infection 
and is more typically found in older women, is more likely to progress to cancer more 
rapidly than HPV-associated-VIN. The five year overall relative survival for vulvar cancer 
in the U.S. is 70.7% [3].  Recurrent vulvar cancer occurs in an average of 24% of cases 
after primary treatment, after surgery with or without radiation [5].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia.  The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance of 
pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [6]    
In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) replaced 
the three grade classification system with the current single grade classification for which 


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only high grade VIN (2/3) is classified as VIN [7]. In 2012, the Lower Anogenital Squamous 
Terminology (LAST) Standardization Project for HPV-associated lesions applied the term 
high grade squamous intraepithelial lesion (HSIL) to encompass high grade dysplasia [8].  
Therefore, for the purpose of this study, the term vulvar HSIL will be used, which 
encompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to encompass what 
was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [9]. Over time, typically years, vulvar HSIL can progress to invasive 
cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group and median 
13.8 years in another group [10], and from VIN3 patients, mean = 2.5 years, range: 4 – 
216 months [11].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity against 
vulvar HSIL and have not achieved universal uptake, leaving a population of susceptible 
and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to visual 
inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for vulvar 
HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, often 
requiring multiple, repeat treatments. Progression to vulvar cancer following current vulvar 
HSIL treatments can also occur within 1 year of treatment and for up to 20 years post 
treatment. The current treatment options for vulvar HSIL are surgical excision, laser 
ablation, and off-label medical therapy. The rate of HPV-associated vulvar HSIL 
recurrence after surgical treatment is high; post-treatment recurrence rates exceed 30-
50% with all currently available treatment regimens [12, 13].   
Wide local excision is the ‘preferred initial intervention’ by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation.  Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues with 
body image and sexual dysfunction.  Medical therapies have been investigated as a 
means to avoid these negative outcomes.  Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food and 
Drug Administration for this indication.  Inconsistent treatment efficacy results have been 
shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 
of recurrence is slightly higher compared to wide local excision. Laser treatment of vulvar 
HSIL requires destruction of cells through the entire thickness of the epithelium including 
hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation should 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 1.3 
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extend through the dermis. Post-treatment recurrence rates exceed 30% (for all treatment 
regimens), and is higher with positive excision margins [14]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low rate 
of spontaneous resolution.  According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is suspected 
(even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is wide local 
excision (i.e. surgery) [15].  When occult invasion is not a concern, vulvar HSIL can be 
treated with excision, laser ablation, or topical imiquimod as an off-label medical therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [14].  Therefore, many patients have a fear 
of recurrence and progression to cancer [16].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks.  
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid use of toilet paper and to rather rinse with warm water.  
During recovery, common effects include pain in urinating and wiping, soreness, difficulty 
sitting, and feeling tired [17]. In the first week after hospital discharge, common patient-
reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [18].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-being 
[17].  The symptoms and signs of vulvar HSIL can be moderate to severe and include 
painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating [18]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than age-
matched healthy women [19]. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor’s office all the time [17]. 
 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid HPV-associated vulvar HSIL 
and subsequent vulvar cancer. The US-licensed prophylactic HPV vaccines are indicated 
for girls and women ages 9 through 26 years for Gardasil® and Gardasil®9 (Merck & Co. 
Inc.), and ages 9 through 25 years for Cervarix® (GlaxoSmithKline). The early portions of 


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Protocol Version: 1.3 
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these age ranges are generally before sexual debut and thus can allow immunologic 
protection against the anticipated earliest normal exposures to HPV infection. HPV 
prophylactic vaccination is highly effective and safe, and routine vaccination is 
recommended for females in the United States starting at age 11 or 12 years [20]. 
However, the prophylactic vaccines have no therapeutic effect upon existing HPV infection 
or existing HPV-related intraepithelial neoplasia [21]). 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan is used in this study to address the risk of a potential delay 
in treatment of vulvar HSIL.  The feasibility of this approach was demonstrated in the 
Phase 2b study of cervical HSIL.  Given that vulvar disease progresses slowly to vulvar 
cancer if untreated, the proposed enhanced monitoring plan is expected to maintain the 
safety of trial subjects for this study.  First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study investigators.  Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, by 
two independent expert pathologists (pathology adjudication committee). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
[22], is specifically excluded from study entry.  By contrast, HPV-associated vulvar HSIL 
does not progress rapidly, typically taking years to manifest and progress, making 
enhanced monitoring feasible.   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.14).  Colposcopy will also be 
done at baseline and during the study given that concurrent disease in the lower genital 
tract can occur.   A Data Safety Monitoring Board will be utilized to review subject safety 
data and advise on any study-level safety concerns. Investigators always have the option 
of performing ad hoc vulvar biopsies to rule out disease progression.  Additional treatment 
(e.g., additional excision, ablation, or medical therapy) may be carried out, if deemed 
necessary according to Investigator judgement. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA® device represent an integrated investigational 
product designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, 
CIN3) via an immune response directed against HPV-16/18.  Further information about 
VGX-3100 is provided in the Investigator’s Brochure. 
 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA® in vivo electroporation (EP) device. EP is 
a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [23, 24]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 


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10 to 100 fold [25, 26]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as shown 
by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [27].  
This study will use the CELLECTRA® 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no significant 
safety issues identified.  Further information about the CELLECTRA® 2000 device can be 
found in the Investigator’s Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device.  Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 250 
mg of the cream, equivalent to 12.5 mg of imiquimod.  The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod.  The overall aim is to determine if treatment with VGX-3100 could allow women 
with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of concept that 
VGX-3100 can induce resolution of both HPV-associated dysplastic lesions and the 
underlying HPV 16/18 infection was shown in a Phase 2b study of cervical intraepithelial 
neoplasia (CIN).  The similar underlying pathogenic mechanisms between cervical and 
vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could be a non-
surgical therapeutic option for the treatment of vulvar HSIL, which is a significantly under 
met medical condition.  A VGX-3100 with imiquimod-administration arm is also included, 
given the prevalent use of imiquimod as a topical medical treatment of vulvar lesions, to 
investigate if a more robust immune response is achieved with VGX-3100, to potentially 
increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 
responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [28].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Therefore, imiquimod may be able to be used 
synergistically with VGX-3100. 


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Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG).  Published regimens include three times weekly 
application to affected areas for 12 – 20 weeks, with colposcopic assessment at 4-6 week 
intervals during treatment [15].  
The current study will include an arm to explore whether the efficacy of VGX-3100 is able 
to be enhanced by concomitant treatment with Imiquimod.     
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 
reported at the application site [29].  The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity.  In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure including 
anesthesia, post-operative bleeding, infection, or damage to surrounding structures such 
as the clitoris, urethra, or anus. The other potential benefit is that the response to VGX-
3100 is systemic and may clear the underlying HPV infection, which is the root cause of 
vulvar HSIL.  Consequently, there is the potential to reduce the risk of recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL  associated with HPV-16 and/or HPV-18 (HPV-16/18), 
will result in a higher percentage of women with regression of HSIL of the vulva based on 
histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from 
vulvar tissue compared with historical control. 
 
 
 


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2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional treatment).  
2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of  VGX-
3100 delivered IM followed by EP with 
CELLECTRA® 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL11 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/1812 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression13 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
                                                     
11 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
12 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
13 Progression is defined as advancement to carcinoma according to the Pathology Adjudication Committee by 
histology. 


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6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
48, 74 and 96 compared to baseline14. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion size of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).  
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone 
or in combination with imiquimod,  post dose 
3, post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes 
at baseline and Weeks 15, 27, 48, 74 and 
96 visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 
                                                     
14 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe 
the 
efficacy 
of 
VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
vulvar lesion(s), in subjects without a 
complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized photographic imaging at Week 
74 and/or Week 96 compared to baseline15. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in lesion 
area of 0-25%), partial lesion area resolution 
(>25% and <100% reduction), and complete 
lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6  doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, 
as 
measured 
by 
virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of CD8+ and FoxP3 infiltrating 
cells16.  
5. Describe virologic clearance of HPV-16/18 
from other anatomic locations outside the 
vulva   
5. Proportion of subjects who have cleared HPV-
16/18 on specimens from other anatomic 
locations 
without 
surgical 
intervention 
(inclusive of cervix, oropharynx, vagina and 
intra-anus) at Week  48 
6. Characterize 
HLA 
haplotypes 
and 
the 
correlation with efficacy 
6.  Proportion of subjects with regression of HSIL 
on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
7. Vulvoscopy, HPV test results and miRNA 
profile (Day 0, Week 15 and 48) in 
conjunction with histologic regression of 
vulvar HSIL at Week 48 visit 
8. Describe patient reported outcomes for 
subjects treated with VGX-3100 and VGX-
3100 with imiquimod 
8. Patient-reported outcome (PRO) endpoints 
will be obtained prior to first dose (Day 0), on 
the day of and following each of the first four 
doses, and at Weeks 48, 52, 74, 96 and 100.
                                                     
15 Digital photos will be analyzed with a computer program to calculate the total lesion size in cm2.   
16 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA® 2000 alone or in combination with 
imiquimod in adult women with histologically confirmed vulvar HSIL associated with HPV-
16/18. Approximately 36 subjects will be enrolled.  Twenty-four subjects will receive VGX-
3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at 
screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category 
(<45 years vs. ≥45 years). 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be provided and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), and two additional PRO 
questions assessing quality of life after surgery or biopsy. 
To be eligible for the study, subjects must consent to participate and have a minimum of 
a 4 mm vulvar punch biopsy/biopsies with lesion remaining, and photographs of the 
acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, the 
two regions of most advanced and severe disease, as judged by the investigator, should 
be chosen for biopsy using vulvoscopy and documented using standardized high 
resolution photography with a digital single-lens reflex (SLR) camera on the case report 
form. Biopsy slides or tissue will be sent to a Pathology Adjudication Committee (PAC) for 
evaluation prior to enrollment. In order to be eligible for enrollment, the PAC must assign 
the diagnosis of vulvar HSIL based on the biopsy sample(s). Subjects must also have a 
vulvar specimen test positive for HPV genotype 16 and/or 18 to be eligible for participation 
in the study. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 mg 
of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-16/18 
status and all other eligibility criteria but no more than 10 weeks following collection of the 
subject’s biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid, preferred site, 
or anterolateral quadriceps, alternate site) followed immediately by EP with the 
CELLECTRA® 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes.  The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses.  Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator.  
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lesion size from baseline (Subgroups C or D), may receive a sixth dose of VGX-3100 
administered IM with EP at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgement of the Investigator.  All 
subjects will complete the study at Week 100. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will 
apply imiquimod 5% cream to the vulvar lesion beginning in the evening on Day 0, and 
will continue to apply treatment three times per week for 20 weeks (inclusive of 
administration in the evening of VGX-3100 dosing).  Subjects unable to tolerate imiquimod 
treatment may reduce their dosing frequency, and will document their use on the 
imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital imaging, vulvar lesion(s) will also be quantitatively 
measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced and severe disease as judged by the Investigator, and must be a minimum of 4 
mm in length. Visible lesion must remain after screening biopsy to ensure measurement 
on study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 2 for Minimally Required Biopsy 
Procedures). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Figure 2, Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and 
biopsy adjacent to the site of initial biopsy.     
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion size 
or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the Investigator 
has the option to give the subject a 5th dose of VGX-3100 at Week 52, and the subject will 
continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator 
may choose to treat the subject with surgical or standard treatment, and the subject will 
continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 2). If after evaluation of biopsy tissue by 
the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to 
Week 96 for vulvoscopy, and biopsy adjacent to the site of the initial biopsy.   
If HSIL remains but there is a reduction in lesion size or no increase in lesion size from 
baseline (Subgroups C or D), the Investigator has the option to give the subject a 6th dose 
of VGX-3100 at Week 78, and the subject will continue on study with vulvoscopy and 


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biopsy at Week 96. Alternatively, the Investigator may choose to treat the subject with 
surgical or standard treatment, and the subject will continue on study without further 
biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but adjacent to the original site within 
the boundaries of the original lesion (see Table 2). If there is no vulvar HSIL (Subgroups 
A or B), no further procedures are required. If after evaluation of biopsy tissue by the PAC 
there is vulvar HSIL (Subgroups C or D), or worsening disease (Subgroup E), the subject 
will receive surgical or other standard treatment. 
In the event of worsening disease (ie, Subgroup E - any increase in lesion area from 
baseline or worsening of HSIL to cancer), the subject will receive surgical treatment per 
the Investigator’s judgement and will continue on study through Week 100 with 
vulvoscopy, but without further study treatment or biopsy.  For a finding of carcinoma, 
subjects will receive surgical treatment, and be discontinued from study treatment.  The 
event will be reported as an SAE per section 7.1.4. If wide excision is required, the sample 
obtained will be sent to the PAC for evaluation.  
 
Table 2:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original biopsy site within the boundaries of the original 
lesion; 
Acetowhite Lesion 
Vulvar punch biopsy and imaging; biopsy should be 
conducted of the same lesion as study entry, but adjacent to 
the original site within the boundaries of the original lesion; 
biopsy of lesion must include suspected area of most 
advanced disease  
Multiple acetowhite lesions 
Vulvar punch biopsies and imaging; biopsy should be 
conducted of the same two lesions as study entry but 
adjacent to the original site within the boundaries of the 
original lesion; biopsies must include area of most advanced 
and severe disease as determined at screening  
 
  
 DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 3) take into account both histopathologic 
regression of vulvar HSIL and virologic (HPV-16/18) clearance from tissue samples since 
HPV persistence is an important factor in the clinical progression of HSIL.  
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive non-study related medication for treatment of VIN lesions.  A treatment non-
responder is a subject with histologic evidence of vulvar HSIL or vulvar carcinoma at 
evaluation, and/or a subject with evidence of HPV-16/18 at evaluation, or a subject who 
received non-study related medications for treatment of VIN lesions. Any case of 


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histologically confirmed progression is considered a non-responder. Progression is 
defined as advancement to carcinoma by histology. 
Table 3: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSILa  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive non-study 
related medication for treatment of VIN 
lesions. 
 
Subject with histologic evidence of vulvar HSIL or 
vulvar carcinoma at evaluation 
  
AND/OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related 
medication for treatment of VIN lesions 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight.  
The DSMB will meet quarterly to review safety data and regression/clearance results. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. No 
formal interim analysis is planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, Principal Investigator for the trial, and the DSMB. 
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately until 


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a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) and at 
Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and at Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize HPV infection at Screening, Week 48, 74 
and 96. Cervical samples, oropharyngeal (OP) rinse samples, vaginal, and intra-anal 
tissue swab samples will be obtained to characterize HPV infection in samples from study 
subjects taken at Screening (cervical sample only), Day 0 prior to dosing (OP, vaginal and 
intra-anal only) and at Weeks 27, 48, 74 and 96. 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then unstained slides and/or the relevant paraffin blocks will be collected for 
immunohistochemistry (IHC) and in situ hybridization (ISH) for the presence of  
HPV-16/18. Whenever possible, these studies will be performed on tissue sections from 
the diagnostic biopsy (pre-dose) and from tissue obtained post-dose (Week 48, 74 and 
96).  
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Confirmed vulvar infection with HPV types 16 and/or 18 at screening; 
4. Vulvar tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
5. Histologic evidence of vulvar HSIL as confirmed by PAC at screening; 
6. Must be judged by investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
7. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 


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adequate size to ensure that a visible lesion remains after 4 mm screening biopsy;  
8. Must have vulvar HSIL that can be completely demarcated for area measurement; 
9. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months 
or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 12 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method 
with failure rate of less than 1% per year when used consistently and correctly from 
screening until 6 months following the last dose of investigational product. Acceptable 
methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into 
the study, and this male is the sole partner for that subject. 
10. Normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing treatment 
for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. More than 10 weeks have elapsed between date of initial tissue biopsy for screening 
and day of first dose (i.e. Day 0); 
7. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
8. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after 
biopsy; 
9. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension 
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10. History of endocervical curettage (ECC) which showed cervical HSIL indeterminate, 
or insufficient for diagnosis (ECC is not performed as part of study screening) and 
did not receive definitive treatment; 
11. Treatment for genital warts within 4 weeks prior to screening; 
12. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 
4 weeks prior to screening; 
13. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
14. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
15. Presence of any abnormal clinical laboratory values greater than Grade 1 per Common 
Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or 
less than Grade 1 but deemed clinically significant by the investigator; 
16. Immunosuppression as a result of underlying illness or treatment including: 
a. History of or positive serologic test for HIV at screening;  
b. Primary immunodeficiencies; 
c. Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d. Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e.  History of solid organ or bone marrow transplantation; 
f. 
 Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
17. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
18. Received any non-study related non-live vaccine within 2 weeks of Day 0; 
19. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of 
Day 0; 
20. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the investigator; 
21. Current or history of clinically significant, medically unstable disease which, in the 
judgement of the investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the study 
results (e.g. chronic renal failure, angina, myocardial ischemia or infarction, class 3 or 
higher congestive heart failure, cardiomyopathy, or clinically significant arrhythmias); 
22. Malignancy or treatment for malignancy within 2 years of screening, with the exception 
of superficial skin cancers that only require local excision; 
23. Acute or chronic bleeding or clotting disorder that would contraindicate IM injections 
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Day 0; 
24. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
25. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 
mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
26. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
27. Prior major surgery within 4 weeks of Day 0; 
28. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
29. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
30. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment 
site; 
31. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) 
that is located in ipsilateral deltoid injection site (unless deemed acceptable by a 
cardiologist); 
32. Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
33. Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
34. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
35. Active military service personnel; 
36. Study-related staff or family members of study-related staff; 
37. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study treatment/EP 
but will be encouraged to continue follow-up safety assessment through study discharge 
and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that subject. 


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 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw from 
study participation at any time. A subject may be withdrawn at any time at the discretion 
of the investigator for any maternal obstetrical or medical complications after consultation 
with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report form 
(eCRF) and the subject’s source document 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule for 
follow-up and treatment of VIN, and ascertain whether or not the subject wishes to and/or 
should continue in the study based on previous noncompliance. In cases where the 
subject does not return for the rescheduled visit or cannot be reached to reschedule the 
missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls to the subject should be made and if that fails, then a certified letter is sent 
to the subject’s last known mailing address) so that they can be considered withdrawn 
from the study for disposition purposes. These contact attempts should be documented in 
the subject’s medical record. Should the subject continue to be unreachable, then and 
only then will she be considered to have withdrawn from the study with a primary reason 
of “Lost to Follow-up.” For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). At 
a minimum, the investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100).  A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The investigator or study coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the study 
or is withdrawn from the study prior to study completion, all applicable activities scheduled 
for the final study visit should be performed at the time of discontinuation. The investigator 
will make every effort to have all scheduled immune assessment blood samples collected 
as indicated in the Schedule of Events in the synopsis, Table 1. Any AEs and/or SAEs 
present at the time of discontinuation/withdrawal should be followed in accordance with 
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 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 
 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs regardless 
of relation to study drug. 
 
 Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical 
need to withdraw. If the subject gave a reason for withdrawal, it must be recorded 
on the eCRF. This reason does not allow for further data collection and should not 
be selected if follow-up data collection of this subject is anticipated by the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation should 
be discussed with the Sponsor’s Medical Monitor prior to discontinuation of study 
treatments or study withdrawal. 
 
 Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter sent 
by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon®) technology.  The VGX-
3100 formulation to be used in this study is described in Table 4 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum.  There are 24 single-use packets of imiquimod in one box.  The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older.  Although it is not approved by the US Food 
and Drug Administration for the treatment of vulvar HSIL, imiquimod is currently 


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recommended as a non-surgical, off-label treatment option for vulvar dysplasia by the 
American College of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 4. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  The actual product label names the product as 
VGX-3100X; the “X” designation was included to differentiate the current buffer 
formulation from a previous formulation of VGX-3100 in water.  Imiquimod Cream, 5% will 
have both the original manufacturer's label on individual packets and the back of the 
carton, and an investigational label on the front of the carton.  The labels will contain, at 
minimum, the information shown in Figure 6.   


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Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  
 
Figure 6. Example labels for imiquimod 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Opthalmic Use. 
Keep out of reach of children.  This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer’s instructions. Avoid freezing.    


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5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized personnel 
according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. The 
product must be used within 4 hours of removal from the refrigerator. All material removed 
from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 
 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations.  Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks.  Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water.  Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period.  The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 


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5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to 
be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 IP can only 
be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the CELLECTRA® 2000 device are located in the User Manual. 
Each clinical site will receive training for the use of the CELLECTRA® 2000 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 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer.  The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, adverse effects, interfering substances 
or devices, warnings, and precautions.  Each CELLECTRA® 2000 Pulse Generator has a 
unique serial number, and each CELLECTRA® 2000 Applicator has a unique serial 
number. Each CELLECTRA® 2000 Array has a Lot Number, Manufacture Date, and 
Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local authorities 
to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to successfully 
completing device training from sponsor personnel. Individuals whose credentials do not 
meet the relevant local requirements may perform the treatment procedure under both of 
the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or 
an approved Sub-Investigator who has already been trained by the sponsor’s 
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2. The CV and any relevant qualifications of the individual must be reviewed and 
approved by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its 
designee. 
5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 5 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers (as 
applicable) is included at the time of manufacture and may vary from these examples. The 
information found on the actual device labels should always be used to manage, track and 
record investigational product accountability during study conduct. 
 


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Table 5. Example Labels for the CELLECTRA® 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA® 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA® 
2000 5P  
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA® IM 
Array 
 
REF: M01-
002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. This 
includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA® 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA® 2000 IM Applicator is intended to be used multiple times on the same 
subject and then disposed after final use in accordance with accepted medical practice 
and any applicable local, state, and federal laws and regulations. Once the IM applicator 
is assigned to a subject, it may NOT be used on another subject. The used sterile 
disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.10 RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the responsible Study 
Monitor. 
If product is to be destroyed on site, it is the Investigator’s responsibility to ensure that 
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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected 
prior to consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the samples 
sent to the central pathology lab for review by the PAC to assess eligibility.  There will be 
a maximum allowable window of 10 weeks from the date of collection of the qualifying 
biopsy sample(s) (i.e. samples reviewed by PAC with HSIL consensus diagnosis), until 
the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be obtained 
within a reasonable timeframe, an additional biopsy sample should be collected during 
screening following the consent of the subject. The 10 week screening window begins 
upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets other 
eligibility criteria). Subjects whose vulvar specimens also test positive for other HPV 
genotypes are not excluded as long as they have a positive result for HPV-16 and/or HPV-
18.  
The assessments during the screening period will determine the subjects’ eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, which 
must be performed within 30 days prior to Day 0. All screening assessment values must 
be reviewed prior to study treatment. 
 
Signed informed consent 
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG (within 30 days prior to Day 0) 
 
Baseline laboratory evaluations (includes complete blood count [CBC), serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine aminotransferase 
[ALT], creatine phosphokinase [CPK], and urinalysis) to be performed within 30 days 
prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be performed 
once) 
 
Cervical cytology and ThinPrep™ for cervical HPV type 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical areas 
should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photographs of the vulva and the associated lesion must be collected prior to 
and after biopsy at screening.  
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC. If residual vulvar 
tissue is available from entry either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment.  Visit dates and windows must be calculated from Day 0. 


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 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 
 
Review of concomitant medications and adverse events 
 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
OP rinse, vaginal and intra-anal swabs 
 
Baseline vulvoscopy  
 
Vulvar lesion photography 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 4 
The following study evaluations will be performed at Week 4 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 


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 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvoscopy  
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression. 
 
Vulvar lesion photography  
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after study 
treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 
The following study evaluations will be performed at Week 12 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvoscopy  


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 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 and Week 94 unless PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression 
 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 
The following study evaluations will be performed at Week 15 (± 7 days): 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay including miRNA profile 
 WEEK 24 
The following study evaluations will be performed at Week 24 prior to study treatment 
(± 7 days): 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 


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The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 27 
The following study evaluations will be performed at Week 27 (± 7 days): 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. Biopsies should not be performed at any visit other than 
at entry (screening), Week 48, Week 74 or Week 96 unless the PI suspects 
disease progression. All biopsy samples must be sent to the PAC for review 
 
Vulvoscopic visualization of a normal appearing vulva is insufficient evidence 
to confirm disease regression.  
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 WEEK 38 PHONE CALL 
 
Review concomitant medications and adverse events 
 WEEK 48 
The following study evaluations will be performed at Week 48 (± 7 days): 
 
Targeted physical assessment 


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 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected. 
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
 If residual vulvar tissue is available from entry and/or Week 48 
specimen(s) either paraffin blocks or unstained slides should be sent to 
the central pathology laboratory for IHC and testing for presence of HPV-
16 and HPV-18 
 
Patient Reported Outcomes 
 WEEK 52  
Subjects will have a Week 52 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 


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 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 74 
The following study evaluations will be performed at Week 74 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar lesion photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 
 WEEK 78 
Subjects will have a Week 78 consultation (± 14 days) to discuss their biopsy results and 
treatment plan.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 


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Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after study 
treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 
 WEEK 96 
The following study evaluations will be performed at Week 96 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical cytology and ThinPrep™ for HPV type 
 
OP oral rinse, vaginal and intra-anal swabs 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or cervical 
areas should be obtained if lesions are identified.  
 
Vulvoscopy 
 
Visualization of a normal appearing vulva by vulvoscopy is insufficient 
evidence to confirm disease regression. 
 
Vulvar Lesion Photography 
 
Photographs of the vulva and the associated lesion must be collected.  
 
Vulvar biopsy or wide excision as per investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Slides from all excised tissue must be reviewed by the PAC 
If residual vulvar tissue is available either paraffin blocks or unstained slides should be 
sent to the central pathology laboratory for IHC and testing for presence of HPV-16 and 
HPV-18 


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 WEEK 100 
The following study evaluations will be performed at Week 100 (± 14 days): 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, study 
objectives, potential benefits and risks, discomforts/inconveniences, and the subject’s 
rights and responsibilities. The subject is then requested to sign and date the ICF. A copy 
of the signed informed consent documentation must be provided to the subject. The 
qualified study personnel will document the process of obtaining informed consent within 
the source record. Signed ICFs are maintained in the subject’s source records and must 
be accessible for verification at any time. 
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all study-related procedures. SIDs are a combination of a 
up to two alpha letters study code, two alpha letter Country code, two digit site number, 
plus 3-digit subject number starting with 001 (e.g., VNUS01001). Once assigned, SIDs 
cannot be reused for any reason. Information regarding the SID and screen date must be 
documented on a Screening log/system and in the Interactive Response Technology 
(IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated allocation 
schedule.  


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 SAFETY EVALUATIONS 
6.3.3.1 PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100).  It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems.   
A targeted physical assessment will be performed at other visits as determined by 
the investigator or directed per subject complaints. 
6.3.3.2 VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 
 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.3.3 WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.3.4 MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be obtained 
at screening. All relevant (as judged by the investigator) past and present 
conditions, as well as prior surgical procedures will be recorded for the main body 
systems.  
6.3.3.5 SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, history 
of prior cervical dysplasia, and pregnancy history will be obtained at Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to document 
any change from screening. 
6.3.3.6 LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  


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Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 
6.3.3.7 PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.3.8 ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has been 
in a supine position for 10 to 15 minutes. The ECG should include measurements 
of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, Twave as 
well as an investigator assessment of whether the ECG is normal or abnormal 
(automated interpretations of ECG should not be used). Abnormal ECGs should 
be interpreted as “clinically significant (CS)” or “not clinically significant (NCS)” by 
the investigator. 
6.3.3.9 POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after the 
study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 


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The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.3.10 IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA® 2000. Study treatment plus EP must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is implanted 
metal within the same limb. Any device implanted in the chest (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal) excludes the use of the deltoid 
muscle on the same side of the body. The timing of the initial dose will be designated Day 
0 with the subsequent doses scheduled for administration at Weeks 4, 12, 24, and at 
Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 RISKS OF TREATMENT PROCEDURES TO VGX-3100 
No serious related adverse events to VGX-3100 have been observed in the clinical trial 
experience to date.  A summary of potential risks of IM Administration followed by EP with 
CELLECTRA™ can be found in the VGX-3100 + Imiquimod Investigator’s Brochure.   
6.4.1.2 RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
Adverse events reported in clinical trials with imiquimod cream, 5% for external genital 
warts can be found in the imiquimod product label [30], and in the VGX-3100 + Imiquimod 
Investigator’s Brochure. 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 
approximately 1.5 cm diameter amount will be applied with occlusion to the site of injection 
~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who receive 


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a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours after 
receiving medication and should have arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a 
mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.3.6.  
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 minutes 
after each study treatment. Subjects will be advised to record local and systemic AEs for 
7 days after each study treatment on a PD which will be reviewed with study personnel at 
8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject’s CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be 
instructed to use the following grading scale: 
 


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Table 6. 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” 
*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 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes (PRO) 
instruments will be provided. The following PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [31]. SF-36v2™ will be administered at the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [32, 33] and will be 
administered as described below: 


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 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
Administration of PRO instruments will be performed according to the validated procedure 
and guidelines of each respective instrument, except for some assessments for 
exploratory analyses. Additional instructions will be provided separately.    
 
3. Additional Global PRO Questions – regarding quality of life after surgery or biopsy.  
These two questions will be administered at Week 52 only. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity 
may occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-
γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
Profiling of miRNA will occur using plasma obtained at Day 0, Week 15 and 48.  
Assessment of Day 0 samples alone will explore predictive algorithms for response to 
treatment with VGX-3100 prior to dosing.  Assessment of Week 15 and 48 samples will 
be done as a comparison against Day 0, in order to look for changes in miRNA profiles 


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that occur once dosing with VGX-3100 has begun, to explore construction of an algorithm 
to predict treatment success with VGX-3100. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses 
have been rendered, then unstained slides and/or the relevant paraffin blocks may be 
collected for immunohistochemistry (IHC).  Assessment of markers may include, but are 
not limited to, CD8+ and FoxP3+ infiltrating cells as well as assessment of cell death via 
Cleaved Caspase 3 assessment. Additional assessments may include visualization of 
Granulysin, Perforin, CD137, CD103 and PD-L1 in cervical tissue as sample allows.  
Markers listed here may change as new relevant information becomes available. 
6.11 HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 
6.12 VULVAR HPV TESTING 
A 4 mm vulvar punch biopsy sample will be obtained at Screening, Weeks 48, 74, and 96, 
and will be sent to a central laboratory for HPV genotyping by PCR.  In the case of 
multifocal disease, a 4 mm vulvar biopsy will be obtained from two regions of most 
advanced and severe disease as judged by the investigator.  The subject will be requested 
to abstain from sexual activity and refrain from use of douching vulvar biopsy samples to 
eliminate potential interference with the results of HPV testing. 
6.13 COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Screening and at Week 96 for all subjects.  
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep™ test kits at Screening, Weeks 27, 48, 74 
and 96, and read in a central laboratory. HPV PCR will be performed on the ThinPrep™ 
specimen. At each of these visits, menstrual cycle status & recent history will be collected 
via self-report.  If the Pap smear result suggests progression to cancer the investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples to eliminate potential interference with the results of HPV testing. 
6.14 VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL confirmed 
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of the vulva will be captured after application of acetic acid to document the clinical 
findings.  If a biopsy or surgical excision is performed, images of the vulva should be 
collected before and after the procedure.  Each site will be instructed on 1) the technique 
for capturing the proper images using a standard approach, and 2) the process for 
uploading the images to a secure server.   
In the case of multifocal disease, the two lesions which appears to have the highest 
likelihood according to the investigator of most advanced disease and which is of 
adequate size to ensure that a visible lesion remains after punch biopsy should be chosen 
for vulvar biopsy and documented using photography.     
Interval vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96.  An 
unscheduled biopsy may be performed at the discretion of the investigator if there is 
suspicion of disease progression. Guidelines for managing the findings of unscheduled 
biopsies for suspected disease progression are described in Table 7.  Consult the Medical 
Monitor for any planned departures from these guidelines. 
Table 7:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 
Subject safety is paramount in this study. Therefore, if at any time the investigator 
suspects disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over the 
default “Schedule of Events”, Table 1.  Histologic samples and photographic 
documentation should be obtained for these cases.  
6.15 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. Medical procedures performed within 8 weeks prior to 
screening biopsy date of eligible subjects that do not affect subject’s eligibility for 
participation and during the study (including over the counter or herbal), will be recorded 
on the CRFs. This information will be obtained from the subject and abstracted from any 
available medical records. The indication for the medication, dose, and dose regimen will 
be documented. Medication that is considered necessary for the subject’s safety and well-
being may be given at the discretion of the investigator and recorded in the appropriate 
sections of the CRF. 
6.16 RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 


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 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day 
of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic corticosteroids 
are allowed) 
 
Disease 
modifying 
doses 
of 
anti-rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs 
such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at screening and 
throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1).  Lapses in contraceptive use should be reported to investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples.  
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and unsolicited 
AEs will be monitored and reported on an AE CRF, including the event’s seriousness, 
severity, action taken, and relationship to investigational product(s). AEs should be 
followed until resolution or stable and the outcome will be documented on the appropriate 
CRF. All AEs should be recorded in standard medical terminology rather than the subject’s 
own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of study drug). 


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 
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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.9 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the duration 
of the study, including the follow-up off study drug period will be recorded as an 
AE. 
 
Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit 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 informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
 SERIOUS ADVERSE EVENTS 
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; 
 
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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 2) 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, 3) the 


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development of drug dependency or drug abuse or 4) the development of a 
malignancy; 
 
Is medically significant or requires intervention to prevent one or other of the outcomes 
listed above. 
 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 that 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 nor does it include full day or overnight stays in observation status. 
 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 9.5. 
 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE.  For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of carcinoma should also 
be reported as an SAE.  In both instances the condition for SAE reporting should be 
categorized as a medically important event unless another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal 
product related to any dose, for which a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility; i.e., there is evidence to suggest 
a causal relationship between the product and the adverse event. An unexpected ADR is 
one, the nature or severity of which is not consistent with the applicable product 
information (investigator’s brochure, protocol, and user manual). Reports that add 
significant information on specificity or severity of a known, already documented SAE 


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constitute unexpected events. For example, an event more specific or more severe than 
described in the Investigator's Brochure or protocol would be considered "unexpected.” 
Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent 
new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a 
serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the SUSAR 
will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating investigators of information that might materially influence the 
benefit-risk assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. Examples of such information 
include a clinically important increase in the rate of occurrence of a serious expected 
adverse event, the identification of a significant hazard to the subject population, or a 
major safety finding from a study conducted in animals. 
 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
investigator within 24 hours. Sponsor will assess each device related SAE to determine if 
anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The investigator will grade injection site reactions in accordance with 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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 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be assessed 
as not related to the IP and/or the investigational device. Because the investigator is 
knowledgeable about the subject (e.g., medical history, concomitant medications), 
administers the IP, and monitors the subject’s response to the IP, the investigator is 
responsible for reporting adverse events and judging the relationship between the 
administration of the IP and device and a subsequent AE. 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 IP delivered by EP 
and determine whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation of 
any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the IP and/or the investigational device indicating "yes" or "no" 
accordingly. Causality should be assessed by the investigator as “yes, related” or “no, 
unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications known 
to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory 
or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition of an AE (or SAE) as described in Section 7.1. If the laboratory abnormality 
is part of a syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory 
result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency from 
the baseline condition and meets one of the following criteria will be recorded as an AE: 
 
Requires therapeutic intervention or diagnostic tests 


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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 
 POST-TRIAL 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 or termination visit and the event is deemed by the investigator to be related 
to the study treatment, he/she should promptly document and report the event to the study 
team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be excluded 
from participation in the study. Should a subject become pregnant after enrolling in the 
study, she will not be given any further study treatments. A Pregnancy Form will be 
completed by the site personnel and submitted to the sponsor within 24 hours after 
learning of the pregnancy.  Site personnel will submit the Pregnancy Form to the Sponsor 
as described in Section 7.4.2. 
The investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject’s permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results will 
be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be performed. 
Investigators should use clinical judgment regarding subsequent study-related blood 
collection based on the presence or absence of anemia in each subject. Subjects who are 
not withdrawn will continue to be followed for safety assessments to study discharge per 
protocol.  
All pregnancies that occur from the time of first study treatment through the follow up visits 
must be reported. The investigator will monitor the subject and follow the outcome of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the 
outcome will be reported directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when informed 
consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading 
question such as ‘How have you been feeling since your last visit?’ is asked at 
each visit). 


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2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator 
to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the 
investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
urinalysis) 
 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented  
 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100 delivered with CELLECTRA® 2000 that require expedited communication from the 
site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration recorded 
≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
 
Grade 3 or greater laboratory abnormalities 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and Principal Investigator, the DSMB, and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
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 
Any subject experiences an SAE (or potentially life threatening AE) or death assessed 
as related to Study Treatment; 
 
Three or more subjects experience the same grade 3 or 4 adverse event, assessed 
as related to Study Treatment;  
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
Study Treatment; 
Upon conclusion, the sponsor or designee will notify all investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 
7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), whether 
volunteered by the subject, discovered by investigator or study staff questioning, or 
detected through physical examination, laboratory test or other means, will be collected 
and recorded in the subject’s source documents and followed as appropriate. 
 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
 TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised of 
the period following the signing of the informed consent form until the end of the study. 
Each AE will be assessed to determine whether it meets seriousness criteria. If the AE is 
considered serious, the investigator should record this event in the EDC system and report 
the event to the Sponsor within 24 hours of becoming aware of the event. The investigator 
may also directly report this event to the Ethics Committee according to its standard 
operating procedures. Expectedness of SAEs will be determined by the Sponsor using 
reference safety information specified in the Investigator’s Brochure and protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.6 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.7 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the Institutional Review Board (IRB)/Ethics Committee (EC) as 
soon as is practical, of serious events in writing where this is required by local regulatory 
authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an investigator becomes aware 
of an SAE that is suspected by the investigator to be related to the study drug, the event 
will be reported to the Sponsor or its designee. If the investigator becomes aware of an 
SAE in a study subject after the last scheduled follow-up visit, and considers the event 
related to prior Study Treatment, the investigator will report it to the Sponsor or the 
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SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
 M.D., Ph.D. 
EMAIL:  
  
SAE REPORTING INFORMATION 
EMAIL:  safety.inovio@apcerls.com 
SAFETY FAX: 
 
SAFETY PHONE: 
 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address as 
indicated above.  Any SAE supporting documents provided by facsimile (Fax) are to 
include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The investigator will supply the Sponsor and the IRB with more information as it becomes 
available and any additional requested information. The original SAE form must be kept 
at the study site. The Sponsor or its representative will be responsible for determining 
and in turn, reporting SAEs to regulatory authorities according to the applicable regulatory 
requirements. SAEs must be followed by the investigator until resolution, even if this 
extends beyond the study-reporting period. Resolution of an SAE is defined as the return 
to baseline status or stabilization of the condition with the expectation that it will remain 
chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the investigator will submit a Pregnancy Form to the Sponsor 
or designee to the safety email address or fax number within 24 hours of learning of the 
pregnancy. 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
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regulatory agencies within the time frame specified by local requirements but no later than 
10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 15 days for 
all other SUSARS (see Section 7.1.6 and 7.1.7). 
 REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device such as malfunction, misuse or use error 
and inadequate labeling. A malfunction is defined as the failure of a device to meet its 
performance specifications or otherwise perform as intended. The intended performance 
of a device refers to the intended use for which the device is labeled. All product 
complaints that meet this definition must be reported to the sponsor within 10 days of 
discovery.  Any product complaint that involves an AE or SAE must be also be reported 
per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the 
treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  
Additional instructions on complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple 
sites for safety or administrative reasons at any time. In particular, a site that does not 
recruit at a reasonable rate may be discontinued. Should the study be terminated and/or 
the site closed for whatever reason, all non-source documentation and study product 
pertaining to the study must be returned to Inovio Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research subjects 
are protected. 
8. 
STATISTICAL ANALYSIS PLAN 
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and VGX-
3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and confirmed 
vulvar infection with HPV types 16 and/or 18. The study’s primary endpoint is binary: 
regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from vulvar tissue 
based on tissue collected at Week 48. The primary hypothesis is that each of the treatment 
arms will result in regression of HSIL and clearance. Secondary efficacy analyses pertain 
to regression, clearance of HPV-16 and/or HPV-18 infection, regression to normal, non-
progression, and anatomic extent. Other secondary analyses concern safety and humoral 
and cellular immunological measures. Exploratory efficacy analyses concern extended 
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the vulva, and effect of HLA type on efficacy.  Other exploratory analyses pertain to tissue 
immunological measures and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 
recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 
2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), 
and (d) age category (<45 years vs. ≥45 years).  There are no requirements for the number 
of subjects in each stratum.  The study is open-label. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each arm superior to historical control, assuming the true proportion 
of subjects who achieve the primary endpoint is 20% and 28% for the respective treatment 
arms and 2% for the historical control, and that 90% are evaluable at Week 48 from 
randomization. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized.  Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized.  
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy.  Subjects excluded from the PP population 
will be identified and documented prior to unblinding of the study database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects and will 
include the number and percentage randomized, the number and percentage who 
received each dose and the number who completed the trial.  The number and percentage 
of subjects who discontinued will be summarized overall and by reason.  The number in 
each analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, and 


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percentages for categorical variables, by treatment arm, for the mITT population.  Prior 
and concomitant medications will also be summarized with percentages in this fashion. 
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by 
body system, by treatment arm, for the mITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (within 10 weeks 
prior to Day 0).  Concomitant medications are those used during the course of the trial (on 
or after Day 0).  Partial start dates of prior and concomitant medications will be assumed 
to be the earliest possible date consistent with the partial date.  Partial stop dates of prior 
and concomitant medications will be assumed to be the latest possible date consistent 
with the partial date.  Data for all prior and concomitant medications will be summarized 
with percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true population 
probability of the primary endpoint for each arm. The primary hypothesis of superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment arm separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the method of Clopper-Pearson. Superiority will be concluded if the 
one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds 
0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days prior 
to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) will 
be summarized with point estimates and associated Clopper-Pearson 95% confidence 
intervals. 
An exploratory analysis will examine clearance outside of the vulva.  This will be analyzed 
in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and a) HLA results, b) miRNA results, c) vulvoscopy results, and d) HPV results. 
Relationships will be examined with contingency tables and/or logistic regression models 
which model the primary endpoint versus these results and treatment group as regressor 
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8.10 IMMUNOGENICITY ANALYSIS 
 
Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment arm. 
These frequencies will be presented overall and separately by dose, and will depict 
overall, by system organ class and by preferred term, the percentage of subjects affected. 
Additional frequencies will be presented with respect to maximum severity and to 
strongest relationship to Study Treatment. Multiple occurrences of the same AE will be 
counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of any 
dose.  For this summary, the frequency of preferred term events will be summarized with 
percentages and 95% Clopper-Pearson confidence intervals.  Separate summaries will 
be based on events occurring within 7 days of any dose and regardless of when they 
occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be 
included within specified day-range summaries. AE duration will be calculated as (Stop 
Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment arm. 
Baseline is defined as the last measurement prior to the first treatment administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time point 
will be summarized by treatment arm and by body system, for the mITT population. 


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 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or Clopper-
Pearson 95% CIs, for continuous responses and binary responses, respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 
9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles 
of Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained 
from the applicable IRB/EC and a copy of this approval has been received by the 
sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 During the conduct of the study, submit progress reports to the IRB/EC as 
required.  
 Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 As required, obtain approval from the IRB/EC for protocol amendments and 
for revisions to the consent form or subject recruitment advertisements; 
 Reports on, and reviews of, the trial and its progress will be submitted to the 
IRB by the investigator at intervals stipulated in their guidelines and in 
accordance with pertinent regulations and guidelines. 
 Maintain a file of study-related information that includes all correspondence 
with the IRB; 
 Notify IRB when study is completed (i.e. after the last study visit of the final 
study subject); 
 After study completion provide the IRB with a final report on the study. 


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9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., 
NIH Office of Biotechnology Activities) governing research that involves 
recombinant or synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening 
into the study, and/or from the subject’s legally authorized representative.  The 
process for obtaining informed consent must also be documented in the subject’s 
medical record. 
9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating the 
study and re-approval or review at least annually.  Sponsor is to be notified immediately if 
the responsible IRB/EC has been disqualified or if proceedings leading to disqualification 
have begun.  Copies of all IRB/EC correspondence with the investigator must be provided 
to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and for subjects in the imiquimod 
arm a dosing log during their study participation.  Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation impacting 
Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
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administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject’s name will not be disclosed in these documents. 
The subject’s name may be disclosed to the study sponsor, Sponsor, the governing health 
authorities or the Food and Drug Administration (FDA), if they inspect the study records. 
Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information. 
Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject’s legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA). 
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 the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. Examples 
of these original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subject’s 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 medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be 
present in the source documents. All prescription and nonprescription medications taken 
within l week prior to entry must be recorded on the CRF. Actual or estimated start and 
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10.3 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. The sponsor will inform the investigator/institution as to when these documents 
are no longer needed to be retained. 
10.4 SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial.  The DSMB will 
meet quarterly or as data are available to review safety data and regression/clearance 
results.  If there are no new safety data or regression/clearance results to review for a 
quarterly scheduled meeting the DSMB will be notified and the meeting may be cancelled; 
Ad hoc meetings may be scheduled to review new data as applicable. The DSMB will be 
charged with advising the Sponsor if there appears to be a safety issue. No formal interim 
analysis will be performed. The DSMB Chair, upon consultation with the other voting 
members of the DSMB, has the authority to recommend suspension or stopping the study 
and to request a full DSMB review and ad hoc statistical analyses.  The standard operating 
procedures of the DSMB will be documented in the DSMB charter, including the board’s 
accountability to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of a total of three pathologists. Each specimen will be read by two pathologists 
independently in a masked fashion.  If the two pathologists agree on the diagnosis then 
no further action is required and the clinical disease status for the subject will be 
established. If there is disagreement between the first two pathologists, the third 
pathologist will review and if there is agreement among any two of the three diagnoses, it 
will stand as the clinical disease status for that subject. If there is no agreement after the 
third review, the three reviewers will perform a simultaneous review and come to 
consensus or a majority rule of 2 of 3 if consensus cannot be reached. 
 CLINICAL MONITORING 
Clinical Monitoring of the 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: 


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 
Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure the site is qualified and compliant 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 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 
 
Throughout the study, inspect all source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, and accurate 
(ALCOA).  
 
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 investigational drug and device accountability and reconciliation of  
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date of 
receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CMI 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
EC 
ECC 
EDC 
Ethics Committee 
Endocervical Curettage 
Electronic Data Capture 
EP 
DLT 
Electroporation with CELLECTRA® 2000 
Dose Limiting Toxicity 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 


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IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
PCR  
Pathology Adjudication Committee 
Polymerase Chain Reaction 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Participant Diary  
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper Limit of Normal 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
Page 89 of 90 
 
13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Aldea M, Serrano B, Valencia S, Brotons M, Mena M, Cosano R, 
Muñoz J, Bosch FX, de Sanjosé S, Castellsagué X. Human Papillomavirus and Related 
Diseases in United States of America. Summary Report 2016-02-26. . In. Edited by 
Centre). IICoHaCHI; 2016. 
2. 
Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. 
J Natl Cancer Inst 2015,107:djv086. 
3. 
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
Sheets:  Vulvar Cancer. 2016. 
4. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
5. 
Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
6. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
7. 
Sideri M JR, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. Squamous 
vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology 
Subcommittee. J Reprod Med 2005,50:807-810. 
8. 
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: 
background and consensus recommendations from the College of American Pathologists 
and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 
2012,16:205-242. 
9. 
Inovio Pharmaceuticals. Unpublished assessment. 2015. 
10. 
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
natural history and outcome in 405 women. Obstet Gynecol 2005,106:1319-1326. 
11. 
van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
neoplasia III based on enough evidence? A systematic review of 3322 published patients. 
Gynecol Oncol 2005,97:645-651. 
12. 
Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
13. 
ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 
14. 
Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia 
(VIN) usual type after surgical treatment. Med Sci Monit 2011,17:CR532-535. 
15. 
ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
Obstet Gynecol. 2016,128:e178-182. 


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 21Apr2017 
CONFIDENTIAL 
Protocol Version: 1.3 
Page 90 of 90 
 
16. 
Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
17. 
Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
Market Research. 2016. 
18. 
Senn B, Eicher M, Mueller MD, Hornung R, Fink D, Baessler K, et al. A patient-reported 
outcome measure to identify occurrence and distress of post-surgery symptoms of 
WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study. Gynecol Oncol 
2013,129:234-240. 
19. 
Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
excision for vulvar intraepithelial neoplasia. J Reprod Med 2007,52:23-27. 
20. 
Petrosky E, Bocchini JA, Jr., Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-
valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations 
of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 
2015,64:300-304. 
21. 
Future II Study Group.  Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
22. 
Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a 
practical approach to diagnosis. J Clin Pathol 2014,67:290-294. 
23. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
24. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
25. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
26. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
27. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
28. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
29. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
30. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
31. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
32. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
33. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA™ 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
IND #13683 
 
 
 
 
Version 2.0 
20 November 2017 
 
 


VGX-3100 
lnovio Pharmaceuticals, Inc. 
Medical Monitor Approval Page 
Drug: 
Sponsor: 
Medical Monitor: 
Approval Signature: 
VGX-3100 
lnovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
M.D., Ph.D. 
lnovio Pharmaceuticals, Inc. 
Date 
lnovio Pharmaceuticals, Inc. 
CONFIDENTIAL 
HPV-201 
Clinical Protocol 
The information in this document is considered privileged and confidential by lnovio 
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 lnovio Pharmaceuticals. Any 
supplemental information added to this document is also confidential and proprietary 
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner 
as the contents of this document. 
Protocol Version Date: 20Nov2017 
CONFIDENTIAL 
Page 2 of 94 
Protocol Version: 2.0 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 3 of 94 
 
 
 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI's approval of this protocol 
and provides the necessary assurances that this trial will be conducted in accordance 
with ICH/GCP and ISO guidelines, local legal and regulatory requirements, and all 
stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
____________________________________  
_________________________ 
Insert Principal Investigator Printed Name  
        Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 4 of 94 
 
SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 1.3 dated 21 April 2017 to Version 2.0 
dated 20 November 2017. All other changes are administrative and do not significantly affect 
the safety of subjects, trial scope, or scientific quality of the protocol. 
 
1. On the title page, U.S. BB has been removed from the IND number. The IND number 
remains the same.  
2. To support enrollment, approximately 28 sites will be participating in the trial over the 
initially proposed 20 sites, and although not yet determined, the trial may potentially add 
countries outside of the United States.  
3. Due to the possibility of adding countries outside of the United States, CELLECTRA® 
2000 will use the trademark symbol, CELLECTRA™ 2000. This change has been made 
throughout the protocol. 
4. Secondary Endpoint #4 have been modified to include no evidence of vulvar LSIL 
(VIN1), in addition to no evidence of vulvar HSIL and condyloma at Week 48 in the 
measurement of histologic regression of vulvar HSIL to normal tissue. Normal tissue is 
considered as no histologic evidence of vulvar LSIL, HSIL or condyloma.  
5. Secondary Endpoint #6 and Exploratory Endpoint #1 have been modified to indicate that 
quantitative analysis will be determined from the pre-biopsy image of the qualifying 
lesion(s). A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-
16 and/or HPV-18 positive and have histologically confirmed vulvar HSIL by the 
Pathology Adjudication Committee (PAC) at screening. 
6. Exploratory Endpoint #4 will be evaluated by the assessment of pro-inflammatory and 
immunosuppressive elements in tissue, over the assessment of CD8+ and FoxP3 
infiltrating cells for the immune tissue responses for VGX-3100 and VGX-3100 with 
imiquimod.  
7. Exploratory Objective #8 has been updated to include the Week 15 and 27 time points 
for the administration of the Patient-Reported Outcomes (PROs) as it was inadvertently 
not included in version 1.3 dated 21 Apr 2017.    
8. The WOMAN-PRO (WOMen with vulvAr Neoplasia) Clinical Trial Version 2.0 PRO 
instrument has been included in the protocol to assess both physical and psychosocial 
impacts of VIN and will be administered at the same time points as the EQ-5D-5L.  
 
Section 1.1.15 was added to the protocol amendment to provide background 
information on the development of the WOMAN-PRO  
 
Section 6.8 was updated to include the administration time points of the 
WOMAN-PRO  
 
Section 12: List of abbreviations updated to include WOMAN-PRO 
9. Section 1.1.1 and 1.1.2 modified to include European data of new cases diagnosed with 
HPV infection and vulvar cancer.  
10. The requirement of a minimum 4 mm vulvar biopsy/biopsies has been replaced with a 
punch biopsy of approximately 4 mm in size in order to accommodate smaller lesions 
accessible by punch biopsy.   


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 5 of 94 
 
11. Repeat vulvar punch biopsies will be taken from the same qualifying lesion(s) as trial 
entry, but has been modified to clarify that the region of most advanced disease of the 
same lesion(s) will be obtained.  
 
Table 2: Minimally required Procedure at Biopsy Visit has been updated to reflect 
the change 
12. Inclusion/Exclusion criteria revised as follows: 
i. 
Inclusion Criteria #3: Revised to clarify that vulvar infection with HPV 
types 16 and/or 18 will be confirmed by screening biopsy. Subjects do not 
need to have a confirmed diagnosis of HPV-16 and/or 18 to participate in 
the study  
ii. 
Inclusion Criteria #4: Combined with previous inclusion criteria #5 as 
subjects must have a vulvar tissue specimen/blocks and histological 
confirmed vulvar HSIL from the Pathology Adjudication Committee at 
screening    
iii. 
Inclusion Criteria #6 (previously #7): Modified to accommodate smaller 
lesions accessible to punch biopsy  
iv. 
Inclusion Criteria #8b (previously 9b): Modified to include women who 
have had a bilateral tubal ligation/occlusion performed more than 3 
months prior to screening. Tubal ligation is almost 100% effective for the 
prevention of pregnancy and thus subjects are not required to wait 12 
months prior to screening to be eligible    
v. 
Exclusion Criteria #2, 3 and 4: Subjects who are under the care of a 
healthcare provider for their biopsy-proven VAIN, AIN, or CIN but may not 
be receiving active treatment are eligible for this trial. These criteria were 
modified in consideration of subjects who are under medical surveillance 
by their healthcare provider per standard of care 
vi. 
Exclusion Criteria #6 has been removed to avoid repetition as Inclusion 
Criteria # 4 states that the biopsy must be collected within 10 weeks prior 
to the anticipated 1st dose of the subject  
vii. 
Exclusion Criteria previously #9 and #10: Removed as it falls under the 
Exclusion Criteria #4 (Biopsy-proven Cervical Intraepithelial Neoplasia 
(CIN) 2/3 and are not undergoing medical care and/or treatment for CIN)  
viii. 
Exclusion Criteria #12 has extended the window for use of clinical 
laboratory results at screening from 30 days to 45 days. This allows 
subjects to use safety lab results within 45 days prior to Day 0 to 
determine eligibility 
ix. 
Exclusion Criteria #15 has been modified to ensure that subjects do not 
receive live vaccines within 4 weeks of any of the scheduled doses  
x. 
Exclusion Criteria #16 has been modified to ensure that subjects do not 
receive any non-live vaccines within 2 weeks of any of the scheduled 
doses  
xi. 
Exclusion Criteria previously #22 to #27 now fall under the subgroup of 
exclusion criteria #18 and are numbered as #18a to #18g. These items 
include the list of exclusions that fall under the category of current or 
historically clinically significant, medically unstable disease     


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 6 of 94 
 
xii. 
Exclusion Criteria previously #22 (now #18b): Modified to ensure that only 
subjects with treatment of non-anogenital malignancy within 2 years of 
screening are excluded from the trial. Subjects in this population could be 
expected to have anogential malignancy within 2 years of study start 
which has been treated and therefore should not be excluded from trial 
participation  
xiii. 
Exclusion Criteria previously #30 to #32 now fall under the subgroup of 
inclusion criteria 20 and numbered as #20a, #20b, and #20c accordingly. 
The sub group categorizes subjects with less than two acceptable sites 
for IM injection 
xiv. 
Exclusion Criteria previously #33 to #36 now fall under the category of 
vulnerable populations and are numbered now #21a, #21b, #21c and 
#21d 
13. The time points for cervical cytology and ThinPrep® have been changed and will be 
completed at Day 0 instead of at Screening as it is not required for study eligibility. The 
Week 27 cervical cytology and ThinPrep® has been moved to Week 12 to allow an 
earlier exploration for prediction of lesion regression from a dosed subject prior to the 
efficacy timepoint. The cervical cytology and ThinPrep® at Week 74 has been removed 
and all changes have been updated in the Schedule of Events. 
14. Cervical colposcopy will be completed at Day 0 and Week 96 rather than Screening and 
Week 96 since cervical colposcopy is not required to determine eligibility on study. This 
change has been updated in the Schedule of Events. 
15. Collection of vulvar swabs has been included in Exploratory Objective #7 and the 
Schedule of Events, to explore a potential new method for the detection of HPV in vulvar 
swabs. The collection will be completed at Day 0, Weeks 4, 12, 27, 48, 74 and 96.  
16. Table 3: Definition of Responder and Non-Responder modified to include other 
treatments (e.g. surgical intervention) for vulvar HSIL treatment.  
17. Figures 2, 3 and 4 of the protocol have been modified in Subgroup E to include subjects 
that have worsened to cancer and not limited to subjects that worsen from vulvar HSIL 
alone to cancer.  
18. The screening assessments of 12-lead ECG, complete blood count (CBC), serum 
electrolytes, blood urea nitrogen (BUN), creatinine (Cr), glucose, ALT, CPK and 
urinalysis window has increased to 45 days prior to first dose administration. This was 
intended to allow subjects to complete trial procedures at their initial screening visit and 
avoid a second study visit for safety labs and/or ECG.  
19. Immunohistochemistry (IHC) testing will not be performed for the detection of HPV-16 
and/or HPV-18 in the trial. Sections throughout the protocol regarding ICH testing and in 
situ hybridization have been removed.  
20. Section 5.4.2 (Dispensing and Use of Imiquimod) has been updated to have the 
Investigator contact the Medical Monitor to discuss alternative administration of 
imiquimod for subjects randomized to the imiquimod arm who cannot tolerate treatment.  
21. Section 6.1 and 6.2 (Treatment Procedures) has been revised and updated to reflect the 
changes made on the removal and addition of treatment procedures in the Schedule of 
Events. 
22. Section 6.3.2 (Rescreening of Screen Failures) has been added to allow rescreening of 
subjects after discussion with the Medical Monitor. 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 7 of 94 
 
23. Section 6.4.2 (Management of Anxiety and Pain due to Electroporation procedure) has 
been modified to include Acetaminophen as an example of an analgesic to be provided 
to subjects. The language has been modified to include that the management may be 
offered before or after injection/EP. 
24. Section 6.12 (Vulvar HPV Testing) additional language included in Section 6.12 as 
subjects will be requested to abstain from sexual activity and refrain from use of  
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
vulvar punch biopsy. This is intended to eliminate potential interference with the results 
of HPV testing. 
25. Section 7.1.2 (Serious Adverse Events) has been revised to remove all redundancies in 
the section.   
26. Section 7.3.1 (Adverse Events of Special Interest (AESI)) has been updated to remove 
Grade 3 or greater laboratory abnormalities as an AESI since safety labs are only drawn 
at screening and are not done after the administration of the investigational product 
VGX-3100. 
27. Section 7.4.2 (Trial Reporting Period of Serious Adverse Events) and the Medical 
Monitor Approval Page has been updated to include the new HPV-201 Medical Monitor 
providing oversight of the trial.   
28. Section 7.4.4 (Reporting of Device Related Complaints) has been updated to include an 
email address to report any device related complaints to the sponsor. 
29. Section 8.3 (Sample Size/Power) modified to include the type of error level for each 
hypothesis.  
30. Section 8.8 (Prior and Concomitant Medications) has been revised to the clearly define 
prior and concomitant medications. 
31. Section 10.4.2 (Pathology Adjudication Committee) modified to remove procedural 
content in the protocol and refer to the PAC Charter. 
 
 
 
 
 
 
 
 
 
 
 
 


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 8 of 94 
 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ............................................................. 3 
SUMMARY OF CHANGES ........................................................................................................ 4 
CLINICAL PROTOCOL SYNOPSIS .........................................................................................13 
STUDY SCHEDULE OF EVENTS ............................................................................................27 
1. 
INTRODUCTION ...........................................................................................................29 
1.1 
Background ........................................................................................................29 
 
Human Papillomavirus and Infection ......................................................29 
 
Vulvar Cancer ........................................................................................29 
 
Vulvar Intraepithelial Neoplasia (Vulvar HSIL) ........................................29 
 
Recurrent Disease with Current Therapeutic Options .............................30 
 
Psychological and Physical Impacts of Current Therapeutic Options ......31 
 
Impact of Vulvar HSIL Upon Activities of Daily Living .............................31 
 
Limitations of Prophylactic HPV Vaccines ..............................................32 
 
Enhanced Monitoring Plan .....................................................................32 
 
VGX-3100 ..............................................................................................32 
 Electroporation .......................................................................................33 
 Imiquimod Cream, 5% ............................................................................33 
 Study Rationale ......................................................................................33 
 Dose and Regimen Rationale for VGX-3100 ..........................................33 
 Rationale for imiquimod ..........................................................................34 
 Inclusion of WOMAN-PRO, Clinical trial version 2.0 ...............................34 
 Potential Risks of investigational products ..............................................34 
 Potential Benefits of Study Participation .................................................35 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ..................................................................35 
2.1 
Primary Objective and Endpoint .........................................................................35 
2.2 
Secondary Objectives and Associated Endpoints ..............................................36 
2.3 
Exploratory Objectives and Associated Endpoints .............................................37 
3. 
STUDY DESIGN ...........................................................................................................38 
3.1 
Treatment Regimens .........................................................................................38 
3.2 
Efficacy Assessment ..........................................................................................39 
 
Definition of Responder and Non-Responder .........................................40 
3.3 
Safety Assessment ............................................................................................41 
 
Data Safety & Monitoring Board .............................................................41 


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 2.0 
Page 9 of 94 
 
3.4 
Immunogenicity Assessment .............................................................................42 
3.5 
Virologic Assessment .........................................................................................42 
4. 
SELECTION OF SUBJECTS ........................................................................................42 
4.1 
Inclusion Criteria ................................................................................................42 
4.2 
Exclusion Criteria ...............................................................................................43 
4.3 
Discontinuation/Withdrawal of Study Subjects ...................................................45 
 
Criteria for Discontinuation of Investigational Product .............................45 
 
Criteria for Withdrawal from the Study ....................................................45 
 
Sponsor Notification of Discontinuation/Withdrawal ................................46 
 
Reason for Discontinuation/Withdrawal ..................................................46 
5. 
STUDY TREATMENT ...................................................................................................47 
5.1 
Investigational Products .....................................................................................47 
5.2 
Packaging and Labeling .....................................................................................48 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................48 
5.3 
Handling and Storage ........................................................................................49 
5.4 
Preparation and Dispensing ...............................................................................49 
 
Dispensing of VGX-3100 ........................................................................49 
 
Dispensing and Use of Imiquimod ..........................................................50 
5.5 
Investigational Product Accountability ................................................................50 
5.6 
Return and Destruction of Investigational Product ..............................................50 
5.7 
Use of Investigational Device .............................................................................51 
5.8 
Packaging and Labeling of Investigational Device..............................................51 
5.9 
Investigational Device Accountability .................................................................53 
5.10 
Return of Investigational Devices .......................................................................53 
6. 
STUDY PROCEDURES AND TREATMENTS ..............................................................54 
6.1 
Before Treatment Procedures ............................................................................54 
 
Screening evaluations ............................................................................54 
6.2 
During Treatment Procedures by Visit ................................................................55 
 
Day 0 ......................................................................................................55 
 
8-14 Days Post Dose 1 Phone Call ........................................................56 
 
Week 4 (± 7 days): .................................................................................56 
 
8-14 Days Post Dose 2 Phone Call ........................................................57 
 
Week 12 (± 7 days) ................................................................................57 
 
Week 15 (± 7 days): ...............................................................................58 
 
Week 24 (± 7 days) ................................................................................58 


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Clinical Protocol 
 
 
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 CONFIDENTIAL 
Protocol Version: 2.0 
Page 10 of 94 
 
 
Week 27 (± 7 days) ................................................................................59 
 
Week 38 Phone Call ...............................................................................59 
 Week 48 (± 7 days) ................................................................................59 
 Week 52 (± 14 days) ..............................................................................60 
 Week 74 (± 14 days) ..............................................................................60 
 Week 78 (± 14 days) ..............................................................................61 
 Week 96 (± 14 days) ..............................................................................61 
 Week 100 (± 14 days) ............................................................................62 
6.3 
Evaluations and Procedures ..............................................................................62 
 
Informed Consent ...................................................................................62 
 
Rescreening of Screen Failures .............................................................62 
 
Assignment of Subject Identification Numbers ........................................62 
 
Safety Evaluations ..................................................................................63 
6.4 
Injection and Electroporation (EP) ......................................................................65 
 
Risks of Treatment Procedures ..............................................................65 
 
Management of Anxiety and Pain Due to Electroporation (EP) 
Procedure ...............................................................................................66 
6.5 
Assessment of Laboratory Abnormalities ...........................................................66 
6.6 
Assessment of Clinical Study Adverse Events ...................................................66 
6.7 
Assessment of Injection Site Reactions .............................................................66 
6.8 
Assessment of Patient Reported Outcomes .......................................................67 
6.9 
Peripheral Blood Immunogenicity Assessments .................................................69 
6.10 
Tissue Immunogenicity Assessment ..................................................................69 
6.11 
HLA Typing ........................................................................................................69 
6.12 
Vulvar HPV Testing ............................................................................................70 
6.13 
Colposcopy, PAP Smears and HPV Testing ......................................................70 
6.14 
Vulvoscopy, Photographs, and Biopsies ............................................................70 
6.15 
Concomitant Medications/Treatments ................................................................71 
6.16 
Restrictions ........................................................................................................71 
 Other Restrictions ...................................................................................72 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ................................72 
7.1 
Safety Parameters .............................................................................................72 
 
Adverse Events ......................................................................................72 
 
Serious Adverse Events .........................................................................73 
 
Clarification of Serious Adverse Events ..................................................73 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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 CONFIDENTIAL 
Protocol Version: 2.0 
Page 11 of 94 
 
 
Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ..............................................................74 
 
Unexpected Adverse Drug Reactions and Expedited Reporting .............74 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .........................75 
 
Assessing Severity (Intensity) .................................................................75 
 
Casual Relationship of Clinical Material to Adverse Events ....................75 
 
Abnormal Laboratory Value ....................................................................76 
 Post-Trial Reporting Requirements.........................................................76 
 Procedures for Documenting Pregnancy During Study ...........................77 
7.2 
Methods and Timing of Collection of Safety Data ...............................................77 
7.3 
Safety and Toxicity Management .......................................................................78 
 
Adverse Events of Special Interest .........................................................78 
 
Stopping Rules (Criteria for Pausing of Study) .......................................78 
7.4 
Adverse Experience Reporting ...........................................................................79 
 
Trial Reporting Period of Adverse Events ...............................................79 
 
Trial Reporting Period of Serious Adverse Events ..................................79 
 
Notification of Serious Adverse Events ...................................................80 
 
Reporting of Device Related Complaints ................................................80 
7.5 
Trial Discontinuation ..........................................................................................81 
8. 
STATISTICAL ANALYSIS PLAN ..................................................................................81 
8.1 
General Considerations .....................................................................................81 
8.2 
Randomization and blinding ...............................................................................81 
8.3 
Sample Size/Power ............................................................................................82 
8.4 
Analyses Populations .........................................................................................82 
8.5 
Subject Disposition ............................................................................................82 
8.6 
Demographic and Other Baseline Characteristics ..............................................82 
8.7 
Medical History ..................................................................................................83 
8.8 
Prior and Concomitant Medications ...................................................................83 
8.9 
Efficacy Analysis ................................................................................................83 
8.10 
Immunogenicity Analysis ....................................................................................83 
8.11 
Safety analyses .................................................................................................84 
 Adverse events.......................................................................................84 
 Laboratory data ......................................................................................84 
 Vital Signs ..............................................................................................84 
 Physical Examination .............................................................................84 


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HPV-201 
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 Patient Reported Outcomes ...................................................................85 
 Missing Values .......................................................................................85 
 Interim Analysis ......................................................................................85 
9. 
ETHICS .........................................................................................................................85 
9.1 
Investigator and Sponsor Responsibilities ..........................................................85 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ..................................85 
9.3 
Office of Biotechnology Activities (OBA) ............................................................86 
9.4 
Compliance with Informed Consent Regulations ................................................86 
9.5 
Compliance with IRB/EC Requirements .............................................................86 
9.6 
Compliance with Good Clinical Practice .............................................................86 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 ..........................................................................................................................86 
9.8 
Compliance with Protocol ...................................................................................86 
9.9 
Changes to the Protocol.....................................................................................86 
10. 
DATA COLLECTION, MONITORING AND REPORTING .............................................87 
10.1 
Confidentiality and Privacy .................................................................................87 
10.2 
Source Documents ............................................................................................87 
10.3 
Records Retention .............................................................................................88 
10.4 
Safety and Quality Monitoring ............................................................................88 
 Data & Safety Monitoring Board .............................................................88 
 Pathology Adjudication Committee .........................................................88 
 Clinical Monitoring ..................................................................................88 
11. 
PUBLICATION POLICY ................................................................................................89 
12. 
LIST OF ABBREVIATIONS ..........................................................................................90 
13. 
REFERENCES ..............................................................................................................92 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
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Protocol Version: 2.0 
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CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA™ 2000 Alone or in Combination 
with Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 28 sites in the 
United States (US) and potentially other countries not yet determined 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of 
HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3x) from Day 0 through Week 202 
No. of Subjects 
Approximately 36 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar 
HSIL3 and no evidence of HPV-16/18 at Week 48 in vulvar 
tissue samples (i.e. collected via biopsy or excisional 
treatment)4 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
4 A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study related treatment for vulvar 
HSIL. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, or vulvar 
carcinoma at evaluation, or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a subject who 
received non-study related treatment for vulvar HSIL.   


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
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Protocol Version: 2.0 
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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/186 in vulvar tissue samples 
at Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL, no evidence of LSIL 
(VIN1), and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion of subjects with no 
progression7 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of qualifying8 
vulvar lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized pre-
biopsy photographic imaging of 
qualifying8 lesion(s) at Week 48, 74 and 
96 compared to baseline9. Results will 
be classified as: no clinically significant 
lesion resolution (reduction in lesion area 
of 0-25%), partial lesion area resolution 
(>25% and <100% reduction) and 
complete lesion resolution (no visible 
lesion).   
                                                     
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
6 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
7 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
8 A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive and 
have histologically confirmed vulvar HSIL by the PAC at screening. 
9 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96 
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
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Protocol Version: 2.0 
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Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying8 vulvar lesion(s), in subjects who 
did not have complete lesion resolution at Week 
48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
pre-biopsy photographic imaging of 
qualifying8 lesion(s) at Week 74 and/or 
Week 96 compared to baseline10. 
Results will be classified as: no 
clinically significant lesion resolution 
(reduction in lesion area of 0-25%), 
partial lesion area resolution (>25% and 
<100% reduction) and complete lesion 
resolution (no visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue11  
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-
vulvar anatomic locations without 
surgical intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week 48 compared to baseline 
6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
7. Vulvoscopy, HPV test results (vulvar 
swab and vulvar tissue) and miRNA 
profile (Day 0, Week 15 and 48) in 
conjunction with histologic regression of 
vulvar HSIL at Week 48 visit 
                                                     
10 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   
11Additional assessments may include visualization of PD-L1, Granulysin, perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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8. Describe patient reported outcomes (PRO) for 
subjects treated with VGX-3100 and VGX-3100 
with imiquimod 
8.  PRO endpoints will be obtained at Day 
0 prior to first dose, Weeks 4, 12, 24 
after dosing, and at Weeks 15, 27, 48, 
52, 74, 96, and 100. 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
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Study Design:  
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered 
with CELLECTRA™ 2000 alone or in combination with imiquimod in adult women with histologically 
confirmed vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled. 
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-
3100 and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass 
Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To be eligible for the study, subjects must consent to participate and have a vulvar punch 
biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of the acetowhite 
vulvar lesion(s) at the time of screening. In the case of multifocal disease, the two lesions that 
potentially contain the most advanced disease, as judged by the Investigator, should be chosen for 
biopsy using vulvoscopy and documented using standardized high resolution photography with a 
digital single-lens reflex (SLR) camera. Biopsy slides will be sent to the Pathology Adjudication 
Committee (PAC) by the central laboratory for evaluation prior to enrollment. In order to be eligible for 
enrollment, the PAC must assign the diagnosis of vulvar HSIL based on the biopsy sample(s). 
Subjects must also have a vulvar tissue specimen test positive for HPV genotype 16 and/or 18 to be 
eligible for participation in the study. 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™) (Optum), the 
EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvAr Neoplasia) Clincial 
Trial Version 2.0 and two additional PRO questions assessing quality of life after surgery or biopsy. 
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of 
VGX-3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject's biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with 
the CELLECTRA™ 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of 
VGX-3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic 
and lesion area changes. The first dose will be administered on Day 0, the second at Week 4, the 
third at Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 
48 (Subgroups A and B) will receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator. Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator. Subjects in Subgroup E may receive surgical treatment per the 
judgment of the Investigator. All subjects are scheduled to be followed to Week 100.  
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
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Protocol Version: 2.0 
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Figure 1: Study Visit Schedule 
 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will apply imiquimod 
5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to apply 
imiquimod cream three times per week for 20 weeks (inclusive of administration in the evening of 
VGX-3100 dosing). Subjects unable to tolerate imiquimod treatment may reduce their dosing 
frequency, and will document their use on the imiquimod dosing log provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of 
most advanced disease as judged by the Investigator, and must be approximately 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by vulvoscopy is insufficient evidence to confirm disease 
regression. Disease regression will be based on histopathologic assessment at Week 48, 74, and 96. 
Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), defined as areas 
that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0 and Weeks 4, 12, 27, 
48, 74 and 96. Using standardized high resolution digital photographic imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but from the region of potentially most advanced disease based upon the judgment of 
the Investigator (see Table 2 for Minimally Required Biopsy Procedures). If after evaluation of biopsy 
tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to Week 
74 for vulvoscopy, and biopsy of the same lesion as study start.   
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 2.0 
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If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in the qualifying lesion(s) 
size or no change in lesion size from baseline (Subgroups C or D), the Investigator has the option to 
give the subject a 5th dose of VGX-3100 at Week 52, and the subject will continue on study with 
vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator may choose to treat the subject 
with surgical or standard treatment, and the subject will continue on study without further biopsy. A 
qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive 
and have histologically confirmed vulvar HSIL by the PAC at screening. 
 
Figure 2: Decision process at Week 52  
 
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as 
follows: At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Subgroups A or B), the subject will continue to Week 96 for vulvoscopy, and biopsy of the same area 
from the region of potentially most advanced disease based upon the judgment of the Investigator. If 
HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at 
Week 78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and the subject 
will continue on study without further biopsy.   
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
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Figure 3: Decision Process at Week 78 
 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If there is no vulvar HSIL (Subgroups A or B), no further procedures are 
required. If after evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or 
worsening disease (Subgroup E), the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
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Protocol Version: 2.0 
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In the event of worsening disease at any time (i.e., Subgroup E – any increase in lesion area from 
baseline or worsening to cancer), the subject will receive surgical treatment per the Investigator's 
judgment and will continue on study through Week 100 with vulvoscopy, but without further study 
treatment or biopsy. If at any time in the study carcinoma is discovered, subjects will receive surgical 
treatment, and be discontinued from study treatment. The event will be reported as an SAE per 
section 7.1.4.  If wide excision is required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder:Responder and non-responder definitions (Table 3) take 
into account both histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of HSIL. A 
treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no 
evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study 
related treatment for vulvar HSIL. A treatment non-responder is a subject with histologic evidence of 
vulvar HSIL or vulvar carcinoma at evaluation, or a subject with evidence of HPV-16/18 at evaluation, 
or a subject who received non-study related treatment for vulvar HSIL. Any case of histologically 
confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data and 
tissue regression and viral clearance results. The DSMB will be charged with advising the Sponsor if 
there appears to be a safety issue. No formal interim analysis is planned. The following stopping rules 
will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator (PI) for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, PI for the trial, IRB (if applicable) 
and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, PI for 
the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, PI for the trial, IRB (if applicable) 
and the DSMB.  
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding the outcome 
of any investigation stemming from a Study Pause.  
Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (i.e., Screening and 
Day 0 prior to dosing) and Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize vulvar HPV infection at 
Screening, Weeks 48, 74 and 96. Cervical samples, oropharyngeal rinse, vulvar, vaginal, and intra-
anal tissue swab samples will be obtained to characterize HPV infection at the following time points: 
Day 0 prior to dosing (OP, cervical, vulvar, vaginal and intra-anal), Week 4 (Vulvar only), Week 12 
(Cervical and vulvar)  and Weeks 27, 48, 74 and 96 (OP, vulvar, vaginal and intra-anal). At Weeks 48 
and 96, cervical sample will also be collected.  
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
relationship between subject HLA haplotypes and regression.  


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 2.0 
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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above  
3. 
Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. 
Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated date of first 
dose of study drug and have histologically confirmed vulvar HSIL by the Pathology Adjudication 
Committee at screening; 
5. 
Must be judged by the Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
6. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after an approximately 4 mm screening biopsy;  
7. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 3 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system;                                                                                
iv) Male partner sterilization at least 6 months prior to the female subject's entry into the 
study, and this male is the sole partner for that subject. 
9. 
Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the Investigator. 


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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing medical care and/or 
treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical care and/or 
treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing medical care 
and/or treatment for CIN; 
5) Biopsy-proven differentiated VIN; 
6) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
7) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
8) Treatment for genital warts within 4 weeks prior to screening; 
9) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
10) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
11) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last 
dose of investigational product; 
12) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the Investigator; 
13) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
14) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
15) Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of each study 
dose; 
17) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the Investigator; 
18) Current or history of clinically significant, medically unstable disease which, in the judgment of the 
Investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results  
a)   Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher congestive   
  heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision; 
 


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c) 
Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) 
that would contraindicate IM injections within 2 weeks of Day 0; 
d) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) 
Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19) Participation in an interventional study with an investigational compound or device within 4 weeks 
of signing informed consent (participation in an observational study is permitted); 
20) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) (unless 
deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
21) Vulnerable populations:  
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, would interfere 
with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22) 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.  


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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events  
 
 
 
 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days) 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
Xb 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
Xe 
 
Xf 
 
Xe 
 
Xe 
 
Xe 
 
HLA testing g 
       X 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar swabs 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cervical cytology, ThinPrep®  h 
X 
X 
 
 
X 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject VGX-3100 +EP lm 
X 
X 
X 
X 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
Review PD o 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
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b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared). Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 45 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. One additional 8.5 mL yellow 
(ACD) tube to be collected at Day 0, Week 15 and 48 for microRNA analysis. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27.   
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrep® cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected. Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the Investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j  Photography of the acetowhite stained qualifying lesion(s) must be performed prior to and after biopsy, 
and at all vulvoscopy examinations. If a pre-biopsy digital photograph is not available for a historical 
biopsy sample at screening, a post biopsy photo will be sufficient. Additionally, standardized high 
resolution digital photographic imaging should be obtained during examinations of the vagina if lesions 
are identified, for documentation.  
k Tissue specimen from all excised tissue must be reviewed by the PAC and residual vulvar tissue from 
entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) must be sent to the 
central pathology laboratory for HPV testing.  
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod. 
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36v2™, EQ-5D-5L, WOMAN-PRO) plus two additional questions will be assessed as 
described in Section 6.8.     
 
 
 


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1. 
INTRODUCTION  
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause 
cancer, and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the 
most significant amongst high-risk types since they are responsible for most HPV-
caused cancers [1].   
HPV-16/18 is involved in about 83% of HPV-associated vulvar HSIL cases in the U.S. [1] 
and about 72% in Europe [2]. Persistent infection with one or more oncogenic (high-risk) 
HPV genotypes can lead to the development of precancerous, histologic high grade 
squamous intraepithelial lesions (HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS).  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 6,020 new cases and 1,150 
attributable deaths annually for year 2017 in the United States [4] and about 9,776 new 
cases in 2015 in Europe [5]. Vulvar cancers consist largely of squamous cell carcinomas 
and accounts for approximately 5% of all female genital malignancies [6]. Differentiated 
VIN, which is typically not caused by HPV infection and is more typically found in older 
women, is more likely to progress to cancer more rapidly than HPV-associated-VIN. The 
five year overall relative survival for vulvar cancer in the U.S. is 72.1% [4]. Recurrent 
vulvar cancer occurs in an average of 24% of cases after primary treatment, after 
surgery with or without radiation [7].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia. The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance 
of pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [8].    


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In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) 
replaced the three grade classification system with the current single grade classification 
for which only high grade VIN (2/3) is classified as VIN [9]. In 2012, the Lower 
Anogenital Squamous Terminology (LAST) Standardization Project for HPV-associated 
lesions applied the term high grade squamous intraepithelial lesion (HSIL) to encompass 
high grade dysplasia [10]. Therefore, for the purpose of this study, the term vulvar HSIL 
will be used, whichencompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to 
encompass what was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [11]. Over time, typically years, vulvar HSIL can progress to 
invasive cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group 
and median 13.8 years in another group [12], and from VIN3 patients, mean = 2.5 years, 
range: 4 – 216 months [13].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity 
against vulvar HSIL and have not achieved universal uptake, leaving a population of 
susceptible and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to 
visual inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for 
vulvar HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, 
often requiring multiple, repeat treatments. Progression to vulvar cancer following 
current vulvar HSIL treatments can also occur within 1 year of treatment and for up to 20 
years post treatment. The current treatment options for vulvar HSIL are surgical 
excision, laser ablation, and off-label medical therapy. The rate of HPV-associated 
vulvar HSIL recurrence after surgical treatment is high; post-treatment recurrence rates 
are as high as 45% at three years post-treatment with all currently available treatment 
regimens [14, 15].   
Wide local excision is the 'preferred initial intervention' by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation. Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues 
with body image and sexual dysfunction. Medical therapies have been investigated as a 
means to avoid these negative outcomes. Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food 
and Drug Administration for this indication. Inconsistent treatment efficacy results have 
been shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 


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of recurrence is slightly higher compared to wide local excision. Laser treatment of 
vulvar HSIL requires destruction of cells through the entire thickness of the epithelium 
including hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation 
should extend through the dermis. Post-treatment recurrence rates exceed 30% (for all 
treatment regimens), and is higher with positive excision margins [16]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low 
rate of spontaneous resolution. According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is 
suspected (even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is 
wide local excision (i.e. surgery) [17]. When occult invasion is not a concern, vulvar HSIL 
can be treated with excision, laser ablation, or topical imiquimod as an off-label medical 
therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [16]. Therefore, many patients have a fear 
of recurrence and progression to cancer [18].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks. 
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid the use of toilet paper and to rinse with warm water 
instead. During recovery, common effects include pain in urinating and wiping, soreness, 
difficulty sitting, and feeling tired [19]. In the first week after hospital discharge, common 
patient-reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [20].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-
being [19]. The symptoms and signs of vulvar HSIL can be moderate to severe and 
include painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating 
[20]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than 
age-matched healthy women. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor's office all the time [19]. 


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 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid later development of HPV-
associated vulvar HSIL and subsequent vulvar cancer. The US-licensed prophylactic 
HPV vaccines are indicated for girls and women ages 9 through 26 years for Gardasil® 
and Gardasil®9 (Merck & Co. Inc.), and ages 9 through 25 years for Cervarix® 
(GlaxoSmithKline). The early portions of these age ranges are generally before sexual 
debut and thus can allow immunologic protection against the anticipated earliest normal 
exposures to HPV infection. HPV prophylactic vaccination is highly effective and safe, 
and routine vaccination is recommended for females in the United States starting at age 
11 or 12 years [22]. However, these prophylactic vaccines have no therapeutic effect 
upon existing HPV infection or existing HPV-related intraepithelial neoplasia [23]. 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan will be used in this study to address the risk of a potential 
delay in treatment of vulvar HSIL. The feasibility of this approach was demonstrated in 
the Phase 2b study of cervical HSIL. Given that vulvar disease progresses slowly to 
vulvar cancer if untreated, the proposed enhanced monitoring plan is expected to 
maintain the safety of subjects in this study. First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study Investigators. Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, 
by two independent expert pathologists from the PAC (see Section 10.4.2). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
is specifically excluded from study entry. By contrast, HPV-associated vulvar HSIL does 
not progress rapidly, typically taking years to manifest and progress, making enhanced 
monitoring feasible [24].   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.1). Colposcopy will also be 
performed at Day 0 and during the study given that concurrent disease in the lower 
genital tract can occur. A Data Safety Monitoring Board will be utilized to review subject 
safety data and advise on any study-level safety concerns. Investigators always have 
the option of performing ad hoc vulvar biopsies to rule out suspected disease 
progression. Additional treatment (e.g., additional excision, ablation, or medical therapy) 
may be carried out, if deemed necessary according to Investigator judgment. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA™ device represent an integrated 
investigational product designed as a non-surgical treatment of HPV-16/18-related 
cervical HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Further information about VGX-3100 is provided in the Investigator's Brochure. 


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 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP 
is a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [25, 26]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 
10 to 100 fold [27, 28]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as 
shown by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [29].  
This study will use the CELLECTRA™ 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no 
significant safety issues identified. Further information about the CELLECTRA™ 2000 
device can be found in the Investigator's Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device. Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 
250 mg of the cream, equivalent to 12.5 mg of imiquimod. The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod. The overall aim is to determine if treatment with VGX-3100 could allow 
women with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of 
concept that VGX-3100 can induce resolution of both HPV-associated dysplastic lesions 
and the underlying HPV-16/18 infection was shown in a Phase 2b study of cervical 
intraepithelial neoplasia (CIN). The similar underlying pathogenic mechanisms between 
cervical and vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could 
be a non-surgical therapeutic option for the treatment of vulvar HSIL, which is a 
significantly under met medical condition. A VGX-3100 with imiquimod-administration 
arm is also included, given the prevalent use of imiquimod as a topical medical treatment 
of vulvar lesions, to investigate if a more robust immune response is achieved with VGX-
3100, to potentially increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 


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responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [30].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Therefore, imiquimod may be able to be used 
synergistically with VGX-3100. 
Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG). Published regimens include three times 
weekly application to affected areas for 12 – 20 weeks, with colposcopic assessment at 
4-6 week intervals during treatment [17].  
The current study will include an arm to explore whether the efficacy of VGX-3100 is able 
to be enhanced by concomitant treatment with Imiquimod.     
 INCLUSION OF WOMAN-PRO, CLINICAL TRIAL VERSION 2.0  
The original WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) was developed by 
Beate Senn and colleagues [20,31,32] for use following post-surgical intervention. 
Development of the tool was aligned with the FDA PRO Guidance [33]and included a 
review of the literature as well as direct patient and expert input. Preliminary 
measurement properties were assessed in a cross-sectional study. However, despite 
rigorous development and promising initial measurement properties, gaps in the 
development and psychometric evaluation exist. To address these gaps, Inovio and 
collaborators initiated a small qualitative study to confirm the content validity of the tool 
and support a cross-cultural adaptation of the measure for use in a clinical trial setting of 
US English and US Spanish speaking subjects. The results of  this research is the 
Clinical Trial of the WOMAN-PRO (2.0) which is utilized in this study. 
 
The WOMAN-PRO Clinical Trial Version 2.0 is a 31 item self-completed patient reported 
outcome measure designed to assess both physical and psychosocial impacts of VIN.  
The physical domain is comprised of 15 lesion-related symptoms and includes 5 
additional items to measure impact in daily life. Psychosocial constructs are assessment 
through 11 items that address feelings, thoughts and limitations. Each item is scored 
using a 4-point Likert scale with higher scores indicating greater difficulty or severity. The 
recall period is the past week.Details are included in Section 6.8.  
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 


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reported at the application site [34]. The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity. In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding, infection, or damage to surrounding 
structures such as the clitoris, urethra, or anus. The other potential benefit is that the 
response to VGX-3100 is systemic and may clear the underlying HPV infection, which is 
the root cause of vulvar HSIL. Consequently, there is the potential to reduce the risk of 
recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL associated with HPV-16 and/or HPV-18 (HPV-
16/18), will result in a higher percentage of women with regression of HSIL of the vulva 
based on histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-
16/18 from vulvar tissue compared with historical control. 
 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional 
treatment).   


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2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in 
combination with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL5 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/186 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL, no evidence of vulvar LSIL 
(VIN1), and no evidence of condyloma on 
histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression7 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of the qualifying8 vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying8 lesion (s) at Week 
48, 74 and 96 compared to baseline9. Results 
will be classified as: no clinically significant 
lesion resolution (reduction in lesion size of 0-
25%), partial lesion area resolution (>25% 
and <100% reduction), and complete lesion 
resolution (no visible lesion).   
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes at 
baseline and Weeks 15, 27, 48, 74 and 96 
visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying8 vulvar lesion(s), in subjects 
without a complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying8 lesion (s) at Week 
74 and/or Week 96 compared to baseline10. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to 
VGX-3100, and VGX-3100 with imiquimod, 
as measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue11 
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-vulvar 
anatomic locations without surgical 
intervention (inclusive of cervix, oropharynx, 
vagina and intra-anus) at Week 48 compared 
to baseline 
6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV 
testing results with Week 48 histologic 
regression 
7. Vulvoscopy, HPV test results (vulvar swab 
and vulvar tissue) and miRNA profile (Day 
0, Week 15 and 48) in conjunction with 
histologic regression of vulvar HSIL at Week 
48 visit 
8. Describe patient reported outcomes (PRO) 
for subjects treated with VGX-3100 and 
VGX-3100 with imiquimod 
8. PRO endpoints will be obtained at Day 0 
prior to first dose, Weeks 4, 12, 24 after 
dosing, and at Weeks 15, 27, 48, 52, 74, 96 
and 100. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA™ 2000 alone or in combination 
with imiquimod in adult women with histologically confirmed vulvar HSIL associated with 
HPV-16/18. Approximately 36 subjects will be enrolled. Twenty-four subjects will receive 
VGX-3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod 
treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions 
at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age 
category (<45 years vs. ≥45 years). 
To be eligible for the study, subjects must sign consent to participate and have a vulvar 
punch biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of 
the acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, 
the two lesions that potentially contain the most advanced disease, as judged by the 
Investigator, should be chosen for biopsy using vulvoscopy and documented using 
standardized high resolution photography with a digital single-lens reflex (SLR) camera 
on the case report form. Biopsy slides will be sent to a PAC for evaluation prior to 
enrollment. In order to be eligible for enrollment, the PAC must assign the diagnosis of 
vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar specimen 
test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study. 
To assess quality of life and related impacts on subjects, PRO instruments will be 
provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-
5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvar Neoplasia) 
Clinical Trial Version 2.0 and two additional PRO questions assessing quality of life after 
surgery or biopsy. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 
mg of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-
16/18 status and all other eligibility criteria but no more than 10 weeks following 
collection of the subject's biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid preferred site, 
or the anterolateral quadriceps as an alternate site) followed immediately by EP with the 
CELLECTRA™ 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes. The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose at 
Week 52 per the judgment of the Investigator. Subjects with HSIL at Week 74, who have 


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a reduction in lesion size or no increase in lesion size from baseline (Subgroups C or D), 
may receive a sixth dose at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgment of the Investigator. All 
subjects will complete the study at Week 100. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will 
apply imiquimod 5% cream to the vulvar lesion beginning in the evening on Day 0, and 
will continue to apply treatment three times per week for 20 weeks (inclusive of 
administration in the evening of VGX-3100 dosing). Subjects unable to tolerate 
imiquimod treatment may reduce their dosing frequency, and will document their use on 
the imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital photographic imaging, vulvar lesion(s) will also be 
quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced disease as judged by the Investigator, and must be  approximately 4 mm in 
length. Visible lesion must remain after screening biopsy to ensure measurement on 
study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the qualifying lesion as study start from the region of potentially most 
advanced disease based upon the judgment of the Investigator (see Table 2 for 
Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC 
there is no evidence of HSIL (Figure 2, Subgroups A or B), the subject will continue to 
Week 74 for vulvoscopy, and biopsy of the same qualifying lesion as study start from the 
region of potentially most advanced disease based upon the judgment of the 
Investigator. 
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion 
size or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the 
Investigator has the option to give the subject a 5th dose of VGX-3100 at Week 52, and 
the subject will continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and 
the subject will continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as at study start Investigator(see Table 2). If after 
evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), 
the subject will continue to Week 96 for vulvoscopy and biopsy of the same lesion as at 
study start. InvestigatorIf HSIL remains but there is a reduction in lesion size or no 
increase in lesion size from baseline (Subgroups C or D), the Investigator has the option 
to give the subject a 6th dose of VGX-3100 at Week 78, and the subject will continue on 


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study with vulvoscopy and biopsy at Week 96. Alternatively, the Investigator may choose 
to treat the subject with surgical or standard treatment, and the subject will continue on 
study without further biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but from the region of potentially most 
advanced disease based upon the judgment of the Investigator. (see Table 2). If there is 
no vulvar HSIL (Subgroups A or B), no further procedures are required. If after 
evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or 
worsening disease (Subgroup E), the subject will receive surgical or other standard 
treatment. 
In the event of worsening disease (i.e., Subgroup E - any increase in lesion area from 
baseline or worsening to cancer), the subject will receive surgical treatment per the 
Investigator's judgment and will continue on study through Week 100 with vulvoscopy, 
but without further study treatment or biopsy. For a finding of carcinoma, subjects will 
receive surgical treatment, and be discontinued from study treatment. The event will be 
reported as an SAE per section 7.1.4. If wide excision is required, the sample obtained 
will be sent to the PAC for evaluation.  
 
Table 2:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator. 
Acetowhite Lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator.  
Multiple acetowhite lesions 
Vulvar punch biopsies and lesion photography; biopsy should 
be conducted of the same qualifying lesions as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator. 
 
  
 
 DEFINITION OF RESPONDER AND NON-RESPONDER 
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive any non-study related treatment for vulvar HSIL. A treatment non-responder is a 
subject with histologic evidence of vulvar HSIL or vulvar carcinoma at evaluation, or a 
subject with evidence of HPV-16/18 at evaluation, or a subject who received non-study 
related treatment for vulvar HSIL. Any case of histologically confirmed progression is 
considered a non-responder. Progression is defined as advancement to carcinoma by 
histology according to the PAC.  


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Responder and non-responder definitions (Table 3) take into account both 
histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of 
HSIL. 
Table 3: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
 
 
Subject with histologic evidence of vulvar HSIL or  
vulvar carcinoma at evaluation 
  
OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related treatment 
for vulvar HSIL 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight. 
The DSMB will meet quarterly to review safety data and regression/clearance results. 
The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue. No formal interim analysis is planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, PI for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, PI for the 
trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse 
event, assessed as related to study treatment, further enrollment and study 


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treatment will be halted immediately until a thorough investigation has been 
conducted by the Medical Monitor, PI for the trial, and the DSMB. 
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, PI for the 
trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (i.e., Screening and Day 0 prior to dosing) and Weeks 
15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize vulvar HPV infection at Screening, 
Weeks 48, 74 and 96. Cervical samples, oropharyngeal (OP) rinse samples, vulvar, 
vaginal, and intra-anal tissue swab samples will be obtained to characterize HPV 
infection at the following time points: Day 0 prior to dosing (OP, cervical, vulvar, vaginal 
and intra-anal), Week 4 (Vulvar only), Week 12 (Cervical and Vulvar) and Weeks 27, 48, 
74 and 96 (OP, vulvar, vaginal and intra-anal only). At week 48 and 96, a cervical 
sample will also be collected.  
 
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated 
date of first dose of study drug and have confirmed histologically confirmed vulvar HSIL 
by the Pathology Adjudication Committee at screening; 
5. Must be judged by the Investigator to be an appropriate candidate for the protocol-
specified procedure (i.e. excision or biopsy) required at Week 48; 
6. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 


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adequate size to ensure that a visible lesion remains after an approximately 4 mm 
screening biopsy;  
7. Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive 
method with failure rate of less than 1% per year when used consistently and 
correctly from screening until 6 months following the last dose of investigational 
product. Acceptable methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject's preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject's entry 
into the study, and this male is the sole partner for that subject. 
9. Normal screening electrocardiogram (ECG) or screening ECG with no clinically 
significant findings as judged by the Investigator. 
 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical 
care and/or treatment for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
7. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains 
after biopsy; 
8. Treatment for genital warts within 4 weeks prior to screening; 
9. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 


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4 weeks prior to screening; 
10. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
11. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
12. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; 
13. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
14. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
15. Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks 
of each study dose; 
17. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
18. Current or history of clinically significant, medically unstable disease which, in the 
judgment of the Investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results  
a) Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher 
congestive heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the 
exception of superficial skin cancers that only require local excision; 
c) Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of Day 
0; 
d) History of seizures unless seizure free for 5 years with the use of one or 
fewer antiepileptic agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or 


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<90 mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 
bpm at Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
20. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening 
arrhythmia) (unless deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site 
(i.e. electroporation area);  
21. Vulnerable populations: 
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, 
would interfere with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study 
treatment/EP but will be encouraged to continue follow-up safety assessment through 
study discharge and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw 
from study participation at any time. A subject may be withdrawn at any time at the 


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discretion of the Investigator for any maternal obstetrical or medical complications after 
consultation with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report 
form (eCRF) and the subject's source document. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site 
should also counsel the subject on the importance of maintaining the assigned visit 
schedule for follow-up and treatment of VIN, and ascertain whether or not the subject 
wishes to and/or should continue in the study based on previous noncompliance. In 
cases where the subject does not return for the rescheduled visit or cannot be reached 
to reschedule the missed visit, the site should make every effort to regain contact with 
the subject (3 telephone calls to the subject should be made and if that fails, then a 
certified letter is sent to the subject's last known mailing address) so that they can be 
considered withdrawn from the study for disposition purposes. These contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will she be considered to have withdrawn from the 
study with a primary reason of "Lost to Follow-up". For all other subjects withdrawing 
from the study, an alternative reason for discontinuation should be recorded in the 
eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). 
At a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100). A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or study coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an AE. If a subject discontinues from 
the study or is withdrawn from the study prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. The 
Investigator will make every effort to have all scheduled immune assessment blood 
samples collected as indicated in the Schedule of Events in the synopsis, Table 1. Any 
AEs and/or SAEs present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in section 7.1. 
 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 


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 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the Investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs 
regardless of relation to study drug. 
 
Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from 
further participation in the study in the absence of an Investigator-determined 
medical need to withdraw. If the subject gave a reason for withdrawal, it must be 
recorded on the eCRF. This reason does not allow for further data collection and 
should not be selected if follow-up data collection of this subject is anticipated by 
the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study. 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation 
should be discussed with the Sponsor’s Medical Monitor prior to discontinuation 
of study treatments or study withdrawal. 
 
Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter 
sent by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon™) technology. The VGX-
3100 formulation to be used in this study is described in Table 4 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum. There are 24 single-use packets of imiquimod in one box. The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older. Although it is not approved by the US Food and 
Drug Administration for the treatment of vulvar HSIL, imiquimod is currently recommended 
as a non-surgical, off-label treatment option for vulvar dysplasia by the American College 
of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 


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Table 4. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  The actual product label names the product as 
VGX-3100X; the "X" designation was included to differentiate the current buffer 
formulation from a previous formulation of VGX-3100 in water. Imiquimod Cream, 5% will 
have both the original manufacturer's label on individual packets and the back of the 
carton, and an investigational label on the front of the carton. The labels will contain, at 
minimum, the information shown in Figure 6.   
 
 
Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  


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Figure 6. Example labels for imiquimod 
 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: Imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Ophthalmic Use. 
Keep out of reach of children. This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer's instructions. Avoid freezing.    
5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. 
The product must be used within 4 hours of removal from the refrigerator. All material 
removed from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 


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 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations. Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks. Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water. Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. In the event 
that Imiquimod is not tolerated at 3 times per week, alternative administration 
approaches must be discussed and approved by the medical monitor. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period. The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 
5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. 
to be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 


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procedures, and appropriate records of the disposal have been documented. The 
unused IP can only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the CELLECTRA™ 2000 device are located in the User 
Manual. Each clinical site will receive training for the use of the CELLECTRA™ 2000 
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 
The CELLECTRA™ 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA™ 2000 User 
Manual describes all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings, and precautions. Each CELLECTRA™ 2000 Pulse 
Generator has a unique serial number, and each CELLECTRA™ 2000 Applicator has a 
unique serial number. Each CELLECTRA™ 2000 Array has a Lot Number, Manufacture 
Date, and Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to 
successfully completing device training from sponsor personnel. Individuals whose 
credentials do not meet the relevant local requirements may perform the treatment 
procedure under both of the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or 
an approved Sub-Investigator who has already been trained by the sponsor's 
personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and 
approved by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its 
designee. 
5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 5 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers 
(as applicable) is included at the time of manufacture and may vary from these 
examples. The information found on the actual device labels should always be used to 
manage, track and record investigational product accountability during study conduct. 
 


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Table 5. Example Labels for the CELLECTRA™ 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA™ 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA™ 
2000 5P 
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA™ IM 
Array 
 
REF: M01-002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. 
This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA™ 2000 IM Applicator is intended to be used multiple times on the 
same subject and then disposed after final use in accordance with accepted medical 
practice and any applicable local, state, and federal laws and regulations. Once the IM 
applicator is assigned to a subject, it may NOT be used on another subject. The used 
sterile disposable array attachment must be discarded after use in accordance with 
institutional policy regarding disposal of sharp needles/instruments. 
5.10 RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original 
containers. The return of all product identified above should be arranged by the 
responsible Study Monitor. 
If product is to be destroyed on site, it is the Investigator's responsibility to ensure that 
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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation. The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information 
collected prior to consenting and before any additional study specific procedures are 
performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate 
safety concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the 
samples sent to the central pathology lab for review by the PAC to assess eligibility. 
There will be a maximum allowable window of 10 weeks from the date of collection of 
the qualifying biopsy sample(s) (i.e. samples reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, an additional biopsy sample should be collected 
during screening following the consent of the subject. The 10 week screening window 
begins upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose vulvar specimens also test positive for other 
HPV genotypes are not excluded as long as they have a positive result for HPV-16 
and/or HPV-18.  
The assessments during the screening period will determine the subjects'' eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, and 
ECG which must be performed within 45 days prior to Day 0. All screening assessment 
values must be reviewed prior to study treatment. 
 
Signed informed consent  
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG (within 45 days prior to Day 0) 
 
Baseline laboratory evaluations (includes complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine 
aminotransferase [ALT], creatine phosphokinase [CPK], and urinalysis) to be 
performed within 45 days prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be 
performed once) 
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photograph of the vulvar lesion(s) must be collected prior to and after biopsy at 
screening 
 
If a historical biopsy sample is used to determine eligibility at screening and a 
pre-biopsy photograph is not available, a post biopsy photo will be sufficient.  
 
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC.  
 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment. Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 
 
Review of concomitant medications and adverse events 


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 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 WEEK 4 (± 7 DAYS): 
The following study evaluations will be performed at Week 4 prior to study treatment  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 


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 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvar swab 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after 
study treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 (± 7 DAYS) 
The following study evaluations will be performed at Week 12 prior to study treatment:  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history 
 
Vulvar swab 
 
Vulvoscopy  


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 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 (± 7 DAYS): 
The following study evaluations will be performed at Week 15: 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay including miRNA profile 
 WEEK 24 (± 7 DAYS) 
The following study evaluations will be performed at Week 24 prior to study treatment: 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 


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 WEEK 27 (± 7 DAYS) 
The following study evaluations will be performed at Week 27: 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
  WEEK 38 PHONE CALL 
 
Review concomitant medications and adverse events 
  WEEK 48 (± 7 DAYS) 
The following study evaluations will be performed at Week 48: 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 


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 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 
Patient Reported Outcomes 
 WEEK 52 (± 14 DAYS) 
Subjects will have a Week 52 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
  WEEK 74 (± 14 DAYS) 
The following study evaluations will be performed at Week 74: 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 


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 
All biopsy samples must be sent to the PAC for review 
  WEEK 78 (± 14 DAYS) 
Subjects will have a Week 78 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 
  WEEK 96 (± 14 DAYS) 
The following study evaluations will be performed at Week 96: 
 
Review of concomitant medications and adverse events 
 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 


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 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
  WEEK 100 (± 14 DAYS) 
The following study evaluations will be performed at Week 100: 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, 
study objectives, potential benefits and risks, discomforts/inconveniences, and the 
subject’s rights and responsibilities. The subject is then requested to sign and date the 
ICF. A copy of the signed informed consent documentation must be provided to the 
subject. The qualified study personnel will document the process of obtaining informed 
consent within the source record. Signed ICFs are maintained in the subject's source 
records and must be accessible for verification at any time. 
 RESCREENING OF SCREEN FAILURES 
 
Subjects who sign the informed consent and are assigned a subject identification     
 
number (SID) but do not meet the eligibility criteria or fall outside of the screening 
 
window will be considered screen failures. If the Investigator believes rescreening is 
 
warranted, the Investigator must contact the medical monitor to discuss.  
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique SID, which identifies the subject 
for all study-related procedures. SIDs are a combination of a up to two alpha letters 
study code, two alpha letter Country code, two digit site number, plus 3-digit subject 
number starting with 001 (e.g., VNUS01001). Once assigned, SIDs cannot be reused for 


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any reason. Information regarding the SID and screen date must be documented on a 
Screening log/system and in the Interactive Response Technology (IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated 
allocation schedule.  
 SAFETY EVALUATIONS 
6.3.4.1 
PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100). It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems. All assessments not completed should be marked as not 
done.  
A targeted physical assessment will be performed at other visits as determined 
by the Investigator or directed per subject complaints. 
6.3.4.2 
VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 
 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.4.3 
WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.4.4 
MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be 
obtained at screening. All relevant (as judged by the Investigator) past and 
present conditions, as well as prior surgical procedures will be recorded for the 
main body systems.  
6.3.4.5 
SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, 
history of prior cervical dysplasia, and pregnancy history will be obtained at 
Screening.  
 


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At Weeks 48 and 100, socio-behavioral assessment will be performed to 
document any change from screening. 
6.3.4.6 
LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 
6.3.4.7 
PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.4.8 
ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has 
been in a supine position for 10 to 15 minutes. The ECG should include 
measurements of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST 
segment, T wave as well as an Investigator assessment of whether the ECG is 
normal or abnormal (automated interpretations of ECG should not be used). 
Abnormal ECGs should be interpreted as "clinically significant (CS)" or "not 
clinically significant (NCS)" by the Investigator. 
6.3.4.9 
POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after 
the study treatment.  


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The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.4.10 
IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 2000. Study treatment plus EP 
must not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is 
implanted metal within the same limb. Any device implanted in the chest (e.g., cardiac 
pacemaker, defibrillator or retained leads following device removal) excludes the use of 
the deltoid muscle on the same side of the body. The timing of the initial dose will be 
designated Day 0 with the subsequent doses scheduled for administration at Weeks 4, 
12, 24, and at Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 
RISKS OF TREATMENT PROCEDURES TO VGX-3100 
No serious related adverse events to VGX-3100 have been observed in the clinical trial 
experience to date. A summary of potential risks of IM Administration followed by EP 
with CELLECTRA™ can be found in the VGX-3100 + Imiquimod Investigator's Brochure.   
6.4.1.2 
RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
Adverse events reported in clinical trials with imiquimod cream, 5% for external genital 
warts can be found in the imiquimod product label [35], and in the VGX-3100 + 
Imiquimod Investigator's Brochure. 


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 MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION 
(EP) PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 
approximately 1.5 cm diameter amount will be applied with occlusion to the site of 
injection ~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who 
receive a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours 
after receiving medication and should have arranged transportation to depart the study 
site. 
Subjects may be offered an analgesic (e.g. acetaminophen, ibuprofen, ketorolac) before 
or after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, acetaminophen, 
ibuprofen, ketorolac or a mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.4.6.   
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 
minutes after each study treatment. Subjects will be advised to record local and systemic 
AEs for 7 days after each study treatment on a PD which will be reviewed with study 
personnel at 8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject's CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale: 
 


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Table 6. 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" 
*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 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes 
(PRO) instruments will be provided. Administration of PRO instruments will be performed 
according to the validated or otherwise developed procedures and instructions of each 
respective instrument. The following PRO questionnaires will be used: 
1. WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) Clinical Trial Version – 2.0 
(Beate Senn; version modified by Inovio Pharmaceuticals and RTI Health Solutions): is a 
31 item self-completed patient reported outcome measure designed to assess both 
physical and psychosocial impacts of VIN. The recall period is the past week.[20]. 
The WOMAN-PRO will be administered on paper only and should be the first PRO 
instrument administrated (i.e. before all other PROs) at each of the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 


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 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
2. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six 
items covering eight domains (Physical functioning, Role limitations due to physical 
problems, Bodily pain, General health, Vitality, Social functioning, Role limitations due to 
emotional problems, and Mental health) [36]. SF-36v2™ will be administered at the 
following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
3. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual 
activity, Pain/discomfort, Anxiety/depression, and Global health status) [37, 38] and will 
be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
4. Additional Global PRO Questions – regarding quality of life after surgery or biopsy. 
These two questions will be administered on paper at Week 52 only. 


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6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 
antibody response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune 
activity may occur via the application of the Interferon-γ enzyme-linked immunosorbent 
spot (IFN-γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
Profiling of miRNA will occur using plasma obtained at Day 0, Week 15 and 48.  
Assessment of Day 0 samples alone will explore predictive algorithms for response to 
treatment with VGX-3100 prior to dosing. Assessment of Week 15 and 48 samples will 
be done as a comparison against Day 0, in order to look for changes in miRNA profiles 
that occur once dosing with VGX-3100 has begun, to explore construction of an 
algorithm to predict treatment success with VGX-3100. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after HPV genotyping 
and histologic diagnoses have been rendered at Screening, Weeks 48, 74 and 96, then 
unstained slides and/or the relevant paraffin blocks may be collected for assessment of 
pro-inflammatory and immunosuppressive elements in tissue, where feasible. 
Assessment of markers may include, but are not limited to, CD8+ and FoxP3+ infiltrating 
cells as well as assessment of cell death via Cleaved Caspase 3 assessment. Additional 
assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-
L1 in cervical tissue as sample allows. Markers listed here may change as new relevant 
information becomes available. 
6.11 HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 


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6.12 VULVAR HPV TESTING 
At Screening, Weeks 48, 74, and 96, a vulvar punch biopsy sample of approximately      
4 mm will be obtained and sent to a central laboratory for HPV genotyping by PCR. In 
the case of multifocal disease, a vulvar biopsy of approximately 4 mm will be obtained 
from two lesions that potentially contain the most advanced disease as judged by the 
Investigator. The subject will be requested to abstain from sexual activity and refrain 
from use of douching to eliminate potential interference with the results of HPV testing. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
vulvar punch biopsy to eliminate potential interference with the results of HPV testing. 
6.13 COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Day 0 and at Week 96 for all subjects. 
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep® test kits at Day 0, Weeks 12, 48 and 96, 
and read in a central laboratory. HPV PCR will be performed on the ThinPrep® 
specimen. At each of these visits, menstrual cycle status & recent gynecologic history 
will be collected. If the Pap smear result suggests progression to cancer the Investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep® samples to eliminate potential interference with the results of HPV testing. 
6.14 VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL 
confirmed by the PAC. Subjects will undergo vulvoscopy to identify the lesion(s). Interval 
vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96. Vulvoscopic 
visualization of a normal appearing vulva is insufficient evidence to confirm disease 
regression. An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. 
Digital photographs of the vulva will be captured after application of acetic acid to 
document the clinical findings. If a biopsy or surgical excision is performed, images of 
the vulva should be collected before and after the procedure. Each site will be instructed 
on 1) the technique for capturing the proper images using a standard approach, and 2) 
the process for uploading the images to a secure server.   
In the case of multifocal disease, the two lesions that potentially contain the most 
advanced disease as judged by the Investigator and which is of adequate size to ensure 
that a visible lesion remains after punch biopsy should be chosen for vulvar biopsy and 
documented using photography.     
Biopsies should not be performed at any visit other than at entry (screening), Week 48, 
Week 74 or Week 96 unless the PI suspects disease progression. All biopsy samples 
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unscheduled biopsies for suspected disease progression are described in Table 7.  
Consult the Medical Monitor for any planned departures from these guidelines. 
Table 7:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 
Subject safety is paramount in this study. Therefore, if at any time the Investigator 
suspects disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over 
the Schedule of Events on Table 1.  Histologic samples and photographic 
documentation should be obtained for these cases.  
6.15 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to 
screening biopsy date of eligible subjects must be recorded on the CRF. Actual or 
estimated start and stop dates must be provided. Medical procedures performed within 8 
weeks prior to screening biopsy date of eligible subjects that do not affect subject's 
eligibility for participation and during the study (including over the counter or herbal), will 
be recorded on the CRFs. This information will be obtained from the subject and 
abstracted from any available medical records. The indication for the medication, dose, 
and dose regimen will be documented. Medication that is considered necessary for the 
subject's safety and well-being may be given per Investigator discretion and recorded in 
the appropriate sections of the CRF. 
6.16 RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic 
corticosteroids are allowed) 
 
Disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at 
screening and throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
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 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
Investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1). Lapses in contraceptive use should be reported to Investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep® samples.  
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and 
unsolicited AEs will be monitored and reported on an AE CRF, including the event's 
seriousness, severity, action taken, and relationship to investigational product(s). AEs 
should be followed until resolution or stable and the outcome will be documented on the 
appropriate CRF. All AEs should be recorded in standard medical terminology rather 
than the subject's own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.11 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the 
duration of the study, including the follow-up off study drug period will be 
recorded as an AE. 
 
Conditions that lead to a medical or surgical procedure. 
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 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit 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 informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
 SERIOUS ADVERSE EVENTS 
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; 
 
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 (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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, 2) blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, 3) the development of drug dependency or drug abuse or 4) the 
development of a malignancy; 
 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 
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 
Inpatient hospitalization means that 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 nor does it include full day or overnight stays in observation status. 
 
The Investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 
Serious adverse events that are ongoing should be followed until resolution or are 
clinically stable. The reporting period for SAEs is described in Section 7.4.2. 
 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE. For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of carcinoma should 
also be reported as an SAE. In both instances the condition for SAE reporting should be 
categorized as a medically important event unless another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a 
medicinal product related to any dose, for which a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility (i.e., there is 
evidence to suggest a causal relationship between the product and the adverse event). 
An unexpected ADR is one, the nature or severity of which is not consistent with the 
applicable product information (Investigator's brochure, protocol, and user manual). 
Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be 
considered “unexpected”. Specific examples would be (a) acute renal failure as a 
labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a 
first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is 
a serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating Investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the 
SUSAR will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating Investigators of information that might materially influence 
the benefit-risk assessment of a medicinal product, sufficient to consider changes in 
product administration or overall conduct of a clinical investigation. Examples of such 
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expected adverse event, the identification of a significant hazard to the subject 
population, or a major safety finding from a study conducted in animals. 
 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
Investigator within 24 hours. Sponsor will assess each device related SAE to determine 
if anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The Investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The Investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be 
assessed as not related to the IP and/or the investigational device. Because the 
Investigator is knowledgeable about the subject (e.g., medical history, concomitant 
medications), administers the IP, and monitors the subject’s response to the IP, the 
Investigator is responsible for reporting adverse events and judging the relationship 
between the administration of the IP and device and a subsequent AE. 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 IP 
delivered by EP and determine whether to report expeditiously to the regulatory 
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Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation 
of any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the IP and/or the investigational device indicating "yes" or 
"no" accordingly. Causality should be assessed by the Investigator as “yes, related” or 
“no, unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational 
device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to IP 
interruption or discontinuation must be recorded as an AE, or SAE, if applicable. In 
addition, laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital 
signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE (or SAE) as described in Section 7.1. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., 
anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the Investigator as clinically significant 
 POST-TRIAL 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 or termination visit and the event is deemed by the Investigator to be related 


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to the study treatment, he/she should promptly document and report the event to the 
study team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be 
excluded from participation in the study. Should a subject become pregnant after 
enrolling in the study, she will not be given any further study treatments. A Pregnancy 
Form will be completed by the site personnel and submitted to the sponsor within 24 
hours after learning of the pregnancy. Site personnel will submit the Pregnancy Form to 
the Sponsor as described in Section 7.4.2. 
The Investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject's permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results 
will be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be 
performed. Investigators should use clinical judgment regarding subsequent study-
related blood collection based on the presence or absence of anemia in each subject. 
Subjects who are not withdrawn will continue to be followed for safety assessments to 
study discharge per protocol.  
All pregnancies that occur from the time of first study treatment through the follow up 
visits must be reported. The Investigator will monitor the subject and follow the outcome 
of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome will be reported directly to the study team and the medical 
monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when 
informed consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject's response to questions about her health (a standard non-leading 
question such as ''How have you been feeling since your last visit?'' is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the 
Investigator to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject's health becoming known to the 
Investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  


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7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
urinalysis) 
 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented.  
 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 2000 that require expedited communication 
from the site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration 
recorded ≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and PI, the DSMB, and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
Treatment;  
 
Any subject experiences an SAE (or potentially life threatening AE) or death 
assessed as related to Study Treatment; 
 
Three or more subjects experience the same grade 3 or 4 adverse event, assessed 
as related to Study Treatment;  
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
Study Treatment; 
Upon conclusion, the sponsor or designee will notify all Investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 


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7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), 
whether volunteered by the subject, discovered by Investigator or study staff 
questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded in the subject's source documents and followed as 
appropriate. 
 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
 TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised 
of the period following the signing of the informed consent form until the end of the 
study. Each AE will be assessed to determine whether it meets serious criteria. If the AE 
is considered serious, the Investigator should record this event in the EDC system and 
report the event to the Sponsor within 24 hours of becoming aware of the event. The 
Investigator may also directly report this event to the Ethics Committee according to its 
standard operating procedures. Expectedness of SAEs will be determined by the 
Sponsor using reference safety information specified in the Investigator's Brochure and 
protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.5 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.6 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All Investigators will receive a safety letter notifying them of relevant SUSAR reports. 
The Investigator should notify the Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as is practical, of serious events in writing where this is required by local 
regulatory authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an Investigator becomes 
aware of an SAE that is suspected by the Investigator to be related to the study drug, the 
event will be reported to the Sponsor or its designee. If the Investigator becomes aware 
of an SAE in a study subject after the last scheduled follow-up visit, and considers the 
event related to prior Study Treatment, the Investigator will report it to the Sponsor or the 
appropriate designee. 
  
 
 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
 M.D., Ph.D. 
EMAIL:  
 
 
 


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SAE REPORTING INFORMATION 
EMAIL:  safety.inovio@apcerls.com 
SAFETY FAX: 
SAFETY PHONE: 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address 
as indicated above. Any SAE supporting documents provided by facsimile (Fax) are to 
include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The Investigator will supply the Sponsor and the IRB with more information as it 
becomes available and any additional requested information. The original SAE form 
must be kept at the study site. The Sponsor or its representative will be responsible for 
determining and in turn, reporting SAEs to regulatory authorities according to the 
applicable regulatory requirements. SAEs must be followed by the Investigator until 
resolution, even if this extends beyond the study-reporting period. Resolution of an SAE 
is defined as the return to baseline status or stabilization of the condition with the 
expectation that it will remain chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the Investigator will submit a Pregnancy Form to the 
Sponsor or designee to the safety email address or fax number within 24 hours of 
learning of the pregnancy. 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating Investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later 
than 10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 
15 days for all other SUSARS (see Section 7.1.5 and 7.1.6). 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, 


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reliability, safety, effectiveness, or performance of a device such as malfunction, misuse 
or use error and inadequate labeling. A malfunction is defined as the failure of a device 
to meet its performance specifications or otherwise perform as intended. The intended 
performance of a device refers to the intended use for which the device is labeled. All 
product complaints that meet this definition must be reported to the sponsor within 10 
days of discovery. Any product complaint that involves an AE or SAE must be also be 
reported per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error 
messages displayed on the device screen following treatment or errors that occur during 
the treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  
All complaints must be sent to ClinicalComplaint@inovio.com. Additional instructions on 
complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at 
multiple sites for safety or administrative reasons at any time. In particular, a site that 
does not recruit at a reasonable rate may be discontinued. Should the study be 
terminated and/or the site closed for whatever reason, all non-source documentation and 
study product pertaining to the study must be returned to Inovio Pharmaceuticals or its 
representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research 
subjects are protected. 
8.
STATISTICAL ANALYSIS PLAN
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and 
VGX-3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and 
confirmed vulvar infection with HPV types 16 and/or 18. The study's primary endpoint is 
binary: regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from 
vulvar tissue based on tissue collected at Week 48. The primary hypothesis is that each 
of the treatment arms will result in regression of HSIL and clearance. Secondary efficacy 
analyses pertain to regression, clearance of HPV-16 and/or HPV-18 infection, regression 
to normal, non-progression, and anatomic extent. Other secondary analyses concern 
safety and humoral and cellular immunological measures. Exploratory efficacy analyses 
concern extended dosing with respect to regression, clearance, and anatomic extent, 
clearance outside of the vulva, and effect of HLA type on efficacy. Other exploratory 
analyses pertain to tissue immunological measures and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 


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recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 
vs. 2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 
kg/m2), and (d) age category (<45 years vs. ≥45 years). There are no requirements for 
the number of subjects in each stratum. The study is open-label. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each arm superior to historical control with a one-sided 0.025 type 
1 error level for each hypothesis, assuming the true proportion of subjects who achieve 
the primary endpoint is 20% and 28% for the respective treatment arms and 2% for the 
historical control, and that 90% are evaluable at Week 48 from randomization. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized. Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized. 
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy. Subjects excluded from the PP 
population will be identified and documented prior to unblinding of the study 
database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects and will 
include the number and percentage randomized, the number and percentage who 
received each dose and the number who completed the trial. The number and 
percentage of subjects who discontinued will be summarized overall and by reason. The 
number in each analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, 
and percentages for categorical variables, by treatment arm, for the mITT population. 
Prior and concomitant medications will also be summarized with percentages in this 
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8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system, by treatment arm, for the mITT population. 
 
 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are considered those medications taken prior to the first dose of study 
drug (i.e., Day 0). Concomitant medications are those used on or after Day 0. Partial 
start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial 
date. Data for all prior and concomitant medications will be summarized with 
percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint for each arm. The primary hypothesis of 
superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment arm separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI 
exceeds 0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) 
will be summarized with point estimates and associated exact Clopper-Pearson 95% 
confidence intervals. 
An exploratory analysis will examine clearance outside of the vulva. This will be 
analyzed in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and a) HLA results, b) miRNA results, c) vulvoscopy results, and d) HPV 
results. Relationships will be examined with contingency tables and/or logistic regression 
models which model the primary endpoint versus these results and treatment group as 
regressor variables. 
8.10 IMMUNOGENICITY ANALYSIS 
 


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Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment 
arm. These frequencies will be presented overall and separately by dose, and will depict 
overall, by system organ class and by preferred term, the percentage of subjects 
affected. Additional frequencies will be presented with respect to maximum severity and 
to strongest relationship to Study Treatment. Multiple occurrences of the same AE will 
be counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of 
any dose. For this summary, the frequency of preferred term events will be summarized 
with percentages and exact Clopper-Pearson 95% confidence intervals. Separate 
summaries will be based on events occurring within 7 days of any dose and regardless 
of when they occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not 
be included within specified day-range summaries. AE duration will be calculated as 
(Stop Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment 
arm. Baseline is defined as the last measurement prior to the first treatment 
administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population. Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time 
point will be summarized by treatment arm and by body system, for the mITT population. 


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 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or exact 
Clopper-Pearson 95% CIs, for continuous responses and binary responses, 
respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 
9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles of 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The Investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained from 
the applicable IRB/EC and a copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 
During the conduct of the study, submit progress reports to the IRB/EC as required.  
 
Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 
If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 
As required, obtain approval from the IRB/EC for protocol amendments and for 
revisions to the consent form or subject recruitment advertisements; 
 
Reports on, and reviews of, the trial and its progress will be submitted to the IRB by 
the Investigator at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines. 
 
Maintain a file of study-related information that includes all correspondence with the 
IRB; 
 
Notify IRB when study is completed (i.e. after the last study visit of the final study 
subject); 
 
After study completion provide the IRB with a final report on the study. 


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9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., NIH 
Office of Biotechnology Activities) governing research that involves recombinant or 
synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening into the 
study, and/or from the subject's legally authorized representative. The process for 
obtaining informed consent must also be documented in the subject's medical record. 
9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating 
the study and re-approval or review at least annually. Sponsor is to be notified 
immediately if the responsible IRB/EC has been disqualified or if proceedings leading to 
disqualification have begun. Copies of all IRB/EC correspondence with the Investigator 
must be provided to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and for subjects in the imiquimod 
arm a dosing log during their study participation. Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
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10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject's name will not be disclosed in these documents. 
The subject's name may be disclosed to the study sponsor, Sponsor, the governing 
health authorities or the Food and Drug Administration (FDA), if they inspect the study 
records. Appropriate precautions will be taken to maintain confidentiality of medical 
records and personal information. 
Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject's legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA)). 
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 the research subject to revoke their authorization for use of their 
PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. 
Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subject's 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 medical records and within 
information technology systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must 
be present in the source documents. All prescription and nonprescription medications 
taken within l week prior to entry must be recorded on the CRF. Actual or estimated start 
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10.3 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The sponsor will inform the Investigator/institution as to when 
these documents are no longer needed to be retained. 
10.4 SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial. The DSMB will 
meet quarterly or as data are available to review safety data and regression/clearance 
results. If there are no new safety data or regression/clearance results to review for a 
quarterly scheduled meeting the DSMB will be notified and the meeting may be 
cancelled; Ad hoc meetings may be scheduled to review new data as applicable. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. 
No formal interim analysis will be performed. The DSMB Chair, upon consultation with 
the other voting members of the DSMB, has the authority to recommend suspension or 
stopping the study and to request a full DSMB review and ad hoc statistical analyses. 
The standard operating procedures of the DSMB will be documented in the DSMB 
charter, including the board's accountability to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of up to four pathologists. Each specimen will be read by two pathologists independently 
in a masked fashion. The responsibilities and membership structure of the PAC is 
outlined in the PAC Charter, including the reporting of results.  
 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant with all applicable 
requirements. 
 
All clinical site monitoring visits will be documented. 


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 
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 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 
 
Throughout the study, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, original, 
and accurate (ALCOAC).  
 
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 investigational drug and device accountability and reconciliation of 
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date 
of receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Forms 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data & Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
EP 
Electroporation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
HSIL 
High grade squamous intraepithelial lesion 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-γ 
Interferon Gamma 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response Technology 
LAST 
Lower Anogenital Squamous Terminology 
mITT 
Modified Intent to Treat 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
Participant Diary  
PE 
Physical exam 


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PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
PRO 
Patient Reported Outcomes 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
WOMAN-PRO                  WOMen with vulvAr Neoplasia PRO 
 
 
 
 


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26. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
27. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
28. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
29. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
30. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
31. 
Senn B. Creating and Validating a Patient-Reported Outcome Instrument for Women with 
Vulvar Neoplasia after Surgical-Treatment - A Mixed-Methods Project, Institute of Nursing 
Science (INS) University of Basel, University Hospital Berne, Switzerland. 2012. 
32. 
Senn B, Mueller MD, Hasenburg A, Blankenstein T, Kammermann B, Hartmann A, et al. 
Development of a postsurgical patient-reported outcome instrument for women with vulvar 
neoplasia. Oncol Nurs Forum 2012,39:E489-498. 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 20Nov2017 
 CONFIDENTIAL 
Protocol Version: 2.0 
Page 94 of 94 
 
33. 
U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER) CfBEaRC, Center for Devices and Radiological 
Health (CDRH). Guidance for Industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims. December 2009. 2009. 
34. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
35. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
36. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
37. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
38. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA™ 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
IND #13683 
 
 
 
 
Version 2.1 
01 December 2017 
 
 


VGX-3100 
lnovio Pharmaceuticals, Inc. 
Medical Monitor Approval Page 
Drug: 
Sponsor: 
Medical Monitor: 
Approval Signature: 
M.D., Ph.D. 
VGX-3100 
lnovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 11 O 
Plymouth Meeting, PA 19462 
M.D., Ph.D. 
t 
lnovio Pharmaceuticals, Inc. 
Date 
lnovio Pharmaceuticals, Inc. 
CONFIDENTIAL 
HPV-201 
Clinical Protocol 
The information in this document is considered privileged and confidential by lnovio 
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 lnovio Pharmaceuticals. Any 
supplemental information added to this document is also confidential and proprietary 
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner 
as the contents of this document. 
Protocol Version Date: 01 Dec2017 
CONFIDENTIAL 
Page 2 of 94 
Protocol Version: 2.1 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 01Dec2017 
 CONFIDENTIAL 
Protocol Version: 2.1 
Page 3 of 94 
 
 
 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI's approval of this protocol 
and provides the necessary assurances that this trial will be conducted in accordance 
with ICH/GCP and ISO guidelines, local legal and regulatory requirements, and all 
stipulations of the protocol. 
 
 
Principal Investigator Signature: ___________________________________ 
 
 
 
________________________________  
    ____________________ 
Print Name of Principal Investigator 
 
    Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 01Dec2017 
 CONFIDENTIAL 
Protocol Version: 2.1 
Page 4 of 94 
 
SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 1.3 dated 21 April 2017 to Version 2.1 
dated 01 Dec 2017. All other changes are administrative and do not significantly affect the 
safety of subjects, trial scope, or scientific quality of the protocol. 
 
1. On the title page, U.S. BB has been removed from the IND number. The IND number 
remains the same.  
2. To support enrollment, approximately 28 sites will be participating in the trial over the 
initially proposed 20 sites, and although not yet determined, the trial may potentially add 
countries outside of the United States.  
3. Due to the possibility of adding countries outside of the United States, CELLECTRA® 
2000 will use the trademark symbol, CELLECTRA™ 2000. This change has been made 
throughout the protocol. 
4. Secondary Endpoint #4 have been modified to include no evidence of vulvar LSIL 
(VIN1), in addition to no evidence of vulvar HSIL and condyloma at Week 48 in the 
measurement of histologic regression of vulvar HSIL to normal tissue. Normal tissue is 
considered as no histologic evidence of vulvar LSIL, HSIL or condyloma.  
5. Secondary Endpoint #6 and Exploratory Endpoint #1 have been modified to indicate that 
quantitative analysis will be determined from the pre-biopsy image of the qualifying 
lesion(s). A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-
16 and/or HPV-18 positive and have histologically confirmed vulvar HSIL by the 
Pathology Adjudication Committee (PAC) at screening. 
6. Exploratory Endpoint #4 will be evaluated by the assessment of pro-inflammatory and 
immunosuppressive elements in tissue, over the assessment of CD8+ and FoxP3 
infiltrating cells for the immune tissue responses for VGX-3100 and VGX-3100 with 
imiquimod.  
7. Exploratory Objective #8 has been updated to include the Week 15 and 27 time points 
for the administration of the Patient-Reported Outcomes (PROs) as it was inadvertently 
not included in version 1.3 dated 21 Apr 2017.    
8. The WOMAN-PRO (WOMen with vulvAr Neoplasia) Clinical Trial Version 2.0 PRO 
instrument has been included in the protocol to assess both physical and psychosocial 
impacts of VIN and will be administered at the same time points as the EQ-5D-5L.  
 
Section 1.1.15 was added to the protocol amendment to provide background 
information on the development of the WOMAN-PRO  
 
Section 6.8 was updated to include the administration time points of the 
WOMAN-PRO  
 
Section 12: List of abbreviations updated to include WOMAN-PRO 
9. Section 1.1.1 and 1.1.2 modified to include European data of new cases diagnosed with 
HPV infection and vulvar cancer.  
10. The requirement of a minimum 4 mm vulvar biopsy/biopsies has been replaced with a 
punch biopsy of approximately 4 mm in size in order to accommodate smaller lesions 
accessible by punch biopsy.   


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Clinical Protocol 
 
 
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Protocol Version: 2.1 
Page 5 of 94 
 
11. Repeat vulvar punch biopsies will be taken from the same qualifying lesion(s) as trial 
entry, but has been modified to clarify that the region of most advanced disease of the 
same lesion(s) will be obtained.  
 
Table 2: Minimally required Procedure at Biopsy Visit has been updated to reflect 
the change 
12. Inclusion/Exclusion criteria revised as follows: 
i. 
Inclusion Criteria #3: Revised to clarify that vulvar infection with HPV 
types 16 and/or 18 will be confirmed by screening biopsy. Subjects do not 
need to have a confirmed diagnosis of HPV-16 and/or 18 to participate in 
the study  
ii. 
Inclusion Criteria #4: Combined with previous inclusion criteria #5 as 
subjects must have a vulvar tissue specimen/blocks and histological 
confirmed vulvar HSIL from the Pathology Adjudication Committee at 
screening    
iii. 
Inclusion Criteria #6 (previously #7): Modified to accommodate smaller 
lesions accessible to punch biopsy  
iv. 
Inclusion Criteria #8b (previously 9b): Modified to include women who 
have had a bilateral tubal ligation/occlusion performed more than 3 
months prior to screening. Tubal ligation is almost 100% effective for the 
prevention of pregnancy and thus subjects are not required to wait 12 
months prior to screening to be eligible    
v. 
Exclusion Criteria #2, 3 and 4: Subjects who are under the care of a 
healthcare provider for their biopsy-proven VAIN, AIN, or CIN but may not 
be receiving active treatment are eligible for this trial. These criteria were 
modified in consideration of subjects who are under medical surveillance 
by their healthcare provider per standard of care 
vi. 
Exclusion Criteria #6 has been removed to avoid repetition as Inclusion 
Criteria # 4 states that the biopsy must be collected within 10 weeks prior 
to the anticipated 1st dose of the subject  
vii. 
Exclusion Criteria previously #9 and #10: Removed as it falls under the 
Exclusion Criteria #4 (Biopsy-proven Cervical Intraepithelial Neoplasia 
(CIN) 2/3 and are not undergoing medical care and/or treatment for CIN)  
viii. 
Exclusion Criteria #12 has extended the window for use of clinical 
laboratory results at screening from 30 days to 45 days. This allows 
subjects to use safety lab results within 45 days prior to Day 0 to 
determine eligibility 
ix. 
Exclusion Criteria #15 has been modified to ensure that subjects do not 
receive live vaccines within 4 weeks of any of the scheduled doses  
x. 
Exclusion Criteria #16 has been modified to ensure that subjects do not 
receive any non-live vaccines within 2 weeks of any of the scheduled 
doses  
xi. 
Exclusion Criteria previously #22 to #27 now fall under the subgroup of 
exclusion criteria #18 and are numbered as #18a to #18g. These items 
include the list of exclusions that fall under the category of current or 
historically clinically significant, medically unstable disease     


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 01Dec2017 
 CONFIDENTIAL 
Protocol Version: 2.1 
Page 6 of 94 
 
xii. 
Exclusion Criteria previously #22 (now #18b): Modified to ensure that only 
subjects with treatment of non-anogenital malignancy within 2 years of 
screening are excluded from the trial. Subjects in this population could be 
expected to have anogential malignancy within 2 years of study start 
which has been treated and therefore should not be excluded from trial 
participation  
xiii. 
Exclusion Criteria previously #30 to #32 now fall under the subgroup of 
inclusion criteria 20 and numbered as #20a, #20b, and #20c accordingly. 
The sub group categorizes subjects with less than two acceptable sites 
for IM injection 
xiv. 
Exclusion Criteria previously #33 to #36 now fall under the category of 
vulnerable populations and are numbered now #21a, #21b, #21c and 
#21d 
13. The time points for cervical cytology and ThinPrep® have been changed and will be 
completed at Day 0 instead of at Screening as it is not required for study eligibility. The 
Week 27 cervical cytology and ThinPrep® has been moved to Week 12 to allow an 
earlier exploration for prediction of lesion regression from a dosed subject prior to the 
efficacy timepoint. The cervical cytology and ThinPrep® at Week 74 has been removed 
and all changes have been updated in the Schedule of Events. 
14. Cervical colposcopy will be completed at Day 0 and Week 96 rather than Screening and 
Week 96 since cervical colposcopy is not required to determine eligibility on study. This 
change has been updated in the Schedule of Events. 
15. Collection of vulvar swabs has been included in Exploratory Objective #7 and the 
Schedule of Events, to explore a potential new method for the detection of HPV in vulvar 
swabs. The collection will be completed at Day 0, Weeks 4, 12, 27, 48, 74 and 96.  
16. Table 3: Definition of Responder and Non-Responder modified to include other 
treatments (e.g. surgical intervention) for vulvar HSIL treatment.  
17. Figures 2, 3 and 4 of the protocol have been modified in Subgroup E to include subjects 
that have worsened to cancer and not limited to subjects that worsen from vulvar HSIL 
alone to cancer.  
18. The screening assessments of 12-lead ECG, complete blood count (CBC), serum 
electrolytes, blood urea nitrogen (BUN), creatinine (Cr), glucose, ALT, CPK and 
urinalysis window has increased to 45 days prior to first dose administration. This was 
intended to allow subjects to complete trial procedures at their initial screening visit and 
avoid a second study visit for safety labs and/or ECG.  
19. Immunohistochemistry (IHC) testing will not be performed for the detection of HPV-16 
and/or HPV-18 in the trial. Sections throughout the protocol regarding IHC testing and in 
situ hybridization have been removed.  
20. Section 5.4.2 (Dispensing and Use of Imiquimod) has been updated to have the 
Investigator contact the Medical Monitor to discuss alternative administration of 
imiquimod for subjects randomized to the imiquimod arm who cannot tolerate treatment.  
21. Section 5.7 (Use of Investigational Device) has been modified to remove the allowance 
for individuals whose credentials do not meet the local requirements to administer 
treatment to subjects on the study. Treatment must be performed by qualified personnel 
whose credentials meet local requirements to administer parenteral injections.  


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22. Section 6.1 and 6.2 (Treatment Procedures) has been revised and updated to reflect the 
changes made on the removal and addition of treatment procedures in the Schedule of 
Events. 
23. Section 6.3.2 (Rescreening of Screen Failures) has been added to allow rescreening of 
subjects after discussion with the Medical Monitor. 
24. Section 6.4.2 (Management of Anxiety and Pain due to Electroporation procedure) has 
been modified to include Acetaminophen as an example of an analgesic to be provided 
to subjects. The language has been modified to include that the management may be 
offered before or after injection/EP. 
25. Section 6.12 (Vulvar HPV Testing) additional language included in Section 6.12 as 
subjects will be requested to abstain from sexual activity and refrain from use of  
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
vulvar punch biopsy. This is intended to eliminate potential interference with the results 
of HPV testing. 
26. Section 7.1.2 (Serious Adverse Events) has been revised to remove all redundancies in 
the section.   
27. Section 7.3.1 (Adverse Events of Special Interest (AESI)) has been updated to remove 
Grade 3 or greater laboratory abnormalities as an AESI since safety labs are only drawn 
at screening and are not done after the administration of the investigational product 
VGX-3100. 
28. Section 7.4.2 (Trial Reporting Period of Serious Adverse Events) and the Medical 
Monitor Approval Page has been updated to include the new HPV-201 Medical Monitor 
providing oversight of the trial.   
29. Section 7.4.4 (Reporting of Device Related Complaints) has been updated to include an 
email address to report any device related complaints to the sponsor. 
30. Section 8.3 (Sample Size/Power) modified to include the type of error level for each 
hypothesis.  
31. Section 8.8 (Prior and Concomitant Medications) has been revised to the clearly define 
prior and concomitant medications. 
32. Section 10.4.2 (Pathology Adjudication Committee) modified to remove procedural 
content in the protocol and refer to the PAC Charter. 
 
 
 
 
 
 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 01Dec2017 
 CONFIDENTIAL 
Protocol Version: 2.1 
Page 8 of 94 
 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ............................................................. 3 
SUMMARY OF CHANGES ........................................................................................................ 4 
CLINICAL PROTOCOL SYNOPSIS .........................................................................................13 
STUDY SCHEDULE OF EVENTS ............................................................................................27 
1. 
INTRODUCTION ...........................................................................................................29 
1.1 
Background ........................................................................................................29 
 
Human Papillomavirus and Infection ......................................................29 
 
Vulvar Cancer ........................................................................................29 
 
Vulvar Intraepithelial Neoplasia (Vulvar HSIL) ........................................29 
 
Recurrent Disease with Current Therapeutic Options .............................30 
 
Psychological and Physical Impacts of Current Therapeutic Options ......31 
 
Impact of Vulvar HSIL Upon Activities of Daily Living .............................31 
 
Limitations of Prophylactic HPV Vaccines ..............................................32 
 
Enhanced Monitoring Plan .....................................................................32 
 
VGX-3100 ..............................................................................................32 
 Electroporation .......................................................................................33 
 Imiquimod Cream, 5% ............................................................................33 
 Study Rationale ......................................................................................33 
 Dose and Regimen Rationale for VGX-3100 ..........................................33 
 Rationale for imiquimod ..........................................................................34 
 Inclusion of WOMAN-PRO, Clinical trial version 2.0 ...............................34 
 Potential Risks of investigational products ..............................................34 
 Potential Benefits of Study Participation .................................................35 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ..................................................................35 
2.1 
Primary Objective and Endpoint .........................................................................35 
2.2 
Secondary Objectives and Associated Endpoints ..............................................36 
2.3 
Exploratory Objectives and Associated Endpoints .............................................37 
3. 
STUDY DESIGN ...........................................................................................................38 
3.1 
Treatment Regimens .........................................................................................38 
3.2 
Efficacy Assessment ..........................................................................................39 
 
Definition of Responder and Non-Responder .........................................40 
3.3 
Safety Assessment ............................................................................................41 
 
Data Safety & Monitoring Board .............................................................41 


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Clinical Protocol 
 
 
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3.4 
Immunogenicity Assessment .............................................................................42 
3.5 
Virologic Assessment .........................................................................................42 
4. 
SELECTION OF SUBJECTS ........................................................................................42 
4.1 
Inclusion Criteria ................................................................................................42 
4.2 
Exclusion Criteria ...............................................................................................43 
4.3 
Discontinuation/Withdrawal of Study Subjects ...................................................45 
 
Criteria for Discontinuation of Investigational Product .............................45 
 
Criteria for Withdrawal from the Study ....................................................45 
 
Sponsor Notification of Discontinuation/Withdrawal ................................46 
 
Reason for Discontinuation/Withdrawal ..................................................46 
5. 
STUDY TREATMENT ...................................................................................................47 
5.1 
Investigational Products .....................................................................................47 
5.2 
Packaging and Labeling .....................................................................................48 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................48 
5.3 
Handling and Storage ........................................................................................49 
5.4 
Preparation and Dispensing ...............................................................................49 
 
Dispensing of VGX-3100 ........................................................................49 
 
Dispensing and Use of Imiquimod ..........................................................50 
5.5 
Investigational Product Accountability ................................................................50 
5.6 
Return and Destruction of Investigational Product ..............................................50 
5.7 
Use of Investigational Device .............................................................................51 
5.8 
Packaging and Labeling of Investigational Device..............................................51 
5.9 
Investigational Device Accountability .................................................................53 
5.10 
Return of Investigational Devices .......................................................................53 
6. 
STUDY PROCEDURES AND TREATMENTS ..............................................................54 
6.1 
Before Treatment Procedures ............................................................................54 
 
Screening evaluations ............................................................................54 
6.2 
During Treatment Procedures by Visit ................................................................55 
 
Day 0 ......................................................................................................55 
 
8-14 Days Post Dose 1 Phone Call ........................................................56 
 
Week 4 (± 7 days): .................................................................................56 
 
8-14 Days Post Dose 2 Phone Call ........................................................57 
 
Week 12 (± 7 days) ................................................................................57 
 
Week 15 (± 7 days): ...............................................................................58 
 
Week 24 (± 7 days) ................................................................................58 


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Clinical Protocol 
 
 
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Protocol Version: 2.1 
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Week 27 (± 7 days) ................................................................................59 
 
Week 38 Phone Call ...............................................................................59 
 Week 48 (± 7 days) ................................................................................59 
 Week 52 (± 14 days) ..............................................................................60 
 Week 74 (± 14 days) ..............................................................................60 
 Week 78 (± 14 days) ..............................................................................61 
 Week 96 (± 14 days) ..............................................................................61 
 Week 100 (± 14 days) ............................................................................62 
6.3 
Evaluations and Procedures ..............................................................................62 
 
Informed Consent ...................................................................................62 
 
Rescreening of Screen Failures .............................................................62 
 
Assignment of Subject Identification Numbers ........................................62 
 
Safety Evaluations ..................................................................................63 
6.4 
Injection and Electroporation (EP) ......................................................................65 
 
Risks of Treatment Procedures ..............................................................65 
 
Management of Anxiety and Pain Due to Electroporation (EP) 
Procedure ...............................................................................................65 
6.5 
Assessment of Laboratory Abnormalities ...........................................................66 
6.6 
Assessment of Clinical Study Adverse Events ...................................................66 
6.7 
Assessment of Injection Site Reactions .............................................................66 
6.8 
Assessment of Patient Reported Outcomes .......................................................67 
6.9 
Peripheral Blood Immunogenicity Assessments .................................................69 
6.10 
Tissue Immunogenicity Assessment ..................................................................69 
6.11 
HLA Typing ........................................................................................................69 
6.12 
Vulvar HPV Testing ............................................................................................70 
6.13 
Colposcopy, PAP Smears and HPV Testing ......................................................70 
6.14 
Vulvoscopy, Photographs, and Biopsies ............................................................70 
6.15 
Concomitant Medications/Treatments ................................................................71 
6.16 
Restrictions ........................................................................................................71 
 Other Restrictions ...................................................................................72 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ................................72 
7.1 
Safety Parameters .............................................................................................72 
 
Adverse Events ......................................................................................72 
 
Serious Adverse Events .........................................................................73 
 
Clarification of Serious Adverse Events ..................................................73 


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Protocol Version: 2.1 
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Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ..............................................................74 
 
Unexpected Adverse Drug Reactions and Expedited Reporting .............74 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .........................75 
 
Assessing Severity (Intensity) .................................................................75 
 
Casual Relationship of Clinical Material to Adverse Events ....................75 
 
Abnormal Laboratory Value ....................................................................76 
 Post-Trial Reporting Requirements.........................................................76 
 Procedures for Documenting Pregnancy During Study ...........................77 
7.2 
Methods and Timing of Collection of Safety Data ...............................................77 
7.3 
Safety and Toxicity Management .......................................................................78 
 
Adverse Events of Special Interest .........................................................78 
 
Stopping Rules (Criteria for Pausing of Study) .......................................78 
7.4 
Adverse Experience Reporting ...........................................................................79 
 
Trial Reporting Period of Adverse Events ...............................................79 
 
Trial Reporting Period of Serious Adverse Events ..................................79 
 
Notification of Serious Adverse Events ...................................................80 
 
Reporting of Device Related Complaints ................................................80 
7.5 
Trial Discontinuation ..........................................................................................81 
8. 
STATISTICAL ANALYSIS PLAN ..................................................................................81 
8.1 
General Considerations .....................................................................................81 
8.2 
Randomization and blinding ...............................................................................81 
8.3 
Sample Size/Power ............................................................................................82 
8.4 
Analyses Populations .........................................................................................82 
8.5 
Subject Disposition ............................................................................................82 
8.6 
Demographic and Other Baseline Characteristics ..............................................82 
8.7 
Medical History ..................................................................................................83 
8.8 
Prior and Concomitant Medications ...................................................................83 
8.9 
Efficacy Analysis ................................................................................................83 
8.10 
Immunogenicity Analysis ....................................................................................83 
8.11 
Safety analyses .................................................................................................84 
 Adverse events.......................................................................................84 
 Laboratory data ......................................................................................84 
 Vital Signs ..............................................................................................84 
 Physical Examination .............................................................................84 


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 Patient Reported Outcomes ...................................................................85 
 Missing Values .......................................................................................85 
 Interim Analysis ......................................................................................85 
9. 
ETHICS .........................................................................................................................85 
9.1 
Investigator and Sponsor Responsibilities ..........................................................85 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ..................................85 
9.3 
Office of Biotechnology Activities (OBA) ............................................................86 
9.4 
Compliance with Informed Consent Regulations ................................................86 
9.5 
Compliance with IRB/EC Requirements .............................................................86 
9.6 
Compliance with Good Clinical Practice .............................................................86 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 ..........................................................................................................................86 
9.8 
Compliance with Protocol ...................................................................................86 
9.9 
Changes to the Protocol.....................................................................................86 
10. 
DATA COLLECTION, MONITORING AND REPORTING .............................................87 
10.1 
Confidentiality and Privacy .................................................................................87 
10.2 
Source Documents ............................................................................................87 
10.3 
Records Retention .............................................................................................88 
10.4 
Safety and Quality Monitoring ............................................................................88 
 Data & Safety Monitoring Board .............................................................88 
 Pathology Adjudication Committee .........................................................88 
 Clinical Monitoring ..................................................................................88 
11. 
PUBLICATION POLICY ................................................................................................89 
12. 
LIST OF ABBREVIATIONS ..........................................................................................90 
13. 
REFERENCES ..............................................................................................................92 
 
 
 


VGX-3100 
 
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Protocol Version: 2.1 
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CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA™ 2000 Alone or in Combination 
with Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 28 sites in the 
United States (US) and potentially other countries not yet determined 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of 
HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3x) from Day 0 through Week 202 
No. of Subjects 
Approximately 36 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar 
HSIL3 and no evidence of HPV-16/18 at Week 48 in vulvar 
tissue samples (i.e. collected via biopsy or excisional 
treatment)4 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
4 A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study related treatment for vulvar 
HSIL. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, or vulvar 
carcinoma at evaluation, or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a subject who 
received non-study related treatment for vulvar HSIL.   


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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/186 in vulvar tissue samples 
at Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL, no evidence of LSIL 
(VIN1), and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion of subjects with no 
progression7 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of qualifying8 
vulvar lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized pre-
biopsy photographic imaging of 
qualifying8 lesion(s) at Week 48, 74 and 
96 compared to baseline9. Results will 
be classified as: no clinically significant 
lesion resolution (reduction in lesion area 
of 0-25%), partial lesion area resolution 
(>25% and <100% reduction) and 
complete lesion resolution (no visible 
lesion).   
                                                     
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
6 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
7 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
8 A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive and 
have histologically confirmed vulvar HSIL by the PAC at screening. 
9 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   


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7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96 
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 


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Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying8 vulvar lesion(s), in subjects who 
did not have complete lesion resolution at Week 
48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
pre-biopsy photographic imaging of 
qualifying8 lesion(s) at Week 74 and/or 
Week 96 compared to baseline10. 
Results will be classified as: no 
clinically significant lesion resolution 
(reduction in lesion area of 0-25%), 
partial lesion area resolution (>25% and 
<100% reduction) and complete lesion 
resolution (no visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue11  
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-
vulvar anatomic locations without 
surgical intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week 48 compared to baseline 
6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
7. Vulvoscopy, HPV test results (vulvar 
swab and vulvar tissue) and miRNA 
profile (Day 0, Week 15 and 48) in 
conjunction with histologic regression of 
vulvar HSIL at Week 48 visit 
                                                     
10 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   
11Additional assessments may include visualization of PD-L1, Granulysin, perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


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8. Describe patient reported outcomes (PRO) for 
subjects treated with VGX-3100 and VGX-3100 
with imiquimod 
8.  PRO endpoints will be obtained at Day 
0 prior to first dose, Weeks 4, 12, 24 
after dosing, and at Weeks 15, 27, 48, 
52, 74, 96, and 100. 
 
 


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Study Design:  
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered 
with CELLECTRA™ 2000 alone or in combination with imiquimod in adult women with histologically 
confirmed vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled. 
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-
3100 and topical imiquimod treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass 
Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To be eligible for the study, subjects must consent to participate and have a vulvar punch 
biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of the acetowhite 
vulvar lesion(s) at the time of screening. In the case of multifocal disease, the two lesions that 
potentially contain the most advanced disease, as judged by the Investigator, should be chosen for 
biopsy using vulvoscopy and documented using standardized high resolution photography with a 
digital single-lens reflex (SLR) camera. Biopsy slides will be sent to the Pathology Adjudication 
Committee (PAC) by the central laboratory for evaluation prior to enrollment. In order to be eligible for 
enrollment, the PAC must assign the diagnosis of vulvar HSIL based on the biopsy sample(s). 
Subjects must also have a vulvar tissue specimen test positive for HPV genotype 16 and/or 18 to be 
eligible for participation in the study. 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™) (Optum), the 
EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvAr Neoplasia) Clincial 
Trial Version 2.0 and two additional PRO questions assessing quality of life after surgery or biopsy. 
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of 
VGX-3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject's biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with 
the CELLECTRA™ 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of 
VGX-3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic 
and lesion area changes. The first dose will be administered on Day 0, the second at Week 4, the 
third at Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 
48 (Subgroups A and B) will receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator. Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator. Subjects in Subgroup E may receive surgical treatment per the 
judgment of the Investigator. All subjects are scheduled to be followed to Week 100.  
 
 


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Figure 1: Study Visit Schedule 
 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will apply imiquimod 
5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to apply 
imiquimod cream three times per week for 20 weeks (inclusive of administration in the evening of 
VGX-3100 dosing). Subjects unable to tolerate imiquimod treatment may reduce their dosing 
frequency, and will document their use on the imiquimod dosing log provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of 
most advanced disease as judged by the Investigator, and must be approximately 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by vulvoscopy is insufficient evidence to confirm disease 
regression. Disease regression will be based on histopathologic assessment at Week 48, 74, and 96. 
Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), defined as areas 
that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0 and Weeks 4, 12, 27, 
48, 74 and 96. Using standardized high resolution digital photographic imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but from the region of potentially most advanced disease based upon the judgment of 
the Investigator (see Table 2 for Minimally Required Biopsy Procedures). If after evaluation of biopsy 
tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to Week 
74 for vulvoscopy, and biopsy of the same lesion as study start.   
 
 
 


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If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in the qualifying lesion(s) 
size or no change in lesion size from baseline (Subgroups C or D), the Investigator has the option to 
give the subject a 5th dose of VGX-3100 at Week 52, and the subject will continue on study with 
vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator may choose to treat the subject 
with surgical or standard treatment, and the subject will continue on study without further biopsy. A 
qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive 
and have histologically confirmed vulvar HSIL by the PAC at screening. 
 
Figure 2: Decision process at Week 52  
 
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as 
follows: At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Subgroups A or B), the subject will continue to Week 96 for vulvoscopy, and biopsy of the same area 
from the region of potentially most advanced disease based upon the judgment of the Investigator. If 
HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at 
Week 78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and the subject 
will continue on study without further biopsy.   
 
 
 


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Figure 3: Decision Process at Week 78 
 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If there is no vulvar HSIL (Subgroups A or B), no further procedures are 
required. If after evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or 
worsening disease (Subgroup E), the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 
 
 
 


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In the event of worsening disease at any time (i.e., Subgroup E – any increase in lesion area from 
baseline or worsening to cancer), the subject will receive surgical treatment per the Investigator's 
judgment and will continue on study through Week 100 with vulvoscopy, but without further study 
treatment or biopsy. If at any time in the study carcinoma is discovered, subjects will receive surgical 
treatment, and be discontinued from study treatment. The event will be reported as an SAE per 
section 7.1.4.  If wide excision is required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder:Responder and non-responder definitions (Table 3) take 
into account both histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of HSIL. A 
treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no 
evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study 
related treatment for vulvar HSIL. A treatment non-responder is a subject with histologic evidence of 
vulvar HSIL or vulvar carcinoma at evaluation, or a subject with evidence of HPV-16/18 at evaluation, 
or a subject who received non-study related treatment for vulvar HSIL. Any case of histologically 
confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data and 
tissue regression and viral clearance results. The DSMB will be charged with advising the Sponsor if 
there appears to be a safety issue. No formal interim analysis is planned. The following stopping rules 
will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator (PI) for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, PI for the trial, IRB (if applicable) 
and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, PI for 
the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, PI for the trial, IRB (if applicable) 
and the DSMB.  
 


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The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding the outcome 
of any investigation stemming from a Study Pause.  
Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (i.e., Screening and 
Day 0 prior to dosing) and Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize vulvar HPV infection at 
Screening, Weeks 48, 74 and 96. Cervical samples, oropharyngeal rinse, vulvar, vaginal, and intra-
anal tissue swab samples will be obtained to characterize HPV infection at the following time points: 
Day 0 prior to dosing (OP, cervical, vulvar, vaginal and intra-anal), Week 4 (Vulvar only), Week 12 
(Cervical and vulvar)  and Weeks 27, 48, 74 and 96 (OP, vulvar, vaginal and intra-anal). At Weeks 48 
and 96, cervical sample will also be collected.  
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
relationship between subject HLA haplotypes and regression.  


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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above  
3. 
Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. 
Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated date of first 
dose of study drug and have histologically confirmed vulvar HSIL by the Pathology Adjudication 
Committee at screening; 
5. 
Must be judged by the Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
6. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after an approximately 4 mm screening biopsy;  
7. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 3 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system;                                                                                
iv) Male partner sterilization at least 6 months prior to the female subject's entry into the 
study, and this male is the sole partner for that subject. 
9. 
Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the Investigator. 


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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing medical care and/or 
treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical care and/or 
treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing medical care 
and/or treatment for CIN; 
5) Biopsy-proven differentiated VIN; 
6) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
7) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
8) Treatment for genital warts within 4 weeks prior to screening; 
9) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
10) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
11) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last 
dose of investigational product; 
12) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the Investigator; 
13) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
14) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
15) Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of each study 
dose; 
17) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the Investigator; 
18) Current or history of clinically significant, medically unstable disease which, in the judgment of the 
Investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results  
a)   Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher congestive   
  heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision; 
 
 


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c) 
Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) 
that would contraindicate IM injections within 2 weeks of Day 0; 
d) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) 
Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19) Participation in an interventional study with an investigational compound or device within 4 weeks 
of signing informed consent (participation in an observational study is permitted); 
20) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) (unless 
deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
21) Vulnerable populations:  
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, would interfere 
with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22) 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.  


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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events  
 
 
 
 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days) 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
Xb 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
Xe 
 
Xf 
 
Xe 
 
Xe 
 
Xe 
 
HLA testing g 
       X 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar swabs 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cervical cytology, ThinPrep®  h 
X 
X 
 
 
X 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject VGX-3100 +EP lm 
X 
X 
X 
X 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
Review PD o 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
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b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared). Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 45 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. One additional 8.5 mL yellow 
(ACD) tube to be collected at Day 0, Week 15 and 48 for microRNA analysis. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27.   
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrep® cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected. Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the Investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j  Photography of the acetowhite stained qualifying lesion(s) must be performed prior to and after biopsy, 
and at all vulvoscopy examinations. If a pre-biopsy digital photograph is not available for a historical 
biopsy sample at screening, a post biopsy photo will be sufficient. Additionally, standardized high 
resolution digital photographic imaging should be obtained during examinations of the vagina if lesions 
are identified, for documentation.  
k Tissue specimen from all excised tissue must be reviewed by the PAC and residual vulvar tissue from 
entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) must be sent to the 
central pathology laboratory for HPV testing.  
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod. 
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36v2™, EQ-5D-5L, WOMAN-PRO) plus two additional questions will be assessed as 
described in Section 6.8.     
 
 
 


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1. 
INTRODUCTION  
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause 
cancer, and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the 
most significant amongst high-risk types since they are responsible for most HPV-
caused cancers [1].   
HPV-16/18 is involved in about 83% of HPV-associated vulvar HSIL cases in the U.S. [1] 
and about 72% in Europe [2]. Persistent infection with one or more oncogenic (high-risk) 
HPV genotypes can lead to the development of precancerous, histologic high grade 
squamous intraepithelial lesions (HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS).  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 6,020 new cases and 1,150 
attributable deaths annually for year 2017 in the United States [4] and about 9,776 new 
cases in 2015 in Europe [5]. Vulvar cancers consist largely of squamous cell carcinomas 
and accounts for approximately 5% of all female genital malignancies [6]. Differentiated 
VIN, which is typically not caused by HPV infection and is more typically found in older 
women, is more likely to progress to cancer more rapidly than HPV-associated-VIN. The 
five year overall relative survival for vulvar cancer in the U.S. is 72.1% [4]. Recurrent 
vulvar cancer occurs in an average of 24% of cases after primary treatment, after 
surgery with or without radiation [7].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia. The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance 
of pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [8].    


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In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) 
replaced the three grade classification system with the current single grade classification 
for which only high grade VIN (2/3) is classified as VIN [9]. In 2012, the Lower 
Anogenital Squamous Terminology (LAST) Standardization Project for HPV-associated 
lesions applied the term high grade squamous intraepithelial lesion (HSIL) to encompass 
high grade dysplasia [10]. Therefore, for the purpose of this study, the term vulvar HSIL 
will be used, whichencompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to 
encompass what was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [11]. Over time, typically years, vulvar HSIL can progress to 
invasive cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group 
and median 13.8 years in another group [12], and from VIN3 patients, mean = 2.5 years, 
range: 4 – 216 months [13].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity 
against vulvar HSIL and have not achieved universal uptake, leaving a population of 
susceptible and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to 
visual inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for 
vulvar HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, 
often requiring multiple, repeat treatments. Progression to vulvar cancer following 
current vulvar HSIL treatments can also occur within 1 year of treatment and for up to 20 
years post treatment. The current treatment options for vulvar HSIL are surgical 
excision, laser ablation, and off-label medical therapy. The rate of HPV-associated 
vulvar HSIL recurrence after surgical treatment is high; post-treatment recurrence rates 
are as high as 45% at three years post-treatment with all currently available treatment 
regimens [14, 15].   
Wide local excision is the 'preferred initial intervention' by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation. Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues 
with body image and sexual dysfunction. Medical therapies have been investigated as a 
means to avoid these negative outcomes. Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food 
and Drug Administration for this indication. Inconsistent treatment efficacy results have 
been shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 


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of recurrence is slightly higher compared to wide local excision. Laser treatment of 
vulvar HSIL requires destruction of cells through the entire thickness of the epithelium 
including hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation 
should extend through the dermis. Post-treatment recurrence rates exceed 30% (for all 
treatment regimens), and is higher with positive excision margins [16]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low 
rate of spontaneous resolution. According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is 
suspected (even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is 
wide local excision (i.e. surgery) [17]. When occult invasion is not a concern, vulvar HSIL 
can be treated with excision, laser ablation, or topical imiquimod as an off-label medical 
therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [16]. Therefore, many patients have a fear 
of recurrence and progression to cancer [18].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks. 
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid the use of toilet paper and to rinse with warm water 
instead. During recovery, common effects include pain in urinating and wiping, soreness, 
difficulty sitting, and feeling tired [19]. In the first week after hospital discharge, common 
patient-reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [20].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-
being [19]. The symptoms and signs of vulvar HSIL can be moderate to severe and 
include painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating 
[20]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than 
age-matched healthy women. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor's office all the time [19]. 


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 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid later development of HPV-
associated vulvar HSIL and subsequent vulvar cancer. The US-licensed prophylactic 
HPV vaccines are indicated for girls and women ages 9 through 26 years for Gardasil® 
and Gardasil®9 (Merck & Co. Inc.), and ages 9 through 25 years for Cervarix® 
(GlaxoSmithKline). The early portions of these age ranges are generally before sexual 
debut and thus can allow immunologic protection against the anticipated earliest normal 
exposures to HPV infection. HPV prophylactic vaccination is highly effective and safe, 
and routine vaccination is recommended for females in the United States starting at age 
11 or 12 years [22]. However, these prophylactic vaccines have no therapeutic effect 
upon existing HPV infection or existing HPV-related intraepithelial neoplasia [23]. 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan will be used in this study to address the risk of a potential 
delay in treatment of vulvar HSIL. The feasibility of this approach was demonstrated in 
the Phase 2b study of cervical HSIL. Given that vulvar disease progresses slowly to 
vulvar cancer if untreated, the proposed enhanced monitoring plan is expected to 
maintain the safety of subjects in this study. First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study Investigators. Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, 
by two independent expert pathologists from the PAC (see Section 10.4.2). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
is specifically excluded from study entry. By contrast, HPV-associated vulvar HSIL does 
not progress rapidly, typically taking years to manifest and progress, making enhanced 
monitoring feasible [24].   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.1). Colposcopy will also be 
performed at Day 0 and during the study given that concurrent disease in the lower 
genital tract can occur. A Data Safety Monitoring Board will be utilized to review subject 
safety data and advise on any study-level safety concerns. Investigators always have 
the option of performing ad hoc vulvar biopsies to rule out suspected disease 
progression. Additional treatment (e.g., additional excision, ablation, or medical therapy) 
may be carried out, if deemed necessary according to Investigator judgment. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA™ device represent an integrated 
investigational product designed as a non-surgical treatment of HPV-16/18-related 
cervical HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Further information about VGX-3100 is provided in the Investigator's Brochure. 


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 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP 
is a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [25, 26]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 
10 to 100 fold [27, 28]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as 
shown by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [29].  
This study will use the CELLECTRA™ 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no 
significant safety issues identified. Further information about the CELLECTRA™ 2000 
device can be found in the Investigator's Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device. Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 
250 mg of the cream, equivalent to 12.5 mg of imiquimod. The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod. The overall aim is to determine if treatment with VGX-3100 could allow 
women with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of 
concept that VGX-3100 can induce resolution of both HPV-associated dysplastic lesions 
and the underlying HPV-16/18 infection was shown in a Phase 2b study of cervical 
intraepithelial neoplasia (CIN). The similar underlying pathogenic mechanisms between 
cervical and vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could 
be a non-surgical therapeutic option for the treatment of vulvar HSIL, which is a 
significantly under met medical condition. A VGX-3100 with imiquimod-administration 
arm is also included, given the prevalent use of imiquimod as a topical medical treatment 
of vulvar lesions, to investigate if a more robust immune response is achieved with VGX-
3100, to potentially increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 


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responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [30].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Therefore, imiquimod may be able to be used 
synergistically with VGX-3100. 
Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG). Published regimens include three times 
weekly application to affected areas for 12 – 20 weeks, with colposcopic assessment at 
4-6 week intervals during treatment [17].  
The current study will include an arm to explore whether the efficacy of VGX-3100 is able 
to be enhanced by concomitant treatment with Imiquimod.     
 INCLUSION OF WOMAN-PRO, CLINICAL TRIAL VERSION 2.0  
The original WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) was developed by 
Beate Senn and colleagues [20,31,32] for use following post-surgical intervention. 
Development of the tool was aligned with the FDA PRO Guidance [33]and included a 
review of the literature as well as direct patient and expert input. Preliminary 
measurement properties were assessed in a cross-sectional study. However, despite 
rigorous development and promising initial measurement properties, gaps in the 
development and psychometric evaluation exist. To address these gaps, Inovio and 
collaborators initiated a small qualitative study to confirm the content validity of the tool 
and support a cross-cultural adaptation of the measure for use in a clinical trial setting of 
US English and US Spanish speaking subjects. The results of  this research is the 
Clinical Trial of the WOMAN-PRO (2.0) which is utilized in this study. 
 
The WOMAN-PRO Clinical Trial Version 2.0 is a 31 item self-completed patient reported 
outcome measure designed to assess both physical and psychosocial impacts of VIN.  
The physical domain is comprised of 15 lesion-related symptoms and includes 5 
additional items to measure impact in daily life. Psychosocial constructs are assessment 
through 11 items that address feelings, thoughts and limitations. Each item is scored 
using a 4-point Likert scale with higher scores indicating greater difficulty or severity. The 
recall period is the past week.Details are included in Section 6.8.  
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 


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reported at the application site [34]. The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity. In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding, infection, or damage to surrounding 
structures such as the clitoris, urethra, or anus. The other potential benefit is that the 
response to VGX-3100 is systemic and may clear the underlying HPV infection, which is 
the root cause of vulvar HSIL. Consequently, there is the potential to reduce the risk of 
recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL associated with HPV-16 and/or HPV-18 (HPV-
16/18), will result in a higher percentage of women with regression of HSIL of the vulva 
based on histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-
16/18 from vulvar tissue compared with historical control. 
 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional 
treatment).   


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2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in 
combination with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL5 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/186 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL, no evidence of vulvar LSIL 
(VIN1), and no evidence of condyloma on 
histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression7 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of the qualifying8 vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying8 lesion (s) at Week 
48, 74 and 96 compared to baseline9. Results 
will be classified as: no clinically significant 
lesion resolution (reduction in lesion size of 0-
25%), partial lesion area resolution (>25% 
and <100% reduction), and complete lesion 
resolution (no visible lesion).   
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes at 
baseline and Weeks 15, 27, 48, 74 and 96 
visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying8 vulvar lesion(s), in subjects 
without a complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying8 lesion (s) at Week 
74 and/or Week 96 compared to baseline10. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to 
VGX-3100, and VGX-3100 with imiquimod, 
as measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue11 
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-vulvar 
anatomic locations without surgical 
intervention (inclusive of cervix, oropharynx, 
vagina and intra-anus) at Week 48 compared 
to baseline 
6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV 
testing results with Week 48 histologic 
regression 
7. Vulvoscopy, HPV test results (vulvar swab 
and vulvar tissue) and miRNA profile (Day 
0, Week 15 and 48) in conjunction with 
histologic regression of vulvar HSIL at Week 
48 visit 
8. Describe patient reported outcomes (PRO) 
for subjects treated with VGX-3100 and 
VGX-3100 with imiquimod 
8. PRO endpoints will be obtained at Day 0 
prior to first dose, Weeks 4, 12, 24 after 
dosing, and at Weeks 15, 27, 48, 52, 74, 96 
and 100. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA™ 2000 alone or in combination 
with imiquimod in adult women with histologically confirmed vulvar HSIL associated with 
HPV-16/18. Approximately 36 subjects will be enrolled. Twenty-four subjects will receive 
VGX-3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod 
treatment.  
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions 
at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age 
category (<45 years vs. ≥45 years). 
To be eligible for the study, subjects must sign consent to participate and have a vulvar 
punch biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of 
the acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, 
the two lesions that potentially contain the most advanced disease, as judged by the 
Investigator, should be chosen for biopsy using vulvoscopy and documented using 
standardized high resolution photography with a digital single-lens reflex (SLR) camera 
on the case report form. Biopsy slides will be sent to a PAC for evaluation prior to 
enrollment. In order to be eligible for enrollment, the PAC must assign the diagnosis of 
vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar specimen 
test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study. 
To assess quality of life and related impacts on subjects, PRO instruments will be 
provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-
5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvar Neoplasia) 
Clinical Trial Version 2.0 and two additional PRO questions assessing quality of life after 
surgery or biopsy. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 
mg of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-
16/18 status and all other eligibility criteria but no more than 10 weeks following 
collection of the subject's biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid preferred site, 
or the anterolateral quadriceps as an alternate site) followed immediately by EP with the 
CELLECTRA™ 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes. The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose at 
Week 52 per the judgment of the Investigator. Subjects with HSIL at Week 74, who have 


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a reduction in lesion size or no increase in lesion size from baseline (Subgroups C or D), 
may receive a sixth dose at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgment of the Investigator. All 
subjects will complete the study at Week 100. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod arm will 
apply imiquimod 5% cream to the vulvar lesion beginning in the evening on Day 0, and 
will continue to apply treatment three times per week for 20 weeks (inclusive of 
administration in the evening of VGX-3100 dosing). Subjects unable to tolerate 
imiquimod treatment may reduce their dosing frequency, and will document their use on 
the imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital photographic imaging, vulvar lesion(s) will also be 
quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced disease as judged by the Investigator, and must be  approximately 4 mm in 
length. Visible lesion must remain after screening biopsy to ensure measurement on 
study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the qualifying lesion as study start from the region of potentially most 
advanced disease based upon the judgment of the Investigator (see Table 2 for 
Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC 
there is no evidence of HSIL (Figure 2, Subgroups A or B), the subject will continue to 
Week 74 for vulvoscopy, and biopsy of the same qualifying lesion as study start from the 
region of potentially most advanced disease based upon the judgment of the 
Investigator. 
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion 
size or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the 
Investigator has the option to give the subject a 5th dose of VGX-3100 at Week 52, and 
the subject will continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and 
the subject will continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as at study start Investigator(see Table 2). If after 
evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), 
the subject will continue to Week 96 for vulvoscopy and biopsy of the same lesion as at 
study start. InvestigatorIf HSIL remains but there is a reduction in lesion size or no 
increase in lesion size from baseline (Subgroups C or D), the Investigator has the option 
to give the subject a 6th dose of VGX-3100 at Week 78, and the subject will continue on 


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study with vulvoscopy and biopsy at Week 96. Alternatively, the Investigator may choose 
to treat the subject with surgical or standard treatment, and the subject will continue on 
study without further biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but from the region of potentially most 
advanced disease based upon the judgment of the Investigator. (see Table 2). If there is 
no vulvar HSIL (Subgroups A or B), no further procedures are required. If after 
evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or 
worsening disease (Subgroup E), the subject will receive surgical or other standard 
treatment. 
In the event of worsening disease (i.e., Subgroup E - any increase in lesion area from 
baseline or worsening to cancer), the subject will receive surgical treatment per the 
Investigator's judgment and will continue on study through Week 100 with vulvoscopy, 
but without further study treatment or biopsy. For a finding of carcinoma, subjects will 
receive surgical treatment, and be discontinued from study treatment. The event will be 
reported as an SAE per section 7.1.4. If wide excision is required, the sample obtained 
will be sent to the PAC for evaluation.  
 
Table 2:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator. 
Acetowhite Lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator.  
Multiple acetowhite lesions 
Vulvar punch biopsies and lesion photography; biopsy should 
be conducted of the same qualifying lesions as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator. 
 
  
 
 DEFINITION OF RESPONDER AND NON-RESPONDER 
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive any non-study related treatment for vulvar HSIL. A treatment non-responder is a 
subject with histologic evidence of vulvar HSIL or vulvar carcinoma at evaluation, or a 
subject with evidence of HPV-16/18 at evaluation, or a subject who received non-study 
related treatment for vulvar HSIL. Any case of histologically confirmed progression is 
considered a non-responder. Progression is defined as advancement to carcinoma by 
histology according to the PAC.  


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Responder and non-responder definitions (Table 3) take into account both 
histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of 
HSIL. 
Table 3: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
 
 
Subject with histologic evidence of vulvar HSIL or  
vulvar carcinoma at evaluation 
  
OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related treatment 
for vulvar HSIL 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight. 
The DSMB will meet quarterly to review safety data and regression/clearance results. 
The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue. No formal interim analysis is planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, PI for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, PI for the 
trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse 
event, assessed as related to study treatment, further enrollment and study 


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treatment will be halted immediately until a thorough investigation has been 
conducted by the Medical Monitor, PI for the trial, and the DSMB. 
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, PI for the 
trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (i.e., Screening and Day 0 prior to dosing) and Weeks 
15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize vulvar HPV infection at Screening, 
Weeks 48, 74 and 96. Cervical samples, oropharyngeal (OP) rinse samples, vulvar, 
vaginal, and intra-anal tissue swab samples will be obtained to characterize HPV 
infection at the following time points: Day 0 prior to dosing (OP, cervical, vulvar, vaginal 
and intra-anal), Week 4 (Vulvar only), Week 12 (Cervical and Vulvar) and Weeks 27, 48, 
74 and 96 (OP, vulvar, vaginal and intra-anal only). At week 48 and 96, a cervical 
sample will also be collected.  
 
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated 
date of first dose of study drug and have confirmed histologically confirmed vulvar HSIL 
by the Pathology Adjudication Committee at screening; 
5. Must be judged by the Investigator to be an appropriate candidate for the protocol-
specified procedure (i.e. excision or biopsy) required at Week 48; 
6. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 


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adequate size to ensure that a visible lesion remains after an approximately 4 mm 
screening biopsy;  
7. Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive 
method with failure rate of less than 1% per year when used consistently and 
correctly from screening until 6 months following the last dose of investigational 
product. Acceptable methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject's preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject's entry 
into the study, and this male is the sole partner for that subject. 
9. Normal screening electrocardiogram (ECG) or screening ECG with no clinically 
significant findings as judged by the Investigator. 
 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical 
care and/or treatment for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
7. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains 
after biopsy; 
8. Treatment for genital warts within 4 weeks prior to screening; 
9. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 


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4 weeks prior to screening; 
10. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; 
11. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
12. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; 
13. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
14. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
15. Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks 
of each study dose; 
17. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
18. Current or history of clinically significant, medically unstable disease which, in the 
judgment of the Investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results  
a) Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher 
congestive heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the 
exception of superficial skin cancers that only require local excision; 
c) Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of Day 
0; 
d) History of seizures unless seizure free for 5 years with the use of one or 
fewer antiepileptic agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or 


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<90 mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 
bpm at Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
20. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening 
arrhythmia) (unless deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site 
(i.e. electroporation area);  
21. Vulnerable populations: 
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, 
would interfere with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study 
treatment/EP but will be encouraged to continue follow-up safety assessment through 
study discharge and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw 
from study participation at any time. A subject may be withdrawn at any time at the 


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discretion of the Investigator for any maternal obstetrical or medical complications after 
consultation with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report 
form (eCRF) and the subject's source document. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site 
should also counsel the subject on the importance of maintaining the assigned visit 
schedule for follow-up and treatment of VIN, and ascertain whether or not the subject 
wishes to and/or should continue in the study based on previous noncompliance. In 
cases where the subject does not return for the rescheduled visit or cannot be reached 
to reschedule the missed visit, the site should make every effort to regain contact with 
the subject (3 telephone calls to the subject should be made and if that fails, then a 
certified letter is sent to the subject's last known mailing address) so that they can be 
considered withdrawn from the study for disposition purposes. These contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will she be considered to have withdrawn from the 
study with a primary reason of "Lost to Follow-up". For all other subjects withdrawing 
from the study, an alternative reason for discontinuation should be recorded in the 
eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). 
At a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100). A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or study coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an AE. If a subject discontinues from 
the study or is withdrawn from the study prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. The 
Investigator will make every effort to have all scheduled immune assessment blood 
samples collected as indicated in the Schedule of Events in the synopsis, Table 1. Any 
AEs and/or SAEs present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in section 7.1. 
 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 


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 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the Investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs 
regardless of relation to study drug. 
 
Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from 
further participation in the study in the absence of an Investigator-determined 
medical need to withdraw. If the subject gave a reason for withdrawal, it must be 
recorded on the eCRF. This reason does not allow for further data collection and 
should not be selected if follow-up data collection of this subject is anticipated by 
the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study. 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation 
should be discussed with the Sponsor’s Medical Monitor prior to discontinuation 
of study treatments or study withdrawal. 
 
Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter 
sent by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon™) technology. The VGX-
3100 formulation to be used in this study is described in Table 4 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum. There are 24 single-use packets of imiquimod in one box. The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older. Although it is not approved by the US Food and 
Drug Administration for the treatment of vulvar HSIL, imiquimod is currently recommended 
as a non-surgical, off-label treatment option for vulvar dysplasia by the American College 
of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 


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Table 4. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  The actual product label names the product as 
VGX-3100X; the "X" designation was included to differentiate the current buffer 
formulation from a previous formulation of VGX-3100 in water. Imiquimod Cream, 5% will 
have both the original manufacturer's label on individual packets and the back of the 
carton, and an investigational label on the front of the carton. The labels will contain, at 
minimum, the information shown in Figure 6.   
 
 
Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  


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Figure 6. Example labels for imiquimod 
 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: Imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Ophthalmic Use. 
Keep out of reach of children. This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer's instructions. Avoid freezing.    
5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. 
The product must be used within 4 hours of removal from the refrigerator. All material 
removed from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 


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 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations. Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks. Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water. Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. In the event 
that Imiquimod is not tolerated at 3 times per week, alternative administration 
approaches must be discussed and approved by the medical monitor. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period. The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 
5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. 
to be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 


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procedures, and appropriate records of the disposal have been documented. The 
unused IP can only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the CELLECTRA™ 2000 device are located in the User 
Manual. Each clinical site will receive training for the use of the CELLECTRA™ 2000 
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 
The CELLECTRA™ 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA™ 2000 User 
Manual describes all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings, and precautions. Each CELLECTRA™ 2000 Pulse 
Generator has a unique serial number, and each CELLECTRA™ 2000 Applicator has a 
unique serial number. Each CELLECTRA™ 2000 Array has a Lot Number, Manufacture 
Date, and Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to 
successfully completing device training from sponsor personnel. 
5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 5 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers 
(as applicable) is included at the time of manufacture and may vary from these 
examples. The information found on the actual device labels should always be used to 
manage, track and record investigational product accountability during study conduct. 
 


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Table 5. Example Labels for the CELLECTRA™ 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA™ 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA™ 
2000 5P 
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA™ IM 
Array 
 
REF: M01-002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. 
This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA™ 2000 IM Applicator is intended to be used multiple times on the 
same subject and then disposed after final use in accordance with accepted medical 
practice and any applicable local, state, and federal laws and regulations. Once the IM 
applicator is assigned to a subject, it may NOT be used on another subject. The used 
sterile disposable array attachment must be discarded after use in accordance with 
institutional policy regarding disposal of sharp needles/instruments. 
5.10 RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original 
containers. The return of all product identified above should be arranged by the 
responsible Study Monitor. 
If product is to be destroyed on site, it is the Investigator's responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted 


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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation. The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information 
collected prior to consenting and before any additional study specific procedures are 
performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate 
safety concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the 
samples sent to the central pathology lab for review by the PAC to assess eligibility. 
There will be a maximum allowable window of 10 weeks from the date of collection of 
the qualifying biopsy sample(s) (i.e. samples reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, an additional biopsy sample should be collected 
during screening following the consent of the subject. The 10 week screening window 
begins upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose vulvar specimens also test positive for other 
HPV genotypes are not excluded as long as they have a positive result for HPV-16 
and/or HPV-18.  
The assessments during the screening period will determine the subjects'' eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, and 
ECG which must be performed within 45 days prior to Day 0. All screening assessment 
values must be reviewed prior to study treatment. 
 
Signed informed consent  
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG within 45 days prior to Day 0 
 
Baseline laboratory evaluations (includes complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine 
aminotransferase [ALT], creatine phosphokinase [CPK], and urinalysis) to be 
performed within 45 days prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be 
performed once) 
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photograph of the vulvar lesion(s) must be collected prior to and after biopsy at 
screening 
 
If a historical biopsy sample is used to determine eligibility at screening and a 
pre-biopsy photograph is not available, a post biopsy photo will be sufficient.  
 
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC.  
 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment. Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 
 
Review of concomitant medications and adverse events 


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 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 WEEK 4 (± 7 DAYS) 
The following study evaluations will be performed at Week 4 prior to study treatment  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 


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 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvar swab 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after 
study treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 (± 7 DAYS) 
The following study evaluations will be performed at Week 12 prior to study treatment:  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history 
 
Vulvar swab 
 
Vulvoscopy  


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 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 (± 7 DAYS) 
The following study evaluations will be performed at Week 15: 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay including miRNA profile 
 WEEK 24 (± 7 DAYS) 
The following study evaluations will be performed at Week 24 prior to study treatment: 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 


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 WEEK 27 (± 7 DAYS) 
The following study evaluations will be performed at Week 27: 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
  WEEK 38 PHONE CALL 
 
Review concomitant medications and adverse events 
  WEEK 48 (± 7 DAYS) 
The following study evaluations will be performed at Week 48: 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 


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 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 PATIENT REPORTED OUTCOMESWEEK 52 (± 14 DAYS) 
Subjects will have a Week 52 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
  WEEK 74 (± 14 DAYS) 
The following study evaluations will be performed at Week 74: 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 


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  WEEK 78 (± 14 DAYS) 
Subjects will have a Week 78 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 
  WEEK 96 (± 14 DAYS) 
The following study evaluations will be performed at Week 96: 
 
Review of concomitant medications and adverse events 
 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabsVulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 


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  WEEK 100 (± 14 DAYS) 
The following study evaluations will be performed at Week 100: 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, 
study objectives, potential benefits and risks, discomforts/inconveniences, and the 
subject’s rights and responsibilities. The subject is then requested to sign and date the 
ICF. A copy of the signed informed consent documentation must be provided to the 
subject. The qualified study personnel will document the process of obtaining informed 
consent within the source record. Signed ICFs are maintained in the subject's source 
records and must be accessible for verification at any time. 
 RESCREENING OF SCREEN FAILURES 
 
Subjects who sign the informed consent and are assigned a subject identification     
 
number (SID) but do not meet the eligibility criteria or fall outside of the screening 
 
window will be considered screen failures. If the Investigator believes rescreening is 
 
warranted, the Investigator must contact the medical monitor to discuss.  
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique SID, which identifies the subject 
for all study-related procedures. SIDs are a combination of a up to two alpha letters 
study code, two alpha letter Country code, two digit site number, plus 3-digit subject 
number starting with 001 (e.g., VNUS01001). Once assigned, SIDs cannot be reused for 
any reason. Information regarding the SID and screen date must be documented on a 
Screening log/system and in the Interactive Response Technology (IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated 
allocation schedule.  


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 SAFETY EVALUATIONS 
6.3.4.1 
PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100). It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems. All assessments not completed should be marked as not 
done.  
A targeted physical assessment will be performed at other visits as determined 
by the Investigator or directed per subject complaints. 
6.3.4.2 
VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 
 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.4.3 
WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.4.4 
MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be 
obtained at screening. All relevant (as judged by the Investigator) past and 
present conditions, as well as prior surgical procedures will be recorded for the 
main body systems.  
6.3.4.5 
SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, 
history of prior cervical dysplasia, and pregnancy history will be obtained at 
Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to 
document any change from screening. 


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6.3.4.6 
LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 
6.3.4.7 
PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.4.8 
ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has 
been in a supine position for 10 to 15 minutes. The ECG should include 
measurements of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST 
segment, T wave as well as an Investigator assessment of whether the ECG is 
normal or abnormal (automated interpretations of ECG should not be used). 
Abnormal ECGs should be interpreted as "clinically significant (CS)" or "not 
clinically significant (NCS)" by the Investigator. 
6.3.4.9 
POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after 
the study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 


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 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.4.10 
IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 2000. Study treatment plus EP 
must not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is 
implanted metal within the same limb. Any device implanted in the chest (e.g., cardiac 
pacemaker, defibrillator or retained leads following device removal) excludes the use of 
the deltoid muscle on the same side of the body. The timing of the initial dose will be 
designated Day 0 with the subsequent doses scheduled for administration at Weeks 4, 
12, 24, and at Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 
RISKS OF TREATMENT PROCEDURES TO VGX-3100 
No serious related adverse events to VGX-3100 have been observed in the clinical trial 
experience to date. A summary of potential risks of IM Administration followed by EP 
with CELLECTRA™ can be found in the VGX-3100 + Imiquimod Investigator's Brochure.   
6.4.1.2 
RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
Adverse events reported in clinical trials with imiquimod cream, 5% for external genital 
warts can be found in the imiquimod product label [35], and in the VGX-3100 + 
Imiquimod Investigator's Brochure. 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION 
(EP) PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 


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approximately 1.5 cm diameter amount will be applied with occlusion to the site of 
injection ~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who 
receive a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours 
after receiving medication and should have arranged transportation to depart the study 
site. 
Subjects may be offered an analgesic (e.g. acetaminophen, ibuprofen, ketorolac) before 
or after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, acetaminophen, 
ibuprofen, ketorolac or a mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.4.6.   
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 
minutes after each study treatment. Subjects will be advised to record local and systemic 
AEs for 7 days after each study treatment on a PD which will be reviewed with study 
personnel at 8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject's CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale: 
 


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Table 6. 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" 
*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 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes 
(PRO) instruments will be provided. Administration of PRO instruments will be performed 
according to the validated or otherwise developed procedures and instructions of each 
respective instrument. The following PRO questionnaires will be used: 
1. WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) Clinical Trial Version – 2.0 
(Beate Senn; version modified by Inovio Pharmaceuticals and RTI Health Solutions): is a 
31 item self-completed patient reported outcome measure designed to assess both 
physical and psychosocial impacts of VIN. The recall period is the past week.[20]. 
The WOMAN-PRO will be administered on paper only and should be the first PRO 
instrument administrated (i.e. before all other PROs) at each of the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 


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 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
2. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six 
items covering eight domains (Physical functioning, Role limitations due to physical 
problems, Bodily pain, General health, Vitality, Social functioning, Role limitations due to 
emotional problems, and Mental health) [36]. SF-36v2™ will be administered at the 
following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
3. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual 
activity, Pain/discomfort, Anxiety/depression, and Global health status) [37, 38] and will 
be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
4. Additional Global PRO Questions – regarding quality of life after surgery or biopsy. 
These two questions will be administered on paper at Week 52 only. 


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6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 
antibody response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune 
activity may occur via the application of the Interferon-γ enzyme-linked immunosorbent 
spot (IFN-γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
Profiling of miRNA will occur using plasma obtained at Day 0, Week 15 and 48.  
Assessment of Day 0 samples alone will explore predictive algorithms for response to 
treatment with VGX-3100 prior to dosing. Assessment of Week 15 and 48 samples will 
be done as a comparison against Day 0, in order to look for changes in miRNA profiles 
that occur once dosing with VGX-3100 has begun, to explore construction of an 
algorithm to predict treatment success with VGX-3100. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after HPV genotyping 
and histologic diagnoses have been rendered at Screening, Weeks 48, 74 and 96, then 
unstained slides and/or the relevant paraffin blocks may be collected for assessment of 
pro-inflammatory and immunosuppressive elements in tissue, where feasible. 
Assessment of markers may include, but are not limited to, CD8+ and FoxP3+ infiltrating 
cells as well as assessment of cell death via Cleaved Caspase 3 assessment. Additional 
assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-
L1 in cervical tissue as sample allows. Markers listed here may change as new relevant 
information becomes available. 
6.11 HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 


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6.12 VULVAR HPV TESTING 
At Screening, Weeks 48, 74, and 96, a vulvar punch biopsy sample of approximately      
4 mm will be obtained and sent to a central laboratory for HPV genotyping by PCR. In 
the case of multifocal disease, a vulvar biopsy of approximately 4 mm will be obtained 
from two lesions that potentially contain the most advanced disease as judged by the 
Investigator. The subject will be requested to abstain from sexual activity and refrain 
from use of douching to eliminate potential interference with the results of HPV testing. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
vulvar punch biopsy to eliminate potential interference with the results of HPV testing. 
6.13 COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Day 0 and at Week 96 for all subjects. 
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep® test kits at Day 0, Weeks 12, 48 and 96, 
and read in a central laboratory. HPV PCR will be performed on the ThinPrep® 
specimen. At each of these visits, menstrual cycle status & recent gynecologic history 
will be collected. If the Pap smear result suggests progression to cancer the Investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep® samples to eliminate potential interference with the results of HPV testing. 
6.14 VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL 
confirmed by the PAC. Subjects will undergo vulvoscopy to identify the lesion(s). Interval 
vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96. Vulvoscopic 
visualization of a normal appearing vulva is insufficient evidence to confirm disease 
regression. An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. 
Digital photographs of the vulva will be captured after application of acetic acid to 
document the clinical findings. If a biopsy or surgical excision is performed, images of 
the vulva should be collected before and after the procedure. Each site will be instructed 
on 1) the technique for capturing the proper images using a standard approach, and 2) 
the process for uploading the images to a secure server.   
In the case of multifocal disease, the two lesions that potentially contain the most 
advanced disease as judged by the Investigator and which is of adequate size to ensure 
that a visible lesion remains after punch biopsy should be chosen for vulvar biopsy and 
documented using photography.     
Biopsies should not be performed at any visit other than at entry (screening), Week 48, 
Week 74 or Week 96 unless the PI suspects disease progression. All biopsy samples 
must be sent to the PAC for review. Investigator guidelines for managing the findings of 


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unscheduled biopsies for suspected disease progression are described in Table 7.  
Consult the Medical Monitor for any planned departures from these guidelines. 
Table 7:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 
Subject safety is paramount in this study. Therefore, if at any time the Investigator 
suspects disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over 
the Schedule of Events on Table 1.  Histologic samples and photographic 
documentation should be obtained for these cases.  
6.15 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to 
screening biopsy date of eligible subjects must be recorded on the CRF. Actual or 
estimated start and stop dates must be provided. Medical procedures performed within 8 
weeks prior to screening biopsy date of eligible subjects that do not affect subject's 
eligibility for participation and during the study (including over the counter or herbal), will 
be recorded on the CRFs. This information will be obtained from the subject and 
abstracted from any available medical records. The indication for the medication, dose, 
and dose regimen will be documented. Medication that is considered necessary for the 
subject's safety and well-being may be given per Investigator discretion and recorded in 
the appropriate sections of the CRF. 
6.16 RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic 
corticosteroids are allowed) 
 
Disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at 
screening and throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
Blood thinners/Anticoagulants within 2 weeks of any study treatment 


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 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
Investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1). Lapses in contraceptive use should be reported to Investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep® samples.  
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and 
unsolicited AEs will be monitored and reported on an AE CRF, including the event's 
seriousness, severity, action taken, and relationship to investigational product(s). AEs 
should be followed until resolution or stable and the outcome will be documented on the 
appropriate CRF. All AEs should be recorded in standard medical terminology rather 
than the subject's own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.11 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the 
duration of the study, including the follow-up off study drug period will be 
recorded as an AE. 
 
Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 


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 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit 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 informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
 SERIOUS ADVERSE EVENTS 
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; 
 
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 (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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, 2) blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, 3) the development of drug dependency or drug abuse or 4) the 
development of a malignancy; 
 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. 


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 
Inpatient hospitalization means that 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 nor does it include full day or overnight stays in observation status. 
 
The Investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 
Serious adverse events that are ongoing should be followed until resolution or are 
clinically stable. The reporting period for SAEs is described in Section 7.4.2. 
 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE. For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of carcinoma should 
also be reported as an SAE. In both instances the condition for SAE reporting should be 
categorized as a medically important event unless another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a 
medicinal product related to any dose, for which a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility (i.e., there is 
evidence to suggest a causal relationship between the product and the adverse event). 
An unexpected ADR is one, the nature or severity of which is not consistent with the 
applicable product information (Investigator's brochure, protocol, and user manual). 
Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be 
considered “unexpected”. Specific examples would be (a) acute renal failure as a 
labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a 
first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is 
a serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating Investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the 
SUSAR will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating Investigators of information that might materially influence 
the benefit-risk assessment of a medicinal product, sufficient to consider changes in 
product administration or overall conduct of a clinical investigation. Examples of such 
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expected adverse event, the identification of a significant hazard to the subject 
population, or a major safety finding from a study conducted in animals. 
 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
Investigator within 24 hours. Sponsor will assess each device related SAE to determine 
if anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The Investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The Investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be 
assessed as not related to the IP and/or the investigational device. Because the 
Investigator is knowledgeable about the subject (e.g., medical history, concomitant 
medications), administers the IP, and monitors the subject’s response to the IP, the 
Investigator is responsible for reporting adverse events and judging the relationship 
between the administration of the IP and device and a subsequent AE. 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 IP 
delivered by EP and determine whether to report expeditiously to the regulatory 
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Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation 
of any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the IP and/or the investigational device indicating "yes" or 
"no" accordingly. Causality should be assessed by the Investigator as “yes, related” or 
“no, unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational 
device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to IP 
interruption or discontinuation must be recorded as an AE, or SAE, if applicable. In 
addition, laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital 
signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE (or SAE) as described in Section 7.1. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., 
anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the Investigator as clinically significant 
 POST-TRIAL 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 or termination visit and the event is deemed by the Investigator to be related 


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to the study treatment, he/she should promptly document and report the event to the 
study team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be 
excluded from participation in the study. Should a subject become pregnant after 
enrolling in the study, she will not be given any further study treatments. A Pregnancy 
Form will be completed by the site personnel and submitted to the sponsor within 24 
hours after learning of the pregnancy. Site personnel will submit the Pregnancy Form to 
the Sponsor as described in Section 7.4.2. 
The Investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject's permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results 
will be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be 
performed. Investigators should use clinical judgment regarding subsequent study-
related blood collection based on the presence or absence of anemia in each subject. 
Subjects who are not withdrawn will continue to be followed for safety assessments to 
study discharge per protocol.  
All pregnancies that occur from the time of first study treatment through the follow up 
visits must be reported. The Investigator will monitor the subject and follow the outcome 
of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome will be reported directly to the study team and the medical 
monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when 
informed consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject's response to questions about her health (a standard non-leading 
question such as ''How have you been feeling since your last visit?'' is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the 
Investigator to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject's health becoming known to the 
Investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  


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7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
urinalysis) 
 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented.  
 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 2000 that require expedited communication 
from the site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration 
recorded ≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and PI, the DSMB, and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
Treatment;  
 
Any subject experiences an SAE (or potentially life threatening AE) or death 
assessed as related to Study Treatment; 
 
Three or more subjects experience the same grade 3 or 4 adverse event, assessed 
as related to Study Treatment;  
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
Study Treatment; 
Upon conclusion, the sponsor or designee will notify all Investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 


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7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), 
whether volunteered by the subject, discovered by Investigator or study staff 
questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded in the subject's source documents and followed as 
appropriate. 
TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised 
of the period following the signing of the informed consent form until the end of the 
study. Each AE will be assessed to determine whether it meets serious criteria. If the AE 
is considered serious, the Investigator should record this event in the EDC system and 
report the event to the Sponsor within 24 hours of becoming aware of the event. The 
Investigator may also directly report this event to the Ethics Committee according to its 
standard operating procedures. Expectedness of SAEs will be determined by the 
Sponsor using reference safety information specified in the Investigator's Brochure and 
protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.5 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.6 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All Investigators will receive a safety letter notifying them of relevant SUSAR reports. 
The Investigator should notify the Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as is practical, of serious events in writing where this is required by local 
regulatory authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an Investigator becomes 
aware of an SAE that is suspected by the Investigator to be related to the study drug, the 
event will be reported to the Sponsor or its designee. If the Investigator becomes aware 
of an SAE in a study subject after the last scheduled follow-up visit, and considers the 
event related to prior Study Treatment, the Investigator will report it to the Sponsor or the 
appropriate designee. 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
 M.D., Ph.D. 
EMAIL:  
 


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SAE REPORTING INFORMATION 
EMAIL:  safety.inovio@apcerls.com 
SAFETY FAX: 
SAFETY PHONE: 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address 
as indicated above. Any SAE supporting documents provided by facsimile (Fax) are to 
include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The Investigator will supply the Sponsor and the IRB with more information as it 
becomes available and any additional requested information. The original SAE form 
must be kept at the study site. The Sponsor or its representative will be responsible for 
determining and in turn, reporting SAEs to regulatory authorities according to the 
applicable regulatory requirements. SAEs must be followed by the Investigator until 
resolution, even if this extends beyond the study-reporting period. Resolution of an SAE 
is defined as the return to baseline status or stabilization of the condition with the 
expectation that it will remain chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the Investigator will submit a Pregnancy Form to the 
Sponsor or designee to the safety email address or fax number within 24 hours of 
learning of the pregnancy. 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating Investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later 
than 10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 
15 days for all other SUSARS (see Section 7.1.5 and 7.1.6). 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, 


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reliability, safety, effectiveness, or performance of a device such as malfunction, misuse 
or use error and inadequate labeling. A malfunction is defined as the failure of a device 
to meet its performance specifications or otherwise perform as intended. The intended 
performance of a device refers to the intended use for which the device is labeled. All 
product complaints that meet this definition must be reported to the sponsor within 10 
days of discovery. Any product complaint that involves an AE or SAE must be also be 
reported per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error 
messages displayed on the device screen following treatment or errors that occur during 
the treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  
All complaints must be sent to ClinicalComplaint@inovio.com. Additional instructions on 
complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at 
multiple sites for safety or administrative reasons at any time. In particular, a site that 
does not recruit at a reasonable rate may be discontinued. Should the study be 
terminated and/or the site closed for whatever reason, all non-source documentation and 
study product pertaining to the study must be returned to Inovio Pharmaceuticals or its 
representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research 
subjects are protected. 
8.
STATISTICAL ANALYSIS PLAN
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and 
VGX-3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and 
confirmed vulvar infection with HPV types 16 and/or 18. The study's primary endpoint is 
binary: regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from 
vulvar tissue based on tissue collected at Week 48. The primary hypothesis is that each 
of the treatment arms will result in regression of HSIL and clearance. Secondary efficacy 
analyses pertain to regression, clearance of HPV-16 and/or HPV-18 infection, regression 
to normal, non-progression, and anatomic extent. Other secondary analyses concern 
safety and humoral and cellular immunological measures. Exploratory efficacy analyses 
concern extended dosing with respect to regression, clearance, and anatomic extent, 
clearance outside of the vulva, and effect of HLA type on efficacy. Other exploratory 
analyses pertain to tissue immunological measures and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 


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recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 
vs. 2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 
kg/m2), and (d) age category (<45 years vs. ≥45 years). There are no requirements for 
the number of subjects in each stratum. The study is open-label. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each arm superior to historical control with a one-sided 0.025 type 
1 error level for each hypothesis, assuming the true proportion of subjects who achieve 
the primary endpoint is 20% and 28% for the respective treatment arms and 2% for the 
historical control, and that 90% are evaluable at Week 48 from randomization. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized. Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized. 
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy. Subjects excluded from the PP 
population will be identified and documented prior to unblinding of the study 
database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects and will 
include the number and percentage randomized, the number and percentage who 
received each dose and the number who completed the trial. The number and 
percentage of subjects who discontinued will be summarized overall and by reason. The 
number in each analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, 
and percentages for categorical variables, by treatment arm, for the mITT population. 
Prior and concomitant medications will also be summarized with percentages in this 
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8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system, by treatment arm, for the mITT population. 
 
 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are considered those medications taken prior to the first dose of study 
drug (i.e., Day 0). Concomitant medications are those used on or after Day 0. Partial 
start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial 
date. Data for all prior and concomitant medications will be summarized with 
percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint for each arm. The primary hypothesis of 
superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment arm separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI 
exceeds 0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) 
will be summarized with point estimates and associated exact Clopper-Pearson 95% 
confidence intervals. 
An exploratory analysis will examine clearance outside of the vulva. This will be 
analyzed in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and a) HLA results, b) miRNA results, c) vulvoscopy results, and d) HPV 
results. Relationships will be examined with contingency tables and/or logistic regression 
models which model the primary endpoint versus these results and treatment group as 
regressor variables. 
8.10 IMMUNOGENICITY ANALYSIS 
 


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Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment 
arm. These frequencies will be presented overall and separately by dose, and will depict 
overall, by system organ class and by preferred term, the percentage of subjects 
affected. Additional frequencies will be presented with respect to maximum severity and 
to strongest relationship to Study Treatment. Multiple occurrences of the same AE will 
be counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of 
any dose. For this summary, the frequency of preferred term events will be summarized 
with percentages and exact Clopper-Pearson 95% confidence intervals. Separate 
summaries will be based on events occurring within 7 days of any dose and regardless 
of when they occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not 
be included within specified day-range summaries. AE duration will be calculated as 
(Stop Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment 
arm. Baseline is defined as the last measurement prior to the first treatment 
administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population. Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time 
point will be summarized by treatment arm and by body system, for the mITT population. 


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 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or exact 
Clopper-Pearson 95% CIs, for continuous responses and binary responses, 
respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 
9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles of 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The Investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained from 
the applicable IRB/EC and a copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 
During the conduct of the study, submit progress reports to the IRB/EC as required.  
 
Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 
If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 
As required, obtain approval from the IRB/EC for protocol amendments and for 
revisions to the consent form or subject recruitment advertisements; 
 
Reports on, and reviews of, the trial and its progress will be submitted to the IRB by 
the Investigator at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines. 
 
Maintain a file of study-related information that includes all correspondence with the 
IRB; 
 
Notify IRB when study is completed (i.e. after the last study visit of the final study 
subject); 
 
After study completion provide the IRB with a final report on the study. 


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9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., NIH 
Office of Biotechnology Activities) governing research that involves recombinant or 
synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening into the 
study, and/or from the subject's legally authorized representative. The process for 
obtaining informed consent must also be documented in the subject's medical record. 
9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating 
the study and re-approval or review at least annually. Sponsor is to be notified 
immediately if the responsible IRB/EC has been disqualified or if proceedings leading to 
disqualification have begun. Copies of all IRB/EC correspondence with the Investigator 
must be provided to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and for subjects in the imiquimod 
arm a dosing log during their study participation. Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
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10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject's name will not be disclosed in these documents. 
The subject's name may be disclosed to the study sponsor, Sponsor, the governing 
health authorities or the Food and Drug Administration (FDA), if they inspect the study 
records. Appropriate precautions will be taken to maintain confidentiality of medical 
records and personal information. 
Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject's legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA)). 
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 the research subject to revoke their authorization for use of their 
PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. 
Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subject's 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 medical records and within 
information technology systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must 
be present in the source documents. All prescription and nonprescription medications 
taken within l week prior to entry must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. 


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10.3 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The sponsor will inform the Investigator/institution as to when 
these documents are no longer needed to be retained. 
10.4 SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial. The DSMB will 
meet quarterly or as data are available to review safety data and regression/clearance 
results. If there are no new safety data or regression/clearance results to review for a 
quarterly scheduled meeting the DSMB will be notified and the meeting may be 
cancelled; Ad hoc meetings may be scheduled to review new data as applicable. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. 
No formal interim analysis will be performed. The DSMB Chair, upon consultation with 
the other voting members of the DSMB, has the authority to recommend suspension or 
stopping the study and to request a full DSMB review and ad hoc statistical analyses. 
The standard operating procedures of the DSMB will be documented in the DSMB 
charter, including the board's accountability to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of up to four pathologists. Each specimen will be read by two pathologists independently 
in a masked fashion. The responsibilities and membership structure of the PAC is 
outlined in the PAC Charter, including the reporting of results.  
 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant with all applicable 
requirements. 
 
All clinical site monitoring visits will be documented. 


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 
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 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 
 
Throughout the study, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, original, 
and accurate (ALCOAC).  
 
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 investigational drug and device accountability and reconciliation of 
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date 
of receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Forms 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data & Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
EP 
Electroporation with Cellectra™ 2000 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
HSIL 
High grade squamous intraepithelial lesion 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-γ 
Interferon Gamma 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response Technology 
LAST 
Lower Anogenital Squamous Terminology 
mITT 
Modified Intent to Treat 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
Participant Diary  
PE 
Physical exam 


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PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
PRO 
Patient Reported Outcomes 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
WOMAN-PRO                  WOMen with vulvAr Neoplasia PRO 
 
 
 
 


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13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé 
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Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé 
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HPV and Cancer (HPV Information Centre)  Summary Report 30 June 2017. 2017. 
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Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
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National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
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Hartwig S, St Guily JL, Dominiak-Felden G, Alemany L, de Sanjose S. Estimation of the 
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Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
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Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
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Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
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Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, et al. Squamous vulvar 
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Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
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Inovio Pharmaceuticals. Unpublished assessment. 2015. 
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Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
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van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
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Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
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ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 


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Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
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ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
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Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
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Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
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outcome measure to identify occurrence and distress of post-surgery symptoms of 
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Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
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Senn B. Creating and Validating a Patient-Reported Outcome Instrument for Women with 
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Senn B, Mueller MD, Hasenburg A, Blankenstein T, Kammermann B, Hartmann A, et al. 
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Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA™ 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
IND #13683 
 
 
 
 
Version 3.0 
26 March 2019 
 
 


VGX-3100 
lnovio Pharmaceuticals, Inc. 
Medical Monitor Approval Page 
Drug: 
Sponsor: 
Medical Monitor: 
Approval Signature: 
M.D., h.D. 
VGX-3100 
lnovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
M.D., Ph.D. 
lnovio Pharmaceuticals, Inc. 
lnovio Pharmaceuticals, Inc. 
CONFIDENTIAL 
HPV-201 
Clinical Protocol 
The information in this document is considered privileged and confidential by lnovio 
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 lnovio Pharmaceuticals. Any 
supplemental information added to this document is also confidential and proprietary 
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner 
as the contents of this document. 
Protocol Version Date: 26Mar2019 
CONFIDENTIAL 
Page 2 of 91 
Protocol Version: 3.0 


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PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI's approval of this protocol 
and provides the necessary assurances that this trial will be conducted in accordance 
with ICH/GCP and ISO guidelines, local legal and regulatory requirements, and all 
stipulations of the protocol. 
 
 
Principal Investigator Signature: ___________________________________ 
 
 
 
________________________________  
    ____________________ 
Print Name of Principal Investigator 
 
    Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 


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SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 2.1 dated 01 December 2017 to 
Version 3.0 dated 26 March 2019.  
 
1. The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical imiquimod 
study group.  Inovio no longer plans to develop a treatment of VGX-3100 in combination with 
topical imiquimod.  All subjects who have already been enrolled into the VGX-3100 with imiquimod 
study group will continue with all study visits per protocol and the data will be analysed as planned, 
but no further participants will be enrolled into this group. 
 
 


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HPV-201 
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Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ............................................................. 3 
SUMMARY OF CHANGES ........................................................................................................ 4 
CLINICAL PROTOCOL SYNOPSIS .........................................................................................10 
STUDY SCHEDULE OF EVENTS ............................................................................................24 
1. 
INTRODUCTION ...........................................................................................................26 
1.1 
Background ........................................................................................................26 
 
Human Papillomavirus and Infection ......................................................26 
 
Vulvar Cancer ........................................................................................26 
 
Vulvar Intraepithelial Neoplasia (Vulvar HSIL) ........................................26 
 
Recurrent Disease with Current Therapeutic Options .............................27 
 
Psychological and Physical Impacts of Current Therapeutic Options ......28 
 
Impact of Vulvar HSIL Upon Activities of Daily Living .............................28 
 
Limitations of Prophylactic HPV Vaccines ..............................................29 
 
Enhanced Monitoring Plan .....................................................................29 
 
VGX-3100 ..............................................................................................29 
 Electroporation .......................................................................................30 
 Imiquimod Cream, 5% ............................................................................30 
 Study Rationale ......................................................................................30 
 Dose and Regimen Rationale for VGX-3100 ..........................................30 
 Rationale for imiquimod ..........................................................................31 
 Inclusion of WOMAN-PRO, Clinical trial version 2.0 ...............................31 
 Potential Risks of investigational products ..............................................31 
 Potential Benefits of Study Participation .................................................32 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ..................................................................32 
2.1 
Primary Objective and Endpoint .........................................................................32 
2.2 
Secondary Objectives and Associated Endpoints ..............................................33 
2.3 
Exploratory Objectives and Associated Endpoints .............................................34 
3. 
STUDY DESIGN ...........................................................................................................35 
3.1 
Treatment Regimens .........................................................................................35 
3.2 
Efficacy Assessment ..........................................................................................36 
 
Definition of Responder and Non-Responder .........................................37 
3.3 
Safety Assessment ............................................................................................38 
 
Data Safety & Monitoring Board .............................................................38 


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HPV-201 
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3.4 
Immunogenicity Assessment .............................................................................39 
3.5 
Virologic Assessment .........................................................................................39 
4. 
SELECTION OF SUBJECTS ........................................................................................39 
4.1 
Inclusion Criteria ................................................................................................39 
4.2 
Exclusion Criteria ...............................................................................................40 
4.3 
Discontinuation/Withdrawal of Study Subjects ...................................................42 
 
Criteria for Discontinuation of Investigational Product .............................42 
 
Criteria for Withdrawal from the Study ....................................................43 
 
Sponsor Notification of Discontinuation/Withdrawal ................................43 
 
Reason for Discontinuation/Withdrawal ..................................................44 
5. 
STUDY TREATMENT ...................................................................................................44 
5.1 
Investigational Products .....................................................................................44 
5.2 
Packaging and Labeling .....................................................................................45 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................45 
5.3 
Handling and Storage ........................................................................................46 
5.4 
Preparation and Dispensing ...............................................................................46 
 
Dispensing of VGX-3100 ........................................................................46 
 
Dispensing and Use of Imiquimod ..........................................................47 
5.5 
Investigational Product Accountability ................................................................47 
5.6 
Return and Destruction of Investigational Product ..............................................47 
5.7 
Use of Investigational Device .............................................................................48 
5.8 
Packaging and Labeling of Investigational Device..............................................48 
5.9 
Investigational Device Accountability .................................................................50 
5.10 
Return of Investigational Devices .......................................................................50 
6. 
STUDY PROCEDURES AND TREATMENTS ..............................................................51 
6.1 
Before Treatment Procedures ............................................................................51 
 
Screening evaluations ............................................................................51 
6.2 
During Treatment Procedures by Visit ................................................................52 
 
Day 0 ......................................................................................................52 
 
8-14 Days Post Dose 1 Phone Call ........................................................53 
 
Week 4 (± 7 days): .................................................................................53 
 
8-14 Days Post Dose 2 Phone Call ........................................................54 
 
Week 12 (± 7 days) ................................................................................54 
 
Week 15 (± 7 days): ...............................................................................55 
 
Week 24 (± 7 days) ................................................................................55 


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Clinical Protocol 
 
 
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Week 27 (± 7 days) ................................................................................56 
 
Week 38 Phone Call ...............................................................................56 
 Week 48 (± 7 days) ................................................................................56 
 Week 52 (± 14 days) ..............................................................................57 
 Week 74 (± 14 days) ..............................................................................57 
 Week 78 (± 14 days) ..............................................................................58 
 Week 96 (± 14 days) ..............................................................................58 
 Week 100 (± 14 days) ............................................................................59 
6.3 
Evaluations and Procedures ..............................................................................59 
 
Informed Consent ...................................................................................59 
 
Rescreening of Screen Failures .............................................................59 
 
Assignment of Subject Identification Numbers ........................................59 
 
Safety Evaluations ..................................................................................60 
6.4 
Injection and Electroporation (EP) ......................................................................62 
 
Risks of Treatment Procedures ..............................................................62 
 
Management of Anxiety and Pain Due to Electroporation (EP) 
Procedure ...............................................................................................62 
6.5 
Assessment of Laboratory Abnormalities ...........................................................63 
6.6 
Assessment of Clinical Study Adverse Events ...................................................63 
6.7 
Assessment of Injection Site Reactions .............................................................63 
6.8 
Assessment of Patient Reported Outcomes .......................................................64 
6.9 
Peripheral Blood Immunogenicity Assessments .................................................66 
6.10 
Tissue Immunogenicity Assessment ..................................................................66 
6.11 
HLA Typing ........................................................................................................66 
6.12 
Vulvar HPV Testing ............................................................................................67 
6.13 
Colposcopy, PAP Smears and HPV Testing ......................................................67 
6.14 
Vulvoscopy, Photographs, and Biopsies ............................................................67 
6.15 
Concomitant Medications/Treatments ................................................................68 
6.16 
Restrictions ........................................................................................................68 
 Other Restrictions ...................................................................................69 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ................................69 
7.1 
Safety Parameters .............................................................................................69 
 
Adverse Events ......................................................................................69 
 
Serious Adverse Events .........................................................................70 
 
Clarification of Serious Adverse Events ..................................................70 


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Clinical Protocol 
 
 
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Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ..............................................................71 
 
Unexpected Adverse Drug Reactions and Expedited Reporting .............71 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .........................72 
 
Assessing Severity (Intensity) .................................................................72 
 
Casual Relationship of Clinical Material to Adverse Events ....................72 
 
Abnormal Laboratory Value ....................................................................73 
 Post-Trial Reporting Requirements.........................................................73 
 Procedures for Documenting Pregnancy During Study ...........................74 
7.2 
Methods and Timing of Collection of Safety Data ...............................................74 
7.3 
Safety and Toxicity Management .......................................................................75 
 
Adverse Events of Special Interest .........................................................75 
 
Stopping Rules (Criteria for Pausing of Study) .......................................75 
7.4 
Adverse Experience Reporting ...........................................................................76 
 
Trial Reporting Period of Adverse Events ...............................................76 
 
Trial Reporting Period of Serious Adverse Events ..................................76 
 
Notification of Serious Adverse Events ...................................................77 
 
Reporting of Device Related Complaints ................................................77 
7.5 
Trial Discontinuation ..........................................................................................78 
8. 
STATISTICAL ANALYSIS PLAN ..................................................................................78 
8.1 
General Considerations .....................................................................................78 
8.2 
Randomization and blinding ...............................................................................78 
8.3 
Sample Size/Power ............................................................................................79 
8.4 
Analyses Populations .........................................................................................79 
8.5 
Subject Disposition ............................................................................................79 
8.6 
Demographic and Other Baseline Characteristics ..............................................80 
8.7 
Medical History ..................................................................................................80 
8.8 
Prior and Concomitant Medications ...................................................................80 
8.9 
Efficacy Analysis ................................................................................................80 
8.10 
Immunogenicity Analysis ....................................................................................81 
8.11 
Safety analyses .................................................................................................81 
 Adverse events.......................................................................................81 
 Laboratory data ......................................................................................81 
 Vital Signs ..............................................................................................81 
 Physical Examination .............................................................................82 


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Clinical Protocol 
 
 
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 Patient Reported Outcomes ...................................................................82 
 Missing Values .......................................................................................82 
 Interim Analysis ......................................................................................82 
9. 
ETHICS .........................................................................................................................82 
9.1 
Investigator and Sponsor Responsibilities ..........................................................82 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ..................................82 
9.3 
Office of Biotechnology Activities (OBA) ............................................................83 
9.4 
Compliance with Informed Consent Regulations ................................................83 
9.5 
Compliance with IRB/EC Requirements .............................................................83 
9.6 
Compliance with Good Clinical Practice .............................................................83 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 ..........................................................................................................................83 
9.8 
Compliance with Protocol ...................................................................................83 
9.9 
Changes to the Protocol.....................................................................................84 
10. 
DATA COLLECTION, MONITORING AND REPORTING .............................................84 
10.1 
Confidentiality and Privacy .................................................................................84 
10.2 
Source Documents ............................................................................................84 
10.3 
Records Retention .............................................................................................85 
10.4 
Safety and Quality Monitoring ............................................................................85 
 Data & Safety Monitoring Board .............................................................85 
 Pathology Adjudication Committee .........................................................85 
 Clinical Monitoring ..................................................................................86 
11. 
PUBLICATION POLICY ................................................................................................86 
12. 
LIST OF ABBREVIATIONS ..........................................................................................87 
13. 
REFERENCES ..............................................................................................................89 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
Page 10 of 91 
 
CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA™ 2000 Alone or in Combination 
with Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 28 sites in the 
United States (US) and potentially other countries not yet determined 
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of 
HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3x) from Day 0 through Week 202 
No. of Subjects 
Approximately 363 subjects 
Study Duration 
100 weeks 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar 
HSIL4 and no evidence of HPV-16/18 at Week 48 in vulvar 
tissue samples (i.e. collected via biopsy or excisional 
treatment)5 
                                                     
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous 
Terminology (LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College 
of American Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3 The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical imiquimod study group.  All 
subjects who have already been enrolled into the VGX-3100 with imiquimod study group will continue with all 
study visits per protocol, but no further participants will be enrolled into this group. 
4 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
5 A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no evidence of HPV-
16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study related treatment for vulvar 
HSIL. A treatment non-responder is defined as a subject with histologic evidence of vulvar HSIL, or vulvar 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar HSIL6 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/187 in vulvar tissue samples 
at Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL, no evidence of LSIL 
(VIN1), and no evidence of condyloma 
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion of subjects with no 
progression8 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
                                                     
carcinoma at evaluation, or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a subject who 
received non-study related treatment for vulvar HSIL.   
6 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
7 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
8 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 


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HPV-201 
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Clinical Protocol 
 
 
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Protocol Version: 3.0 
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6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of qualifying9 
vulvar lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized pre-
biopsy photographic imaging of 
qualifying9 lesion(s) at Week 48, 74 and 
96 compared to baseline10. Results will 
be classified as: no clinically significant 
lesion resolution (reduction in lesion area 
of 0-25%), partial lesion area resolution 
(>25% and <100% reduction) and 
complete lesion resolution (no visible 
lesion).   
7. Describe the humoral and cellular immune 
response to VGX-3100, administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74 and 96 
visits 
7b. Interferon-γ ELISpot response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
7c. Flow Cytometry response magnitudes 
at baseline and Week 27 visits 
                                                     
9 A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive and 
have histologically confirmed vulvar HSIL by the PAC at screening. 
10 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
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Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying9 vulvar lesion(s), in subjects who 
did not have complete lesion resolution at Week 
48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
pre-biopsy photographic imaging of 
qualifying9 lesion(s) at Week 74 and/or 
Week 96 compared to baseline11. 
Results will be classified as: no 
clinically significant lesion resolution 
(reduction in lesion area of 0-25%), 
partial lesion area resolution (>25% and 
<100% reduction) and complete lesion 
resolution (no visible lesion).   
2. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the efficacy of more than 4 doses of 
VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue12  
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-
vulvar anatomic locations without 
surgical intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week 48 compared to baseline 
6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
7. Vulvoscopy, HPV test results (vulvar 
swab and vulvar tissue) and miRNA 
profile (Day 0, Week 15 and 48) in 
conjunction with histologic regression of 
vulvar HSIL at Week 48 visit 
                                                     
11 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   
12Additional assessments may include visualization of PD-L1, Granulysin, perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 3.0 
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8. Describe patient reported outcomes (PRO) for 
subjects treated with VGX-3100 and VGX-3100 
with imiquimod 
8.  PRO endpoints will be obtained at Day 
0 prior to first dose, Weeks 4, 12, 24 
after dosing, and at Weeks 15, 27, 48, 
52, 74, 96, and 100. 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
Page 15 of 91 
 
Study Design:  
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered 
with CELLECTRA™ 2000 alone or in combination with imiquimod in adult women with histologically 
confirmed vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled. 
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-
3100 and topical imiquimod treatment. The Version 3.0 protocol amendment halts enrollment of the 
VGX-3100 with topical imiquimod study group.  All subjects who have already been enrolled into the 
VGX-3100 with imiquimod study group will continue with all study visits per protocol, but no further 
participants will be enrolled into this group. 
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass 
Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years).   
To be eligible for the study, subjects must consent to participate and have a vulvar punch 
biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of the acetowhite 
vulvar lesion(s) at the time of screening. In the case of multifocal disease, the two lesions that 
potentially contain the most advanced disease, as judged by the Investigator, should be chosen for 
biopsy using vulvoscopy and documented using standardized high resolution photography with a 
digital single-lens reflex (SLR) camera. Biopsy slides will be sent to the Pathology Adjudication 
Committee (PAC) by the central laboratory for evaluation prior to enrollment. In order to be eligible for 
enrollment, the PAC must assign the diagnosis of vulvar HSIL based on the biopsy sample(s). 
Subjects must also have a vulvar tissue specimen test positive for HPV genotype 16 and/or 18 to be 
eligible for participation in the study. 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™) (Optum), the 
EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvAr Neoplasia) Clincial 
Trial Version 2.0 and two additional PRO questions assessing quality of life after surgery or biopsy. 
All eligible subjects who consent to participate in the study will receive four to six doses of 6 mg of 
VGX-3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject's biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with 
the CELLECTRA™ 2000 device. As shown in Figure 1, study subjects will receive at least 4 doses of 
VGX-3100 and potentially a 5th and 6th dose depending upon their disposition with regard to histologic 
and lesion area changes. The first dose will be administered on Day 0, the second at Week 4, the 
third at Week 12, and the fourth dose will be administered at Week 24. Subjects with no HSIL at Week 
48 (Subgroups A and B) will receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in 
lesion size or no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator. Subjects with 
HSIL at Week 74, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a sixth dose of VGX-3100 administered IM with EP at Week 78 per 
the judgment of the Investigator. Subjects in Subgroup E may receive surgical treatment per the 
judgment of the Investigator. All subjects are scheduled to be followed to Week 100.  


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
Page 16 of 91 
 
 
 
Figure 1: Study Visit Schedule 
 
 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod study group will apply 
imiquimod 5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to 
apply imiquimod cream three times per week for 20 weeks (inclusive of administration in the evening 
of VGX-3100 dosing). Subjects unable to tolerate imiquimod treatment may reduce their dosing 
frequency, and will document their use on the imiquimod dosing log provided. 
Efficacy Assessment: Biopsies obtained as part of the study at Screening will be from the region of 
most advanced disease as judged by the Investigator, and must be approximately 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by vulvoscopy is insufficient evidence to confirm disease 
regression. Disease regression will be based on histopathologic assessment at Week 48, 74, and 96. 
Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), defined as areas 
that stain acetowhite, will be assessed during vulvoscopy at Screening, Day 0 and Weeks 4, 12, 27, 
48, 74 and 96. Using standardized high resolution digital photographic imaging, vulvar lesion(s) will 
also be quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, but from the region of potentially most advanced disease based upon the judgment of 
the Investigator (see Table 2 for Minimally Required Biopsy Procedures). If after evaluation of biopsy 
tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the subject will continue to Week 
74 for vulvoscopy, and biopsy of the same lesion as study start.   
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
Page 17 of 91 
 
 
 
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in the qualifying lesion(s) 
size or no change in lesion size from baseline (Subgroups C or D), the Investigator has the option to 
give the subject a 5th dose of VGX-3100 at Week 52, and the subject will continue on study with 
vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator may choose to treat the subject 
with surgical or standard treatment, and the subject will continue on study without further biopsy. A 
qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive 
and have histologically confirmed vulvar HSIL by the PAC at screening. 
 
Figure 2: Decision process at Week 52  
 
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and as 
follows: At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL 
(Subgroups A or B), the subject will continue to Week 96 for vulvoscopy, and biopsy of the same area 
from the region of potentially most advanced disease based upon the judgment of the Investigator. If 
HSIL remains but there is a reduction in lesion size or no change in lesion size from baseline 
(Subgroups C or D), the Investigator has the option to give the subject a 6th dose of VGX-3100 at 
Week 78, and the subject will continue on study with vulvoscopy and biopsy at Week 96. Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and the subject 
will continue on study without further biopsy.   
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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Figure 3: Decision Process at Week 78 
 
The decision process following results of the Week 74 biopsy are as described in Figure 4 and as 
follows: At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If there is no vulvar HSIL (Subgroups A or B), no further procedures are 
required. If after evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or 
worsening disease (Subgroup E), the subject will receive surgical or other standard treatment.     
 
Figure 4: Evaluation process at Week 100 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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In the event of worsening disease at any time (i.e., Subgroup E – any increase in lesion area from 
baseline or worsening to cancer), the subject will receive surgical treatment per the Investigator's 
judgment and will continue on study through Week 100 with vulvoscopy, but without further study 
treatment or biopsy. If at any time in the study carcinoma is discovered, subjects will receive surgical 
treatment, and be discontinued from study treatment. The event will be reported as an SAE per 
section 7.1.4.  If wide excision is required, the sample obtained will be sent to the PAC for evaluation.   
Definition of Responder and Non-responder:Responder and non-responder definitions (Table 3) take 
into account both histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of HSIL. A 
treatment responder is defined as a subject with no histologic evidence of vulvar HSIL and no 
evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study 
related treatment for vulvar HSIL. A treatment non-responder is a subject with histologic evidence of 
vulvar HSIL or vulvar carcinoma at evaluation, or a subject with evidence of HPV-16/18 at evaluation, 
or a subject who received non-study related treatment for vulvar HSIL. Any case of histologically 
confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs for the duration 
of the study. 
All subjects will be followed for 100 weeks. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data and 
tissue regression and viral clearance results. The DSMB will be charged with advising the Sponsor if 
there appears to be a safety issue. No formal interim analysis is planned. The following stopping rules 
will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI), further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator (PI) for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, PI for the trial, IRB (if applicable) 
and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, PI for 
the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, PI for the trial, IRB (if applicable) 
and the DSMB.  


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
Page 20 of 91 
 
 
The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding the outcome 
of any investigation stemming from a Study Pause.  
Immunogenicity Assessment: The study will explore humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (i.e., Screening and 
Day 0 prior to dosing) and Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and Weeks 48, 74 and 96. 
Virologic Assessment: Tissue samples will be obtained to characterize vulvar HPV infection at 
Screening, Weeks 48, 74 and 96. Cervical samples, oropharyngeal rinse, vulvar, vaginal, and intra-
anal tissue swab samples will be obtained to characterize HPV infection at the following time points: 
Day 0 prior to dosing (OP, cervical, vulvar, vaginal and intra-anal), Week 4 (Vulvar only), Week 12 
(Cervical and vulvar)  and Weeks 27, 48, 74 and 96 (OP, vulvar, vaginal and intra-anal). At Weeks 48 
and 96, cervical sample will also be collected.  
HLA haplotyping: A sample from one time point during the study will be tested to explore the 
relationship between subject HLA haplotypes and regression.  


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above  
3. 
Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. 
Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated date of first 
dose of study drug and have histologically confirmed vulvar HSIL by the Pathology Adjudication 
Committee at screening; 
5. 
Must be judged by the Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
6. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after an approximately 4 mm screening biopsy;  
7. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 3 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system;                                                                                
iv) Male partner sterilization at least 6 months prior to the female subject's entry into the 
study, and this male is the sole partner for that subject. 
9. 
Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the Investigator. 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing medical care and/or 
treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical care and/or 
treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing medical care 
and/or treatment for CIN; 
5) Biopsy-proven differentiated VIN; 
6) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
7) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
8) Treatment for genital warts within 4 weeks prior to screening; 
9) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
10) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream for subjects 
enrolled prior to Protocol Amendment v3.0 (dated 26Mar2019); 
11) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last 
dose of investigational product; 
12) Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity 
Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to Day 0 or less than Grade 1 but 
deemed clinically significant by the Investigator; 
13) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
14) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
15) Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of each study 
dose; 
17) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the Investigator; 
18) Current or history of clinically significant, medically unstable disease which, in the judgment of the 
Investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results  
a)   Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher congestive   
  heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision; 
 


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
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c) 
Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) 
that would contraindicate IM injections within 2 weeks of Day 0; 
d) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) 
Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19) Participation in an interventional study with an investigational compound or device within 4 weeks 
of signing informed consent (participation in an observational study is permitted); 
20) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) (unless 
deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
21) Vulnerable populations:  
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, would interfere 
with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22) 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.  


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events  
 
 
 
 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days) 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
Xb 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Screening safety (12 lead ECG, 
labs) c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xe 
 
Xf 
 
Xe 
 
Xe 
 
Xe 
 
HLA testing g 
       X 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar swabs 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cervical cytology, ThinPrep®  h 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Vulvoscopy i 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography j 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy k 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping l 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject VGX-3100 +EP lm 
 
X 
 
X 
 
X 
 
X 
 
 
 
Xm 
 
Xm 
 
 
Post treatment reaction 
assessment 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log n 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
Review PD o 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes 
(PROs)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
a Full PE mandatory at screening and study discharge (Week 100), otherwise targeted PE as determined 
by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE. 


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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b Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared). Weight will be measured at all dosing visits. 
c Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 45 days prior to first dose 
administration. 
d Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
e At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. One additional 8.5 mL yellow 
(ACD) tube to be collected at Day 0, Week 15 and 48 for microRNA analysis. 
f  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27.   
g HLA testing will performed once from an existing PBMC sample. 
h HPV genotyping and Pap smears are performed on the same ThinPrep® cervical specimen. 
i An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected. Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, and Weeks 74 and 96 for 
Subgroups C and D unless the Investigator suspects invasive cancer. All biopsy samples and/or excision 
samples must be sent to the PAC for review. 
j  Photography of the acetowhite stained qualifying lesion(s) must be performed prior to and after biopsy, 
and at all vulvoscopy examinations. If a pre-biopsy digital photograph is not available for a historical 
biopsy sample at screening, a post biopsy photo will be sufficient. Additionally, standardized high 
resolution digital photographic imaging should be obtained during examinations of the vagina if lesions 
are identified, for documentation.  
k Tissue specimen from all excised tissue must be reviewed by the PAC and residual vulvar tissue from 
entry, Week 48, 74 or Week 96 specimen(s) (paraffin blocks or unstained slides) must be sent to the 
central pathology laboratory for HPV testing.  
l HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
m Potential dosing at Week 52 and Week 78 is applicable for partial responders only.  
n Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod. 
Administration of imiquimod begins on Day 0. 
o A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
p PRO measures (SF-36v2™, EQ-5D-5L, WOMAN-PRO) plus two additional questions will be assessed as 
described in Section 6.8.     
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
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Protocol Version: 3.0 
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1. 
INTRODUCTION  
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause 
cancer, and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the 
most significant amongst high-risk types since they are responsible for most HPV-
caused cancers [1].   
HPV-16/18 is involved in about 83% of HPV-associated vulvar HSIL cases in the U.S. [1] 
and about 72% in Europe [2]. Persistent infection with one or more oncogenic (high-risk) 
HPV genotypes can lead to the development of precancerous, histologic high grade 
squamous intraepithelial lesions (HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS).  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 6,020 new cases and 1,150 
attributable deaths annually for year 2017 in the United States [4] and about 9,776 new 
cases in 2015 in Europe [5]. Vulvar cancers consist largely of squamous cell carcinomas 
and accounts for approximately 5% of all female genital malignancies [6]. Differentiated 
VIN, which is typically not caused by HPV infection and is more typically found in older 
women, is more likely to progress to cancer more rapidly than HPV-associated-VIN. The 
five year overall relative survival for vulvar cancer in the U.S. is 72.1% [4]. Recurrent 
vulvar cancer occurs in an average of 24% of cases after primary treatment, after 
surgery with or without radiation [7].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia. The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance 
of pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [8].    


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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
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In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) 
replaced the three grade classification system with the current single grade classification 
for which only high grade VIN (2/3) is classified as VIN [9]. In 2012, the Lower 
Anogenital Squamous Terminology (LAST) Standardization Project for HPV-associated 
lesions applied the term high grade squamous intraepithelial lesion (HSIL) to encompass 
high grade dysplasia [10]. Therefore, for the purpose of this study, the term vulvar HSIL 
will be used, whichencompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to 
encompass what was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [11]. Over time, typically years, vulvar HSIL can progress to 
invasive cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group 
and median 13.8 years in another group [12], and from VIN3 patients, mean = 2.5 years, 
range: 4 – 216 months [13].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity 
against vulvar HSIL and have not achieved universal uptake, leaving a population of 
susceptible and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to 
visual inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for 
vulvar HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, 
often requiring multiple, repeat treatments. Progression to vulvar cancer following 
current vulvar HSIL treatments can also occur within 1 year of treatment and for up to 20 
years post treatment. The current treatment options for vulvar HSIL are surgical 
excision, laser ablation, and off-label medical therapy. The rate of HPV-associated 
vulvar HSIL recurrence after surgical treatment is high; post-treatment recurrence rates 
are as high as 45% at three years post-treatment with all currently available treatment 
regimens [14, 15].   
Wide local excision is the 'preferred initial intervention' by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation. Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues 
with body image and sexual dysfunction. Medical therapies have been investigated as a 
means to avoid these negative outcomes. Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food 
and Drug Administration for this indication. Inconsistent treatment efficacy results have 
been shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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of recurrence is slightly higher compared to wide local excision. Laser treatment of 
vulvar HSIL requires destruction of cells through the entire thickness of the epithelium 
including hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation 
should extend through the dermis. Post-treatment recurrence rates exceed 30% (for all 
treatment regimens), and is higher with positive excision margins [16]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low 
rate of spontaneous resolution. According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is 
suspected (even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is 
wide local excision (i.e. surgery) [17]. When occult invasion is not a concern, vulvar HSIL 
can be treated with excision, laser ablation, or topical imiquimod as an off-label medical 
therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [16]. Therefore, many patients have a fear 
of recurrence and progression to cancer [18].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks. 
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid the use of toilet paper and to rinse with warm water 
instead. During recovery, common effects include pain in urinating and wiping, soreness, 
difficulty sitting, and feeling tired [19]. In the first week after hospital discharge, common 
patient-reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [20].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-
being [19]. The symptoms and signs of vulvar HSIL can be moderate to severe and 
include painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating 
[20]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than 
age-matched healthy women. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor's office all the time [19]. 


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 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid later development of HPV-
associated vulvar HSIL and subsequent vulvar cancer. The US-licensed prophylactic 
HPV vaccines are indicated for girls and women ages 9 through 26 years for Gardasil® 
and Gardasil®9 (Merck & Co. Inc.), and ages 9 through 25 years for Cervarix® 
(GlaxoSmithKline). The early portions of these age ranges are generally before sexual 
debut and thus can allow immunologic protection against the anticipated earliest normal 
exposures to HPV infection. HPV prophylactic vaccination is highly effective and safe, 
and routine vaccination is recommended for females in the United States starting at age 
11 or 12 years [22]. However, these prophylactic vaccines have no therapeutic effect 
upon existing HPV infection or existing HPV-related intraepithelial neoplasia [23]. 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan will be used in this study to address the risk of a potential 
delay in treatment of vulvar HSIL. The feasibility of this approach was demonstrated in 
the Phase 2b study of cervical HSIL. Given that vulvar disease progresses slowly to 
vulvar cancer if untreated, the proposed enhanced monitoring plan is expected to 
maintain the safety of subjects in this study. First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study Investigators. Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, 
by two independent expert pathologists from the PAC (see Section 10.4.2). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
is specifically excluded from study entry. By contrast, HPV-associated vulvar HSIL does 
not progress rapidly, typically taking years to manifest and progress, making enhanced 
monitoring feasible [24].   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.1). Colposcopy will also be 
performed at Day 0 and during the study given that concurrent disease in the lower 
genital tract can occur. A Data Safety Monitoring Board will be utilized to review subject 
safety data and advise on any study-level safety concerns. Investigators always have 
the option of performing ad hoc vulvar biopsies to rule out suspected disease 
progression. Additional treatment (e.g., additional excision, ablation, or medical therapy) 
may be carried out, if deemed necessary according to Investigator judgment. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA™ device represent an integrated 
investigational product designed as a non-surgical treatment of HPV-16/18-related 
cervical HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Further information about VGX-3100 is provided in the Investigator's Brochure. 


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 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP 
is a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [25, 26]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 
10 to 100 fold [27, 28]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as 
shown by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [29].  
This study will use the CELLECTRA™ 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no 
significant safety issues identified. Further information about the CELLECTRA™ 2000 
device can be found in the Investigator's Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device. Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 
250 mg of the cream, equivalent to 12.5 mg of imiquimod. The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod. The overall aim is to determine if treatment with VGX-3100 could allow 
women with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of 
concept that VGX-3100 can induce resolution of both HPV-associated dysplastic lesions 
and the underlying HPV-16/18 infection was shown in a Phase 2b study of cervical 
intraepithelial neoplasia (CIN). The similar underlying pathogenic mechanisms between 
cervical and vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could 
be a non-surgical therapeutic option for the treatment of vulvar HSIL, which is a 
significantly under met medical condition. A VGX-3100 with imiquimod-administration  
study drug is also included, given the prevalent use of imiquimod as a topical medical 
treatment of vulvar lesions, to investigate if a more robust immune response is achieved 
with VGX-3100, to potentially increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 


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responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [30].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Therefore, imiquimod may be able to be used 
synergistically with VGX-3100. 
Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG). Published regimens include three times 
weekly application to affected areas for 12 – 20 weeks, with colposcopic assessment at 
4-6 week intervals during treatment [17].  
This  study will include a study group to explore whether the efficacy of VGX-3100 is able 
to be enhanced by concomitant treatment with Imiquimod.  The Version 3.0 protocol 
amendment halts enrollment of the VGX-3100 with topical imiquimod study group.  All 
subjects who have already been enrolled into the VGX-3100 with imiquimod study group 
will continue with all study visits per protocol, but no further participants will be enrolled 
into this group.   
 INCLUSION OF WOMAN-PRO, CLINICAL TRIAL VERSION 2.0  
The original WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) was developed by 
Beate Senn and colleagues [20,31,32] for use following post-surgical intervention. 
Development of the tool was aligned with the FDA PRO Guidance [33]and included a 
review of the literature as well as direct patient and expert input. Preliminary 
measurement properties were assessed in a cross-sectional study. However, despite 
rigorous development and promising initial measurement properties, gaps in the 
development and psychometric evaluation exist. To address these gaps, Inovio and 
collaborators initiated a small qualitative study to confirm the content validity of the tool 
and support a cross-cultural adaptation of the measure for use in a clinical trial setting of 
US English and US Spanish speaking subjects. The results of  this research is the 
Clinical Trial of the WOMAN-PRO (2.0) which is utilized in this study. 
 
The WOMAN-PRO Clinical Trial Version 2.0 is a 31 item self-completed patient reported 
outcome measure designed to assess both physical and psychosocial impacts of VIN.  
The physical domain is comprised of 15 lesion-related symptoms and includes 5 
additional items to measure impact in daily life. Psychosocial constructs are assessment 
through 11 items that address feelings, thoughts and limitations. Each item is scored 
using a 4-point Likert scale with higher scores indicating greater difficulty or severity. The 
recall period is the past week.Details are included in Section 6.8.  
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 


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duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 
reported at the application site [34]. The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity. In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding, infection, or damage to surrounding 
structures such as the clitoris, urethra, or anus. The other potential benefit is that the 
response to VGX-3100 is systemic and may clear the underlying HPV infection, which is 
the root cause of vulvar HSIL. Consequently, there is the potential to reduce the risk of 
recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL associated with HPV-16 and/or HPV-18 (HPV-
16/18), will result in a higher percentage of women with regression of HSIL of the vulva 
based on histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-
16/18 from vulvar tissue compared with historical control. 
 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional 
treatment).   


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2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in 
combination with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit) 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL6 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/187 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL, no evidence of vulvar LSIL 
(VIN1), and no evidence of condyloma on 
histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression8 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of the qualifying9 vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying9 lesion (s) at Week 
48, 74 and 96 compared to baseline10. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion size of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).   
7. Describe the humoral and cellular immune 
response of VGX-3100 administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
7a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
7b. Interferon-γ ELISpot response magnitudes at 
baseline and Weeks 15, 27, 48, 74 and 96 
visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
 


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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying9 vulvar lesion(s), in subjects 
without a complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying9 lesion (s) at Week 
74 and/or Week 96 compared to baseline11. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).   
2. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the efficacy of 5 or 6 doses of VGX-
3100, alone or in combination with prior 
imiquimod, as measured by virologic 
clearance of HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to 
VGX-3100, and VGX-3100 with imiquimod, 
as measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue12 
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-vulvar 
anatomic locations without surgical 
intervention (inclusive of cervix, oropharynx, 
vagina and intra-anus) at Week 48 compared 
to baseline 
6. Characterize HLA haplotypes and the 
correlation with efficacy 
6.  Proportion of subjects with regression of 
HSIL on histology (i.e. biopsies or excisional 
treatment) at Week 48 visit  
7. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV 
testing results with Week 48 histologic 
regression 
7. Vulvoscopy, HPV test results (vulvar swab 
and vulvar tissue) and miRNA profile (Day 
0, Week 15 and 48) in conjunction with 
histologic regression of vulvar HSIL at Week 
48 visit 
8. Describe patient reported outcomes (PRO) 
for subjects treated with VGX-3100 and 
VGX-3100 with imiquimod 
8. PRO endpoints will be obtained at Day 0 
prior to first dose, Weeks 4, 12, 24 after 
dosing, and at Weeks 15, 27, 48, 52, 74, 96 
and 100. 


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3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA™ 2000 alone or in combination 
with imiquimod in adult women with histologically confirmed vulvar HSIL associated with 
HPV-16/18. Approximately 36 subjects will be enrolled. Twenty-four subjects will receive 
VGX-3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod 
treatment.  The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with 
topical imiquimod study group.  All subjects who have already been enrolled into the 
VGX-3100 with imiquimod study group will continue with all study visits per protocol, but 
no further participants will be enrolled into this group. 
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions 
at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2), and (d) age 
category (<45 years vs. ≥45 years). 
To be eligible for the study, subjects must sign consent to participate and have a vulvar 
punch biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of 
the acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, 
the two lesions that potentially contain the most advanced disease, as judged by the 
Investigator, should be chosen for biopsy using vulvoscopy and documented using 
standardized high resolution photography with a digital single-lens reflex (SLR) camera 
on the case report form. Biopsy slides will be sent to a PAC for evaluation prior to 
enrollment. In order to be eligible for enrollment, the PAC must assign the diagnosis of 
vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar specimen 
test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study. 
To assess quality of life and related impacts on subjects, PRO instruments will be 
provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-
5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvar Neoplasia) 
Clinical Trial Version 2.0 and two additional PRO questions assessing quality of life after 
surgery or biopsy. 
The total duration of the study is up to 10 weeks for the screening period and 100 weeks 
for the treatment and follow-up periods. 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 
mg of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-
16/18 status and all other eligibility criteria but no more than 10 weeks following 
collection of the subject's biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid preferred site, 
or the anterolateral quadriceps as an alternate site) followed immediately by EP with the 
CELLECTRA™ 2000 device. As shown in Figure 1, study subjects will receive at least 4 
doses of VGX-3100 and potentially a 5th and 6th dose depending upon their disposition 
with regard to histologic and lesion area changes. The first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be 
administered at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 


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receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose at 
Week 52 per the judgment of the Investigator. Subjects with HSIL at Week 74, who have 
a reduction in lesion size or no increase in lesion size from baseline (Subgroups C or D), 
may receive a sixth dose at Week 78 per the judgment of the Investigator.  Subjects in 
Subgroup E should receive surgical treatment per the judgment of the Investigator. All 
subjects will complete the study at Week 100. 
Imiquimod treatment – Participants who have been enrolled in the VGX-3100 with 
imiquimod study group will continue with study visits per protocol, but no further 
participants will be enrolled into this study group.  Subjects randomized to the VGX-3100 
with imiquimod study group will apply imiquimod 5% cream to the vulvar lesion 
beginning in the evening on Day 0, and will continue to apply treatment three times per 
week for 20 weeks (inclusive of administration in the evening of VGX-3100 dosing). 
Subjects unable to tolerate imiquimod treatment may reduce their dosing frequency, and 
will document their use on the imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74 and 96. Subjects will be monitored during the course of the study by 
vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed during 
vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96 visits. Using 
standardized high resolution digital photographic imaging, vulvar lesion(s) will also be 
quantitatively measured at Screening, Day 0, and Weeks 4, 12, 27, 48, 74 and 96.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced disease as judged by the Investigator, and must be  approximately 4 mm in 
length. Visible lesion must remain after screening biopsy to ensure measurement on 
study.  
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the qualifying lesion as study start from the region of potentially most 
advanced disease based upon the judgment of the Investigator (see Table 2 for 
Minimally Required Biopsy Procedures). If after evaluation of biopsy tissue by the PAC 
there is no evidence of HSIL (Figure 2, Subgroups A or B), the subject will continue to 
Week 74 for vulvoscopy, and biopsy of the same qualifying lesion as study start from the 
region of potentially most advanced disease based upon the judgment of the 
Investigator. 
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion 
size or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the 
Investigator has the option to give the subject a 5th dose of VGX-3100 at Week 52, and 
the subject will continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and 
the subject will continue on study without further biopsy. 
The decision process following results of the Week 74 biopsy are described in Figure 3 
and are as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as at study start Investigator(see Table 2). If after 


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evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), 
the subject will continue to Week 96 for vulvoscopy and biopsy of the same lesion as at 
study start. InvestigatorIf HSIL remains but there is a reduction in lesion size or no 
increase in lesion size from baseline (Subgroups C or D), the Investigator has the option 
to give the subject a 6th dose of VGX-3100 at Week 78, and the subject will continue on 
study with vulvoscopy and biopsy at Week 96. Alternatively, the Investigator may choose 
to treat the subject with surgical or standard treatment, and the subject will continue on 
study without further biopsy. 
The decision process following results of the Week 74 biopsy are as described in Figure 
4 and are as follows: At Week 96, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start, but from the region of potentially most 
advanced disease based upon the judgment of the Investigator. (see Table 2). If there is 
no vulvar HSIL (Subgroups A or B), no further procedures are required. If after 
evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or D), or 
worsening disease (Subgroup E), the subject will receive surgical or other standard 
treatment. 
In the event of worsening disease (i.e., Subgroup E - any increase in lesion area from 
baseline or worsening to cancer), the subject will receive surgical treatment per the 
Investigator's judgment and will continue on study through Week 100 with vulvoscopy, 
but without further study treatment or biopsy. For a finding of carcinoma, subjects will 
receive surgical treatment, and be discontinued from study treatment. The event will be 
reported as an SAE per section 7.1.4. If wide excision is required, the sample obtained 
will be sent to the PAC for evaluation.  
 
Table 2:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator. 
Acetowhite Lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator.  
Multiple acetowhite lesions 
Vulvar punch biopsies and lesion photography; biopsy should 
be conducted of the same qualifying lesions as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator. 
 
  
 
 DEFINITION OF RESPONDER AND NON-RESPONDER 
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive any non-study related treatment for vulvar HSIL. A treatment non-responder is a 
subject with histologic evidence of vulvar HSIL or vulvar carcinoma at evaluation, or a 
subject with evidence of HPV-16/18 at evaluation, or a subject who received non-study 


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related treatment for vulvar HSIL. Any case of histologically confirmed progression is 
considered a non-responder. Progression is defined as advancement to carcinoma by 
histology according to the PAC.  
Responder and non-responder definitions (Table 3) take into account both 
histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of 
HSIL. 
Table 3: Definition of Responder and Non-responder  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
 
 
Subject with histologic evidence of vulvar HSIL or  
vulvar carcinoma at evaluation 
  
OR 
 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
 
OR 
 
Subject who received non-study related treatment 
for vulvar HSIL 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, SUSARs, UADEs, and other unexpected AEs 
for the duration of the study. 
All subjects will be followed for 100 weeks.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight. 
The DSMB will meet quarterly to review safety data and regression/clearance results. 
The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue. No formal interim analysis is planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest, further enrollment and study treatment will be 
halted immediately until a thorough investigation has been conducted by the Medical 
Monitor, PI for the trial, and the DSMB.  
 
If any SAE (or potentially life-threatening AE) or death assessed as related to study 
treatment occurs, further enrollment and study treatment will be halted immediately 


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until a thorough investigation has been conducted by the Medical Monitor, PI for the 
trial, IRB (if applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 adverse 
event, assessed as related to study treatment, further enrollment and study 
treatment will be halted immediately until a thorough investigation has been 
conducted by the Medical Monitor, PI for the trial, and the DSMB. 
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, PI for the 
trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study will explore humoral and cell mediated immune responses to VGX-3100 in 
blood samples taken at baseline (i.e., Screening and Day 0 prior to dosing) and Weeks 
15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune 
responses at Screening and Weeks 48, 74 and 96.  
A blood sample from one time point during the study will be tested to explore the 
relationship between subject HLA types and regression. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize vulvar HPV infection at Screening, 
Weeks 48, 74 and 96. Cervical samples, oropharyngeal (OP) rinse samples, vulvar, 
vaginal, and intra-anal tissue swab samples will be obtained to characterize HPV 
infection at the following time points: Day 0 prior to dosing (OP, cervical, vulvar, vaginal 
and intra-anal), Week 4 (Vulvar only), Week 12 (Cervical and Vulvar) and Weeks 27, 48, 
74 and 96 (OP, vulvar, vaginal and intra-anal only). At week 48 and 96, a cervical 
sample will also be collected.  
 
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated 
date of first dose of study drug and have confirmed histologically confirmed vulvar HSIL 
by the Pathology Adjudication Committee at screening; 


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5. Must be judged by the Investigator to be an appropriate candidate for the protocol-
specified procedure (i.e. excision or biopsy) required at Week 48; 
6. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 
adequate size to ensure that a visible lesion remains after an approximately 4 mm 
screening biopsy;  
7. Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive 
method with failure rate of less than 1% per year when used consistently and 
correctly from screening until 6 months following the last dose of investigational 
product. Acceptable methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject's preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject's entry 
into the study, and this male is the sole partner for that subject. 
9. Normal screening electrocardiogram (ECG) or screening ECG with no clinically 
significant findings as judged by the Investigator. 
 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical 
care and/or treatment for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
7. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains 
after biopsy; 


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8. Treatment for genital warts within 4 weeks prior to screening; 
9. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 
4 weeks prior to screening; 
10. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream 
for subjects enrolled prior to Protocol Amendment v3.0 (dated 26Mar2019); 
11. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
12. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; 
13. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
14. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
15. Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks 
of each study dose; 
17. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
18. Current or history of clinically significant, medically unstable disease which, in the 
judgment of the Investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results  
a) Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher 
congestive heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the 
exception of superficial skin cancers that only require local excision; 
c) Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of Day 
0; 


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d) History of seizures unless seizure free for 5 years with the use of one or 
fewer antiepileptic agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or 
<90 mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 
bpm at Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
20. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening 
arrhythmia) (unless deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site 
(i.e. electroporation area);  
21. Vulnerable populations: 
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, 
would interfere with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study 
treatment/EP but will be encouraged to continue follow-up safety assessment through 
study discharge and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 


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 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw 
from study participation at any time. A subject may be withdrawn at any time at the 
discretion of the Investigator for any maternal obstetrical or medical complications after 
consultation with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report 
form (eCRF) and the subject's source document. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site 
should also counsel the subject on the importance of maintaining the assigned visit 
schedule for follow-up and treatment of VIN, and ascertain whether or not the subject 
wishes to and/or should continue in the study based on previous noncompliance. In 
cases where the subject does not return for the rescheduled visit or cannot be reached 
to reschedule the missed visit, the site should make every effort to regain contact with 
the subject (3 telephone calls to the subject should be made and if that fails, then a 
certified letter is sent to the subject's last known mailing address) so that they can be 
considered withdrawn from the study for disposition purposes. These contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will she be considered to have withdrawn from the 
study with a primary reason of "Lost to Follow-up". For all other subjects withdrawing 
from the study, an alternative reason for discontinuation should be recorded in the 
eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). 
At a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 100). A subject will be considered 
to have completed the study when she completes all scheduled study treatments and 
follow-up visits.  
 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or study coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an AE. If a subject discontinues from 
the study or is withdrawn from the study prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. The 
Investigator will make every effort to have all scheduled immune assessment blood 
samples collected as indicated in the Schedule of Events in the synopsis, Table 1. Any 
AEs and/or SAEs present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in section 7.1. 


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 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 
 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the Investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs 
regardless of relation to study drug. 
 
Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from 
further participation in the study in the absence of an Investigator-determined 
medical need to withdraw. If the subject gave a reason for withdrawal, it must be 
recorded on the eCRF. This reason does not allow for further data collection and 
should not be selected if follow-up data collection of this subject is anticipated by 
the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study. 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation 
should be discussed with the Sponsor’s Medical Monitor prior to discontinuation 
of study treatments or study withdrawal. 
 
Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter 
sent by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon™) technology. The VGX-
3100 formulation to be used in this study is described in Table 4 and will be presented in 
a clear glass vial for intramuscular injection. 
Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum. There are 24 single-use packets of imiquimod in one box. The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older. Although it is not approved by the US Food and 
Drug Administration for the treatment of vulvar HSIL, imiquimod is currently recommended 


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as a non-surgical, off-label treatment option for vulvar dysplasia by the American College 
of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 4. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  The actual product label names the product as 
VGX-3100X; the "X" designation was included to differentiate the current buffer 
formulation from a previous formulation of VGX-3100 in water. Imiquimod Cream, 5% will 
have both the original manufacturer's label on individual packets and the back of the 
carton, and an investigational label on the front of the carton. The labels will contain, at 
minimum, the information shown in Figure 6.   
 
 
Figure 5. Example Labels for VGX-3100 
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  


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Figure 6. Example labels for imiquimod 
 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: Imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Ophthalmic Use. 
Keep out of reach of children. This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer's instructions. Avoid freezing.    
5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. 
The product must be used within 4 hours of removal from the refrigerator. All material 
removed from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 


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 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations. Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks. Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water. Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. In the event 
that Imiquimod is not tolerated at 3 times per week, alternative administration 
approaches must be discussed and approved by the medical monitor. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period. The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 
5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. 
to be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor. 
If IP(s) 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 


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procedures, and appropriate records of the disposal have been documented. The 
unused IP can only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc. or designated Study Monitor. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the CELLECTRA™ 2000 device are located in the User 
Manual. Each clinical site will receive training for the use of the CELLECTRA™ 2000 
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 
The CELLECTRA™ 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA™ 2000 User 
Manual describes all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings, and precautions. Each CELLECTRA™ 2000 Pulse 
Generator has a unique serial number, and each CELLECTRA™ 2000 Applicator has a 
unique serial number. Each CELLECTRA™ 2000 Array has a Lot Number, Manufacture 
Date, and Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to 
successfully completing device training from sponsor personnel. 
5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 5 below are presented 
as examples. Please note, information such as expiration date, lot and serial numbers 
(as applicable) is included at the time of manufacture and may vary from these 
examples. The information found on the actual device labels should always be used to 
manage, track and record investigational product accountability during study conduct. 
 


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Table 5. Example Labels for the CELLECTRA™ 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA™ 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA™ 
2000 5P 
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 


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CELLECTRA™ IM 
Array 
 
REF: M01-002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. 
This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA™ 2000 IM Applicator is intended to be used multiple times on the 
same subject and then disposed after final use in accordance with accepted medical 
practice and any applicable local, state, and federal laws and regulations. Once the IM 
applicator is assigned to a subject, it may NOT be used on another subject. The used 
sterile disposable array attachment must be discarded after use in accordance with 
institutional policy regarding disposal of sharp needles/instruments. 
5.10 RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused 
components must be returned to Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original 
containers. The return of all product identified above should be arranged by the 
responsible Study Monitor. 
If product is to be destroyed on site, it is the Investigator's responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted 


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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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation. The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information 
collected prior to consenting and before any additional study specific procedures are 
performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate 
safety concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the 
samples sent to the central pathology lab for review by the PAC to assess eligibility. 
There will be a maximum allowable window of 10 weeks from the date of collection of 
the qualifying biopsy sample(s) (i.e. samples reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, an additional biopsy sample should be collected 
during screening following the consent of the subject. The 10 week screening window 
begins upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose vulvar specimens also test positive for other 
HPV genotypes are not excluded as long as they have a positive result for HPV-16 
and/or HPV-18.  
The assessments during the screening period will determine the subjects'' eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, and 
ECG which must be performed within 45 days prior to Day 0. All screening assessment 
values must be reviewed prior to study treatment. 
 
Signed informed consent  
 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 


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 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG within 45 days prior to Day 0 
 
Baseline laboratory evaluations (includes complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine 
aminotransferase [ALT], creatine phosphokinase [CPK], and urinalysis) to be 
performed within 45 days prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
HLA typing (may be performed at any time during study; only required to be 
performed once) 
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photograph of the vulvar lesion(s) must be collected prior to and after biopsy at 
screening 
 
If a historical biopsy sample is used to determine eligibility at screening and a 
pre-biopsy photograph is not available, a post biopsy photo will be sufficient.  
 
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC.  
 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment. Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 
 
Review of concomitant medications and adverse events 


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 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AE and injection site reaction assessment within 30-45 minutes 
after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 WEEK 4 (± 7 DAYS) 
The following study evaluations will be performed at Week 4 prior to study treatment  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 


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 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvar swab 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment injection site reaction assessment within 30-45 minutes after 
study treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device within 24 – 48 hours of study treatment 
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 (± 7 DAYS) 
The following study evaluations will be performed at Week 12 prior to study treatment:  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history 
 
Vulvar swab 
 
Vulvoscopy  


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 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device within 24 – 48 hours of study treatment 
 WEEK 15 (± 7 DAYS) 
The following study evaluations will be performed at Week 15: 
 
Review Adverse Events 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay including miRNA profile 
 WEEK 24 (± 7 DAYS) 
The following study evaluations will be performed at Week 24 prior to study treatment: 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod study group  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device within 24 – 48 hours of study treatment 


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 WEEK 27 (± 7 DAYS) 
The following study evaluations will be performed at Week 27: 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
  WEEK 38 PHONE CALL 
 
Review concomitant medications and adverse events 
  WEEK 48 (± 7 DAYS) 
The following study evaluations will be performed at Week 48: 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 


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 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 PATIENT REPORTED OUTCOMESWEEK 52 (± 14 DAYS) 
Subjects will have a Week 52 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Distribute Participant Diary 
Download EP data from device within 24 – 48 hours of study treatment 
  WEEK 74 (± 14 DAYS) 
The following study evaluations will be performed at Week 74: 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 


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  WEEK 78 (± 14 DAYS) 
Subjects will have a Week 78 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test (for subjects receiving a 6th dose only) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment injection site reaction assessment within 30-45 minutes after 
study treatment 
 
Distribute Participant Diary 
Download EP data from device within 24-48 hours of study treatment 
  WEEK 96 (± 14 DAYS) 
The following study evaluations will be performed at Week 96: 
 
Review of concomitant medications and adverse events 
 
Review Week 78 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabsVulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 


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  WEEK 100 (± 14 DAYS) 
The following study evaluations will be performed at Week 100: 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, 
study objectives, potential benefits and risks, discomforts/inconveniences, and the 
subject’s rights and responsibilities. The subject is then requested to sign and date the 
ICF. A copy of the signed informed consent documentation must be provided to the 
subject. The qualified study personnel will document the process of obtaining informed 
consent within the source record. Signed ICFs are maintained in the subject's source 
records and must be accessible for verification at any time. 
 RESCREENING OF SCREEN FAILURES 
 
Subjects who sign the informed consent and are assigned a subject identification     
 
number (SID) but do not meet the eligibility criteria or fall outside of the screening 
 
window will be considered screen failures. If the Investigator believes rescreening is 
 
warranted, the Investigator must contact the medical monitor to discuss.  
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique SID, which identifies the subject 
for all study-related procedures. SIDs are a combination of a up to two alpha letters 
study code, two alpha letter Country code, two digit site number, plus 3-digit subject 
number starting with 001 (e.g., VNUS01001). Once assigned, SIDs cannot be reused for 
any reason. Information regarding the SID and screen date must be documented on a 
Screening log/system and in the Interactive Response Technology (IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated 
allocation schedule.  


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 SAFETY EVALUATIONS 
6.3.4.1 
PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge (Week 100). It will include an assessment of the following: general 
appearance, skin, head, eyes, ears, nose, and throat, and lymph nodes, and 
respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and 
neurological systems. All assessments not completed should be marked as not 
done.  
A targeted physical assessment will be performed at other visits as determined 
by the Investigator or directed per subject complaints. 
6.3.4.2 
VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 
 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.4.3 
WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
6.3.4.4 
MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be 
obtained at screening. All relevant (as judged by the Investigator) past and 
present conditions, as well as prior surgical procedures will be recorded for the 
main body systems.  
6.3.4.5 
SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, 
history of prior cervical dysplasia, and pregnancy history will be obtained at 
Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to 
document any change from screening. 


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6.3.4.6 
LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 
6.3.4.7 
PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.4.8 
ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has 
been in a supine position for 10 to 15 minutes. The ECG should include 
measurements of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST 
segment, T wave as well as an Investigator assessment of whether the ECG is 
normal or abnormal (automated interpretations of ECG should not be used). 
Abnormal ECGs should be interpreted as "clinically significant (CS)" or "not 
clinically significant (NCS)" by the Investigator. 
6.3.4.9 
POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after 
the study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 


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 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.4.10 
IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 2000. Study treatment plus EP 
must not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is 
implanted metal within the same limb. Any device implanted in the chest (e.g., cardiac 
pacemaker, defibrillator or retained leads following device removal) excludes the use of 
the deltoid muscle on the same side of the body. The timing of the initial dose will be 
designated Day 0 with the subsequent doses scheduled for administration at Weeks 4, 
12, 24, and at Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 
RISKS OF TREATMENT PROCEDURES TO VGX-3100 
No serious related adverse events to VGX-3100 have been observed in the clinical trial 
experience to date. A summary of potential risks of IM Administration followed by EP 
with CELLECTRA™ can be found in the VGX-3100 + Imiquimod Investigator's Brochure.   
6.4.1.2 
RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
Adverse events reported in clinical trials with imiquimod cream, 5% for external genital 
warts can be found in the imiquimod product label [35], and in the VGX-3100 + 
Imiquimod Investigator's Brochure. 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION 
(EP) PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 


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approximately 1.5 cm diameter amount will be applied with occlusion to the site of 
injection ~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to treatment at day 0, Weeks 4 and/or 12. Subjects who 
receive a mild sedative should not be allowed to operate a motor vehicle for 3-4 hours 
after receiving medication and should have arranged transportation to depart the study 
site. 
Subjects may be offered an analgesic (e.g. acetaminophen, ibuprofen, ketorolac) before 
or after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, acetaminophen, 
ibuprofen, ketorolac or a mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.4.6.   
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 
minutes after each study treatment. Subjects will be advised to record local and systemic 
AEs for 7 days after each study treatment on a PD which will be reviewed with study 
personnel at 8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject's CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale: 
 


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Table 6. 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" 
*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 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes 
(PRO) instruments will be provided. Administration of PRO instruments will be performed 
according to the validated or otherwise developed procedures and instructions of each 
respective instrument. The following PRO questionnaires will be used: 
1. WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) Clinical Trial Version – 2.0 
(Beate Senn; version modified by Inovio Pharmaceuticals and RTI Health Solutions): is a 
31 item self-completed patient reported outcome measure designed to assess both 
physical and psychosocial impacts of VIN. The recall period is the past week.[20]. 
The WOMAN-PRO will be administered on paper only and should be the first PRO 
instrument administrated (i.e. before all other PROs) at each of the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 


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 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
2. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six 
items covering eight domains (Physical functioning, Role limitations due to physical 
problems, Bodily pain, General health, Vitality, Social functioning, Role limitations due to 
emotional problems, and Mental health) [36]. SF-36v2™ will be administered at the 
following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
3. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual 
activity, Pain/discomfort, Anxiety/depression, and Global health status) [37, 38] and will 
be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
4. Additional Global PRO Questions – regarding quality of life after surgery or biopsy. 
These two questions will be administered on paper at Week 52 only. 


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6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74 and 96. Details of the immunology sample 
collection and shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 
antibody response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune 
activity may occur via the application of the Interferon-γ enzyme-linked immunosorbent 
spot (IFN-γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
Profiling of miRNA will occur using plasma obtained at Day 0, Week 15 and 48.  
Assessment of Day 0 samples alone will explore predictive algorithms for response to 
treatment with VGX-3100 prior to dosing. Assessment of Week 15 and 48 samples will 
be done as a comparison against Day 0, in order to look for changes in miRNA profiles 
that occur once dosing with VGX-3100 has begun, to explore construction of an 
algorithm to predict treatment success with VGX-3100. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after HPV genotyping 
and histologic diagnoses have been rendered at Screening, Weeks 48, 74 and 96, then 
unstained slides and/or the relevant paraffin blocks may be collected for assessment of 
pro-inflammatory and immunosuppressive elements in tissue, where feasible. 
Assessment of markers may include, but are not limited to, CD8+ and FoxP3+ infiltrating 
cells as well as assessment of cell death via Cleaved Caspase 3 assessment. Additional 
assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-
L1 in cervical tissue as sample allows. Markers listed here may change as new relevant 
information becomes available. 
6.11 HLA TYPING 
HLA testing will be performed on PBMC from a single blood sample collected for 
immunogenicity analysis if available.  
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. 


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6.12 VULVAR HPV TESTING 
At Screening, Weeks 48, 74, and 96, a vulvar punch biopsy sample of approximately     
4 mm will be obtained and sent to a central laboratory for HPV genotyping by PCR. In 
the case of multifocal disease, a vulvar biopsy of approximately 4 mm will be obtained 
from two lesions that potentially contain the most advanced disease as judged by the 
Investigator. The subject will be requested to abstain from sexual activity and refrain 
from use of douching to eliminate potential interference with the results of HPV testing. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
vulvar punch biopsy to eliminate potential interference with the results of HPV testing. 
6.13 COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Day 0 and at Week 96 for all subjects. 
Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep® test kits at Day 0, Weeks 12, 48 and 96, 
and read in a central laboratory. HPV PCR will be performed on the ThinPrep® 
specimen. At each of these visits, menstrual cycle status & recent gynecologic history 
will be collected. If the Pap smear result suggests progression to cancer the Investigator 
may schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically 
indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep® samples to eliminate potential interference with the results of HPV testing. 
6.14 VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL 
confirmed by the PAC. Subjects will undergo vulvoscopy to identify the lesion(s). Interval 
vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74 and 96. Vulvoscopic 
visualization of a normal appearing vulva is insufficient evidence to confirm disease 
regression. An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. 
Digital photographs of the vulva will be captured after application of acetic acid to 
document the clinical findings. If a biopsy or surgical excision is performed, images of 
the vulva should be collected before and after the procedure. Each site will be instructed 
on 1) the technique for capturing the proper images using a standard approach, and 2) 
the process for uploading the images to a secure server.   
In the case of multifocal disease, the two lesions that potentially contain the most 
advanced disease as judged by the Investigator and which is of adequate size to ensure 
that a visible lesion remains after punch biopsy should be chosen for vulvar biopsy and 
documented using photography.     
Biopsies should not be performed at any visit other than at entry (screening), Week 48, 
Week 74 or Week 96 unless the PI suspects disease progression. All biopsy samples 
must be sent to the PAC for review. Investigator guidelines for managing the findings of 


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unscheduled biopsies for suspected disease progression are described in Table 7.  
Consult the Medical Monitor for any planned departures from these guidelines. 
Table 7:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
Subject safety is paramount in this study. Therefore, if at any time the Investigator 
suspects disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over 
the Schedule of Events on Table 1.  Histologic samples and photographic 
documentation should be obtained for these cases.  
6.15 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to 
screening biopsy date of eligible subjects must be recorded on the CRF. Actual or 
estimated start and stop dates must be provided. Medical procedures performed within 8 
weeks prior to screening biopsy date of eligible subjects that do not affect subject's 
eligibility for participation and during the study (including over the counter or herbal), will 
be recorded on the CRFs. This information will be obtained from the subject and 
abstracted from any available medical records. The indication for the medication, dose, 
and dose regimen will be documented. Medication that is considered necessary for the 
subject's safety and well-being may be given per Investigator discretion and recorded in 
the appropriate sections of the CRF. 
6.16 RESTRICTIONS 
The following medications and treatments are prohibited: 

Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening

Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20
mg/day of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic
corticosteroids are allowed)

Disease modifying doses of anti-rheumatic drugs (e.g., azathioprine,
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at
screening and throughout the study

Administration of any non-study related, non-live vaccine within 2 weeks of any study
treatment or within 4 weeks of any study treatment for any non-study related live
vaccine

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 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
Investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1). Lapses in contraceptive use should be reported to Investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep® samples.  
7.
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY
7.1 
SAFETY PARAMETERS 
ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and 
unsolicited AEs will be monitored and reported on an AE CRF, including the event's 
seriousness, severity, action taken, and relationship to investigational product(s). AEs 
should be followed until resolution or stable and the outcome will be documented on the 
appropriate CRF. All AEs should be recorded in standard medical terminology rather 
than the subject's own words. 
AEs include the following: 

Pre- or post-treatment complications that occur as a result of protocol mandated
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see
Section 7.1.11 for additional information.

AEs that occur from the study screening visit onwards and throughout the
duration of the study, including the follow-up off study drug period will be
recorded as an AE.

Conditions that lead to a medical or surgical procedure.
AEs do not include the following:


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
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction,
transfusion) performed as a result of an AE.

Pre-existing diseases or conditions or laboratory abnormalities present or detected
before the screening visit 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 informed consent form is signed is not an AE. It is considered to be
pre-existing and will be documented on the medical history CRF.

Uncomplicated pregnancy.

An induced elective abortion to terminate a pregnancy without medical reason.
SERIOUS ADVERSE EVENTS
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;

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 (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;

Results in persistent or significant disability/incapacity or substantial disruption of the
ability to conduct normal life functions;

Results in congenital anomaly or birth defect;

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 1)
allergic bronchospasm requiring intensive treatment in an emergency room or at
home, 2) blood dyscrasias or convulsions that do not result in inpatient
hospitalization, 3) the development of drug dependency or drug abuse or 4) the
development of a malignancy;
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.


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
Inpatient hospitalization means that 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 nor does it include full day or overnight stays in observation status.
The Investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
Serious adverse events that are ongoing should be followed until resolution or are 
clinically stable. The reporting period for SAEs is described in Section 7.4.2. 
EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE. For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of carcinoma should 
also be reported as an SAE. In both instances the condition for SAE reporting should be 
categorized as a medically important event unless another criterion is met. 
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a 
medicinal product related to any dose, for which a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility (i.e., there is 
evidence to suggest a causal relationship between the product and the adverse event). 
An unexpected ADR is one, the nature or severity of which is not consistent with the 
applicable product information (Investigator's brochure, protocol, and user manual). 
Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be 
considered “unexpected”. Specific examples would be (a) acute renal failure as a 
labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a 
first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is 
a serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating Investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the 
SUSAR will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating Investigators of information that might materially influence 
the benefit-risk assessment of a medicinal product, sufficient to consider changes in 
product administration or overall conduct of a clinical investigation. Examples of such 
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expected adverse event, the identification of a significant hazard to the subject 
population, or a major safety finding from a study conducted in animals. 
 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
Investigator within 24 hours. Sponsor will assess each device related SAE to determine 
if anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The Investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 
for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The Investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be 
assessed as not related to the IP and/or the investigational device. Because the 
Investigator is knowledgeable about the subject (e.g., medical history, concomitant 
medications), administers the IP, and monitors the subject’s response to the IP, the 
Investigator is responsible for reporting adverse events and judging the relationship 
between the administration of the IP and device and a subsequent AE. 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 IP 
delivered by EP and determine whether to report expeditiously to the regulatory 
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Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation 
of any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the IP and/or the investigational device indicating "yes" or 
"no" accordingly. Causality should be assessed by the Investigator as “yes, related” or 
“no, unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or the investigational 
device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to IP 
interruption or discontinuation must be recorded as an AE, or SAE, if applicable. In 
addition, laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital 
signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE (or SAE) as described in Section 7.1. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., 
anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the Investigator as clinically significant 
 POST-TRIAL 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 
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to the study treatment, he/she should promptly document and report the event to the 
study team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be 
excluded from participation in the study. Should a subject become pregnant after 
enrolling in the study, she will not be given any further study treatments. A Pregnancy 
Form will be completed by the site personnel and submitted to the sponsor within 24 
hours after learning of the pregnancy. Site personnel will submit the Pregnancy Form to 
the Sponsor as described in Section 7.4.2. 
The Investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject's permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results 
will be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be 
performed. Investigators should use clinical judgment regarding subsequent study-
related blood collection based on the presence or absence of anemia in each subject. 
Subjects who are not withdrawn will continue to be followed for safety assessments to 
study discharge per protocol.  
All pregnancies that occur from the time of first study treatment through the follow up 
visits must be reported. The Investigator will monitor the subject and follow the outcome 
of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome will be reported directly to the study team and the medical 
monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when 
informed consent is obtained through Week 100. 
The sources of AEs cover: 
1. 
The subject's response to questions about her health (a standard non-leading 
question such as ''How have you been feeling since your last visit?'' is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the 
Investigator to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject's health becoming known to the 
Investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  


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7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and 
urinalysis) 
 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented.  
 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 2000 that require expedited communication 
from the site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration 
recorded ≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted immediately until a thorough investigation has been conducted by the Medical 
Monitor and PI, the DSMB, and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI assessed as related to Study 
Treatment;  
 
Any subject experiences an SAE (or potentially life threatening AE) or death 
assessed as related to Study Treatment; 
 
Three or more subjects experience the same grade 3 or 4 adverse event, assessed 
as related to Study Treatment;  
 
In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to 
Study Treatment; 
Upon conclusion, the sponsor or designee will notify all Investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 


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7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), 
whether volunteered by the subject, discovered by Investigator or study staff 
questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded in the subject's source documents and followed as 
appropriate. 
TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised 
of the period following the signing of the informed consent form until the end of the 
study. Each AE will be assessed to determine whether it meets serious criteria. If the AE 
is considered serious, the Investigator should record this event in the EDC system and 
report the event to the Sponsor within 24 hours of becoming aware of the event. The 
Investigator may also directly report this event to the Ethics Committee according to its 
standard operating procedures. Expectedness of SAEs will be determined by the 
Sponsor using reference safety information specified in the Investigator's Brochure and 
protocol.  
An event may quality for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.5 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.6 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All Investigators will receive a safety letter notifying them of relevant SUSAR reports. 
The Investigator should notify the Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as is practical, of serious events in writing where this is required by local 
regulatory authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an Investigator becomes 
aware of an SAE that is suspected by the Investigator to be related to the study drug, the 
event will be reported to the Sponsor or its designee. If the Investigator becomes aware 
of an SAE in a study subject after the last scheduled follow-up visit, and considers the 
event related to prior Study Treatment, the Investigator will report it to the Sponsor or the 
appropriate designee. 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
 M.D., Ph.D. 
EMAIL:  
 


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SAE REPORTING INFORMATION 
EMAIL:  safety.inovio@apcerls.com 
SAFETY FAX: 
SAFETY PHONE: 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address 
as indicated above. Any SAE supporting documents provided by facsimile (Fax) are to 
include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The Investigator will supply the Sponsor and the IRB with more information as it 
becomes available and any additional requested information. The original SAE form 
must be kept at the study site. The Sponsor or its representative will be responsible for 
determining and in turn, reporting SAEs to regulatory authorities according to the 
applicable regulatory requirements. SAEs must be followed by the Investigator until 
resolution, even if this extends beyond the study-reporting period. Resolution of an SAE 
is defined as the return to baseline status or stabilization of the condition with the 
expectation that it will remain chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the 
Sponsor.  
In the event of a pregnancy, the Investigator will submit a Pregnancy Form to the 
Sponsor or designee to the safety email address or fax number within 24 hours of 
learning of the pregnancy. 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating Investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later 
than 10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 
15 days for all other SUSARS (see Section 7.1.5 and 7.1.6). 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
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reliability, safety, effectiveness, or performance of a device such as malfunction, misuse 
or use error and inadequate labeling. A malfunction is defined as the failure of a device 
to meet its performance specifications or otherwise perform as intended. The intended 
performance of a device refers to the intended use for which the device is labeled. All 
product complaints that meet this definition must be reported to the sponsor within 10 
days of discovery. Any product complaint that involves an AE or SAE must be also be 
reported per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error 
messages displayed on the device screen following treatment or errors that occur during 
the treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  
All complaints must be sent to ClinicalComplaint@inovio.com. Additional instructions on 
complaint reporting to be provided separately. 
7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at 
multiple sites for safety or administrative reasons at any time. In particular, a site that 
does not recruit at a reasonable rate may be discontinued. Should the study be 
terminated and/or the site closed for whatever reason, all non-source documentation and 
study product pertaining to the study must be returned to Inovio Pharmaceuticals or its 
representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research 
subjects are protected. 
8.
STATISTICAL ANALYSIS PLAN
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and 
VGX-3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and 
confirmed vulvar infection with HPV types 16 and/or 18. The study's primary endpoint is 
binary: regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from 
vulvar tissue based on tissue collected at Week 48. The primary hypothesis is that each 
of the treatment arms will result in regression of HSIL and clearance. Secondary efficacy 
analyses pertain to regression, clearance of HPV-16 and/or HPV-18 infection, regression 
to normal, non-progression, and anatomic extent. Other secondary analyses concern 
safety and humoral and cellular immunological measures. Exploratory efficacy analyses 
concern extended dosing with respect to regression, clearance, and anatomic extent, 
and clearance outside of the vulva, and effect of HLA type on efficacy. Other exploratory 
analyses pertain to tissue immunological measures and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 


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recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 
vs. 2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 
kg/m2), and (d) age category (<45 years vs. ≥45 years). There are no requirements for 
the number of subjects in each stratum. The study is open-label. 
The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical 
imiquimod study group.  All subjects who have already been enrolled into the VGX-3100 
with imiquimod study group will continue with all study visits per protocol, but no further 
participants will be enrolled into this group. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each study group superior to historical control with a one-sided 
0.025 type 1 error level for each hypothesis, assuming the true proportion of subjects 
who achieve the primary endpoint is 20% and 28% for the respective treatment arms 
and 2% for the historical control, and that 90% are evaluable at Week 48 from 
randomization. 
The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical 
imiquimod study group.  All subjects who have already been enrolled into the VGX-3100 
with imiquimod study group will continue with all study visits per protocol, but no further 
participants will be enrolled into this group. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized. Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized. 
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy. Subjects excluded from the PP 
population will be identified and documented prior to unblinding of the study 
database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment  for all randomized subjects and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial. The number and percentage of subjects 
who discontinued will be summarized overall and by reason. The number in each 
analysis population will also be presented. 


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8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, 
and percentages for categorical variables, by treatment arm, for the mITT population. 
Prior and concomitant medications will also be summarized with percentages in this 
fashion. 
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system, by treatment arm, for the mITT population. 
 
 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are considered those medications taken prior to the first dose of study 
drug (i.e., Day 0). Concomitant medications are those used on or after Day 0. Partial 
start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial 
date. Data for all prior and concomitant medications will be summarized with 
percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint for each arm. The primary hypothesis of 
superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment study group separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI 
exceeds 0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. 
For the analyses, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week.   
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) 
will be summarized with point estimates and associated exact Clopper-Pearson 95% 
confidence intervals. 
An exploratory analysis will examine clearance outside of the vulva. This will be 
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An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and a) HLA results, b) miRNA results, c) vulvoscopy results, and d) HPV 
results. Relationships will be examined with contingency tables and/or logistic regression 
models which model the primary endpoint versus these results and treatment group as 
regressor variables. 
8.10 IMMUNOGENICITY ANALYSIS 
 
Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 SAFETY ANALYSES 
 ADVERSE EVENTS 
All AEs will be summarized among the safety population by frequency per treatment 
arm. These frequencies will be presented overall and separately by dose, and will depict 
overall, by system organ class and by preferred term, the percentage of subjects 
affected. Additional frequencies will be presented with respect to maximum severity and 
to strongest relationship to Study Treatment. Multiple occurrences of the same AE will 
be counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of 
any dose. For this summary, the frequency of preferred term events will be summarized 
with percentages and exact Clopper-Pearson 95% confidence intervals. Separate 
summaries will be based on events occurring within 7 days of any dose and regardless 
of when they occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not 
be included within specified day-range summaries. AE duration will be calculated as 
(Stop Date – Start Date) + 1. 
 LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be 
summarized with mean, median, minimum, and maximum values, and categorical 
response variables will be summarized per time point with percentages, by treatment 
arm. Baseline is defined as the last measurement prior to the first treatment 
administration. 
 VITAL SIGNS 
Measurements for vital signs as well as changes from baseline will be summarized with 
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by time point and treatment arm, for the mITT population. Baseline is defined as the last 
measurement prior to the first treatment administration. 
 PHYSICAL EXAMINATION 
The percentage of subjects with abnormal physical examination findings at each time 
point will be summarized by treatment study group and by body system, for the mITT 
population. 
 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or exact 
Clopper-Pearson 95% CIs, for continuous responses and binary responses, 
respectively. 
 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study. 
9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles of 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The Investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained from 
the applicable IRB/EC and a copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 
During the conduct of the study, submit progress reports to the IRB/EC as required.  
 
Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 
If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 
As required, obtain approval from the IRB/EC for protocol amendments and for 
revisions to the consent form or subject recruitment advertisements; 
 
Reports on, and reviews of, the trial and its progress will be submitted to the IRB by 
the Investigator at intervals stipulated in their guidelines and in accordance with 
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 
Maintain a file of study-related information that includes all correspondence with the 
IRB; 
 
Notify IRB when study is completed (i.e. after the last study visit of the final study 
subject); 
 
After study completion provide the IRB with a final report on the study. 
9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., NIH 
Office of Biotechnology Activities) governing research that involves recombinant or 
synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening into the 
study, and/or from the subject's legally authorized representative. The process for 
obtaining informed consent must also be documented in the subject's medical record. 
9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating 
the study and re-approval or review at least annually. Sponsor is to be notified 
immediately if the responsible IRB/EC has been disqualified or if proceedings leading to 
disqualification have begun. Copies of all IRB/EC correspondence with the Investigator 
must be provided to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and, for subjects in the imiquimod 
study group, a dosing log during their study participation. Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 


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9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject's name will not be disclosed in these documents. 
The subject's name may be disclosed to the study sponsor, Sponsor, the governing 
health authorities or the Food and Drug Administration (FDA), if they inspect the study 
records. Appropriate precautions will be taken to maintain confidentiality of medical 
records and personal information. 
Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject's legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA)). 
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 the research subject to revoke their authorization for use of their 
PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. 
Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subject's diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, 
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and records kept at the pharmacy, at the laboratories, and at medical records and within 
information technology systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must 
be present in the source documents. All prescription and nonprescription medications 
taken within l week prior to entry must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. 
10.3 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The sponsor will inform the Investigator/institution as to when 
these documents are no longer needed to be retained. 
10.4 SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial. The DSMB will 
meet quarterly or as data are available to review safety data and regression/clearance 
results. If there are no new safety data or regression/clearance results to review for a 
quarterly scheduled meeting the DSMB will be notified and the meeting may be 
cancelled; Ad hoc meetings may be scheduled to review new data as applicable. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. 
No formal interim analysis will be performed. The DSMB Chair, upon consultation with 
the other voting members of the DSMB, has the authority to recommend suspension or 
stopping the study and to request a full DSMB review and ad hoc statistical analyses. 
The standard operating procedures of the DSMB will be documented in the DSMB 
charter, including the board's accountability to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of up to four pathologists. Each specimen will be read by two pathologists independently 
in a masked fashion. The responsibilities and membership structure of the PAC is 
outlined in the PAC Charter, including the reporting of results.  


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 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant 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 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 
 
Throughout the study, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, original, 
and accurate (ALCOAC).  
 
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 investigational drug and device accountability and reconciliation of 
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date 
of receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 


VGX-3100 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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Protocol Version: 3.0 
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12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Forms 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data & Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
EP 
Electroporation with Cellectra™ 2000 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
HSIL 
High grade squamous intraepithelial lesion 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-γ 
Interferon Gamma 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response Technology 
LAST 
Lower Anogenital Squamous Terminology 
mITT 
Modified Intent to Treat 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
Participant Diary  
PE 
Physical exam 


VGX-3100 
 
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Inovio Pharmaceuticals, Inc. 
 
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PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
PRO 
Patient Reported Outcomes 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
WOMAN-PRO                  WOMen with vulvAr Neoplasia PRO 
 
 
 
 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
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13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé 
S. . Human Papillomavirus and Related Diseases in USA., ICO Information Centre on 
HPV and Cancer (HPV Information Centre), Summary Report 30 June 2017. 2017. 
2. 
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé 
S. Human Papillomavirus and Related Diseases in Europe.  ICO Information Centre on 
HPV and Cancer (HPV Information Centre)  Summary Report 30 June 2017. 2017. 
3. 
Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. 
J Natl Cancer Inst 2015,107:djv086. 
4. 
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
Sheets:  Vulvar Cancer. 2016. 
5. 
Hartwig S, St Guily JL, Dominiak-Felden G, Alemany L, de Sanjose S. Estimation of the 
overall burden of cancers, precancerous lesions, and genital warts attributable to 9-valent 
HPV vaccine types in women and men in Europe. Infect Agent Cancer 2017,12:19. 
6. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
7. 
Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
8. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
9. 
Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, et al. Squamous vulvar 
intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology 
Subcommittee. J Reprod Med 2005,50:807-810. 
10. 
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: 
background and consensus recommendations from the College of American Pathologists 
and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 
2012,16:205-242. 
11. 
Inovio Pharmaceuticals. Unpublished assessment. 2015. 
12. 
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
natural history and outcome in 405 women. Obstet Gynecol 2005,106:1319-1326. 
13. 
van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
neoplasia III based on enough evidence? A systematic review of 3322 published patients. 
Gynecol Oncol 2005,97:645-651. 
14. 
Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
15. 
ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
Page 90 of 91 
 
16. 
Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia 
(VIN) usual type after surgical treatment. Med Sci Monit 2011,17:CR532-535. 
17. 
ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
Obstet Gynecol. 2016,128:e178-182. 
18. 
Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
19. 
Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
Market Research. 2016. 
20. 
Senn B, Eicher M, Mueller MD, Hornung R, Fink D, Baessler K, et al. A patient-reported 
outcome measure to identify occurrence and distress of post-surgery symptoms of 
WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study. Gynecol Oncol 
2013,129:234-240. 
21. 
Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
excision for vulvar intraepithelial neoplasia. J Reprod Med 2007,52:23-27. 
22. 
Petrosky E, Bocchini JA, Jr., Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-
valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations 
of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 
2015,64:300-304. 
23. 
Future II Study Group.  Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
24. 
Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a 
practical approach to diagnosis. J Clin Pathol 2014,67:290-294. 
25. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
26. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
27. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
28. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
29. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
30. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
31. 
Senn B. Creating and Validating a Patient-Reported Outcome Instrument for Women with 
Vulvar Neoplasia after Surgical-Treatment - A Mixed-Methods Project, Institute of Nursing 
Science (INS) University of Basel, University Hospital Berne, Switzerland. 2012. 
32. 
Senn B, Mueller MD, Hasenburg A, Blankenstein T, Kammermann B, Hartmann A, et al. 
Development of a postsurgical patient-reported outcome instrument for women with vulvar 
neoplasia. Oncol Nurs Forum 2012,39:E489-498. 


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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
Protocol Version Date: 26Mar2019 
 CONFIDENTIAL 
Protocol Version: 3.0 
Page 91 of 91 
 
33. 
U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER) CfBEaRC, Center for Devices and Radiological 
Health (CDRH). Guidance for Industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims. December 2009. 2009. 
34. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
35. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
36. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
37. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
38. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 


 
 
 
 
HPV-201 
 
 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF VGX-3100 
DELIVERED INTRAMUSCULARLY FOLLOWED BY ELECTROPORATION WITH 
CELLECTRA™ 2000 ALONE OR IN COMBINATION WITH IMIQUIMOD, FOR THE 
TREATMENT OF HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
 
 
IND #13683 
 
 
 
 
Version 5.0 
19 December 2019 
 
 


VGX-3100 
lnovio Pharmaceuticals, Inc. 
Medical Monitor Approval Page 
Drug: 
Sponsor: 
Medical Monitor: 
Approval Signature: 
M.D., Ph.D. 
VGX-3100 
lnovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
M.D., Ph.D. 
lnovio Pharmaceuticals, Inc. 
Date 
lnovio Pharmaceuticals, Inc. 
CONFIDENTIAL 
HPV-201 
Clinical Protocol 
The information in this document is considered privileged and confidential by lnovio 
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 lnovio Pharmaceuticals. Any 
supplemental information added to this document is also confidential and proprietary 
information of lnovio Pharmaceuticals and must be kept in confidence in the same manner 
as the contents of this document. 
Protocol Version Date: 19Dec2019 
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Page 2 of 99 
Protocol Version: 5.0 


VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
 
 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
 
 
I have read and understood this Protocol and agree that it contains all necessary details 
for carrying out the trial described. I understand that it must be reviewed by the 
Institutional Review Board or Independent Ethics Committee overseeing the conduct of 
the trial and approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator (PI) constitutes the PI's approval of this protocol 
and provides the necessary assurances that this trial will be conducted in accordance 
with ICH/GCP and ISO guidelines, local legal and regulatory requirements, and all 
stipulations of the protocol. 
 
 
Principal Investigator Signature: ___________________________________ 
 
 
 
________________________________  
    ____________________ 
Print Name of Principal Investigator 
 
    Date (DDMMMYYY)       
 
 
 
 
 
 
Site Number: ____________________________ 
 
Site Name: ______________________________ 
 
 
 
 
 
 
     
 
  
 
 
 
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Clinical Protocol 
 
 
SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 3.0 dated 26 March 2019 to Version 
5.0 dated 19 December 2019.  Protocol Amendment 4.0 was prepared by the Sponsor, but was 
not distributed to sites nor submitted to the FDA.  Since Version 4.0 was finalized internally and 
never implemented, it was not be incorporated into this protocol.  This amendment notes 
changes since Version 3.0 only.  Changes not listed in this summary are administrative and do 
not affect the safety or subjects, trial scope, or scientific quality of the protocol. 
 
1. Protocol HPV-201 has been amended to end at Week 78 instead of Week 100.  This 
change is prompted by a decision to focus on a 4-dose regimen for the development of 
VGX-3100 for vulvar HSIL, with the potential for a booster dose at Week 52.  A 6th dose 
will not be pursued, therefore optional dose 6 and the corresponding visits at Weeks 96 
and 100 have been removed.  Subjects who were already beyond Week 78 or who had 
received dose 6 prior to Amendment 5.0, will complete the study at the next scheduled 
timepoint following consent on the associated IRB-approved informed consent form and 
data collected will be analysed.  Cervical colposcopy, scheduled for Week 96, will be done 
at Week 74 or discharge, for subjects who end the study at Week 78.  The socio-behavioral 
evaluation scheduled for Week 100, will be done at the subjects final discharge visit.     
2. The estimated number of Study Centers and Countries/Regions has been updated to 
more accurately reflect site participation.  
3. Secondary endpoint #1b (Protocol Synopsis and Section 2.2) was updated to include 
adverse events of special interest (AESIs) which is included amongst the adverse events 
evaluated for secondary objective #1, but was inadvertently not mentioned. 
4. Secondary Endpoint #6 was modified to remove Week 74 and 96 from the secondary 
endpoint analysis since these timepoints are evaluated in Exploratory Endpoint #1. 
5. Secondary Endpoints #7a and #7b have been moved to Exploratory Endpoint #8a and 
#8b.   
6. Secondary Endpoint #8 and Exploratory Endpoint #9 have been added to evaluate the 
efficacy of VGX-3100 treatment alone or in combination with imiquimod, on HPV-16/18 
positive vulvar HSIL at Week 48, as HPV-16/18 associated HSIL is considered a 
significantly higher risk for vulvar cancer.  
7. Exploratory Endpoints #2, #3, and #9 have been updated to include the efficacy of four 
doses as well as more than 4 doses.  Clarifying text has been added to Section 8.9 
regarding the analysis as it relates to the Week 74 and 96 evaluation according to number 
of doses received.   
8. HLA haplotyping and associated Exploratory Endpoint #6 have been removed from the 
protocol due to consideration of the results from Inovio’s Phase 2 cervical study which 
showed no clear association of HLA background as a predictor of response.  No testing 
has been performed on HPV-201 subject samples.  HLA testing has been removed from 
all applicable protocol sections and the ICF has been updated to remove this procedure. 
9. Section 3.2 and the Protocol Synopsis have been updated to indicate that sites will biopsy 
all lesions at Weeks 48, 74, and 96 (as applicable).  New lesions, and lesions that did not 
qualify at Screening, should be biopsied post-screening and sent for evaluation.  
Pathology and genotyping results will be included in the determination of efficacy for the 
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primary, secondary, and exploratory endpoints.  This has been updated accordingly in 
Section 8.9 of the protocol. 
10. Responder and non-responder definitions for the Secondary/Exploratory endpoints have 
been provided in Section 3.2.      
11. The Efficacy Assessment (Protocol Synopsis and Section 3.2) has been updated to 
differentiate between lesion photographs and lesion measurements.  Lesion 
measurements are only done at Screening, Day 0, Week 48, Week 74, and at Week 96 
as applicable.    
12. Figure 2 has been updated to align with wording in the protocol indicating that subjects in 
Subgroup E continue on study with vulvoscopy, but without further study treatment or 
biopsy, in place of the previous inconsistent wording that subjects in Subgroup E are 
followed for safety only.  All procedures outlined in the schedule of events are conducted 
on subjects in Subgroup E, except for biopsy or additional study treatment. 
13. The Decision process at Week 52 in the Efficacy Assessment (Protocol Synopsis and 
Section 3.2) has been updated to include new lesions identified at evaluation.  A 
discussion will take place between the Medical Monitor and the Principal Investigator to 
determine if additional dosing is appropriate when new HPV-16/18 high-grade vulvar 
lesions are identified. 
14. The stopping rules in the protocol synopsis and in Section 7.3.2 have been updated to 
account for the verification process required following entry of an adverse event into the 
database.   
15. Protocol Administrative Memo #2 (dated 20Dec2017) and #3 (dated 20Aug2018) have 
been incorporated into the protocol as follows: 
 
Exclusion Criteria #15 (in Protocol Version 1.3 dated 21Apr2017, Exclusion criteria 
#12 in the current protocol) was intended to exclude subjects with unresolved lab 
abnormalities.  If the lab is redrawn and the result from the redrawn sample no longer 
meets exclusion criteria, then the subject should not be excluded on the basis of this 
criterion.  
 
Exclusion Criteria #12 was clarified to indicate that subjects with the presence of any 
unresolved abnormal clinical laboratory value greater than Grade 1 per CTCAE v4.03 
within 45 days prior to Day 0, or less than or equal to Grade 1, but deemed clinically 
significant by the investigator, will be excluded from the protocol. 
 
Section 8.11.2 has been removed as safety labs are done only once at screening, 
therefore changes in laboratory parameters cannot be analyzed.  
16. Section 5.6 has been updated to indicate that authorized site representatives can return 
unused IP in the absence of the Study Monitor.  In addition, as sites adhere to their SOPs 
for the destruction of unused IP, reconciliation of IP must be provided to the Sponsor or 
Sponsor designee for review prior to on-site destruction.      
17. Section 5.10 has been updated to indicate that an Inovio representative will provide 
instructions for the destruction and/or return of device materials. 
18. Sections 6.2.10, 6.2.12, and 6.2.14 were updated to clarify that lesion photograpy is done 
pre and post biopsy, and quantitative measurement is done pre-biopsy only 
19. The 24 – 48 hour timeframe for download of EP data from the device was removed from 
Sections 6.2.1, 6.2.3, 6.2.5, 6.2.7, 6.2.11, and 6.2.13.  It is essential that data is 
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downloaded, however the requirement to complete this task within 24 – 48 hours of 
electroporation was unnecessarily restrictive. 
20. The timeframe around daily activity for grading injection site reactions has been defined 
in Table 11.  The Sponsor defined timeframe for daily activity, is an impact lasting ≥ 24 
hours. 
21. Changes in safety lab parameters as an assessment performed by the Medical Monitor 
has been removed from Section 7.3 since safety labs are done only once at screening.  
Adverse events that arise as a consequence of lab abnormalities will be recorded as AEs 
per section 7.1.9 and will be assessed by the Medical Monitor.  
22. The Medical Monitor for this study has changed.  The contact information for the Medical 
Monitor has been updated on the Medical Monitor Approval Page and in Section 7.4.2. 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ............................................................. 3 
SUMMARY OF CHANGES ........................................................................................................ 4 
CLINICAL PROTOCOL SYNOPSIS .........................................................................................12 
STUDY SCHEDULE OF EVENTS ............................................................................................25 
1. 
INTRODUCTION ...........................................................................................................27 
1.1 
Background ........................................................................................................27 
 
Human Papillomavirus and Infection ......................................................27 
 
Vulvar Cancer ........................................................................................27 
 
Vulvar Intraepithelial Neoplasia (Vulvar HSIL) ........................................27 
 
Recurrent Disease with Current Therapeutic Options .............................28 
 
Psychological and Physical Impacts of Current Therapeutic Options ......29 
 
Impact of Vulvar HSIL Upon Activities of Daily Living .............................29 
 
Limitations of Prophylactic HPV Vaccines ..............................................30 
 
Enhanced Monitoring Plan .....................................................................30 
 
VGX-3100 ..............................................................................................30 
 Electroporation .......................................................................................31 
 Imiquimod Cream, 5% ............................................................................31 
 Study Rationale ......................................................................................31 
 Dose and Regimen Rationale for VGX-3100 ..........................................31 
 Rationale for imiquimod ..........................................................................32 
 Inclusion of WOMAN-PRO, Clinical trial version 2.0 ...............................32 
 Potential Risks of investigational products ..............................................32 
 Potential Benefits of Study Participation .................................................33 
2. 
HYPOTHESIS AND STUDY OBJECTIVES ..................................................................33 
2.1 
Primary Objective and Endpoint .........................................................................33 
2.2 
Secondary Objectives and Associated Endpoints ..............................................34 
2.3 
Exploratory Objectives and Associated Endpoints .............................................35 
3. 
STUDY DESIGN ...........................................................................................................36 
3.1 
Treatment Regimens .........................................................................................37 
3.2 
Efficacy Assessment ..........................................................................................37 
 
Definition of Responder and Non-Responder for the Primary 
Endpoint .................................................................................................39 
 
Definition of Responder and Non-Responder for the Secondary AND 
EXPLORATORY Endpoints ....................................................................40 
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3.3 
Safety Assessment ............................................................................................41 
 
Data Safety & Monitoring Board .............................................................41 
3.4 
Immunogenicity Assessment .............................................................................42 
3.5 
Virologic Assessment .........................................................................................42 
4. 
SELECTION OF SUBJECTS ........................................................................................42 
4.1 
Inclusion Criteria ................................................................................................42 
4.2 
Exclusion Criteria ...............................................................................................43 
4.3 
Discontinuation/Withdrawal of Study Subjects ...................................................45 
 
Criteria for Discontinuation of Investigational Product .............................45 
 
Criteria for Withdrawal from the Study ....................................................46 
 
Sponsor Notification of Discontinuation/Withdrawal ................................47 
 
Reason for Discontinuation/Withdrawal ..................................................47 
5. 
STUDY TREATMENT ...................................................................................................47 
5.1 
Investigational Products .....................................................................................47 
5.2 
Packaging and Labeling .....................................................................................48 
 
Packaging and Labeling of VGX-3100 and Imiquimod ............................48 
5.3 
Handling and Storage ........................................................................................49 
5.4 
Preparation and Dispensing ...............................................................................50 
 
Dispensing of VGX-3100 ........................................................................50 
 
Dispensing and Use of Imiquimod ..........................................................50 
5.5 
Investigational Product Accountability ................................................................50 
5.6 
Return and Destruction of Investigational Product ..............................................51 
5.7 
Use of Investigational Device .............................................................................51 
5.8 
Packaging and Labeling of Investigational Device..............................................52 
5.9 
Investigational Device Accountability .................................................................54 
5.10 
Return AND DESTRUCTION of Investigational Devices ....................................54 
6. 
STUDY PROCEDURES AND TREATMENTS ..............................................................55 
6.1 
Before Treatment Procedures ............................................................................55 
 
Screening evaluations ............................................................................55 
6.2 
During Treatment Procedures by Visit ................................................................56 
 
Day 0 ......................................................................................................56 
 
8-14 Days Post Dose 1 Phone Call ........................................................57 
 
Week 4 (± 7 days) ..................................................................................57 
 
8-14 Days Post Dose 2 Phone Call ........................................................58 
 
Week 12 (± 7 days) ................................................................................58 
 
Week 15 (± 7 days) ................................................................................59 
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Week 24 (± 7 days) ................................................................................59 
 
Week 27 (± 7 days) ................................................................................60 
 
Week 38 Phone Call ...............................................................................60 
 Week 48 (± 7 days) ................................................................................60 
 Week 52 (± 14 days) ..............................................................................61 
 Week 74 (± 14 days) ..............................................................................61 
 Week 78 (± 14 days) ..............................................................................62 
 Week 96 (± 14 days) ..............................................................................62 
 Week 100 (± 14 days) ............................................................................63 
6.3 
Evaluations and Procedures ..............................................................................63 
 
Informed Consent ...................................................................................63 
 
Rescreening of Screen Failures .............................................................64 
 
Assignment of Subject Identification Numbers ........................................64 
 
Safety Evaluations ..................................................................................64 
6.4 
Injection and Electroporation (EP) ......................................................................66 
 
Risks of Treatment Procedures ..............................................................67 
 
Management of Anxiety and Pain Due to Electroporation (EP) 
Procedure ...............................................................................................67 
6.5 
Assessment of Laboratory Abnormalities ...........................................................67 
6.6 
Assessment of Clinical Study Adverse Events ...................................................68 
6.7 
Assessment of Injection Site Reactions .............................................................68 
6.8 
Assessment of Patient Reported Outcomes .......................................................69 
6.9 
Peripheral Blood Immunogenicity Assessments .................................................70 
6.10 
Tissue Immunogenicity Assessment ..................................................................71 
6.11 
Vulvar HPV Testing ............................................................................................71 
6.12 
Colposcopy, PAP Smears and HPV Testing ......................................................71 
6.13 
Vulvoscopy, Photographs, and Biopsies ............................................................72 
6.14 
Concomitant Medications/Treatments ................................................................73 
6.15 
Restrictions ........................................................................................................73 
 Other Restrictions ...................................................................................73 
7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ................................74 
7.1 
Safety Parameters .............................................................................................74 
 
Adverse Events ......................................................................................74 
 
Serious Adverse Events .........................................................................75 
 
Clarification of Serious Adverse Events ..................................................75 
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Clinical Protocol 
 
 
 
Event Reporting for Disease Progression or Exclusionary Histologic 
Findings Post-Study Treatment ..............................................................76 
 
Unexpected Adverse Drug Reactions and Expedited Reporting .............76 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .........................76 
 
Assessing Severity (Intensity) .................................................................77 
 
Casual Relationship of Clinical Material to Adverse Events ....................77 
 
Abnormal Laboratory Value ....................................................................78 
 Post-Trial Reporting Requirements.........................................................78 
 Procedures for Documenting Pregnancy During Study ...........................78 
7.2 
Methods and Timing of Collection of Safety Data ...............................................79 
7.3 
Safety and Toxicity Management .......................................................................79 
 
Adverse Events of Special Interest .........................................................80 
 
Stopping Rules (Criteria for Pausing of Study) .......................................80 
7.4 
Adverse Experience Reporting ...........................................................................80 
 
Trial Reporting Period of Adverse Events ...............................................80 
 
Trial Reporting Period of Serious Adverse Events ..................................81 
 
Notification of Serious Adverse Events ...................................................82 
 
Reporting of Device Related Complaints ................................................82 
7.5 
Trial Discontinuation ..........................................................................................83 
8. 
STATISTICAL ANALYSIS PLAN ..................................................................................83 
8.1 
General Considerations .....................................................................................83 
8.2 
Randomization and blinding ...............................................................................83 
8.3 
Sample Size/Power ............................................................................................83 
8.4 
Analyses Populations .........................................................................................84 
8.5 
Subject Disposition ............................................................................................84 
8.6 
Demographic and Other Baseline Characteristics ..............................................84 
8.7 
Medical History ..................................................................................................84 
8.8 
Prior and Concomitant Medications ...................................................................85 
8.9 
Efficacy Analysis ................................................................................................85 
8.10 
Immunogenicity Analysis ....................................................................................85 
8.11 
Safety analyses .................................................................................................86 
8.12 
Patient Reported Outcomes ...............................................................................86 
8.13 
Missing Values ...................................................................................................86 
8.14 
Interim analyses .................................................................................................86 
9. 
ETHICS .........................................................................................................................87 
9.1 
Investigator and Sponsor Responsibilities ..........................................................87 
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Clinical Protocol 
 
 
9.2 
Institutional Review Board or Ethics Committee (IRB/EC) ..................................87 
9.3 
Office of Biotechnology Activities (OBA) ............................................................87 
9.4 
Compliance with Informed Consent Regulations ................................................87 
9.5 
Compliance with IRB/EC Requirements .............................................................87 
9.6 
Compliance with Good Clinical Practice .............................................................88 
9.7 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11)
 ..........................................................................................................................88 
9.8 
Compliance with Protocol ...................................................................................88 
9.9 
Changes to the Protocol.....................................................................................88 
10. 
DATA COLLECTION, MONITORING AND REPORTING .............................................88 
10.1 
Confidentiality and Privacy .................................................................................88 
10.2 
Source Documents ............................................................................................89 
10.3 
Records Retention .............................................................................................89 
10.4 
Safety and Quality Monitoring ............................................................................90 
 Data & Safety Monitoring Board .............................................................90 
 Pathology Adjudication Committee .........................................................90 
 Clinical Monitoring ..................................................................................90 
11. 
PUBLICATION POLICY ................................................................................................91 
12. 
LIST OF ABBREVIATIONS ..........................................................................................92 
13. 
REFERENCES ..............................................................................................................94 
14. 
APPENDICES ...............................................................................................................97 
Appendix A: Figure 1. Study Visit Schedule, Original Study Design ..................................97 
Appendix B: Figure 3. Decision Process at Week 78, Original Study Design .....................98 
Appendix C: Figure 4. Evaluation Process at Week 100, Original Study Design ................99 
 
 
 
 
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HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
CLINICAL PROTOCOL SYNOPSIS 
Title of Study: A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation with CELLECTRA™ 2000 Alone or in Combination 
with Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous 
Intraepithelial Lesion (HSIL) of the Vulva  
Estimated Number of Study Centers and Countries/Regions: Approximately 20 sites in the 
United States (US)  
Study Phase: 2 
Hypothesis: Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of 
HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 given alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL1 associated with HPV-16 and/or HPV-18 (HPV-16/18), will 
result in a higher percentage of women with regression of HSIL of the vulva based on histology 
(i.e. biopsies or excisional treatment) and virologic clearance of HPV-16/18 from vulvar tissue 
compared with historical control. 
Dose of VGX-3100 
6 mg (1 mL) 
Dose of Imiquimod 
12.5 mg imiquimod 5% topical cream 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 
2000 device alone or in combination with topical imiquimod 
VGX-3100 Dosing Schedule 
Day 0, Weeks 4, 12, and 24, with additional doses given to 
partial responders at Weeks 52 and 78 
Imiquimod Dosing Schedule 
Three times per week (3x) from Day 0 through Week 202 
No. of Subjects 
Approximately 363 subjects 
Study Duration 
Up to 100 weeks4 
Primary Objective 
Determine the efficacy of four doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined 
histopathologic regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Primary Endpoint 
Proportion of subjects with no histologic evidence of vulvar 
HSIL5 and no evidence of HPV-16/18 at Week 48 in vulvar 
1 Throughout this protocol high grade disease (previously known as VIN2 or VIN3) is referred to as vulvar HSIL 
according to the 2015 International Society for the Study of Vulvovaginal Disease (ISSVD) Terminology of Vulvar 
Squamous Intraepithelial Lesions and 2012 consensus recommendation on Lower Anogenital Squamous Terminology 
(LAST) from the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College of American 
Pathologists (CAP). 
2 Inclusive of administration on day of dosing. 
3 The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical imiquimod study group.  All 
subjects who have already been enrolled into the VGX-3100 with imiquimod study group will continue with all 
study visits per protocol, but no further participants will be enrolled into this group. 
4 Protocol amendment 5.0 removes Week 96 and 100 from the schedule of events as well as optional dose 6 at Week 
78.  Data collected on subjects who have already completed these visits and received dose 6 at the time of IRB 
approval, will be analysed as planned 
5 No evidence of vulvar HSIL is defined as normal tissue or vulvar LSIL (VIN 1) or condyloma 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
tissue samples (i.e. collected via biopsy or excisional 
treatment)6 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in combination 
with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary.   
1b. All adverse events including SAEs, 
AESIs, SUSARs, UADEs, and other 
unexpected AEs for the duration of the 
study (through Week 100 visit)4 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2.  Proportion of subjects with no 
evidence of vulvar HSIL5 on histology 
(i.e. biopsies or excisional treatment) at 
Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by virologic clearance of HPV-
16/18 in vulvar tissue 
3. Proportion of subjects with no evidence 
of HPV-16/187 in vulvar tissue samples 
at Week 48 visit 
4. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence 
of vulvar HSIL, no evidence of LSIL 
(VIN1), and no evidence of condyloma  
on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
as measured by non-progression of vulvar 
HSIL to vulvar cancer as determined by 
histology  
5. Proportion of subjects with no 
progression8 of vulvar HSIL to vulvar 
cancer from baseline to Week 48 visit 
6 A treatment responder for the primary endpoint is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not receive any non-study related 
treatment for vulvar HSIL. A treatment non-responder is defined as a subject with histologic evidence of vulvar 
HSIL or vulvar carcinoma at evaluation, or a subject with evidence of HPV-16/18 in vulvar tissue at evaluation, or a 
subject who received non-study related treatment for vulvar HSIL.   
7 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
8 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication 
Committee. 
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Clinical Protocol 
 
 
6. Determine the efficacy of VGX-3100, alone or in 
combination with imiquimod, as measured by 
reduction in the surface area of qualifying9 
vulvar lesion(s) 
6. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized pre-
biopsy photographic imaging of 
qualifying lesion(s) at Week 48 
compared to baseline10. Results will be 
classified as: no clinically significant 
lesion resolution (reduction in lesion area 
of 0-25%), partial lesion area resolution 
(>25% and <100% reduction) and 
complete lesion resolution (no visible 
lesion).   
7. Describe the cellular immune response to 
VGX-3100, administered alone or in 
combination with imiquimod,  post dose 4 
7. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
8. Determine the efficacy of four doses of VGX-
3100 alone or in combination with imiquimod 
with respect to histopathologic regression of 
vulvar HSIL or virologic clearance of HPV-16/18 
in vulvar tissue  
8.   Proportion of subjects with no histologic 
evidence of vulvar HSIL5 or no 
evidence of HPV-16/18 at Week 48 in 
vulvar tissue samples (i.e. collected via 
biopsy or excisional treatment) 
9 A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive and 
have histologically confirmed vulvar HSIL by the PAC at screening. 
10 Baseline photographic imaging is defined as photographs obtained at Day 0 prior to the first study dose. Digital 
photos will be analyzed with a computer program to calculate the total lesion size in cm².   
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Clinical Protocol 
 
 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying9 vulvar lesion(s), in subjects who 
did not have complete lesion resolution at Week 
48 
1. Percent reduction in the cumulative 
surface area of the acetowhite vulvar 
lesion(s) as determined by the 
quantitative analysis of standardized 
pre-biopsy photographic imaging of 
qualifying lesion(s) at Week 74 and/or 
Week 96 compared to baseline10. 
Results will be classified as: no 
clinically significant lesion resolution 
(reduction in lesion area of 0-25%), 
partial lesion area resolution (>25% and 
<100% reduction) and complete lesion 
resolution (no visible lesion).   
2. Describe the long term efficacy of VGX-3100, 
alone or in combination with prior imiquimod, as 
measured by histologic regression of vulvar 
HSIL 
2. Proportion of subjects with no evidence 
of vulvar HSIL on histology (i.e. biopsies 
or excisional treatment) at Week 74 for 
subjects who receive 5 doses of VGX-
3100 and at Week 96 for subjects who 
receive 6 doses of VGX-3100 
3. Describe the long term efficacy of VGX-3100, 
alone or in combination with prior imiquimod, as 
measured by virologic clearance of HPV-
16/18  
3. Proportion of subjects with no evidence 
of HPV-16/18 in vulvar tissue samples at 
Week 74 and/or Week 96. 
4. Evaluate tissue immune responses to VGX-
3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue11  
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared 
HPV-16/18 on specimens from non-
vulvar anatomic locations without 
surgical intervention (inclusive of cervix, 
oropharynx, vagina and intra-anus) at 
Week 48 compared to baseline 
6. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
6. Vulvoscopy, HPV test results (vulvar 
swab and vulvar tissue) and miRNA 
profile (Day 0, Week 15 and 48) in 
conjunction with histologic regression of 
vulvar HSIL at Week 48 visit 
7. Describe patient reported outcomes (PRO) for 
subjects treated with VGX-3100 and VGX-3100 
with imiquimod 
7.  PRO endpoints will be obtained at Day 
0 prior to first dose, Weeks 4, 12, 24 
after dosing, and at Weeks 15, 27, 48, 
52, 74, and Weeks 96, and 100 as 
applicable. 
11 Additional assessments may include visualization of PD-L1, Granulysin, perforin, CD137, CD103 and possibly 
other relevant markers identified in the literature in vulvar tissue as sample allows. 
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Clinical Protocol 
 
 
8. Describe the humoral and cellular immune 
response of VGX-3100 administered alone or 
in combination with imiquimod, post dose 3, 
post dose 4, and after additional dosing 
8a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Weeks 15, 27, 48, 74, and 96 
visits 
8b. 
Interferon-γ 
ELISpot 
response 
magnitudes at baseline and Weeks 15, 
27, 48, 74 and 96 visits 
9. Determine the long term efficacy of VGX-3100 
alone or in combination with imiquimod with 
respect to histopathologic regression of vulvar 
HSIL or virologic clearance of HPV-16/18 in 
vulvar tissue  
9.   Proportion of subjects with no histologic 
evidence of vulvar HSIL5 or no evidence 
of HPV-16/18 at Week 74 and 96 in 
vulvar tissue samples (i.e. collected via 
biopsy or excisional treatment) 
 
 
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VGX-3100 
 
HPV-201 
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Clinical Protocol 
 
 
Study Design:  
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids encoding 
E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed by EP delivered 
with CELLECTRA™ 2000 alone or in combination with imiquimod in adult women with histologically 
confirmed vulvar HSIL associated with HPV-16 and/or 18. Approximately 36 subjects will be enrolled. 
Approximately twenty-four subjects will receive VGX-3100 alone and 12 subjects will receive VGX-
3100 and topical imiquimod treatment. The Version 3.0 protocol amendment halts enrollment of the 
VGX-3100 with topical imiquimod study group.  All subjects who have already been enrolled into the 
VGX-3100 with imiquimod study group will continue with all study visits per protocol, but no further 
participants will be enrolled into this group. 
Subjects are randomized in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 
or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass 
Index (BMI) category (≤25 vs. >25 kg/m2) on Day 0, and (d) age category (<45 years vs. ≥45 years) 
on Day 0.   
To be eligible for the study, subjects must consent to participate and have a vulvar punch 
biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of the acetowhite 
vulvar lesion(s) at the time of screening. In the case of multifocal disease, the two lesions that 
potentially contain the most advanced disease, as judged by the Investigator, should be chosen for 
biopsy using vulvoscopy and documented using standardized high resolution photography with a 
digital single-lens reflex (SLR) camera. Biopsy slides will be sent to the Pathology Adjudication 
Committee (PAC) by the central laboratory for evaluation prior to enrollment. In order to be eligible for 
enrollment, the PAC must assign the diagnosis of vulvar HSIL based on the biopsy sample(s). 
Subjects must also have a vulvar tissue specimen test positive for HPV genotype 16 and/or 18 to be 
eligible for participation in the study. 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) instruments 
will be provided and will include the Short Form Health Survey version 2 (SF-36v2™) (Optum), the 
EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvAr Neoplasia) Clincial 
Trial Version 2.0 and two additional PRO questions assessing quality of life after surgery or biopsy. 
All eligible subjects who consent to participate in the study will receive at least four doses of 6 mg of 
VGX-3100 administered by IM injection followed by EP. The first dose will be administered as soon as 
possible following confirmation of the HSIL diagnosis, HPV-16/18 status and all other eligibility criteria, 
but no more than 10 weeks following collection of the subject's biopsy specimen used for diagnosis by 
the PAC.  
Each dose of VGX-3100 will be administered in a 1 mL volume IM followed immediately by EP with 
the CELLECTRA™ 2000 device. Figure 1 (Appendix A) shows the original study visit schedule in 
which study subjects receive 4 doses of VGX-3100 and potentially a 5th and 6th dose depending upon 
their disposition with regard to histologic and lesion area changes. Figure 1a below shows the revised 
visit schedule per Protocol Amendment 5.0.  In both schedules, the first dose will be administered on 
Day 0, the second at Week 4, the third at Week 12, and the fourth dose will be administered at Week 
24. Subjects with no HSIL at Week 48 (Subgroups A and B) will receive 4 doses. Subjects with HSIL 
at Week 48, who have a reduction in lesion size or no increase in lesion size from baseline 
(Subgroups C or D), may receive a fifth dose of VGX-3100 administered IM with EP at Week 52 per 
the judgment of the Investigator.  
 
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VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
 
Figure 1a: Revised Study Visit Schedule, Protocol Amendment 5.0 
 
 
 
With Amendment 5.0, subjects will complete the study at Week 78 and will not be offered a 6th dose.  
Subjects who were beyond Week 78 at the time of IRB approval of Amendment 5.0, will return for 
their final visit at their next scheduled timepoint as outlined in Table 1.  Subjects must sign the IRB-
approved informed consent document for Amendment 5.0 prior to the initiation of procedures for their 
final study visit. 
Imiquimod treatment - Subjects randomized to the VGX-3100 with imiquimod study group will apply 
imiquimod 5% cream to the vulvar lesion(s) beginning in the evening on Day 0, and will continue to 
apply imiquimod cream three times per week for 20 weeks (inclusive of administration in the evening 
of VGX-3100 dosing). Subjects unable to tolerate imiquimod treatment may reduce their dosing 
frequency, and will document their use on the imiquimod dosing log provided. 
Efficacy Assessment:  Biopsies obtained as part of the study at Screening will be from the region of 
most advanced disease as judged by the Investigator, and must be approximately 4 mm in length. 
Visible lesion must remain after screening biopsy to ensure measurement on study. 
Visualization of a normal appearing vulva by vulvoscopy is insufficient evidence to confirm disease 
regression. Disease regression will be based on histopathologic assessment at Week 48, 74, and at 
Week 96 for subjects reaching Week 96 prior to Amendment 5.0 or for whom this is the final visit.  
Subjects will be monitored during the course of the study by vulvoscopy. Lesion(s), defined as areas 
that stain acetowhite, will be assessed and photographed during vulvoscopy at Screening, Day 0 and 
Weeks 4, 12, 27, 48, 74, and at Week 96 for subjects who have reached this timepoint prior to 
Amendment 5.0 or for whom this is the final visit. Using standardized high resolution digital 
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VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
photographic imaging, vulvar lesion(s) will also be quantitatively measured at Screening, Day 0, 
Weeks 48, 74, and at Week 96 for subjects who have reached that timepoint prior to Amendment 5.0 
or for whom this is their final visit.  
The decision process following results of the Week 48 biopsy are described in Figure 2 below and as 
follows: At Week 48, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion 
as study start, from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2 for Minimally Required Biopsy Procedures).   
If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Subgroups A or B), the 
subject will continue to Week 74 for vulvoscopy, and biopsy of the same lesion(s) as study start.   
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in the qualifying lesion(s) 
size or no change in lesion size from baseline (Subgroups C or D), the Investigator has the option to 
give the subject a 5th dose of VGX-3100 at Week 52, and the subject will continue on study with 
vulvoscopy and biopsy at Week 74.  Alternatively, the Investigator may choose to treat the subject 
with surgical or standard treatment, and the subject will continue on study without further biopsy. A 
qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 and/or HPV-18 positive 
and have histologically confirmed vulvar HSIL by the PAC at screening. 
 
Figure 2: Decision process at Week 52  
  
 
The decision process following results of the Week 74 biopsy for subjects who completed this visit 
prior to Amendment 5.0 are described in Figure 3 (Appendix B) for the original study design.  The 
evaluation process following results of the Week 74 biopsy under Amendment 5.0 are described in 
Figure 3a below and as follows: At Week 74, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesion as study start from the region of potentially most advanced disease 
based upon the judgment of the Investigator (see Table 2).  
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Clinical Protocol 
 
 
Figure 3a: Evaluation Process at Week 78, Amendment 5.0 
 
If, after evaluation of Week 74 biopsy tissue by the PAC, there is no evidence of HSIL (Subgroups A 
or B), the Investigator will use their clinical judgment regarding follow-up care of the subject (not part 
of study activities).    
If, after evaluation of the biopsy tissue HSIL remains, but there is a reduction in the qualifying lesion(s) 
size or no change in lesion size from baseline (Subgroups C or D), the subject will receive further 
standard of care treatment (not part of study activities) per the Investigator’s judgment.     
The decision process for subjects who are beyond Week 78 at the time of IRB approval of 
Amendment 5.0 can be found in Appendix C.  These subjects will complete the study at their next 
scheduled visit as outlined in Table 1. Subjects must sign the IRB-approved informed consent 
document for Amendment 5.0 prior to the initiation of procedures for their final study visit.In the event 
of worsening disease prior to the end of the study (i.e., Subgroup E), the subject will receive surgical 
treatment per the Investigator's judgment and will continue on study with vulvoscopy, but without 
further study treatment or biopsy. In the event of worsening disease at the final visit, the subject will 
receive standard of care treatment (not part of study activities) per their treating physician.  If wide 
excision is conducted at or prior to the subjects last on site visit, the sample obtained will be sent to 
the PAC for evaluation.   
If at any time in the study carcinoma is discovered, subjects will receive surgical treatment, and be 
discontinued from study treatment. The event will be reported as an SAE per section 7.1.4.  If wide 
excision is required, the sample obtained will be sent to the PAC for evaluation.   
All visible lesions should be biopsied at Week 48.  For subjects whom Week 78 is their final visit, all 
visible lesions should be biopsied at Week 74.  For subjects whom the final visit is Week 96, all visible 
lesions should be biopsied at Week 96. 
If there is a new lesion identified at evaluation, or a non-qualifying lesion is rebiopsied and confirmed 
on study to be vulvar HSIL and HPV-16/18 positive at evaluation, a discussion will take place between 
the Medical Monitor and the Principal Investigator to determine if additional dosing is appropriate. 
Definition of Responder and Non-responder for the Primary Endpoint: Responder and non-responder 
definitions (Table 3) take into account both histopathologic regression of vulvar HSIL and virologic 
(HPV-16/18) clearance from  tissue samples since HPV persistence is an important factor in the 
clinical progression of HSIL. A treatment responder is defined as a subject with no histologic evidence 
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VGX-3100 
 
HPV-201 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
of vulvar HSIL and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive any non-study related treatment for vulvar HSIL. A treatment non-responder is a subject with 
histologic evidence of vulvar HSIL or vulvar carcinoma at evaluation, or a subject with evidence of 
HPV-16/18 at evaluation, or a subject who received non-study related treatment for vulvar HSIL. Any 
case of histologically confirmed progression from HSIL to carcinoma is considered a non-responder. 
Safety Assessment: Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the Participant 
Diary  
2) All adverse events including SAEs, AESIs, SUSARs, UADEs, and other unexpected AEs for the 
duration of the study. 
All subjects will be followed through Week 78 under Amendment 5.0, or up to 100 weeks if beyond 
week 78 at the time of Amendment 5.0. 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review safety data and 
tissue regression and viral clearance results. The DSMB will be charged with advising the Sponsor if 
there appears to be a safety issue. No formal interim analysis is planned. The following stopping rules 
will be applied: 
• 
If at any time during the study one-third (1/3) or more of the subjects experience an Adverse 
Event of Special Interest (AESI) verified per protocol definition, further enrollment and study 
treatment will be halted until a thorough review has been conducted by the Medical Monitor, 
Principal Investigator (PI) for the trial, and the DSMB.  
• 
If any SAE (or potentially life-threatening AE) or death verified as related to study treatment 
occurs, further enrollment and study treatment will be halted until a thorough review has been 
conducted by the Medical Monitor, PI for the trial, IRB (if applicable) and the DSMB. 
• 
If three or more subjects in this study experience the same Grade 3 or 4 unexpected adverse 
event, verified per protocol definition and assessed as related to study treatment, further 
enrollment and study treatment will be halted until a thorough review has been conducted by 
the Medical Monitor, PI for the trial, and the DSMB. 
• 
In the event of two identical, unexpected, Grade 4 toxicities,verified per protocol definition and 
assessed as related to study treatment, further enrollment and study treatment will be halted 
until a thorough review has been conducted by the Medical Monitor, PI for the trial, IRB (if 
applicable) and the DSMB.  
The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding the outcome 
of any investigation stemming from a Study Pause.  
Immunogenicity Assessment: The study explores humoral and cell mediated immune responses to 
VGX-3100, and VGX-3100 with imiquimod, in blood samples taken at baseline (i.e., Screening and 
Day 0 prior to dosing) and Weeks 15, 27, 48, 74 and 96. Vulvar samples will also be analyzed for 
evidence of immune responses at Screening and Weeks 48, 74 and 96.  Samples will not be obtained 
at Week 96 for subjects who complete the study prior to this timepoint, per Amendment 5.0. 
Virologic Assessment: Tissue samples will be obtained to characterize vulvar HPV infection at 
Screening, Weeks 48, 74 and 96. Cervical samples, oropharyngeal rinse, vulvar, vaginal, and intra-
anal tissue swab samples will be obtained to characterize HPV infection at the following time points: 
Day 0 prior to dosing (OP, cervical, vulvar, vaginal and intra-anal), Week 4 (Vulvar only), Week 12 
(Cervical and vulvar)  and Weeks 27, 48, 74 and 96 (OP, vulvar, vaginal and intra-anal). Samples will 
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not be obtained at Week 96 for subjects who complete the study prior to this timepoint, per 
Amendment 5.0.  At Weeks 48 and 96, a cervical sample will also be collected.  
 
Study Population: 
Inclusion: 
1. 
Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form prior 
to study-related activities;  
2. 
Women aged 18 and above  
3. 
Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. 
Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated date of first 
dose of study drug and have histologically confirmed vulvar HSIL by the Pathology Adjudication 
Committee at screening; 
5. 
Must be judged by the Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision or biopsy) required at Week 48; 
6. 
Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of adequate size 
to ensure that a visible lesion remains after an approximately 4 mm screening biopsy;  
7. 
Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. 
Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 3 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening until 
6 months following the last dose of investigational product. Acceptable methods are the 
following: 
i) 
Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must 
not be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, 
pulmonary embolism); 
ii) 
Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii) Intrauterine device or intrauterine system;                                                                                
iv) Male partner sterilization at least 6 months prior to the female subject's entry into the 
study, and this male is the sole partner for that subject. 
9. 
Has normal screening electrocardiogram (ECG) or screening ECG with no clinically significant 
findings as judged by the Investigator. 
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Exclusion: 
1) Untreated microinvasive or invasive cancer; 
2) Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing medical care and/or 
treatment for VAIN;  
3) Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical care and/or 
treatment for AIN; 
4) Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing medical care 
and/or treatment for CIN; 
5) Biopsy-proven differentiated VIN; 
6) Vulvar HSIL that is not accessible for sampling by biopsy instrument; 
7) Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains after biopsy; 
8) Treatment for genital warts within 4 weeks prior to screening; 
9) Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 4 weeks prior 
to screening; 
10) Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream for subjects 
enrolled prior to Protocol Amendment v3.0 (dated 26Mar2019); 
11) Is pregnant, breastfeeding or considering becoming pregnant within 6 months following the last 
dose of investigational product; 
12) Presence of any unresolved abnormal clinical laboratory values greater than Grade 1 per Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03 within 45 days prior to Day 0 or less than 
or equal to Grade 1 but deemed clinically significant by the Investigator; 
13) Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
autoimmune disease that may jeopardize the safety of the subject or require therapy that would 
interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results. 
14) History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, 
e.g. Gardasil®9, Gardasil®, Cervarix®); 
15) Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16) Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of each study 
dose; 
17) Significant acute or chronic medical illness that could be negatively impacted by the electroporation 
treatment as deemed by the Investigator; 
18) Current or history of clinically significant, medically unstable disease which, in the judgment of the 
Investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results  
a)   Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher congestive   
  heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision; 
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c) 
Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) 
that would contraindicate IM injections within 2 weeks of Day 0; 
d) History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) 
Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19) Participation in an interventional study with an investigational compound or device within 4 weeks 
of signing informed consent (participation in an observational study is permitted); 
20) Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) (unless 
deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site (i.e. 
electroporation area);  
21) Vulnerable populations:  
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, would interfere 
with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22) 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.  
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STUDY SCHEDULE OF EVENTS 
 
Table 1: Schedule of Events  
 
 
 
 
Tests 
Screen  (-10 wk to -1d) 
Day 0 
8-14 days post dose 1 
Phone Call  
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call  
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27  (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days)  
Week 74 (±14 days) 
*Week 78 (± 14 days) 
Phone Call 
Week 96 (± 14 days) 
Week 100 (± 14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Socio-behavioral assessment a 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Xa 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment b 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Xb 
X 
X 
Vital signs 
Xc 
X 
X 
X 
X 
X 
 
X 
X 
X 
Xc 
X 
X 
Screening safety (12 lead ECG, 
labs) d 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing e 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
 
Blood immunologic samples 
Xf 
Xf 
Xf 
 
Xg 
 
Xf 
 
Xf 
 
Xf 
 
OP rinse, vaginal, and intra-anal 
swabs 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Vulvar swabs 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Cervical colposcopy h  
 
X 
 
 
 
 
 
 
 
 
 
 
Xh 
 
Xh 
 
Cervical cytology, ThinPrep®  i 
X 
X 
 
 
X 
 
 
 
X 
 
Vulvoscopy j 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Vulvar lesion standardized 
photography k 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Biopsy l 
X 
 
 
X 
 
X 
 
X 
 
Vulvar HPV genotyping m 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Inject VGX-3100 +EP n 
X 
X 
X 
X 
 
 
Xn 
 
Xn 
 
 
Post treatment reaction 
assessment 
X 
X 
X 
X 
 
 
Xn 
 
Xn 
 
 
Dispense imiquimod + distribute 
imiquimod dosing log o 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Review imiquimod dosing log and 
usage 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Distribute Participant Diary (PD) 
X 
X 
X 
X 
 
 
Xn 
 
Xn 
 
 
Review PD p 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes 
(PROs)q 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
*Under Protocol Amendment 5.0, subjects will complete the study at Week 78, which may be completed by phone.  Subjects who are 
beyond Week 78 at the time of IRB approval of the amendment, will complete the study at their next scheduled visit. 
a Subjects completing the study before Week 100 per Amendment 5.0, will have the final socio-
behavioral assessment done at their final discharge visit.  This may be obtained by phone. 
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b Full PE mandatory at screening and study discharge (Week 100 for subjects completing this visit before 
Amendment 5.0), otherwise targeted PE as determined by the Investigator or per subject complaints 
unless signs or symptoms dictate the need for a full PE.  PE will not be conducted on subjects 
completing the study with a Week 78 phone call, per Amendment 5.0. 
c Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in 
kilograms divided by height in meters squared). Weight will be measured at all dosing visits. Vital signs 
will not be collected on subjects completing the study with a Week 78 phone call, per Amendment 5.0. 
d Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 45 days prior to first dose 
administration. 
e Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy 
and biopsy/surgical excision. 
f At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 
mL whole blood and 8 mL serum should be collected prior to first dose. One additional 8.5 mL yellow 
(ACD) tube to be collected at Day 0, Week 15 and 48 for microRNA analysis. 
g  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 
27.   
h Cervical colposcopy will be performed once at Day 0, and once at Week 96. For subjects completing the 
study at Week 78, the repeat cervical colposcopy will be performed at Week 74 or the discharge visit.   
i HPV genotyping and Pap smears are performed on the same ThinPrep® cervical specimen. 
j An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected. Biopsies 
should not be performed at any visit other than at entry (Screening), Week 48, Week 74, and Week 96 
for subjects in Subgroups C and D prior to Amendment 5.0, unless the Investigator suspects invasive 
cancer. All biopsy samples and/or excision samples obtained prior to or at the subjects final discharge 
visit (if not a phone visit) must be sent to the PAC for review. 
k  Photography of the acetowhite stained qualifying lesion(s) must be performed prior to and after biopsy, 
and at all vulvoscopy examinations. If a pre-biopsy digital photograph is not available for a historical 
biopsy sample at screening, a post biopsy photo will be sufficient. Additionally, standardized high 
resolution digital photographic imaging should be obtained during examinations of the vagina if lesions 
are identified, for documentation.  
l Tissue specimen from all excised tissue obtained prior to or at the subjects in-person discharge visit must 
be reviewed by the PAC and will be sent to the central laboratory for HPV testing. All lesions will be 
biopsied at Week 48, 74, and 96 (as applicable), per Amendment 5.0. 
m HPV genotyping is performed on vulvar tissue specimen using a PCR based assay. 
n Potential dosing, post-treatment assessment, and distribution of the Participant Diary at Week 52 and 
Week 78 is applicable for partial responders only.  Partial responders who reach Week 78 after 
Amendment 5.0 will not be offered a 6th dose.  
o Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod. 
Administration of imiquimod begins on Day 0. 
p A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 
1 and 2. The patient will be expected to bring the PD to the next visit for review. 
q PRO measures (SF-36v2™, EQ-5D-5L, WOMAN-PRO) plus two additional questions will be assessed as 
described in Section 6.8.       
 
 
 
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1. 
INTRODUCTION  
1.1 
BACKGROUND 
 HUMAN PAPILLOMAVIRUS AND INFECTION 
Human papillomaviruses (HPV) are double-stranded DNA viruses with more than 100 
genotypes some of which can lead to malignant neoplasia, localized primarily in the 
anogenital area and aerodigestive tract, in both men and women. HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause 
cancer, and low-risk (LR) causing generally benign lesions. HPV-16 and HPV-18 are the 
most significant amongst high-risk types since they are responsible for most HPV-
caused cancers [1].   
HPV-16/18 is involved in about 83% of HPV-associated vulvar HSIL cases in the U.S. [1] 
and about 72% in Europe [2]. Persistent infection with one or more oncogenic (high-risk) 
HPV genotypes can lead to the development of precancerous, histologic high grade 
squamous intraepithelial lesions (HSIL).  
HPV causes more cancers than any other virus. In U.S. archival tissues of cancers 
diagnosed from 1993 to 2005, HPV DNA was detected in 68.8% of vulvar, 90.6% of 
cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of oropharyngeal, 63.3% of penile, 
32.0% of oral cavity, and 20.9% of laryngeal cancers, as well as in 98.8% of cervical 
cancer in situ (CCIS).  
 VULVAR CANCER 
Vulvar HSIL can lead to vulvar cancer with an estimated 6,020 new cases and 1,150 
attributable deaths annually for year 2017 in the United States [4] and about 9,776 new 
cases in 2015 in Europe [5]. Vulvar cancers consist largely of squamous cell carcinomas 
and accounts for approximately 5% of all female genital malignancies [6]. Differentiated 
VIN, which is typically not caused by HPV infection and is more typically found in older 
women, is more likely to progress to cancer more rapidly than HPV-associated-VIN. The 
five year overall relative survival for vulvar cancer in the U.S. is 72.1% [4]. Recurrent 
vulvar cancer occurs in an average of 24% of cases after primary treatment, after 
surgery with or without radiation [7].  
 VULVAR INTRAEPITHELIAL NEOPLASIA (VULVAR HSIL) 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 
one or more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins 
constitutively, which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia. The basis for 
progression to cancer is, therefore, attributed to the viral proteins E6 and E7.  VGX-3100 
specifically induces immune responses against E6 and E7, thereby enabling clearance 
of pre-malignant cells as demonstrated in the Phase 2 study of cervical HSIL [8].    
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In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) 
replaced the three grade classification system with the current single grade classification 
for which only high grade VIN (2/3) is classified as VIN [9]. In 2012, the Lower 
Anogenital Squamous Terminology (LAST) Standardization Project for HPV-associated 
lesions applied the term high grade squamous intraepithelial lesion (HSIL) to encompass 
high grade dysplasia [10]. Therefore, for the purpose of this study, the term vulvar HSIL 
will be used, whichencompasses VIN 2 and VIN 3; the term ‘vulvar LSIL’ will be used to 
encompass what was previously known as VIN 1. 
Once vulvar HSIL has developed, spontaneous regression is rare, likely occurring in only 
1.5% to 5% of women [11]. Over time, typically years, vulvar HSIL can progress to 
invasive cancer of the vulva, e.g. from treated patients, median: 2.4 years in one group 
and median 13.8 years in another group [12], and from VIN3 patients, mean = 2.5 years, 
range: 4 – 216 months [13].  
Vulvar HSIL remains a significantly undermet medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently 
used surgical and medical approaches is extremely high, 2) there is a high psychological 
and physical negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts 
activities of daily living, 4) prophylactic HPV vaccines have no therapeutic activity 
against vulvar HSIL and have not achieved universal uptake, leaving a population of 
susceptible and impacted women, and 5) the early diagnosis of vulvar HSIL is limited to 
visual inspection with biopsy. 
 RECURRENT DISEASE WITH CURRENT THERAPEUTIC OPTIONS 
There remains an unmet medical need with regard to effective treatment options for 
vulvar HSIL. Current treatment options show a significant risk of vulvar HSIL recurrence, 
often requiring multiple, repeat treatments. Progression to vulvar cancer following 
current vulvar HSIL treatments can also occur within 1 year of treatment and for up to 20 
years post treatment. The current treatment options for vulvar HSIL are surgical 
excision, laser ablation, and off-label medical therapy. The rate of HPV-associated 
vulvar HSIL recurrence after surgical treatment is high; post-treatment recurrence rates 
are as high as 45% at three years post-treatment with all currently available treatment 
regimens [14, 15].   
Wide local excision is the 'preferred initial intervention' by ACOG if invasive carcinoma is 
suspected, and, vulvar biopsy shows vulvar HSIL. If occult invasive disease is not 
suspected, vulvar HSIL treatment includes surgery: wide local excision, partial 
vulvectomy, skinning vulvectomy, or simple vulvectomy, laser ablation. Surgical 
treatments are associated with disruption of normal anatomy and subsequent issues 
with body image and sexual dysfunction. Medical therapies have been investigated as a 
means to avoid these negative outcomes. Clinical trials have shown the application of 
topical imiquimod to be effective however it has not been approved by the U.S. Food 
and Drug Administration for this indication. Inconsistent treatment efficacy results have 
been shown with photodynamic therapy, topical cidofovir and topical 5-flourouracil. 
Vulvar HSIL may be followed (with interim observation, but, no intervention) if the patient 
is young, and, or, if the immune-compromised state is being corrected. Women with 
pathologic clear margins (no vulvar HSIL) after surgical excision have a lower, yet 
significant, risk of recurrence compared to women with involved margins. Laser ablation 
is acceptable treatment for vulvar HSIL when cancer is not suspected, although the risk 
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of recurrence is slightly higher compared to wide local excision. Laser treatment of 
vulvar HSIL requires destruction of cells through the entire thickness of the epithelium 
including hair follicles (in hair-bearing areas of the vulva). In areas without hair, ablation 
should extend through the dermis. Post-treatment recurrence rates exceed 30% (for all 
treatment regimens), and is higher with positive excision margins [16]. 
 PSYCHOLOGICAL AND PHYSICAL IMPACTS OF CURRENT 
THERAPEUTIC OPTIONS 
Virtually all patients with HPV-related Vulvar HSIL will require treatment, given the low 
rate of spontaneous resolution. According to the current ACOG & ASCCP guideline for 
management of VIN, because of the potential for occult invasion and if cancer is 
suspected (even if biopsy shows vulvar HSIL), the standard treatment of vulvar HSIL is 
wide local excision (i.e. surgery) [17]. When occult invasion is not a concern, vulvar HSIL 
can be treated with excision, laser ablation, or topical imiquimod as an off-label medical 
therapy.   
Current treatment options are associated with pain, disfigurement and a recurrence rate 
as high as 45% at three years post-treatment [16]. Therefore, many patients have a fear 
of recurrence and progression to cancer [18].   
In excisional treatment, patients are advised to rest for two weeks, including delaying 
return to work for up to one week, and to avoid sexual intercourse for up to 5 weeks. 
Furthermore, patients are instructed to avoid baths and exercise for a few weeks, and 
some women are advised to avoid the use of toilet paper and to rinse with warm water 
instead. During recovery, common effects include pain in urinating and wiping, soreness, 
difficulty sitting, and feeling tired [19]. In the first week after hospital discharge, common 
patient-reported symptoms and other effects include swelling, drainage, pain, bleeding, 
numbness, redness, hardness, burning, pressure, unusual odor, changed skin color, 
opening of suture, warmth, itching, scarred skin, tiredness (including some feeling of 
exhaustion), insecurity, feeling of changed body, sexual concerns, anxiety, sadness, 
changed feeling in self-confidence, and difficulties in partnership [20].  
 IMPACT OF VULVAR HSIL UPON ACTIVITIES OF DAILY LIVING 
The presence of vulvar HSIL is frightening and can have long-lasting effects on well-
being [19]. The symptoms and signs of vulvar HSIL can be moderate to severe and 
include painful sexual intercourse, itching or burning, and visible lesions.  
In the first week after hospital discharge from surgical excision, common patient-reported 
impacts on daily life include difficulties sitting, wearing clothes (e.g. underwear, pants), 
carrying out activities (e.g. climbing stairs, cooking), bowel movements, and urinating 
[20]. 
In a study of sexual function and quality of life after excisional treatment, vulvar HSIL 
patients reported significantly poorer scores in sexual function and quality of life than 
age-matched healthy women. During the post-treatment follow-up phase of about one 
year, until given assurance of lesion clearance some patients report the sense that they 
are in the doctor's office all the time [19]. 
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 LIMITATIONS OF PROPHYLACTIC HPV VACCINES 
Immunization with prophylactic vaccines represents the initial recommended approach 
within the pediatric and young female populations to avoid later development of HPV-
associated vulvar HSIL and subsequent vulvar cancer. The US-licensed prophylactic 
HPV vaccines are indicated for girls and women ages 9 through 26 years for Gardasil® 
and Gardasil®9 (Merck & Co. Inc.), and ages 9 through 25 years for Cervarix® 
(GlaxoSmithKline). The early portions of these age ranges are generally before sexual 
debut and thus can allow immunologic protection against the anticipated earliest normal 
exposures to HPV infection. HPV prophylactic vaccination is highly effective and safe, 
and routine vaccination is recommended for females in the United States starting at age 
11 or 12 years [22]. However, these prophylactic vaccines have no therapeutic effect 
upon existing HPV infection or existing HPV-related intraepithelial neoplasia [23]. 
 ENHANCED MONITORING PLAN 
An enhanced monitoring plan will be used in this study to address the risk of a potential 
delay in treatment of vulvar HSIL. The feasibility of this approach was demonstrated in 
the Phase 2b study of cervical HSIL. Given that vulvar disease progresses slowly to 
vulvar cancer if untreated, the proposed enhanced monitoring plan is expected to 
maintain the safety of subjects in this study. First, only Gynecology-Oncologists and 
Gynecologists who are well experienced in the monitoring and management of vulvar 
disease will be used as study Investigators. Inclusion into the study will require histologic 
confirmation of the diagnosis of the vulvar disease as vulvar HSIL, and not carcinoma, 
by two independent expert pathologists from the PAC (see Section 10.4.2). Women with 
differentiated VIN, which is more likely to progress faster and is not typically HPV-related 
is specifically excluded from study entry. By contrast, HPV-associated vulvar HSIL does 
not progress rapidly, typically taking years to manifest and progress, making enhanced 
monitoring feasible [24].   
Throughout the study, there will be frequent vulvoscopy as well as photographic 
documentation and analysis of the lesion size (see Section 6.1). Colposcopy will also be 
performed at Day 0 and during the study given that concurrent disease in the lower 
genital tract can occur. A Data Safety Monitoring Board will be utilized to review subject 
safety data and advise on any study-level safety concerns. Investigators always have 
the option of performing ad hoc vulvar biopsies to rule out suspected disease 
progression. Additional treatment (e.g., additional excision, ablation, or medical therapy) 
may be carried out, if deemed necessary according to Investigator judgment. 
 VGX-3100 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using proprietary synthetic vaccine (SynCon™) technology. 
This process involves synthetically deriving consensus genes across multiple strains and 
optimizing DNA inserts at the genetic level to allow high expression in human cells. 
Together, VGX-3100 and the CELLECTRA™ device represent an integrated 
investigational product designed as a non-surgical treatment of HPV-16/18-related 
cervical HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Further information about VGX-3100 is provided in the Investigator's Brochure. 
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 ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP 
is a physical method of tissue transfection whereby the generation of short, controlled 
electrical pulses creates a localized electric field at the injection site of the DNA vaccine 
which increases cell membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [25, 26]. Electroporation increases the uptake of plasmid 
DNA, thereby enabling increased expression and enhanced vaccine immunogenicity by 
10 to 100 fold [27, 28]. This technology has been used for more than three decades by 
molecular biologists for cell transfection and has demonstrated versatility in use, as 
shown by its functionality in combination with a range of molecules, tissue types, disease 
indications, and across species [29].  
This study will use the CELLECTRA™ 2000 device which has been used in 26 trials with 
3795 doses administered to human subjects as of September 30, 2016 with no 
significant safety issues identified. Further information about the CELLECTRA™ 2000 
device can be found in the Investigator's Brochure and device User Manual. 
 IMIQUIMOD CREAM, 5% 
Imiquimod Cream, 5% is a licensed product intended to be used in this study 
concomitantly with the investigational product and device. Imiquimod Cream, 5% will be 
centrally sourced, supplied in single-use packets (24 per box), each of which contains 
250 mg of the cream, equivalent to 12.5 mg of imiquimod. The product manufacturer is 
Perrigo, Yeruham 80500, Israel. 
 STUDY RATIONALE 
This pilot study is being conducted in a population with vulvar dysplasia using a 
randomized, open-label design to demonstrate the efficacy of VGX-3100 followed by EP 
in women with vulvar HSIL associated with HPV-16/18 either alone or in combination 
imiquimod. The overall aim is to determine if treatment with VGX-3100 could allow 
women with vulvar HSIL to avoid or minimize surgical treatment procedures. Proof of 
concept that VGX-3100 can induce resolution of both HPV-associated dysplastic lesions 
and the underlying HPV-16/18 infection was shown in a Phase 2b study of cervical 
intraepithelial neoplasia (CIN). The similar underlying pathogenic mechanisms between 
cervical and vulvar HSIL form the basis of the clinical hypothesis that VGX-3100 could 
be a non-surgical therapeutic option for the treatment of vulvar HSIL, which is a 
significantly under met medical condition. A VGX-3100 with imiquimod-administration  
study drug is also included, given the prevalent use of imiquimod as a topical medical 
treatment of vulvar lesions, to investigate if a more robust immune response is achieved 
with VGX-3100, to potentially increase regression of vulvar HSIL.        
 DOSE AND REGIMEN RATIONALE FOR VGX-3100 
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous 
human experience with VGX-3100, preclinical data with VGX-3100 and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, 
and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot 
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responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant 
safety issues [30].  
 RATIONALE FOR IMIQUIMOD 
Imiquimod cream is prescribed for the topical treatment of certain skin growths including 
external genital and perianal warts. Therefore, imiquimod may be able to be used 
synergistically with VGX-3100. 
Randomized controlled trials have shown that the application of topical imiquimod 5% is 
effective for the treatment of vulvar HSIL although it is not approved by the US Food and 
Drug Administration for this purpose. Imiquimod is currently recommended as a non-
surgical, off-label treatment option for vulvar dysplasia by the American College of 
Obstetricians and Gynecologists (ACOG). Published regimens include three times 
weekly application to affected areas for 12 – 20 weeks, with colposcopic assessment at 
4-6 week intervals during treatment [17].  
This  study will include a study group to explore whether the efficacy of VGX-3100 is able 
to be enhanced by concomitant treatment with Imiquimod.  The Version 3.0 protocol 
amendment halts enrollment of the VGX-3100 with topical imiquimod study group.  All 
subjects who have already been enrolled into the VGX-3100 with imiquimod study group 
will continue with all study visits per protocol, but no further participants will be enrolled 
into this group.   
 INCLUSION OF WOMAN-PRO, CLINICAL TRIAL VERSION 2.0  
The original WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) was developed by 
Beate Senn and colleagues [20,31,32] for use following post-surgical intervention. 
Development of the tool was aligned with the FDA PRO Guidance [33]and included a 
review of the literature as well as direct patient and expert input. Preliminary 
measurement properties were assessed in a cross-sectional study. However, despite 
rigorous development and promising initial measurement properties, gaps in the 
development and psychometric evaluation exist. To address these gaps, Inovio and 
collaborators initiated a small qualitative study to confirm the content validity of the tool 
and support a cross-cultural adaptation of the measure for use in a clinical trial setting of 
US English and US Spanish speaking subjects. The results of  this research is the 
Clinical Trial of the WOMAN-PRO (2.0) which is utilized in this study. 
 
The WOMAN-PRO Clinical Trial Version 2.0 is a 31 item self-completed patient reported 
outcome measure designed to assess both physical and psychosocial impacts of VIN.  
The physical domain is comprised of 15 lesion-related symptoms and includes 5 
additional items to measure impact in daily life. Psychosocial constructs are assessment 
through 11 items that address feelings, thoughts and limitations. Each item is scored 
using a 4-point Likert scale with higher scores indicating greater difficulty or severity. The 
recall period is the past week.Details are included in Section 6.8.  
 POTENTIAL RISKS OF INVESTIGATIONAL PRODUCTS 
Based on the phase 1 and 2 clinical experience, the injection site reactions associated 
with the IM injection and electroporation are generally mild and limited to a few days in 
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duration at most. The full risk profile for VGX-3100 is described in the Investigator 
Brochure. 
Local skin and application site reactions are the most frequently reported adverse 
reactions associated with topical imiquimod 5% treatment. Erythema, erosion, 
excoriation/flaking, edema, induration, ulceration, scabbing, and vesicles have been 
reported at the application site [34]. The full risk profile of imiquimod 5% treatment is 
available in the package insert and prescribing information. 
 POTENTIAL BENEFITS OF STUDY PARTICIPATION 
This study has been designed to provide non-surgical treatment with the aim of avoiding 
the need for surgical excision or laser ablation, which can be disfiguring and have 
significant associated morbidity. In the absence of complete resolution of vulvar lesions, 
there would still be potential benefit from a partial response, which would minimize the 
amount of excisional therapy that may be needed. All currently accepted surgical 
treatments for VIN are associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding, infection, or damage to surrounding 
structures such as the clitoris, urethra, or anus. The other potential benefit is that the 
response to VGX-3100 is systemic and may clear the underlying HPV infection, which is 
the root cause of vulvar HSIL. Consequently, there is the potential to reduce the risk of 
recurrent disease. 
2. 
HYPOTHESIS AND STUDY OBJECTIVES 
Four 6 mg doses of VGX-3100 (DNA plasmids encoding E6 and E7 proteins of HPV-16 
and HPV-18) delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA™ 2000 alone or in combination with imiquimod to adult women with 
histologically confirmed vulvar HSIL associated with HPV-16 and/or HPV-18 (HPV-
16/18), will result in a higher percentage of women with regression of HSIL of the vulva 
based on histology (i.e. biopsies or excisional treatment) and virologic clearance of HPV-
16/18 from vulvar tissue compared with historical control. 
 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine the efficacy of four doses of VGX-
3100, alone or in combination with imiquimod, 
with respect to combined histopathologic 
regression of vulvar HSIL and virologic 
clearance of HPV-16/18 in vulvar tissue 
Proportion of subjects with no histologic 
evidence of vulvar HSIL5 and no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples 
(i.e. collected via biopsy or excisional 
treatment)6.   
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2.2 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in 
combination with imiquimod  
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary. 
1b. All adverse events including SAEs, AESI’s, 
SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through 
Week 100 visit)4 
2. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by histologic 
regression of vulvar HSIL 
2.  Proportion of subjects with no evidence of 
vulvar HSIL5 on histology (i.e. biopsies or 
excisional treatment) at Week 48 visit 
3. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by virologic 
clearance of HPV-16/18 in vulvar tissue 
3. Proportion of subjects with no evidence of 
HPV-16/187 in vulvar tissue samples at Week 
48 visit 
4. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by histologic regression of 
vulvar HSIL to normal tissue 
4. Proportion of subjects with no evidence of 
vulvar HSIL, no evidence of vulvar LSIL 
(VIN1), and no evidence of condyloma on 
histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit 
5. Determine the efficacy of four doses of VGX-
3100, alone or in combination with 
imiquimod, as measured by non-
progression of vulvar HSIL to vulvar cancer 
as determined by histology 
5. Proportion of subjects with no progression8 
of vulvar HSIL to vulvar cancer from baseline 
to Week 48 visit 
6. Determine the efficacy of VGX-3100, alone 
or in combination with imiquimod, as 
measured by reduction in the surface area 
of the qualifying9 vulvar lesion(s) 
6. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying lesion (s) at Week 
48 compared to baseline10. Results will be 
classified as: no clinically significant lesion 
resolution (reduction in lesion size of 0-25%), 
partial lesion area resolution (>25% and 
<100% reduction), and complete lesion 
resolution (no visible lesion).   
7. Describe the cellular immune response of 
VGX-3100 
administered 
alone 
or 
in 
combination with imiquimod,  post dose 4 
7. Flow Cytometry response magnitudes at 
baseline and Week 27 visits 
8. Determine the efficacy of four doses of VGX-
3100 alone or in combination with imiquimod 
with respect to histopathologic regression of 
vulvar HSIL or viologic clearance of HPV-
16/18 in vulvar tissue   
8. Proportion of subjects with no histologic 
evidence of vulvar HSIL5 or no evidence of HPV-
16/18 at Week 48 in vulvar tissue samples (i.e. 
collected via biopsy or excisional treatment) 
 
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2.3 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of VGX-3100, 
administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as 
measured by reduction in the surface area of 
the qualifying9 vulvar lesion(s), in subjects 
without a complete resolution at Week 48 
1. Percent reduction in the cumulative surface 
area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of 
standardized pre-biopsy photographic 
imaging of the qualifying lesion (s) at Week 
74 and/or Week 96 compared to baseline10. 
Results will be classified as: no clinically 
significant lesion resolution (reduction in 
lesion area of 0-25%), partial lesion area 
resolution (>25% and <100% reduction), and 
complete lesion resolution (no visible lesion).   
2. Describe the long term efficacy of VGX-3100, 
alone or in combination with prior imiquimod, 
as measured by histologic regression of 
vulvar HSIL 
2. Proportion of subjects with no evidence of 
vulvar HSILon histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects 
who receive 5 doses of VGX-3100 and at 
Week 96 for subjects who receive 6 doses of 
VGX-3100. 
3. Describe the long term efficacy of VGX-3100, 
alone or in combination with prior imiquimod, 
as measured by virologic clearance of 
HPV-16/18  
3. Proportion of subjects with no evidence of 
HPV-16/18 in vulvar tissue samples at Week 
74 and/or Week 96. 
4. Evaluate tissue immune responses to 
VGX-3100, and VGX-3100 with imiquimod, 
as measured in vulvar tissue samples 
4. Assessment of pro-inflammatory and 
immunosuppressive elements in tissue11 
5. Describe virologic clearance of HPV-16/18 
from non-vulvar anatomic locations  
5. Proportion of subjects who have cleared HPV-
16/18 on specimens from non-vulvar 
anatomic locations without surgical 
intervention (inclusive of cervix, oropharynx, 
vagina and intra-anus) at Week 48 compared 
to baseline 
6. Describe association of microRNA (miRNA) 
profile, previous vulvoscopy, and HPV testing 
results with Week 48 histologic regression 
6.   Vulvoscopy, HPV test results (vulvar swab 
and vulvar tissue) and miRNA profile (Day 
0, Week 15 and 48) in conjunction with 
histologic regression of vulvar HSIL at 
Week 48 visit 
7. Describe patient reported outcomes (PRO) 
for subjects treated with VGX-3100 and VGX-
3100 with imiquimod 
7. PRO endpoints will be obtained at Day 0 
prior to first dose, Weeks 4, 12, 24 after 
dosing, and at Weeks 15, 27, 48, 52, 74, 
and Weeks 96, and 100 as applicable. 
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8. Describe the humoral and cellular immune 
response of VGX-3100 administered alone or in 
combination with imiquimod, post dose 3, post 
dose 4, and after additional dosing 
8a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline and Weeks 15, 27, 48, 74 and 96 
visits 
 
9. Determine the long term efficacy of VGX-3100 
alone or in combination with imiquimod with 
respect to histopathologic regression of vulvar 
HSIL or virologic clearance of HPV-16/18 in 
vulvar tissue  
9. Proportion of subjects with no histologic 
evidence of vulvar HSIL5 or no evidence of 
HPV-16/18 at Week 74 and 96 in vulvar 
tissue samples (i.e. collected via biopsy or 
excisional treatment) 
3. 
STUDY DESIGN 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA 
plasmids encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM 
injection followed by EP delivered with CELLECTRA™ 2000 alone or in combination 
with imiquimod in adult women with histologically confirmed vulvar HSIL associated with 
HPV-16/18. Approximately 36 subjects will be enrolled. Twenty-four subjects will receive 
VGX-3100 alone and 12 subjects will receive VGX-3100 and topical imiquimod 
treatment.  The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with 
topical imiquimod study group.  All subjects who have already been enrolled into the 
VGX-3100 with imiquimod study group will continue with all study visits per protocol, but 
no further participants will be enrolled into this group. 
Subjects are randomized in a stratified manner according to (a) recurrent disease at 
screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 vs. 2 or more lesions 
at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 kg/m2) on Day 0, and (d) 
age category (<45 years vs. ≥45 years) on Day 0. 
To be eligible for the study, subjects must sign consent to participate and have a vulvar 
punch biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of 
the acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, 
the two lesions that potentially contain the most advanced disease, as judged by the 
Investigator, should be chosen for biopsy using vulvoscopy and documented using 
standardized high resolution photography with a digital single-lens reflex (SLR) camera 
on the case report form. Biopsy slides will be sent to a PAC for evaluation prior to 
enrollment. In order to be eligible for enrollment, the PAC must assign the diagnosis of 
vulvar HSIL based on the biopsy sample(s). Subjects must also have a vulvar specimen 
test positive for HPV genotype 16 and/or 18 to be eligible for participation in the study. 
To assess quality of life and related impacts on subjects, PRO instruments will be 
provided and will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-
5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen with vulvar Neoplasia) 
Clinical Trial Version 2.0 and two additional PRO questions assessing quality of life after 
surgery or biopsy. 
The total duration of the study is up to 10 weeks for the screening period, and 100 
weeks for the treatment and follow-up periods.  Amendment 5.0 reduces the study 
duration to 78 weeks for subjects not reaching the Week 78 visit at the time of the 
amendment 
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Clinical Protocol 
 
 
3.1 
TREATMENT REGIMENS 
All eligible subjects who consent to participate in the study will receive four doses of 6 
mg of VGX-3100 administered by IM injection followed by EP. The first dose will be 
administered as soon as possible following confirmation of the HSIL diagnosis, HPV-
16/18 status and all other eligibility criteria but no more than 10 weeks following 
collection of the subject's biopsy specimen used for diagnosis by the PAC.   
Each dose of VGX-3100 will be administered in a 1 mL volume IM (deltoid preferred site, 
or the anterolateral quadriceps as an alternate site) followed immediately by EP with the 
CELLECTRA™ 2000 device. Figure 1 (Appendix A) shows the original study visit 
schedule, in which study subjects will receive at least 4 doses of VGX-3100 and 
potentially a 5th and 6th dose depending upon their disposition with regard to histologic 
and lesion area changes.  Figure 1a shows the revised visit schedule per Protocol 
Amendment 5.0.  In both schedules, the first dose will be administered on Day 0, the 
second at Week 4, the third at Week 12, and the fourth dose will be administered at 
Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will receive 4 doses. 
Subjects with HSIL at Week 48, who have a reduction in lesion size or no increase in 
lesion size from baseline (Subgroups C or D), may receive a fifth dose at Week 52 per 
the judgment of the Investigator.  
With Amendment 5.0, subjects will complete the study at Week 78 and will not be 
offered a 6th dose.  Subjects who were beyond Week 78 at the time of IRB approval of 
Amendment 5.0, will return for their final visit at their next scheduled timepoint as 
outlined in Table 1.  Subjects must sign the IRB-approved informed consent document 
for Amendment 5.0 prior to the initiation of procedures for their final study visit. 
Imiquimod treatment – Participants who have been enrolled in the VGX-3100 with 
imiquimod study group will continue with study visits per protocol, but no further 
participants will be enrolled into this study group.  Subjects randomized to the VGX-3100 
with imiquimod study group will apply imiquimod 5% cream to the vulvar lesion 
beginning in the evening on Day 0, and will continue to apply treatment three times per 
week for 20 weeks (inclusive of administration in the evening of VGX-3100 dosing). 
Subjects unable to tolerate imiquimod treatment may reduce their dosing frequency, and 
will document their use on the imiquimod dosing log provided. 
3.2 
EFFICACY ASSESSMENT 
The efficacy assessment will be based upon histopathology. Visualization of a normal 
appearing vulva by visual inspection with vulvoscopy is insufficient evidence to confirm 
disease regression. Disease regression will be based on histopathologic assessment at 
Week 48, 74, and at Week 96 for subjects reaching Week 96 prior to Amendment 5.0 or 
for whom that is the final visit. Subjects will be monitored during the course of the study 
by vulvoscopy. Lesion(s), defined as areas that stain acetowhite, will be assessed and 
photographed during vulvoscopy at Screening, Day 0, and Weeks 4, 12, 27, 48, 74, and 
at Week 96 for subjects who have reached this timepoint prior to Amendment 5.0 or for 
whom this is the final visit. Using standardized high resolution digital photographic 
imaging, vulvar lesion(s) will also be quantitatively measured at Screening, Day 0, and 
Weeks 48, 74, and at Week 96 for subjects who have reached that timepoint prior to 
Amendment 5.0 or for whom that is their final visit.  
Biopsies obtained as part of the study at Screening will be from the region of most 
advanced disease as judged by the Investigator, and must be approximately 4 mm in 
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Clinical Protocol 
 
 
length. Visible lesion must remain after screening biopsy to ensure measurement on 
study. A qualifying lesion is defined as a vulvar lesion which is confirmed to be HPV-16 
and/or HPV-18 positive and have histologically confirmed vulvar HSIL by the PAC at 
screening. 
The decision process following results of the Week 48 biopsy are described in Figure 2 
and are as follows: At Week 48, the subject will undergo repeat vulvar punch 
biopsy/biopsies of the same lesions as study start, from the region of most advanced 
disease based upon the judgment of the Investigator (see Table 2 for Minimally 
Required Biopsy Procedures).  
If after evaluation of biopsy tissue by the PAC there is no evidence of HSIL (Figure 2, 
Subgroups A or B), the subject will continue to Week 74 for vulvoscopy, and biopsy of 
the same lesion(s) as study start. 
If after evaluation of the biopsy tissue HSIL remains, but there is a reduction in lesion 
size or no increase in lesion size from baseline (Figure 2, Subgroups C or D), the 
Investigator has the option to give the subject a 5th dose of VGX-3100 at Week 52, and 
the subject will continue on study with vulvoscopy and biopsy at Week 74.  Alternatively, 
the Investigator may choose to treat the subject with surgical or standard treatment, and 
the subject will continue on study without further biopsy.  
The decision process following results of the Week 74 biopsy for subjects who 
completed this visit prior to Amendment 5.0 are described in Figure 3 (Appendix B) for 
the original study design.  The evaluation process following results of the Week 74 
biopsy under Amendment 5.0 are described in Figure 3a and are as follows: At Week 
74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion as at 
study start Investigator(see Table 2). If, after evaluation of Week 74 biopsy tissue by the 
PAC, there is no evidence of HSIL (Subgroups A or B), the Investigator will use their 
clinical judgment regarding follow-up care of the subject (not part of study activities).    
If, after evaluation of the biopsy tissue HSIL remains, but there is a reduction in the 
qualifying lesion(s) size or no change in lesion size from baseline (Subgroups C or D), 
the subject will receive further standard of care treatment (not part of study activities) per 
the Investigator’s judgment.   
The decision process for subjects who are beyond Week 78 at the time of IRB approval 
of Amendment 5.0 can be found in Appendix C.  These subjects will complete the study 
at their next scheduled visit as outlined in Table 1. Subjects must sign the IRB-approved 
informed consent document for Amendment 5.0 prior to the initiation of procedures for 
their final study visit. 
In the event of worsening disease prior to the end of the study (i.e., Subgroup E), the 
subject will receive surgical treatment per the Investigator's judgment and will continue 
on study with vulvoscopy, but without further study treatment or biopsy.  In the event of 
worsening disease at the final visit, the subject will receive standard of care treatment 
(not part of study activities) per their treating physician.  If wide excision is conducted at 
or prior to the subjects last on site visit, the sample obtained will be sent to the PAC for 
evaluation.  For a finding of carcinoma, subjects will receive surgical treatment, and be 
discontinued from study treatment. The event will be reported as an SAE per section 
7.1.4.  
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All visible lesions should be biopsied at Week 48.  For subjects for whom Week 78 is 
their final visit, all visible lesions should be biopsied at Week 74.  For subjects for whom 
the final visit is Week 96, all visible lesions should be biopsied at Week 96.  
If there is a new lesion identified at evaluation, or a non-qualifying lesion that is 
rebiopsied and confirmed to be vulvar HSIL and HPV-16/18 positive at evaluation, a 
discussion will take place between the Medical Monitor and the Principal Investigator to 
determine if additional dosing at Week 52 is appropriate. 
 
Table 2:  Minimally Required Procedure at Biopsy Visit 
Pre-biopsy Vulvoscopy 
Finding  
Minimally required procedure  
No acetowhite lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator; new lesions or lesions that 
did not qualify at baseline should be biopsied at evaluation. 
Acetowhite Lesion 
Vulvar punch biopsy and lesion photography; biopsy should 
be conducted of the same qualifying lesion as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator; new lesions or lesions that 
did not qualify at baseline should be biopsied at evaluation  
Multiple acetowhite lesions 
Vulvar punch biopsies and lesion photography; biopsy should 
be conducted of the same qualifying lesions as study entry 
from the region of potentially most advanced disease based 
upon judgment of the Investigator; new lesions or lesions that 
did not qualify at baseline should be biopsied at evaluation 
 
  
 
 DEFINITION OF RESPONDER AND NON-RESPONDER FOR THE 
PRIMARY ENDPOINT 
A treatment responder is defined as a subject with no histologic evidence of vulvar HSIL 
and no evidence of HPV-16 or HPV-18 in vulvar tissue at evaluation and who did not 
receive any non-study related treatment for vulvar HSIL. A treatment non-responder is a 
subject with histologic evidence of vulvar HSIL or vulvar carcinoma at evaluation, or a 
subject with evidence of HPV-16/18 at evaluation, or a subject who received non-study 
related treatment for vulvar HSIL. Any case of histologically confirmed progression to 
carcinoma according to the PAC is considered a non-responder.  
Responder and non-responder definitions (Table 3) take into account both 
histopathologic regression of vulvar HSIL and virologic (HPV-16/18) clearance from 
tissue samples since HPV persistence is an important factor in the clinical progression of 
HSIL. 
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Clinical Protocol 
 
 
Table 3: Definition of Responder and Non-responder for the Primary Endpoint 
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL  
AND 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
Subject with histologic evidence of vulvar HSIL or  
vulvar carcinoma at evaluation 
OR 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
OR 
Subject who received non-study related treatment 
for vulvar HSIL 
 
 DEFINITION OF RESPONDER AND NON-RESPONDER FOR THE 
SECONDARY AND EXPLORATORY ENDPOINTS 
Table 4: Definition of Responder and Non-responder for HSIL Regression Endpoint   
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
Subject with histologic evidence of vulvar HSIL or  
vulvar carcinoma at evaluation  
OR 
Subject who received non-study related treatment 
for vulvar HSIL 
 
Table 5: Definition of  Responder and Non-responder for Viral Clearance Endpoint  
Responder 
Non-Responder 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation  
OR 
Subject who received non-study related treatment 
for vulvar HSIL 
 
Table 6: Definition of Responder and Non-responder for Complete HSIL Regression 
Endpoint  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL, LSIL (VIN1), or condyloma  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
Subject with histologic evidence of vulvar HSIL, 
LSIL (VIN1), or condyloma at evaluation  
OR 
Subject who received non-study related treatment 
for vulvar HSIL 
 
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Table 7: Definition of Responder and Non-responder for Disease Non-Progression 
Endpoint 
Responder 
Non-Responder 
Subject with no histologic evidence of a 
worsening vulvar condition to vulvar 
cancer at Week 48 relative to baseline 
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL 
Subject with histologic evidence of worsening of 
vulvar condition to vulvar cancer at Week 48 
relative to baseline 
OR 
Subject who received non-study related treatment 
for vulvar HSIL 
 
 
Table 8: Definition of Responder and Non-responder for HSIL Regression or Viral 
Clearance Endpoint  
Responder 
Non-Responder 
Subject with no histologic evidence of 
vulvar HSIL  
OR 
Subject with no evidence of HPV-16 or 
HPV-18 in vulvar tissue at evaluation  
AND 
Subject who did not receive any non-
study related treatment for vulvar HSIL  
 
Subject with histologic evidence of vulvar HSIL or 
vulvar carcinoma at evaluation  
 
AND 
Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation  
OR 
Subject who received non-study related treatment 
for vulvar HSIL 
 
3.3 
SAFETY ASSESSMENT 
Safety monitoring will include: 
1) 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary  
2) 
All adverse events including SAEs, AESIs, SUSARs, UADEs, and other 
unexpected AEs for the duration of the study. 
All subjects will be followed through Week 78 under Amendment 5.0, or up to 100 weeks 
if beyond Week 78 at the time of Amendment 5.0.   
 DATA SAFETY & MONITORING BOARD  
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight. 
The DSMB will meet quarterly to review safety data and regression/clearance results. 
The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue. No formal interim analysis is planned. The following stopping rules will be applied: 
 
If at any time during the study one-third (1/3) or more of the subjects experience an 
Adverse Event of Special Interest verified per protocol definition, further enrollment 
and study treatment will be halted until a thorough review has been conducted by the 
Medical Monitor, PI for the trial, and the DSMB.  
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 
If any SAE (or potentially life-threatening AE) or death verified as related to study 
treatment occurs, further enrollment and study treatment will be halted until a 
thorough review has been conducted by the Medical Monitor, PI for the trial, IRB (if 
applicable) and the DSMB. 
 
If three or more subjects in this study experience the same Grade 3 or 4 unexpected 
adverse event, verified per protocol definition and assessed as related to study 
treatment, further enrollment and study treatment will be halted until a thorough 
review has been conducted by the Medical Monitor, PI for the trial, and the DSMB. 
 
In the event of two identical, unexpected, Grade 4 toxicities, verified per protocol 
definition and assessed as related to study treatment, further enrollment and study 
treatment will be halted until a thorough review has been conducted by the Medical 
Monitor, PI for the trial, IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all Investigators and IRBs/EC (if required) regarding 
the outcome of any investigation stemming from a Study Pause. 
3.4 
IMMUNOGENICITY ASSESSMENT 
The study explores humoral and cell mediated immune responses to VGX-3100 in blood 
samples taken at baseline (i.e., Screening and Day 0 prior to dosing) and Weeks 15, 27, 
48, 74 and 96. Vulvar samples will also be analyzed for evidence of immune responses 
at Screening and Weeks 48, 74 and 96. Samples will not be obtained at Week 96 for 
subjects who complete the study prior to this timepoint, per Amendment 5.0. 
3.5 
VIROLOGIC ASSESSMENT 
Tissue samples will be obtained to characterize vulvar HPV infection at Screening, 
Weeks 48, 74 and 96. Cervical samples, oropharyngeal (OP) rinse samples, vulvar, 
vaginal, and intra-anal tissue swab samples will be obtained to characterize HPV 
infection at the following time points: Day 0 prior to dosing (OP, cervical, vulvar, vaginal 
and intra-anal), Week 4 (Vulvar only), Week 12 (Cervical and Vulvar) and Weeks 27, 48, 
74 and 96 (OP, vulvar, vaginal and intra-anal only). Samples will not be obtained at 
Week 96 for subjects who complete the study prior to this timepoint, per Amendment 
5.0.  At week 48 and 96, a cervical sample will also be collected.  
4. 
SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Must understand, agree and be able to comply with the requirements of the protocol. 
Subjects must be willing and able to provide voluntary consent to participate and sign a 
Consent Form prior to study-related activities;  
2. Women aged 18 and above; 
3. Vulvar infection with HPV types 16 and/or 18 confirmed by screening biopsy; 
4. Vulvar tissue specimen/blocks must be collected within 10 weeks prior to anticipated 
date of first dose of study drug and have confirmed histologically confirmed vulvar HSIL 
by the Pathology Adjudication Committee at screening; 
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5. Must be judged by the Investigator to be an appropriate candidate for the protocol-
specified procedure (i.e. excision or biopsy) required at Week 48; 
6. Must have vulvar HSIL that is accessible for sampling by biopsy instrument and of 
adequate size to ensure that a visible lesion remains after an approximately 4 mm 
screening biopsy;  
7. Must have vulvar HSIL that can be completely demarcated for area measurement; 
8. Must meet one of the following criteria with respect to their reproductive capacity: 
a. Is post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b. Is surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to screening; 
c. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive 
method with failure rate of less than 1% per year when used consistently and 
correctly from screening until 6 months following the last dose of investigational 
product. Acceptable methods are the following: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. 
Hormonal contraceptives must not be used in subjects with a history of 
hypercoagulability (e.g., deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject's preferred 
and usual lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject's entry 
into the study, and this male is the sole partner for that subject. 
9. Normal screening electrocardiogram (ECG) or screening ECG with no clinically 
significant findings as judged by the Investigator. 
 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Untreated microinvasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAIN;  
3. Biopsy-proven Anal Intraepithelial Neoplasia (AIN) and are not undergoing medical 
care and/or treatment for AIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CIN; 
5. Biopsy-proven differentiated VIN; 
6. Vulvar HSIL that is not accessible for sampling by biopsy instrument;  
7. Vulvar HSIL that is not of adequate size to ensure that a visible lesion remains 
after biopsy; 
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8. Treatment for genital warts within 4 weeks prior to screening; 
9. Any previous treatment for vulvar HSIL (e.g. with surgery and/or imiquimod) within 
4 weeks prior to screening; 
10. Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream 
for subjects enrolled prior to Protocol Amendment v3.0 (dated 26Mar2019); 
11. Is pregnant, breastfeeding or considering becoming pregnant within 6 months 
following the last dose of investigational product; 
12. Presence of any unresolved abnormal clinical laboratory values greater than Grade 1 
per Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 within 45 
days prior to Day 0 or less than or equal to Grade 1 but deemed clinically significant 
by the Investigator; 
13. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening;  
b) Primary immunodeficiencies; 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic, and ophthalmic 
corticosteroids are allowed); 
d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or 
etanercept); 
e)  History of solid organ or bone marrow transplantation; 
f)  Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed autoimmune disease that may jeopardize the safety of the subject or 
require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
14. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil®, Cervarix®); 
15. Received any non-study related non-live vaccine within 2 weeks of each study dose; 
16. Received any non-study related live vaccine (e.g. measles vaccine) within 4 weeks 
of each study dose; 
17. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
18. Current or history of clinically significant, medically unstable disease which, in the 
judgment of the Investigator, would jeopardize the safety of the subject, interfere with 
study assessments or endpoint evaluation, or otherwise impact the validity of the 
study results  
a) Chronic renal failure, angina, myocardial ischemia or infarction, class 3 or higher 
congestive heart failure, cardiomyopathy, or clinically significant arrhythmias; 
b) Treatment for non-anogenital malignancy within 2 years of screening, with the 
exception of superficial skin cancers that only require local excision; 
c) Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of Day 
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0; 
d) History of seizures unless seizure free for 5 years with the use of one or 
fewer antiepileptic agents; 
e) Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or 
<90 mm Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
f) Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 
bpm at Screening or Day 0; 
g) Prior major surgery within 4 weeks of Day 0; 
19. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent (participation in an observational study is 
permitted); 
20. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
a) Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
treatment site; 
b) Cardioverter-defibrillator or pacemaker (to prevent a life-threatening 
arrhythmia) (unless deemed acceptable by a cardiologist); 
c) Metal implants or implantable medical device within the intended treatment site 
(i.e. electroporation area);  
21. Vulnerable populations: 
a) Active drug or alcohol use or dependence that, in the opinion of the Investigator, 
would interfere with adherence to study requirements; 
b) Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (i.e. infectious disease) illness; 
c) Active military service personnel who have the potential to be relocated; 
d) Study-related staff or family members of study-related staff; 
22. 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. 
4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from the study treatment. Subjects will not receive further study 
treatment/EP but will be encouraged to continue follow-up safety assessment through 
study discharge and not discontinue from the study.  
 
If a subject manifests a Grade 3 toxicity attributable to study treatment/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
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 CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All subjects who begin treatment should be encouraged to complete all phases of the 
study, including those who discontinue treatment. A subject may voluntarily withdraw 
from study participation at any time. A subject may be withdrawn at any time at the 
discretion of the Investigator for any maternal obstetrical or medical complications after 
consultation with the medical monitor.   
Subjects who become ineligible to continue on study based on no longer meeting 
exclusion criteria should be discontinued from study treatment, managed per routine 
standard of care and should continue on study without further biopsy.  
Subjects who are withdrawn from study participation after starting treatment will not be 
replaced. Reasons for study withdrawal will be recorded in the electronic case report 
form (eCRF) and the subject's source document. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site 
should also counsel the subject on the importance of maintaining the assigned visit 
schedule for follow-up and treatment of VIN, and ascertain whether or not the subject 
wishes to and/or should continue in the study based on previous noncompliance. In 
cases where the subject does not return for the rescheduled visit or cannot be reached 
to reschedule the missed visit, the site should make every effort to regain contact with 
the subject (3 telephone calls to the subject should be made and if that fails, then a 
certified letter is sent to the subject's last known mailing address) so that they can be 
considered withdrawn from the study for disposition purposes. These contact attempts 
should be documented in the subject's medical record. Should the subject continue to be 
unreachable, then and only then will she be considered to have withdrawn from the 
study with a primary reason of "Lost to Follow-up". For all other subjects withdrawing 
from the study, an alternative reason for discontinuation should be recorded in the 
eCRF. 
If a subject elects to discontinue treatment/EP she should be encouraged to stay in the 
study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). 
At a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit, Week 100 for subjects completing the 
study prior to Amendment 5.0.  
For subjects completing the study under Amendment 5.0, the discharge visit will be 
Week 78 unless the subject was beyond Week 78, then the discharge visit will be the 
next scheduled visit per the schedule of events. The updated consent for Amendment 
5.0 must be obtained before final visit procedures are performed.  For subjects 
completing the study at Week 78, the repeat cervical colposcopy will be performed at 
Week 74 or the discharge visit. The socio-behaviorial assessment scheduled for Week 
100 will be done at the final discharge visit for subjects completing the study before 
Week 100.  A subject will be considered to have completed the study when all scheduled 
study treatments and follow-up visits are completed.  
 
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 SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or study coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an AE. If a subject discontinues from 
the study or is withdrawn from the study prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of discontinuation. The 
Investigator will make every effort to have all scheduled immune assessment blood 
samples collected as indicated in the Schedule of Events in the synopsis, Table 1. Any 
AEs and/or SAEs present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in section 7.1. 
 REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the 
study itself is to be selected from the following standard categories and recorded on the 
eCRF: 
 
Adverse event (adverse reaction): Clinical or laboratory events occurred that, in 
the medical judgment of the Investigator for the best interest of the subject, are 
grounds for discontinuation. This includes serious and non-serious AEs 
regardless of relation to study drug. 
 
Death 
 
Subject voluntarily withdrew consent: The subject desired to withdraw from 
further participation in the study in the absence of an Investigator-determined 
medical need to withdraw. If the subject gave a reason for withdrawal, it must be 
recorded on the eCRF. This reason does not allow for further data collection and 
should not be selected if follow-up data collection of this subject is anticipated by 
the subject. 
 
Investigator decision to withdraw the subject from participation: Investigator 
determined a maternal obstetrical or medical need to withdraw the subject. 
Investigator must consult the medical monitor before withdrawing a subject from 
participation in the study. 
 
Protocol violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., treatment 
noncompliance, failure to return for defined number of visits). The violation 
should be discussed with the Sponsor’s Medical Monitor prior to discontinuation 
of study treatments or study withdrawal. 
 
Lost to follow-up: The subject fails to attend study visits and study personnel are 
unable to contact the subject after at least 3 repeated attempts including letter 
sent by certified mail or equivalent. 
5. 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
The VGX-3100 drug product contains DNA plasmids for expression of HPV-16 E6/E7 
(pGX3001) and HPV-18 E6/E7 (pGX3002) antigens that have been designed and 
constructed using proprietary synthetic consensus DNA (SynCon™) technology. The VGX-
3100 formulation to be used in this study is described in Table 9 and will be presented in 
a clear glass vial for intramuscular injection. 
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Imiquimod 5% is a topical cream for external use and is supplied in single-use packets 
containing 250 mg of cream. Each gram of the 5% cream contains 50 mg of imiquimod in 
an off-white oil-in-water vanishing cream base. Inactive ingredients include benzyl alcohol, 
cetyl alcohol, glycerin, methylparaben, oleic acid, oleyl alcohol, polysorbate 60, 
propylparaben, purified water, stearyl alcohol, sorbitan monostearate, white petrolatum, 
and xanthan gum. There are 24 single-use packets of imiquimod in one box. The product 
manufacturer is Perrigo, Yeruham 80500, Israel.   
Imiquimod is indicated for the treatment of external genital and perianal warts/condyloma 
acuminate in patients 12 year old or older. Although it is not approved by the US Food and 
Drug Administration for the treatment of vulvar HSIL, imiquimod is currently recommended 
as a non-surgical, off-label treatment option for vulvar dysplasia by the American College 
of Obstetricians and Gynecologists (ACOG).   
VGX-3100 and imiquimod will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 9. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 
E6/E7 plasmids) in 150 mM sodium chloride and 15 
mM sodium citrate 
1 mL 
Imiquimod Cream, 
5% 
12.5 mg imiquimod per 250 mg single-use packet   
250 mg 
5.2 
PACKAGING AND LABELING 
 PACKAGING AND LABELING OF VGX-3100 AND IMIQUIMOD 
Each vial of VGX-3100 will be labeled with a single-panel label that will include, at a 
minimum, the information in Figure 5.  The actual product label names the product as 
VGX-3100X; the "X" designation was included to differentiate the current buffer 
formulation from a previous formulation of VGX-3100 in water. Imiquimod Cream, 5% will 
have both the original manufacturer's label on individual packets and the back of the 
carton, and an investigational label on the front of the carton. The labels will contain, at 
minimum, the information shown in Figure 6.   
 
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Figure 5. Example Labels for VGX-3100 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 6. Example labels for imiquimod 
 
Box 
(secondary package) 
Study ID 
Imiquimod Cream, 5% 
 
Composition: 
One 0.25 g single-use packet contains: Imiquimod 12.5 mg 
Store at 4 – 25oC (39-77oF). Avoid freezing. 
 
For Dermatologic Use Only. Not for Ophthalmic Use. 
Keep out of reach of children. This package is not child resistant. 
CAUTION: New Drug - Limited by United States Law to Investigational 
Use 
Inovio Pharmaceuticals, Inc. 
5.3 
HANDLING AND STORAGE 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the 
Investigational Product (IP) is adequate for the duration of the trial. Unless otherwise 
specified, VGX-3100 will be shipped in a refrigerated condition with a temperature 
monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately.   
Upon arrival, VGX-3100 should be transferred from the shipping container into 2–8 °C (36-
46 °F) storage, in a secure area, according to local regulations. The Sponsor should be 
notified of any deviations from this recommended storage condition. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
Imiquimod will be shipped and stored at room temperature (4 – 25oC) according to the 
manufacturer's instructions. Avoid freezing.    
SynConTM VGX-3100 [6 mg/mL]    
1 mL/Vial Single Use Vial 
Date of Manufacture: _______ 
Expiry Date: _______ 
Refrigerate at 2-8oC 
CAUTION: NEW DRUG - LIMITED BY FEDERAL 
LAW TO CLINICAL TRIAL USE ONLY 
Inovio Pharmaceuticals, Inc.  
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5.4 
PREPARATION AND DISPENSING 
 DISPENSING OF VGX-3100 
It is the responsibility of the Investigator to ensure that VGX-3100 is only dispensed to 
study subjects. It must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
VGX-3100 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee. The designated staff member will be responsible for 
dispensing the appropriate volume (1mL) of VGX-3100. No mixing or dilutions will be 
required. 
VGX-3100 should be removed from the refrigerator and brought to room temperature. 
The product must be used within 4 hours of removal from the refrigerator. All material 
removed from the refrigerator must not be re-refrigerated. 
Detailed instructions on handling and dispensing of VGX-3100 are provided in the 
Pharmacy Manual. 
 DISPENSING AND USE OF IMIQUIMOD 
It is the responsibility of the Investigator to ensure that imiquimod labeled for study use is 
only dispensed to study subjects. It must be dispensed from official study sites only, by 
authorized personnel according to local regulations. Subjects will be given 1 box of 
imiquimod (24 single-use packets per box) at Day 0, one box at Week 4, and one box at 
Week 12. Subjects will be instructed to apply imiquimod externally to the vulvar lesion 3x 
per week prior to normal sleeping hours, for 20 weeks. Imiquimod should be left on the 
skin for 6 – 10 hours and then removed by washing the treated area with mild soap and 
water. Examples of 3 times per week application schedules are: Monday, Wednesday, 
Friday, or Tuesday, Thursday, Saturday application prior to sleeping hours. In the event 
that Imiquimod is not tolerated at 3 times per week, alternative administration 
approaches must be discussed and approved by the medical monitor. 
Subjects will be provided with an imiquimod dosing log to record their use during the 20 
week treatment period. The imiquimod dosing log should be brought to the clinic with the 
used imiquimod box, at Week 4, 12, and 24 for review with study personnel. 
5.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product is maintained at the study site. 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 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 
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5.6 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be returned to Inovio 
Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. 
to be destroyed at the site. 
All IP 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 disposal of 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 IP(s) should be arranged by the 
responsible Study Monitor or by the authorized site representative if the Study Monitor is 
not present. 
If IP(s) 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. 
Reconciliation of any unused IP must be performed and provided to the responsible 
Inovio Pharmaceuticals, Inc. or designated Study Monitor for review prior to on-site 
destruction. 
5.7 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the CELLECTRA™ 2000 device are located in the User 
Manual. Each clinical site will receive training for the use of the CELLECTRA™ 2000 
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 
The CELLECTRA™ 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA™ 2000 User 
Manual describes all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings, and precautions. Each CELLECTRA™ 2000 Pulse 
Generator has a unique serial number, and each CELLECTRA™ 2000 Applicator has a 
unique serial number. Each CELLECTRA™ 2000 Array has a Lot Number, Manufacture 
Date, and Expiration Date.  
The treatment procedure must be performed by qualified personnel. Any individual 
designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g. MD, DO, RN) in addition to 
successfully completing device training from sponsor personnel. 
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5.8 
PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. The investigational labels in Table 10 below are 
presented as examples. Please note, information such as expiration date, lot and serial 
numbers (as applicable) is included at the time of manufacture and may vary from these 
examples. The information found on the actual device labels should always be used to 
manage, track and record investigational product accountability during study conduct. 
 
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Table 10. Example Labels for the CELLECTRA™ 2000 Device (Pulse Generator, Applicator and Array) 
Device 
Component 
EXAMPLE Label 
 
CELLECTRA™ 
2000 Pulse 
Generator 
 
Model 14510 
 
Part Number: 
M01-003188 
 
 
 
 
CELLECTRA™ 
2000 5P 
Applicator 
 
Model 14506 
 
Part Number: 
M01-002535 
 
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CELLECTRA™ IM 
Array 
 
REF: M01-002537 
 
 
 
5.9 
INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and 
accountability logs. The device must have full traceability from the receipt of the products 
through the subject use, disposal or return of the products. The Site must document 
acknowledgement of receipt and notify Inovio upon receipt of investigational product. 
This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 2000 serial number, applicator serial number, and array lot number. 
The CELLECTRA™ 2000 IM Applicator is intended to be used multiple times on the 
same subject and then disposed after final use in accordance with accepted medical 
practice and any applicable local, state, and federal laws and regulations. Once the IM 
applicator is assigned to a subject, it may NOT be used on another subject. The used 
sterile disposable array attachment must be discarded after use in accordance with 
institutional policy regarding disposal of sharp needles/instruments. 
5.10 RETURN AND DESTRUCTION OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, an Inovio representative will provide 
instructions regarding which materials should be destroyed onsite, and/or returned to 
Inovio Pharmaceuticals, Inc. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original 
containers. The return of all product identified above should be arranged by an Inovio 
representative. 
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If product is to be destroyed on site, it is the Investigator's responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted 
by 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. 
6. 
STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation. The 
timing of each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information 
collected prior to consenting and before any additional study specific procedures are 
performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate 
safety concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
 SCREENING EVALUATIONS 
Subjects who consent to participate and have paraffin-embedded tissue block(s) from 
vulvar tissue samples (formalin fixed tissue) from a previous biopsy, can have the 
samples sent to the central pathology lab for review by the PAC to assess eligibility. 
There will be a maximum allowable window of 10 weeks from the date of collection of 
the qualifying biopsy sample(s) (i.e. samples reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).   
For those individuals diagnosed with vulvar HSIL by a local pathologist, where the initial 
biopsy tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, an additional biopsy sample should be collected 
during screening following the consent of the subject. The 10 week screening window 
begins upon collection of the biopsy sample that will be evaluated by the PAC. 
Subjects must have a diagnosis of histologic vulvar HSIL confirmed by the PAC at 
screening, and a screening vulvar specimen test positive for HPV-16 and/or HPV-18 by 
PCR to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose vulvar specimens also test positive for other 
HPV genotypes are not excluded as long as they have a positive result for HPV-16 
and/or HPV-18.  
The assessments during the screening period will determine the subjects'' eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. 
The following screening evaluations will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0, except for the safety laboratory collections/assessments, and 
ECG which must be performed within 45 days prior to Day 0. All screening assessment 
values must be reviewed prior to study treatment. 
 
Signed informed consent  
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 
Medical history/demographics, including history of prior vulvar HSIL and vulvar 
excisions 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
 
Prior/concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Physical Exam (a full physical exam is mandatory at Screening) 
 
Vital signs (including body temperature, respiratory rate, blood pressure and heart 
rate), and height, weight and BMI measurements 
 
12-lead ECG within 45 days prior to Day 0 
 
Baseline laboratory evaluations (includes complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine, glucose, alanine 
aminotransferase [ALT], creatine phosphokinase [CPK], and urinalysis) to be 
performed within 45 days prior to Day 0 
 
Urine Pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for baseline immunologic assay 
 
Vulvoscopy 
 
Screening vulvoscopy is optional if vulvoscopy was performed upon collection of 
initial biopsy and corresponding lesion photography is available. 
 
Vulvar Lesion Photography  
 
Photograph of the vulvar lesion(s) must be collected prior to and after biopsy at 
screening 
 
If a historical biopsy sample is used to determine eligibility at screening and a 
pre-biopsy photograph is not available, a post biopsy photo will be sufficient.  
 
 
Biopsy:  
 
Slides from all excised tissue must be reviewed by the PAC.  
 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study 
treatment. Visit dates and windows must be calculated from Day 0. 
 DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 
Determination of eligibility per Inclusion/Exclusion Criteria 
 
Review of concomitant medications and adverse events 
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 
Randomization 
 
Patient Reported Outcomes 
 
Targeted physical assessment  
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
Study treatment will be administered and the following evaluations will be performed on 
Day 0 after study treatment: 
 
Post treatment AEs including injection site reaction assessment within 30-45 
minutes after study treatment  
 
Distribute Participant Diary (PD) 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device  
 8-14 DAYS POST DOSE 1 PHONE CALL 
 
Review Adverse Events 
 
Patient Reported Outcomes 
 
Review Day 0 PD  
 
After completing a review of PD and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 WEEK 4 (± 7 DAYS) 
The following study evaluations will be performed at Week 4 prior to study treatment  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
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 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Vulvar swab 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 4 after study treatment: 
 
Post treatment AEs including injection site reaction assessment within 30-45 
minutes after study treatment  
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log (for subjects in the 
imiquimod arm) 
Download EP data from device  
 8-14 DAYS POST DOSE 2 PHONE CALL 
 
Review Adverse Events and concomitant medications 
 
Patient Reported Outcomes 
 
Review Week 4 PD 
 
After completing a review of PD and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine 
whether an office visit is needed for further evaluation. 
 WEEK 12 (± 7 DAYS) 
The following study evaluations will be performed at Week 12 prior to study treatment:  
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment 
 
Vital signs 
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod arm 
 
Urine pregnancy test 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history 
 
Vulvar swab 
 
Vulvoscopy  
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 
Vulvar lesion photography of the qualifying lesion(s) 
The following study evaluations will be performed at Week 12 after study treatment: 
 
Post-treatment AEs including injection site reaction assessment within 30-45 
minutes after study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
 
Distribute 1 box of imiquimod and the imiquimod dosing log to subjects in the 
imiquimod arm 
Download EP data from device  
 WEEK 15 (± 7 DAYS) 
The following study evaluations will be performed at Week 15: 
 
Review Adverse Events and concomitant medications 
 
Review Week 12 Participant Diary 
 
Patient Reported Outcomes 
 
Whole blood and serum for immunologic assay including miRNA profile 
 WEEK 24 (± 7 DAYS) 
The following study evaluations will be performed at Week 24 prior to study treatment: 
 
Review of concomitant medications and adverse events  
 
Review imiquimod dosing log and usage (accountability of returned product) for 
subjects in the imiquimod study group  
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
The following study evaluations will be performed at Week 24 after study treatment: 
 
Post-treatment AEs including injection site reaction assessment within 30-45 
minutes after study treatment 
 
Patient Reported Outcomes 
 
Distribute PD 
Download EP data from device  
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 WEEK 27 (± 7 DAYS) 
The following study evaluations will be performed at Week 27: 
 
 
Review of concomitant medications and adverse events 
 
Review Week 24 Participant Diary 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
 
Vulvar lesion photography of the qualifying lesion(s) 
  WEEK 38 PHONE CALL 
 
Review concomitant medications and adverse events 
  WEEK 48 (± 7 DAYS) 
The following study evaluations will be performed at Week 48: 
 
Targeted physical assessment 
 
Vital signs 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay including miRNA profile 
 
Cervical cytology and ThinPrep®  for cervical HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Vulvoscopy  
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 
Vulvar lesion photography (pre-and post biosy), and quantitative measurement 
(pre-biopsy)  of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
 WEEK 52 (± 14 DAYS) 
Subjects will have a Week 52 consultation to discuss their biopsy results and treatment 
plan. The following assessments will also be performed:   
 
Review of concomitant medications and adverse events 
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test (for subjects receiving a 5th dose only) 
Subjects receiving a 5th dose will have the following evaluations performed at Week 52 
after study treatment: 
 
Post-treatment AEs including injection site reaction assessment within 30-45 
minutes after study treatment 
 
Distribute Participant Diary 
Download EP data from device  
  WEEK 74 (± 14 DAYS) 
The following study evaluations will be performed at Week 74: 
 
Review of concomitant medications and adverse events 
 
Review Week 52 Participant Diary for subjects receiving a 5th dose  
 
Targeted physical assessment 
 
Vital signs 
 
Patient Reported Outcomes 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
OP oral rinse, vulvar, vaginal and intra-anal swabs 
 
Cervical colposcopy (for subjects ending the study at Week 78 per Amendment 
5.0) 
 
Vulvoscopy 
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 
Vulvar lesion photography (pre-and post biosy), and quantitative measurement 
(pre-biopsy) of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
  WEEK 78 (± 14 DAYS) 
Subjects will have a Week 78 consultation to discuss their biopsy results and treatment 
plan. This will be the final visit for subjects reaching this timepoint under Amendment 
5.0, and may occur via phone.  The following assessments will also be performed:   
 
Review of concomitant medications and adverse events  
 
Targeted physical assessment (or full physical exam for subjects completing the 
study in-person at Week 78) 
 
Vital signs (for in-person visit only) 
 
Urine pregnancy test (for subjects receiving a 6th dose prior to Amendment 5.0 
only) 
 
Socio-behavioral evaluation (for subjects completing the study at Week 78 per 
Amendment 5.0) 
Subjects receiving a 6th dose will have the following evaluations performed at Week 78 
after study treatment: 
 
Post-treatment AEs including injection site reaction assessment within 30-45 
minutes after study treatment 
 
Distribute Participant Diary 
Download EP data from device  
  WEEK 96 (± 14 DAYS) 
The following study evaluations will be performed at Week 96 for subjects who have 
reached this timepoint before Amendment 5.0, or for whom this will be the final visit: 
 
Review of concomitant medications and adverse events 
 
Review Week 78 Participant Diary for subjects receiving a 6th dose prior to 
Amendment 5.0 
 
Targeted physical assessment (or full exam for subjects completing the study at 
Week 96) 
 
Vital signs 
 
Patient Reported Outcomes 
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 
Socio-behavioral evaluation (for subjects completing the study at Week 96 per 
Amendment 5.0) 
 
Urine pregnancy test 
 
Whole blood and serum for immunologic assay 
 
Cervical colposcopy  
 
Photographs during colposcopic examinations of the vagina and/or 
cervical areas should be obtained if lesions are identified.  
 
Cervical cytology and ThinPrep®  for HPV type 
 
Collect menstrual cycle status and recent gynecologic history  
 
OP oral rinse, vulvar, vaginal and intra-anal swabsVulvoscopy 
 
Vulvar lesion photography of the qualifying lesion(s) 
 
Vulvar biopsy or wide excision as per Investigator discretion: 
 
All biopsy samples must be sent to the PAC for review 
  WEEK 100 (± 14 DAYS) 
The following study evaluations will be performed at Week 100 for subjects who have 
reached this timepoint before Amendment 5.0 or for whom this will be the final visit: 
 
Review of concomitant medications and adverse events 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-
reported exposure to second-hand smoke, self-reported alcohol intake history, 
contraceptive history 
 
Full physical assessment 
 
Vital signs 
 
Urine pregnancy test 
6.3 
EVALUATIONS AND PROCEDURES 
 INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being 
performed (i.e., prior to any screening activities). The informed consent documentation 
must be in accordance with applicable regulations and GCP. Qualified 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, study treatments and follow-up procedures, in a language 
understandable to the subject. Explanation of the study includes, but is not limited to, 
study objectives, potential benefits and risks, discomforts/inconveniences, and the 
subject’s rights and responsibilities. The subject is then requested to sign and date the 
ICF. A copy of the signed informed consent documentation must be provided to the 
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subject. The qualified study personnel will document the process of obtaining informed 
consent within the source record. Signed ICFs are maintained in the subject's source 
records and must be accessible for verification at any time. 
 RESCREENING OF SCREEN FAILURES 
 
Subjects who sign the informed consent and are assigned a subject identification     
 
number (SID) but do not meet the eligibility criteria or fall outside of the screening 
 
window will be considered screen failures. If the Investigator believes rescreening is 
 
warranted, the Investigator must contact the medical monitor to discuss.  
 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique SID, which identifies the subject 
for all study-related procedures. SIDs are a combination of a up to two alpha letters 
study code, two alpha letter Country code, two digit site number, plus 3-digit subject 
number starting with 001 (e.g., VNUS01001). Once assigned, SIDs cannot be reused for 
any reason. Information regarding the SID and screen date must be documented on a 
Screening log/system and in the Interactive Response Technology (IXRS). 
Subjects meeting eligibility criteria will be randomized by a computer generated 
allocation schedule.  
 SAFETY EVALUATIONS 
6.3.4.1 
PHYSICAL EXAMINATION 
A full physical examination (PE) will be conducted during screening and study 
discharge unless otherwise indicated. It will include an assessment of the 
following: general appearance, skin, head, eyes, ears, nose, and throat, and 
lymph nodes, and respiratory, cardiovascular, gastrointestinal, genitourinary, 
musculoskeletal, and neurological systems. All assessments not completed 
should be marked as not done.  
A targeted physical assessment will be performed at other visits as determined 
by the Investigator or directed per subject complaints. 
6.3.4.2 
VITAL SIGNS 
Vital signs will be measured at specified visits and will include: 
 
Sitting systolic and diastolic blood pressures with subject sitting at rest for 
at least 5 minutes before measurement 
 
Respiration rate 
 
Heart rate  
 
Oral temperature measured with an automated thermometer 
6.3.4.3 
WEIGHT AND HEIGHT 
Weight will be measured at all dosing visits and at screening, and height will be 
measured at screening to assess BMI. 
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6.3.4.4 
MEDICAL HISTORY 
Medical history, including smoking history and gynecologic history, will be 
obtained at screening. All relevant (as judged by the Investigator) past and 
present conditions, as well as prior surgical procedures will be recorded for the 
main body systems.  
6.3.4.5 
SOCIO-BEHAVIORAL ASSESSMENT 
Socio-Behavioral Assessment, including self-reported smoking history, self-
reported history of exposure to second-hand smoke, self-reported alcohol intake 
history, self-reported recreational drug use history, self-reported history of 
contraceptive use and type of contraceptive if known, reproductive history, 
history of prior cervical dysplasia, and pregnancy history will be obtained at 
Screening.  
 
At Weeks 48 and 100, socio-behavioral assessment will be performed to 
document any change from screening.  Subjects who complete the study before 
Week 100 per Amendment 5.0, will have a socio-behavioral assessment 
completed at their final discharge visit 
6.3.4.6 
LABORATORY EVALUATIONS 
At screening, blood samples will be taken to be tested for serum chemistry and 
hematology.  
Complete blood count (CBC): 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
 
Serum Chemistry: 
 
Glucose 
 
Alanine aminotransferase (ALT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase (CPK) 
 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a 
microscopic examination should be performed. 
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6.3.4.7 
PREGNANCY TESTING 
For subjects of reproductive potential, a negative spot urine pregnancy test is 
required at screening, and prior to each study treatment, vulvoscopy and surgical 
excision or biopsy. 
6.3.4.8 
ELECTROCARDIOGRAM (ECG) 
A single 12-lead ECG will be obtained during Screening after the subject has 
been in a supine position for 10 to 15 minutes. The ECG should include 
measurements of ventricular rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST 
segment, T wave as well as an Investigator assessment of whether the ECG is 
normal or abnormal (automated interpretations of ECG should not be used). 
Abnormal ECGs should be interpreted as "clinically significant (CS)" or "not 
clinically significant (NCS)" by the Investigator. 
6.3.4.9 
POST-TREATMENT REACTION ASSESSMENTS 
The PD will capture subject reported local and systemic events for 7 days after 
the study treatment.  
The subject will be provided a PD and will be asked to record the following the 
evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PD will be reviewed with the subject and research staff at 8 -14 
Days post-dose. 
The study staff will review the PD for general symptoms (e.g. malaise, fatigue, 
headache, nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. 
pain, erythema and edema), medical events and medications. All reported events 
will be assessed for clinical significance (CS) and reported as adverse event 
accordingly. 
6.3.4.10 
IMIQUIMOD DOSING LOG 
Subjects randomized to the imiquimod arm, will record the dates of imiquimod 
application on the imiquimod dosing log during the 20 week treatment period. 
Subjects will contact site study personnel to report any adverse events and will 
return the log at their next visit.  
6.4 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive four doses of VGX-3100 (6 mg DNA/dose) in a volume of 1 mL by 
intramuscular injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 2000. Study treatment plus EP 
must not be given within 2 cm of a tattoo, keloid or hypertrophic scar, or if there is 
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implanted metal within the same limb. Any device implanted in the chest (e.g., cardiac 
pacemaker, defibrillator or retained leads following device removal) excludes the use of 
the deltoid muscle on the same side of the body. The timing of the initial dose will be 
designated Day 0 with the subsequent doses scheduled for administration at Weeks 4, 
12, 24, and at Weeks 52 and 78 for Subgroups C and D only. 
 RISKS OF TREATMENT PROCEDURES 
6.4.1.1 
RISKS OF TREATMENT PROCEDURES TO VGX-3100 
No serious related adverse events to VGX-3100 have been observed in the clinical trial 
experience to date. A summary of potential risks of IM Administration followed by EP 
with CELLECTRA™ can be found in the VGX-3100 + Imiquimod Investigator's Brochure.   
6.4.1.2 
RISKS OF TREATMENT PROCEDURES TO IMIQUIMOD 
Adverse events reported in clinical trials with imiquimod cream, 5% for external genital 
warts can be found in the imiquimod product label [35], and in the VGX-3100 + 
Imiquimod Investigator's Brochure. 
 MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION 
(EP) PROCEDURE 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent 
significant discomfort from the treatment procedure. If a topical anesthetic is used, an 
approximately 1.5 cm diameter amount will be applied with occlusion to the site of 
injection ~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for 
anxiety related to the treatment procedure. Mild sedatives may be administered 
approximately 1 hour prior to study treatment. Subjects who receive a mild sedative 
should not be allowed to operate a motor vehicle for 3-4 hours after receiving medication 
and should have arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. acetaminophen, ibuprofen, ketorolac) before 
or after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, acetaminophen, 
ibuprofen, ketorolac or a mild sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management EMLA cream or sedatives should be 
added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening for inclusion into the study as listed in section 
6.3.4.6.   
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6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and between 30-45 
minutes after each study treatment. Subjects will be advised to record local and systemic 
AEs for 7 days after each study treatment on a PD which will be reviewed with study 
personnel at 8 – 14 days after dose 1 and 2, and at Weeks 15, 27, 74, and 96.  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset 
illness or disease, as well as contraceptive compliance. Subjects will be reminded to 
contact study personnel and immediately report any event that happens for the duration 
of the study. Unsolicited adverse events will be captured from the time of the informed 
consent to study discharge. These events will be recorded on the subject's CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale: 
 
Table 11. 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" 
*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 
^Sponsor defines daily activity as impact lasting ≥ 24 hours 
 
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6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, patient-reported outcomes 
(PRO) instruments will be provided. Administration of PRO instruments will be performed 
according to the validated or otherwise developed procedures and instructions of each 
respective instrument. PROs will not be completed at Week 96 or 100 for subjects who 
complete the study prior to those timepoints per Amendment 5.0.  The following PRO 
questionnaires will be used: 
1. WOMAN-PRO (WOMen with vulvAr Neoplasia PRO) Clinical Trial Version – 2.0 
(Beate Senn; version modified by Inovio Pharmaceuticals and RTI Health Solutions): is a 
31 item self-completed patient reported outcome measure designed to assess both 
physical and psychosocial impacts of VIN. The recall period is the past week.[20]. 
The WOMAN-PRO will be administered on paper only and should be the first PRO 
instrument administrated (i.e. before all other PROs) at each of the following time 
points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
2. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six 
items covering eight domains (Physical functioning, Role limitations due to physical 
problems, Bodily pain, General health, Vitality, Social functioning, Role limitations due to 
emotional problems, and Mental health) [36]. SF-36v2™ will be administered at the 
following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
8-14 days post dose 2 
 
Week 48 (after biopsy or surgical excision) 
 
Week 100   
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3. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual 
activity, Pain/discomfort, Anxiety/depression, and Global health status) [37, 38] and will 
be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (after study treatment) 
 
8-14 days post dose 2 
 
Week 12 (after study treatment) 
 
Week 15 
 
Week 24 (after study treatment)  
 
Week 27 
 
Week 48 (after biopsy or surgical excision) 
 
Week 74 (after biopsy or surgical excision) 
 
Week 96 (after biopsy or surgical excision) 
 
Week 100 
4. Additional Global PRO Questions – regarding quality of life after surgery or biopsy. 
These two questions will be administered on paper at Week 52 only. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 15, 27, 48, 74, and at Week 96 for subjects who complete that 
timepoint prior to Amendment 5.0. Details of the immunology sample collection and 
shipment information will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 
antibody response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune 
activity may occur via the application of the Interferon-γ enzyme-linked immunosorbent 
spot (IFN-γ ELISpot) assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
Granule Loading assay may examine the following external cellular markers: CD3, CD4, 
CD8 (T cell identification), CD137, CD38 and CD69 (T cell activation markers) as well as 
PD-1 (exhaustion/activation marker). The Lytic Granule Loading assay may additionally 
analyze the following intracellular markers: Granzyme A, Granzyme B, Granulysin and 
Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
Profiling of miRNA will occur using plasma obtained at Day 0, Week 15 and 48.  
Assessment of Day 0 samples alone will explore predictive algorithms for response to 
treatment with VGX-3100 prior to dosing. Assessment of Week 15 and 48 samples will 
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be done as a comparison against Day 0, in order to look for changes in miRNA profiles 
that occur once dosing with VGX-3100 has begun, to explore construction of an 
algorithm to predict treatment success with VGX-3100. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after HPV genotyping 
and histologic diagnoses have been rendered at Screening, Weeks 48, 74 and 96 (for 
subjects who have a Week 96 biopsy visit), then unstained slides and/or the relevant 
paraffin blocks may be collected for assessment of pro-inflammatory and 
immunosuppressive elements in tissue, where feasible. Slides will be scanned for 
visualization of pathology changes.   
Assessment of markers may include, but are not limited to, CD8+ and FoxP3+ infiltrating 
cells as well as assessment of cell death via Cleaved Caspase 3 assessment. Additional 
assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-
L1 in cervical tissue as sample allows. Markers listed here may change as new relevant 
information becomes available. 
6.11 VULVAR HPV TESTING 
At Screening, Weeks 48, 74, and 96, a vulvar punch biopsy sample of approximately      
4 mm will be obtained and sent to a central laboratory for HPV genotyping by PCR. 
Samples will not be obtained at week 96 on subjects who complete the study prior to 
that timepoint per Amendment 5.0.   
In the case of multifocal disease, a vulvar biopsy of approximately 4 mm will be obtained 
from two lesions that potentially contain the most advanced disease as judged by the 
Investigator. The subject will be requested to abstain from sexual activity and refrain 
from use of douching to eliminate potential interference with the results of HPV testing. 
The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
vulvar punch biopsy to eliminate potential interference with the results of HPV testing. 
6.12 COLPOSCOPY, PAP SMEARS AND HPV TESTING 
Cervical colposcopy will be performed at Day 0 and at Week 96 for subjects completing 
the study prior to Amendment 5.0. Subjects completing the study at Week 78 per 
Amendment 5.0 will have the repeat cervical colposcopy performed at Week 74 or 
discharge.  Photographs of the cervix should be obtained if lesions are identified. 
Pap smears will be obtained using ThinPrep® test kits at Day 0, Weeks 12, 48 and 96, 
and read in a central laboratory. Samples will not be obtained at Week 96 on subjects 
who complete the study prior to that timepoint, per Amendment 5.0.   
HPV PCR will be performed on the ThinPrep® specimen. At each of these visits, 
menstrual cycle status & recent gynecologic history will be collected. If the Pap smear 
result suggests progression to cancer the Investigator may schedule an ad hoc visit to 
perform a colposcopy and possible biopsy if clinically indicated. 
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The subject will be requested to abstain from sexual activity and refrain from use of 
douching or vaginal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep® samples to eliminate potential interference with the results of HPV testing. 
6.13 VULVOSCOPY, PHOTOGRAPHS, AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of vulvar HSIL 
confirmed by the PAC. Subjects will undergo vulvoscopy to identify the lesion(s). Interval 
vulvoscopies will be performed at Day 0, Weeks 4, 12, 27, 48, 74, and at Week 96 for 
subjects completing Week 96 prior to or under Amendment 5.0. Vulvoscopic 
visualization of a normal appearing vulva is insufficient evidence to confirm disease 
regression. An additional visit may be scheduled to perform vulvoscopy if worsening of 
disease is suspected. 
Digital photographs of the vulva will be captured after application of acetic acid to 
document the clinical findings. If a biopsy or surgical excision is performed, images of 
the vulva should be collected before and after the procedure. Each site will be instructed 
on 1) the technique for capturing the proper images using a standard approach, and 2) 
the process for uploading the images to a secure server.   
In the case of multifocal disease, the two lesions that potentially contain the most 
advanced disease as judged by the Investigator and which is of adequate size to ensure 
that a visible lesion remains after punch biopsy should be chosen for vulvar biopsy and 
documented using photography.     
Biopsies should not be performed at any visit other than at entry (screening), Week 48, 
Week 74, or at Week 96 for subjects completing these timepoints prior to or under 
Amendment 5.0, unless the PI suspects disease progression. All biopsy samples 
obtained prior to or at the final discharge visit must be sent to the PAC for review. 
Investigator guidelines for managing the findings of unscheduled biopsies for suspected 
disease progression are described in Table 12.  Consult the Medical Monitor for any 
planned departures from these guidelines. 
Table 12:  Guidelines for Managing Findings of Vulvar Biopsies for Suspected Disease 
Progression 
Vulvar Biopsy Results 
Action 
Vulvar HSIL 
May continue study treatment/EP and visits according to protocol 
schedule of events 
Microinvasive or Invasive 
Carcinoma 
Discontinue study treatment/EP and proceed with excisional 
therapy; continue safety follow-up. 
 
Subject safety is paramount in this study. Therefore, if at any time the Investigator 
suspects disease progression and the standard of medical care would be to perform an 
unscheduled biopsy or excision, then his or her medical judgment should prevail over 
the Schedule of Events on Table 1.  Histologic samples and photographic 
documentation should be obtained for these cases.  
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6.14 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to 
screening biopsy date of eligible subjects must be recorded on the CRF. Actual or 
estimated start and stop dates must be provided. Medical procedures performed within 8 
weeks prior to screening biopsy date of eligible subjects that do not affect subject's 
eligibility for participation and during the study (including over the counter or herbal), will 
be recorded on the CRFs. This information will be obtained from the subject and 
abstracted from any available medical records. The indication for the medication, dose, 
and dose regimen will be documented. Medication that is considered necessary for the 
subject's safety and well-being may be given per Investigator discretion and recorded in 
the appropriate sections of the CRF. 
6.15 RESTRICTIONS 
 
The following medications and treatments are prohibited: 
 
Previous treatment with imiquimod for vulvar HSIL within 4 weeks prior to screening 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, nasal, otic and ophthalmic 
corticosteroids are allowed) 
 
Disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying 
drugs such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at 
screening and throughout the study 
 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study related live 
vaccine 
 
Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
Investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures (See Inclusion 
Criteria, Section 4.1). Lapses in contraceptive use should be reported to Investigator 
and/or other study personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep® samples.  
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7. 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
 ADVERSE EVENTS 
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. Throughout the course of the study, all solicited and 
unsolicited AEs will be monitored and reported on an AE CRF, including the event's 
seriousness, severity, action taken, and relationship to investigational product(s). AEs 
should be followed until resolution or stable and the outcome will be documented on the 
appropriate CRF. All AEs should be recorded in standard medical terminology rather 
than the subject's own words. 
AEs include the following: 
 
Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (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 of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic 
pregnancy, fetal demise, still birth, congenital anomaly of fetus/newborn); see 
Section 7.1.11 for additional information. 
 
AEs that occur from the study screening visit onwards and throughout the 
duration of the study, including the follow-up off study drug period will be 
recorded as an AE. 
 
Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion) performed as a result of an AE. 
 
Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the screening visit 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 informed consent form is signed is not an AE. It is considered to be 
pre-existing and will be documented on the medical history CRF. 
 
Uncomplicated pregnancy. 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
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 SERIOUS ADVERSE EVENTS 
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; 
 
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 (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; 
 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
 
Results in congenital anomaly or birth defect; 
 
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 1) 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, 2) blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, 3) the development of drug dependency or drug abuse or 4) the 
development of a malignancy; 
 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 that 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 nor does it include full day or overnight stays in observation status. 
 
The Investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms.  
 
Serious adverse events that are ongoing should be followed until resolution or are 
clinically stable. The reporting period for SAEs is described in Section 7.4.2. 
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 EVENT REPORTING FOR DISEASE PROGRESSION OR 
EXCLUSIONARY HISTOLOGIC FINDINGS POST-STUDY TREATMENT 
After starting study treatment, if there is histologic confirmation of progression of HSIL to 
microinvasive or invasive squamous cell carcinoma, the event must be reported as an 
SAE. For the finding of carcinoma, subjects should be managed per routine standard of 
care (i.e. surgical excision), discontinued from study treatment but continue on study 
without further biopsy. Post-study treatment histologic diagnosis of carcinoma should 
also be reported as an SAE. In both instances the condition for SAE reporting should be 
categorized as a medically important event unless another criterion is met. 
 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a 
medicinal product related to any dose, for which a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility (i.e., there is 
evidence to suggest a causal relationship between the product and the adverse event). 
An unexpected ADR is one, the nature or severity of which is not consistent with the 
applicable product information (Investigator's brochure, protocol, and user manual). 
Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be 
considered “unexpected”. Specific examples would be (a) acute renal failure as a 
labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a 
first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is 
a serious unexpected suspected adverse reaction (SUSAR) which requires prompt 
reporting to regulatory authorities and participating Investigators as an expedited report, 
according to the applicable regulatory requirements. Additional occurrences of the 
SUSAR will be required to be reported on an expedited basis until the applicable product 
information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory 
authorities and participating Investigators of information that might materially influence 
the benefit-risk assessment of a medicinal product, sufficient to consider changes in 
product administration or overall conduct of a clinical investigation. Examples of such 
information include a clinically important increase in the rate of occurrence of a serious 
expected adverse event, the identification of a significant hazard to the subject 
population, or a major safety finding from a study conducted in animals. 
 UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
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Per the definition above, a UADE is a type of serious adverse event (SAE) that requires 
expedited reporting on the part of the sponsor. As a reminder, all SAEs regardless of 
relationship to device, drug or procedure are to be reported to Sponsor by the study 
Investigator within 24 hours. Sponsor will assess each device related SAE to determine 
if anticipated based on prior identification within the investigational plan.  
 ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The Investigator will grade laboratory AEs and clinical AEs with respect to the following 
levels of severity as per Common Terminology Criteria for Adverse Events (CTCAE) v 
4.03 for applicable subject populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4)  
 
Death (Grade 5) 
The Investigator will grade injection site reactions in accordance with September 2007 
FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
 CASUAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
A causally related AE is one judged to have a reasonable possibility of a relationship to 
the administration of the IP and/or the investigational device. An AE may also be 
assessed as not related to the IP and/or the investigational device. Because the 
Investigator is knowledgeable about the subject (e.g., medical history, concomitant 
medications), administers the IP, and monitors the subject’s response to the IP, the 
Investigator is responsible for reporting adverse events and judging the relationship 
between the administration of the IP and device and a subsequent AE. 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 IP 
delivered by EP and determine whether to report expeditiously to the regulatory 
agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding 
the event, available site and non-site laboratory and clinical records, and an evaluation 
of any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the IP and/or the investigational device indicating "yes" or 
"no" accordingly. Causality should be assessed by the Investigator as “yes, related” or 
“no, unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment 
contributed to the event; 
 
No – there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
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 
Temporal relationship of event to administration of IP and/or the investigational 
device; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event 
 ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the 
underlying medical condition that require medical or surgical intervention or lead to IP 
interruption or discontinuation must be recorded as an AE, or SAE, if applicable. In 
addition, laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital 
signs) that are associated with signs and/or symptoms must be recorded as an AE or 
SAE if they meet the definition of an AE (or SAE) as described in Section 7.1. If the 
laboratory abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., 
anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
 
Requires therapeutic intervention or diagnostic tests 
 
Leads to discontinuation of study treatment 
 
Has accompanying or inducing symptoms or signs 
 
Is judged by the Investigator as clinically significant 
 POST-TRIAL 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 or termination visit and the event is deemed by the Investigator to be related 
to the study treatment, he/she should promptly document and report the event to the 
study team and medical monitor. 
 PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study 
up to 6 months following the last study treatment of investigational product will be 
excluded from participation in the study. Should a subject become pregnant after 
enrolling in the study, she will not be given any further study treatments. A Pregnancy 
Form will be completed by the site personnel and submitted to the sponsor within 24 
hours after learning of the pregnancy. Site personnel will submit the Pregnancy Form to 
the Sponsor as described in Section 7.4.2. 
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The Investigator will also report this event to the IRB within 24 hours of becoming aware 
of the pregnancy. Sites must request the subject's permission to query pregnancy 
outcome and follow each subject to determine the outcome of the pregnancy. Results 
will be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed 
for safety assessments without receiving further study treatment. Procedures that are 
contraindicated during pregnancy, including additional treatments, must not be 
performed. Investigators should use clinical judgment regarding subsequent study-
related blood collection based on the presence or absence of anemia in each subject. 
Subjects who are not withdrawn will continue to be followed for safety assessments to 
study discharge per protocol.  
All pregnancies that occur from the time of first study treatment through the follow up 
visits must be reported. The Investigator will monitor the subject and follow the outcome 
of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome will be reported directly to the study team and the medical 
monitor. 
7.2 
METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs will be collected for each subject from the time when 
informed consent is obtained through Week 100, or through the final discharge visit for 
subjects completing the study under Amendment 5.0. 
The sources of AEs cover: 
1. 
The subject's response to questions about her health (a standard non-leading 
question such as ''How have you been feeling since your last visit?'' is asked at 
each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the 
Investigator to be clinically significant changes or abnormalities. 
4. 
Other information relating to the subject's health becoming known to the 
Investigator (e.g. hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE occurring during the course of 
the study must be reported to the sponsor within 24 hours of awareness.  
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred 
term, severity, and relationship to study treatment 
 
Local and systemic injection site review; special attention will be paid to the 
examination of the injection site. Administration site reactions and the subject's 
complaints will be documented.  
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 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 2000 that require expedited communication 
from the site to the Sponsor and meet any of the following criteria: 
 
Grade 3 or greater persistent administration site erythema, and/or induration 
recorded ≥ 2 hours immediately after Study Treatment  
 
Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 
Grade 3 or greater fever 
 
Grade 3 or greater systemic symptoms, including generalized pruritus 
As per the Toxicity Grade for Healthy Adults. The most severe grade for that particular 
event is to be documented in the CRFs. 
Sites will inform the Sponsor of an AESI within 24 hours via method described in Section 
7.4.2, to discuss whether further dosing should continue. 
 STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
If any of the following situations occur then further enrollment and Study Treatments will 
be halted until a thorough review has been conducted by the Medical Monitor and PI for 
the trial, the DSMB, and the IRB/EC (if applicable): 
 
One third or more subjects experience an AESI verified per protocol definition;  
 
Any subject experiences an SAE (or potentially life threatening AE), or death verified 
as related to Study Treatment; 
 
Three or more subjects experience the same grade 3 or 4 unexpected adverse 
event, verified per protocol definition and assessed as related to Study Treatment;  
 
In the event of two identical, unexpected, Grade 4 toxicities, verified per protocol 
definition and assessed as related to Study Treatment; 
Upon conclusion, the sponsor or designee will notify all Investigators and IRBs/EC (if 
required) regarding the outcome of any investigation stemming from a Study Pause.  
 
Guidelines for assessing relatedness are detailed in Section 7.1.8. 
7.4 
ADVERSE EXPERIENCE REPORTING 
To assure the safety of the subjects, information about all AEs (see Section 7.1), 
whether volunteered by the subject, discovered by Investigator or study staff 
questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded in the subject's source documents and followed as 
appropriate. 
 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited adverse events will be collected throughout the study and 
recorded in the electronic data capture (EDC) system. 
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TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS 
The reporting period for SAEs (without regard to causality or relationship) is comprised 
of the period following the signing of the informed consent form until the end of the 
study. Each AE will be assessed to determine whether it meets serious criteria. If the AE 
is considered serious, the Investigator should record this event in the EDC system and 
report the event to the Sponsor within 24 hours of becoming aware of the event. The 
Investigator may also directly report this event to the Ethics Committee according to its 
standard operating procedures. Expectedness of SAEs will be determined by the 
Sponsor using reference safety information specified in the Investigator's Brochure and 
protocol.  
An event may qualify for expedited reporting to regulatory authorities if it is an SAE, 
unexpected per reference safety information and considered related following the 
guidelines in Section 7.1.5 (Suspected Unexpected Serious Adverse Reaction, SUSAR) 
and 7.1.6 (Unanticipated [serious] adverse device effect) in line with relevant legislation. 
All Investigators will receive a safety letter notifying them of relevant SUSAR reports. 
The Investigator should notify the Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as is practical, of serious events in writing where this is required by local 
regulatory authorities, and in accordance with the local institutional policy.  
At any time after completion of the SAE reporting period, if an Investigator becomes 
aware of an SAE that is suspected by the Investigator to be related to the study drug, the 
event will be reported to the Sponsor or its designee. If the Investigator becomes aware 
of an SAE in a study subject after the last scheduled follow-up visit, and considers the 
event related to prior Study Treatment, the Investigator will report it to the Sponsor or the 
appropriate designee. 
SPONSOR CONTACT INFORMATION 
MEDICAL MONITOR: 
 M.D., Ph.D. 
EMAIL:  
 
SAE REPORTING INFORMATION 
EMAIL:  safety.inovio@apcerls.com 
SAFETY FAX: 
SAFETY PHONE: 
The preferred method for providing SAE forms or SAE supporting documents to the 
Sponsor or designee is as an attachment to an e-mail message, to the email address 
as indicated above. Any SAE supporting documents provided by facsimile (Fax) are to 
include a fax coversheet that identifies the reporter name and contact information of the 
study site.    
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All supporting documents for SAE reports, including medical records and diagnostic test 
results, will include reference to the study subject number. The study site will redact all 
other subject identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
The Investigator will supply the Sponsor and the IRB with more information as it 
becomes available and any additional requested information. The original SAE form 
must be kept at the study site. The Sponsor or its representative will be responsible for 
determining and in turn, reporting SAEs to regulatory authorities according to the 
applicable regulatory requirements. SAEs must be followed by the Investigator until 
resolution, even if this extends beyond the study-reporting period. Resolution of an SAE 
is defined as the return to baseline status or stabilization of the condition with the 
expectation that it will remain chronic. 
In the event of death, if an autopsy is performed, a copy of the redacted report will be 
sent to the Sponsor.  
In the event of a pregnancy, the Investigator will submit a Pregnancy Form to the 
Sponsor or designee to the safety email address or fax number within 24 hours of 
learning of the pregnancy. 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating Investigators in a written safety report of any adverse 
experience associated with the use of the product that is both serious and unexpected 
and any significant new safety information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product 
administration or overall conduct of a clinical investigation. The Sponsor will notify 
regulatory agencies within the time frame specified by local requirements but no later 
than 10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 
15 days for all other SUSARS (see Section 7.1.5 and 7.1.6). 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, 
reliability, safety, effectiveness, or performance of a device such as malfunction, misuse 
or use error and inadequate labeling. A malfunction is defined as the failure of a device 
to meet its performance specifications or otherwise perform as intended. The intended 
performance of a device refers to the intended use for which the device is labeled. All 
product complaints that meet this definition must be reported to the sponsor within 10 
days of discovery. Any product complaint that involves an AE or SAE must be also be 
reported per Section 7.4.1 and Section 7.4.2. 
Any problems experienced including potential malfunctions of the device, error 
messages displayed on the device screen following treatment or errors that occur during 
the treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation.  
All complaints must be sent to ClinicalComplaint@inovio.com. Additional instructions on 
complaint reporting to be provided separately. 
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7.5 
TRIAL DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at 
multiple sites for safety or administrative reasons at any time. In particular, a site that 
does not recruit at a reasonable rate may be discontinued. Should the study be 
terminated and/or the site closed for whatever reason, all non-source documentation and 
study product pertaining to the study must be returned to Inovio Pharmaceuticals or its 
representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the 
FDA or other government agencies as part of their duties to ensure that research 
subjects are protected. 
8. 
STATISTICAL ANALYSIS PLAN 
8.1 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, open-label randomized clinical trial of VGX-3100 and 
VGX-3100 with imiquimod, in subjects with a histologic diagnosis vulvar HSIL and 
confirmed vulvar infection with HPV types 16 and/or 18. The study's primary endpoint is 
binary: regression of vulvar HSIL and viral clearance of HPV-16 and/or HPV-18 from 
vulvar tissue based on tissue collected at Week 48. The primary hypothesis is that each 
of the treatment arms will result in regression of HSIL and clearance. Secondary efficacy 
analyses pertain to regression, clearance of HPV-16 and/or HPV-18 infection, regression 
to normal, non-progression, and anatomic extent. Other secondary analyses concern 
safety and cellular immunological measures. Exploratory efficacy analyses concern 
extended dosing with respect to regression, clearance, and anatomic extent, and 
clearance outside of the vulva. Other exploratory analyses pertain to humoral, cellular, 
and tissue immunological measures and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized two to one, VGX-3100 alone: VGX-3100 in combination with 
topical imiquimod. Subjects will be randomized in a stratified manner according to (a) 
recurrent disease at screening (0 vs. 1 or more recurrences), (b) multifocal disease (1 
vs. 2 or more lesions at screening), (c) Body Mass Index (BMI) category (≤25 vs. >25 
kg/m2) on Day 0, and (d) age category (<45 years vs. ≥45 years) on Day 0. There are no 
requirements for the number of subjects in each stratum. The study is open-label. 
The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical 
imiquimod study group.  All subjects who have already been enrolled into the VGX-3100 
with imiquimod study group will continue with all study visits per protocol, but no further 
participants will be enrolled into this group. 
8.3 
SAMPLE SIZE/POWER 
A sample of 36 subjects will be randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 
80% power to declare each study group superior to historical control with a one-sided 
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0.025 type 1 error level for each hypothesis, assuming the true proportion of subjects 
who achieve the primary endpoint is 20% and 28% for the respective treatment arms 
and 2% for the historical control, and that 90% are evaluable at Week 48 from 
randomization. 
The Version 3.0 protocol amendment halts enrollment of the VGX-3100 with topical 
imiquimod study group.  All subjects who have already been enrolled into the VGX-3100 
with imiquimod study group will continue with all study visits per protocol, but no further 
participants will be enrolled into this group. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 
The modified intention to treat (mITT) population includes all subjects who receive at 
least one dose of Study Treatment and who have the analysis endpoint of interest. 
Subjects in this sample will be grouped to treatment arms as randomized. Analysis of 
the mITT population will be primary for the analysis of efficacy in this study. 
 
The per-protocol (PP) population comprises subjects who receive all doses of Study 
Treatments and have no protocol violations and who have the analysis endpoint of 
interest. Subjects in this sample will be grouped to treatment arms as randomized. 
Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy. Subjects excluded from the PP 
population will be identified and documented prior to unblinding of the study 
database. 
 
The safety analysis set includes all subjects who receive at least one does of Study 
Treatment. Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment  for all randomized subjects and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial. The number and percentage of subjects 
who discontinued will be summarized overall and by reason. The number in each 
analysis population will also be presented. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean 
standard deviation, minimum, median, and maximum values for continuous variables, 
and percentages for categorical variables, by treatment arm, for the mITT population. 
Prior and concomitant medications will also be summarized with percentages in this 
fashion. 
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system, by treatment arm, for the mITT population. 
 
 
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8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are considered those medications taken prior to the first dose of study 
drug (i.e., Day 0). Concomitant medications are those used on or after Day 0. Partial 
start dates of prior and concomitant medications will be assumed to be the earliest 
possible date consistent with the partial date. Partial stop dates of prior and concomitant 
medications will be assumed to be the latest possible date consistent with the partial 
date. Data for all prior and concomitant medications will be summarized with 
percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSIS 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint for each arm. The primary hypothesis of 
superiority is:  
H0: p≤ 0.02 vs. H1: p > 0.02, for each treatment study group separately.  
A p-value for these hypothesis tests and corresponding 95% confidence intervals will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.025 and the corresponding lower bound of the 95% CI 
exceeds 0.02.  
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values.  All of the efficacy binary 
endpoints will be analyzed in two ways: a) based on qualifying and new lesions, and b) 
based on all lesions.  Also, the Week 74 binary endpoint will be analyzed overall, and 
according to four or five doses received, and the Week 96 binary endpoint will be 
analyzed overall, and according to four, five, or six doses received.    
For the analyses, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week.      
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
and associated 95% t-distribution based confidence interval. The percentage of subjects 
with no clinically significant lesion resolution (reduction in lesion size of 25% or less), 
partial lesion resolution (26-99% reduction), and complete reduction (100% reduction) 
will be summarized with point estimates and associated exact Clopper-Pearson 95% 
confidence intervals. 
An exploratory analysis will examine clearance outside of the vulva. This will be 
analyzed in the same manner as vulvar clearance. 
An exploratory analysis will examine the relationship between the primary efficacy 
endpoint and a) miRNA results, b) vulvoscopy results, and c) HPV results. Relationships 
will be examined with contingency tables and/or logistic regression models which model 
the primary endpoint versus these results and treatment group as regressor variables. 
8.10 IMMUNOGENICITY ANALYSIS 
 
Post-baseline cellular and humoral response magnitude will be summarized with 
medians and associated non-parametric 95% CIs. Post-baseline tissue response 
magnitude will be summarized with means and associated t-distribution based 95% CIs. 
 
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Valid samples for statistical analysis purposes will be those collected within 7 or 14 days 
of the specified time points (see Table 1). Baseline is defined as the last measurement 
prior to the first treatment administration. 
8.11 SAFETY ANALYSES 
All AEs will be summarized among the safety population by frequency per treatment 
arm. These frequencies will be presented overall and separately by dose, and will depict 
overall, by system organ class and by preferred term, the percentage of subjects 
affected. Additional frequencies will be presented with respect to maximum severity and 
to strongest relationship to Study Treatment. Multiple occurrences of the same AE will 
be counted only once following a worst-case approach with respect to severity and 
relationship to Study Treatment. All serious AEs will also be summarized as above.  
The main summary of safety data will be based on events occurring within 14 days of 
any dose. For this summary, the frequency of preferred term events will be summarized 
with percentages and exact Clopper-Pearson 95% confidence intervals. Separate 
summaries will be based on events occurring within 7 days of any dose and regardless 
of when they occurred. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not 
be included within specified day-range summaries. AE duration will be calculated as 
(Stop Date – Start Date) + 1. 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean standard deviation, minimum, median, and maximum values 
by time point and treatment arm, for the mITT population. Baseline is defined as the last 
measurement prior to the first treatment administration. 
 
The percentage of subjects with abnormal physical examination findings at each time 
point will be summarized by treatment study group and by body system, for the mITT 
population. 
8.12 PATIENT REPORTED OUTCOMES 
 
As an exploratory endpoint, patient reported outcomes will be summarized with medians 
or proportions of subjects with endpoints and associated non-parametric or exact 
Clopper-Pearson 95% CIs, for continuous responses and binary responses, 
respectively. 
8.13 MISSING VALUES 
 
Missing data will not be imputed or replaced, and calculations will be done on reported 
values. 
8.14 INTERIM ANALYSES 
 
No formal interim analyses will be performed for this study. 
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9. 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the Declaration of Helsinki, principles of 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC) 
The Investigator will undertake the study after full approval of the protocol and 
adjunctive materials (e.g., informed consent form, advertising) has been obtained from 
the applicable IRB/EC and a copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 
During the conduct of the study, submit progress reports to the IRB/EC as required.  
 
Notify the Sponsor immediately of any SAEs or serious unanticipated adverse 
device effects. 
 
If Sponsor notifies you about any reportable safety events notify the IRB 
immediately. 
 
As required, obtain approval from the IRB/EC for protocol amendments and for 
revisions to the consent form or subject recruitment advertisements; 
 
Reports on, and reviews of, the trial and its progress will be submitted to the IRB by 
the Investigator at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines. 
 
Maintain a file of study-related information that includes all correspondence with the 
IRB; 
 
Notify IRB when study is completed (i.e. after the last study visit of the final study 
subject); 
 
After study completion provide the IRB with a final report on the study. 
9.3 
OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The Investigator and Sponsor are responsible for ensuring that the clinical study is 
reviewed and approved according to local and applicable global regulations (e.g., NIH 
Office of Biotechnology Activities) governing research that involves recombinant or 
synthetic nucleic acid molecules. 
9.4 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to Screening into the 
study, and/or from the subject's legally authorized representative. The process for 
obtaining informed consent must also be documented in the subject's medical record. 
9.5 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/EC regulations. The 
Investigator must obtain approval from a properly constituted IRB/EC prior to initiating 
the study and re-approval or review at least annually. Sponsor is to be notified 
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immediately if the responsible IRB/EC has been disqualified or if proceedings leading to 
disqualification have begun. Copies of all IRB/EC correspondence with the Investigator 
must be provided to Sponsor. 
9.6 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.7 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.8 
COMPLIANCE WITH PROTOCOL 
Subjects will be asked to complete a participant diary and, for subjects in the imiquimod 
study group, a dosing log during their study participation. Subjects will be provided with 
Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, the Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
9.9 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB of a protocol amendment, except where necessary to eliminate 
immediate hazards to study subjects, or when the changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change of telephone 
numbers). 
10. 
DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study products are legally marketed or may 
ultimately be marketed, but the subject's name will not be disclosed in these documents. 
The subject's name may be disclosed to the study sponsor, Sponsor, the governing 
health authorities or the Food and Drug Administration (FDA), if they inspect the study 
records. Appropriate precautions will be taken to maintain confidentiality of medical 
records and personal information. 
Written Authorization and other documentation in accordance with the relevant country 
and local privacy requirements (where applicable) are to be obtained from each subject 
prior to enrollment into the study, and/or from the subject's legally authorized 
representative in accordance with the applicable privacy requirements (e.g., the Health 
Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information (HIPAA)). 
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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 the research subject to revoke their authorization for use of their 
PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
10.2 SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, 
observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in original source documents. 
Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subject's 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 medical records and within 
information technology systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must 
be present in the source documents. All prescription and nonprescription medications 
taken within l week prior to entry must be recorded on the CRF. Actual or estimated start 
and stop dates must be provided. 
10.3 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/EC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
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 an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The sponsor will inform the Investigator/institution as to when 
these documents are no longer needed to be retained. 
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Clinical Protocol 
 
 
10.4 SAFETY AND QUALITY MONITORING 
 DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research 
subjects through independent analysis of emerging data from the trial. The DSMB will 
meet quarterly or as data are available to review safety data and regression/clearance 
results. If there are no new safety data or regression/clearance results to review for a 
quarterly scheduled meeting the DSMB will be notified and the meeting may be 
cancelled; Ad hoc meetings may be scheduled to review new data as applicable. The 
DSMB will be charged with advising the Sponsor if there appears to be a safety issue. 
No formal interim analysis will be performed. The DSMB Chair, upon consultation with 
the other voting members of the DSMB, has the authority to recommend suspension or 
stopping the study and to request a full DSMB review and ad hoc statistical analyses. 
The standard operating procedures of the DSMB will be documented in the DSMB 
charter, including the board's accountability to Inovio. 
 PATHOLOGY ADJUDICATION COMMITTEE 
All vulvar biopsies will be read by a central expert PAC to ensure consistent assignment 
of disease status for both study eligibility and the efficacy analysis. The PAC will consist 
of up to four pathologists. Each specimen will be read by two pathologists independently 
in a masked fashion. The responsibilities and membership structure of the PAC is 
outlined in the PAC Charter, including the reporting of results.  
 CLINICAL MONITORING 
Clinical Monitoring of the 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 the site is qualified and compliant 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 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 
 
Throughout the study, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, original, 
and accurate (ALCOAC).  
 
Assure that the study facilities continue to be acceptable 
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Clinical Protocol 
 
 
 
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 investigational drug and device accountability and reconciliation of 
records are complete and accurate 
 
Assure that all subject specimens are being stored and forwarded properly for 
testing per laboratory manual requirements 
 
11. 
PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission 
for publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs 
protection. In the event that The Sponsor makes such objection, the researcher(s) shall refrain 
from making such publication or presentation for a maximum of three (3) months from the date 
of receipt of such objection in order for patent application(s) (directed to the patentable subject 
matter contained in the proposed publication or presentation) to be filed with the United States 
Patent and Trademark Office and/or foreign patent office(s). 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
12. 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACOG 
American College of Obstetricians and Gynecologists 
AIN 
Anal Intraepithelial Neoplasia 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Forms 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data & Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
EP 
Electroporation with Cellectra™ 2000 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
HSIL 
High grade squamous intraepithelial lesion 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-γ 
Interferon Gamma 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
IP 
Investigational New Drug Application 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response Technology 
LAST 
Lower Anogenital Squamous Terminology 
mITT 
Modified Intent to Treat 
NIH 
OP 
National Institutes of Health 
Oropharyngeal 
Principal Investigator 
Investigator 
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase Chain Reaction 
PD 
Participant Diary  
PE 
Physical exam 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
PRO 
Patient Reported Outcomes 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated Adverse Device Effect 
VAIN 
Vaginal Intraepithelial Neoplasia 
WOCBP 
Women of Childbearing Potential 
WOMAN-PRO                  WOMen with vulvAr Neoplasia PRO 
 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
13. 
REFERENCES 
 
1. 
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé 
S. . Human Papillomavirus and Related Diseases in USA., ICO Information Centre on 
HPV and Cancer (HPV Information Centre), Summary Report 30 June 2017. 2017. 
2. 
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé 
S. Human Papillomavirus and Related Diseases in Europe.  ICO Information Centre on 
HPV and Cancer (HPV Information Centre)  Summary Report 30 June 2017. 2017. 
3. 
Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, et al. US 
assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. 
J Natl Cancer Inst 2015,107:djv086. 
4. 
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact 
Sheets:  Vulvar Cancer. 2016. 
5. 
Hartwig S, St Guily JL, Dominiak-Felden G, Alemany L, de Sanjose S. Estimation of the 
overall burden of cancers, precancerous lesions, and genital warts attributable to 9-valent 
HPV vaccine types in women and men in Europe. Infect Agent Cancer 2017,12:19. 
6. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
7. 
Salom EM PM. Recurrent vulvar cancer. Curr Treat Options Oncol 2002,3:143-153. 
8. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
9. 
Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, et al. Squamous vulvar 
intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology 
Subcommittee. J Reprod Med 2005,50:807-810. 
10. 
Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower 
Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: 
background and consensus recommendations from the College of American Pathologists 
and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 
2012,16:205-242. 
11. 
Inovio Pharmaceuticals. Unpublished assessment. 2015. 
12. 
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial neoplasia: aspects of the 
natural history and outcome in 405 women. Obstet Gynecol 2005,106:1319-1326. 
13. 
van Seters M vBM, de Craen AJ. Is the assumed natural history of vulvar intraepithelial 
neoplasia III based on enough evidence? A systematic review of 3322 published patients. 
Gynecol Oncol 2005,97:645-651. 
14. 
Inovio Pharmaceuticals. Personal communications from consultants to Inovio. 2015. 
15. 
ACOG. Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstet Gynecol 2011,118:1192-1194. 
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Clinical Protocol 
 
 
16. 
Frega A, Sopracordevole F, Scirpa P, Biamonti A, Lorenzon L, Scarani S, et al. The re-
infection rate of high-risk HPV and the recurrence rate of vulvar intraepithelial neoplasia 
(VIN) usual type after surgical treatment. Med Sci Monit 2011,17:CR532-535. 
17. 
ACOG. Committee Opinion No. 675: Management of Vulvar Intraepithelial Neoplasia. 
Obstet Gynecol. 2016,128:e178-182. 
18. 
Inovio Pharmaceuticals. VGX-3100 Assessment. Unpublished Market Research. 2014. 
19. 
Inovio Pharmaceuticals. Vulvar Intraepithelia Neoplasia Patient Journey. Unpublished 
Market Research. 2016. 
20. 
Senn B, Eicher M, Mueller MD, Hornung R, Fink D, Baessler K, et al. A patient-reported 
outcome measure to identify occurrence and distress of post-surgery symptoms of 
WOMen with vulvAr Neoplasia (WOMAN-PRO) - a cross sectional study. Gynecol Oncol 
2013,129:234-240. 
21. 
Likes WM SC, Tillmanns T, Pruett J. Pilot study of sexual function and quality of life after 
excision for vulvar intraepithelial neoplasia. J Reprod Med 2007,52:23-27. 
22. 
Petrosky E, Bocchini JA, Jr., Hariri S, Chesson H, Curtis CR, Saraiya M, et al. Use of 9-
valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations 
of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 
2015,64:300-304. 
23. 
Future II Study Group.  Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
24. 
Reyes MC, Cooper K. An update on vulvar intraepithelial neoplasia: terminology and a 
practical approach to diagnosis. J Clin Pathol 2014,67:290-294. 
25. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
26. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
27. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for 
success. Curr.Opin.Immunol. 2011,23:421-429. 
28. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
29. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 
2009. 
30. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci 
Transl Med 2012,4:155ra138. 
31. 
Senn B. Creating and Validating a Patient-Reported Outcome Instrument for Women with 
Vulvar Neoplasia after Surgical-Treatment - A Mixed-Methods Project, Institute of Nursing 
Science (INS) University of Basel, University Hospital Berne, Switzerland. 2012. 
32. 
Senn B, Mueller MD, Hasenburg A, Blankenstein T, Kammermann B, Hartmann A, et al. 
Development of a postsurgical patient-reported outcome instrument for women with vulvar 
neoplasia. Oncol Nurs Forum 2012,39:E489-498. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
33. 
U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER) CfBEaRC, Center for Devices and Radiological 
Health (CDRH). Guidance for Industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims. December 2009. 2009. 
34. 
Aldara (imiquimod) Cream. Highlights of Prescribing Information. 2010. 
35. 
Perrigo. Imiquimod Cream, 5%.  Highlights of Prescribing Information. 1997. 
36. 
Maruish M. User's manual for the SF-36v2 Health Survey (3rd ed.). 2011. 
37. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a 
multi-country study. Qual Life Res 2013,22:1717-1727. 
38. 
EuroQol. EuroQol-- a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
 
 
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Clinical Protocol 
 
 
14. 
APPENDICES 
APPENDIX A: FIGURE 1. STUDY VISIT SCHEDULE, ORIGINAL STUDY 
DESIGN 
 
 
 
The first dose is administered on Day 0, the second at Week 4, the third at Week 12, and 
the fourth dose  at Week 24. Subjects with no HSIL at Week 48 (Subgroups A and B) will 
receive 4 doses. Subjects with HSIL at Week 48, who have a reduction in lesion size or 
no increase in lesion size from baseline (Subgroups C or D), may receive a fifth dose of 
VGX-3100 administered IM with EP at Week 52 per the judgment of the Investigator. 
Subjects with HSIL at Week 74, who have a reduction in lesion size or no increase in 
lesion size from baseline (Subgroups C or D), may receive a sixth dose of VGX-3100 
administered IM with EP at Week 78 per the judgment of the Investigator. Subjects in 
Subgroup E may receive surgical treatment per the judgment of the Investigator. All 
subjects are scheduled to be followed to Week 100. 
 
 
 
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Clinical Protocol 
 
 
APPENDIX B: FIGURE 3. DECISION PROCESS AT WEEK 78, 
ORIGINAL STUDY DESIGN 
 
 
 
The decision process following results of the Week 74 biopsy are described in Figure 3 and are 
as follows:  At Week 74, the subject will undergo repeat vulvar punch biopsy/biopsies of the same 
lesion as study start from the region of potentially most advanced disease based upon the 
judgment of the Investigator (see Table 2). If after evaluation of biopsy tissue by the PAC there is 
no evidence of HSIL (Subgroups A or B), the subject will continue to Week 96 for vulvoscopy, and 
biopsy of the same area from the region of potentially most advanced disease based upon the 
judgment of the Investigator. If HSIL remains but there is a reduction in lesion size or no change 
in lesion size from baseline (Subgroups C or D), the Investigator has the option to give the subject 
a 6th dose of VGX-3100 at Week 78, and the subject will continue on study with vulvoscopy and 
biopsy at Week 96. Alternatively, the Investigator may choose to treat the subject with surgical or 
standard treatment, and the subject will continue on study without further biopsy.   
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
 
APPENDIX C: FIGURE 4. EVALUATION PROCESS AT WEEK 100, 
ORIGINAL STUDY DESIGN 
 
 
 
The decision process following results of the Week 96 biopsy are described in Figure 4 and as 
follows:  
At Week 96, the subject will undergo repeat vulvar punch biopsy/biopsies of the same lesion as 
study start from the region of potentially most advanced disease based upon the judgment of the 
Investigator (see Table 2). If there is no vulvar HSIL (Subgroups A or B), no further procedures 
are required. If after evaluation of biopsy tissue by the PAC there is vulvar HSIL (Subgroups C or 
D), or worsening disease (Subgroup E), the subject will receive surgical or other standard 
treatment.     
 
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SAP_001.pdf: 
Official Title: 
NCT Number: 
NCT03180684
Document Dates:
Statistical Analysis Plan Final Version 2.0: 22 March 2021
A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered 
Intramuscularly Followed by Electroporation With CELLECTRA™ 2000 Alone or in 
Combination With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 
Related High Grade Squamous Intraepithelial Lesion (HSIL) of the Vulva


CONFIDENTIAL 
Page 1 of 38 
STATISTICAL ANALYSIS PLAN 
Protocol HPV-201 
A PHASE 2, RANDOMIZED, OPEN LABEL, EFFICACY STUDY OF 
VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ 2000 ALONE OR IN 
COMBINATION WITH IMIQUIMOD, FOR THE TREATMENT OF 
HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS 
INTRAEPITHELIAL LESION (HSIL) OF THE VULVA 
Protocol Number: 
Protocol Version and Date: 
HPV-201 
Version 5.0: 19 December 2019 
Version 4.0: 13 September 2019 
Version 3.0: 26 March 2019 
Version 2.0: 20 November 2017 
Original 1.0: 13 January 2017
Name of Test Drug: 
VGX-3100 
Phase: 
Phase 2 
Methodology: 
Prospective, Randomized, Open-label 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
Tel: (267) 440-4200 
Fax: (267) 440-4242 
Sponsor Representative: 
 PhD 
Analysis Plan Date: 
22 March 2021 
Analysis Plan Version: 
Final Version 2.0 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property 
of Inovio Pharmaceuticals, Inc. and any unauthorized use or disclosure  
of such information without the prior written authorization of  
Inovio Pharmaceuticals, Inc. is expressly prohibited. 


Inovio Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 2 of 38 
APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Phase 2, Randomized, Open Label, Efficacy Study of 
VGX-3100 Delivered Intramuscularly Followed by 
Electroporation with Cellectra™ 2000 Alone or in Combination 
with Imiquimod, for the Treatment of HPV-16 and/or HPV-18 
Related High Grade Squamous Intraepithelial Lesion (HSIL) of 
the Vulva 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
Protocol Number 
HPV-201 
Document Date / Version: 
22 March 2021 / Final Version 2.0 
 
 
Veristat TM, LLC. Author: 
 
 
MS 
 
Approval Signature 
Job Title 
 
 
 
 
Veristat is a trademark of Veristat, LLC. All other trademarks are the property of their respective owners.  
 


Inovio Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 3 of 38 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments. All changes to the 
planned analyses will be described in the clinical study report. 
 
Sponsor Signatory: 
 
 PhD 
 
Approval Signature 
Job Title 
 
 
 
 
 


Inovio Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 4 of 38 
TABLE OF CONTENTS 
1. 
INFORMATION FROM THE STUDY PROTOCOL ...................................................9 
1.1. 
Introduction and Objectives ................................................................................9 
1.1.1. 
Introduction ..........................................................................................9 
1.1.2. 
Statistical Analysis Plan Objectives ...................................................10 
1.1.3. 
Study Objectives ................................................................................10 
1.1.3.1. Primary Objective ...............................................................10 
1.1.3.2. Secondary Objectives ..........................................................10 
1.1.3.3. Exploratory Objectives........................................................11 
1.2. 
Study Design .....................................................................................................11 
1.2.1. 
Synopsis of Study Design ..................................................................11 
1.2.2. 
Randomization Methodology .............................................................12 
1.2.3. 
Stopping Rules and Unblinding .........................................................12 
1.2.4. 
Study Procedures ...............................................................................14 
1.2.5. 
Efficacy, Immunology, and Safety Parameters ..................................17 
1.2.5.1. Efficacy Parameters ............................................................17 
1.2.5.2. Immunology Parameters .....................................................18 
1.2.5.3. Safety Parameters ................................................................18 
2. 
SUBJECT POPULATION ............................................................................................20 
2.1. 
Population Definitions ......................................................................................20 
2.2. 
Protocol Violations ...........................................................................................20 
3. 
GENERAL STATISTICAL METHODS .....................................................................21 
3.1. 
Sample Size Justification ..................................................................................21 
3.2. 
General Methods ...............................................................................................21 
3.3. 
Computing Environment ...................................................................................21 
3.4. 
Baseline Definitions ..........................................................................................21 
3.5. 
Methods of Pooling Data ..................................................................................21 
3.6. 
Adjustments for Covariates ...............................................................................21 
3.7. 
Multiple Comparisons/Multiplicity ...................................................................22 
3.8. 
Subpopulations ..................................................................................................22 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ......................................................22 
3.10. Missing, Unused, and Spurious Data ................................................................22 


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3.11. Visit Windows ...................................................................................................22 
3.12. Interim Analyses ...............................................................................................23 
4. 
STUDY ANALYSES ...................................................................................................24 
4.1. 
Subject Disposition ...........................................................................................24 
4.2. 
Demographics and Baseline Characteristics .....................................................24 
4.3. 
Efficacy Evaluation ...........................................................................................25 
4.3.1. 
Primary Efficacy Endpoint ................................................................25 
4.3.2. 
Secondary and Exploratory Efficacy Endpoints ................................26 
4.3.3. 
Patient-Reported Outcomes ...............................................................29 
4.3.4. 
Immunology Endpoints ......................................................................30 
4.4. 
Safety Analyses .................................................................................................31 
4.4.1. 
Study Drug Exposure .........................................................................31 
4.4.2. 
Adverse Events ..................................................................................31 
4.4.3. 
Laboratory Data .................................................................................34 
4.4.4. 
Vital Signs and Physical Examination ...............................................35 
4.4.5. 
Electrocardiogram ..............................................................................35 
4.4.6. 
Prior and Concomitant Medications ..................................................35 
5. 
CHANGES TO PLANNED ANALYSES ....................................................................36 
6. 
REFERENCES ..............................................................................................................37 
7. 
STATISTICAL OUTPUT .............................................................................................38 
7.1. 
List of Statistical Output to be Generated .........................................................38 
7.2. 
Statistical Table Shells ......................................................................................38 
7.3. 
Data Listing Shells ............................................................................................38 
 


Inovio Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 6 of 38 
TABLES INCLUDED IN THE TEXT 
Table 1-1 
Schedule of Assessments ..................................................................................... 14 
Table 4-1: 
Definition of Responder and Non-Responder ...................................................... 25 
 
 
 


Inovio Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 7 of 38 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ATC 
Anatomic therapeutic class 
BMI 
Body mass index 
CI 
Confidence interval 
CIN 
Cervical intraepithelial neoplasia 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ELISpot 
Enzyme linked immunosorbent spot-forming 
EP 
Electroporation 
HLA 
Human leukocyte antigen 
HPV 
Human papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
HSIL 
High grade squamous intraepithelial lesion 
ICH 
International Conference on Harmonisation 
IFN-γ 
Interferon gamma 
IM 
Intramuscular 
IRB 
Institutional Review Board 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MiRNA 
MicroRNA 
mITT 
Modified intention-to-treat 
PBMC 
Peripheral blood mononuclear cells 
PCS 
Physical Component Summary 
PP 
Per-protocol 
PRO 
Patient reported outcomes 
Rel Day 
Relative study day 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


Inovio Pharmaceuticals, Inc. 
Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 8 of 38 
Abbreviation 
Definition 
SD 
Standard deviation 
SI 
International System of Units 
SLR 
Single-lens reflex 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
VIN 
Vulvar intraepithelial neoplasia 
WOMAN-PRO 
WOMen with vulvAr Neoplasia PRO 
 
 


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Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 9 of 38 
1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
Human papillomaviruses (HPV) are double-stranded deoxyribonucleic acid (DNA) viruses with 
more than 100 genotypes, some of which can lead to malignant neoplasia, localized primarily in 
the anogenital area and aerodigestive tract, in both men and women. HPV-16/18 is involved in 
about 83% of HPV-associated vulvar high grade squamous intraepithelial lesion (HSIL) cases in 
the U.S. [1] and about 72% in Europe [2]. Persistent infection with 1 or more oncogenic (high-
risk) HPV genotypes can lead to the development of precancerous, histologic HSIL. Vulvar 
HSIL can lead to vulvar cancer with an estimated 6,020 new cases and 1,150 attributable deaths 
annually for year 2017 in the United States [3] and about 9,776 new cases in 2015 in Europe [4]. 
Vulvar cancers consist largely of squamous cell carcinomas and accounts for approximately 5% 
of all female genital malignancies [5]. 
HPV-associated vulvar intraepithelial neoplasia (VIN) is a chronic (typically persisting for 
years), premalignant disorder of the vulvar skin that is caused by persistent infection with 1 or 
more high-risk genotypes of HPV. Infected cells produce E6 and E7 oncoproteins constitutively, 
which increases the degradation of cell cycle regulation proteins p53 and pRb, respectively, 
resulting in unrestricted cell growth and neoplasia. The basis for progression to cancer is, 
therefore, attributed to the viral proteins E6 and E7. VGX-3100 specifically induces immune 
responses against E6 and E7, thereby enabling clearance of pre-malignant cells as demonstrated 
in the Phase 2 study of cervical HSIL [6]. 
Vulvar HSIL remains a significantly under met medical condition for the following reasons 
which will be described further: 1) the rate of recurrence of vulvar HSIL under currently used 
surgical and medical approaches is extremely high, 2) there is a high psychological and physical 
negative impact of surgery, 3) vulvar HSIL is symptomatic and impacts activities of daily 
living, 4) prophylactic HPV vaccines have no therapeutic activity against vulvar HSIL and have 
not achieved universal uptake, leaving a population of susceptible and impacted women, and 
5) the early diagnosis of vulvar HSIL is limited to visual inspection with biopsy. 
VGX-3100 encodes HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were designed 
and constructed using proprietary synthetic vaccine (SynCon™) technology. This process 
involves synthetically deriving consensus genes across multiple strains and optimizing DNA 
inserts at the genetic level to allow high expression in human cells. Together, VGX-3100 and 
the CELLECTRA™ device represent an integrated investigational product designed as a non-
surgical treatment of HPV-16/18-related cervical HSIL (CIN2, CIN3) via an immune response 
directed against HPV-16/18. VGX-3100 is delivered using the CELLECTRA™ in vivo 
electroporation (EP) device. EP is a physical method of tissue transfection whereby the 
generation of short, controlled electrical pulses creates a localized electric field at the injection 
site of the DNA vaccine which increases cell membrane permeability and improves the 
transfection of DNA and subsequent immunogenicity [7, 8]. 
A dose of 6 mg VGX-3100 DNA has been selected for this study based on previous human 
experience with VGX-3100, preclinical data with VGX-3100 and other DNA vaccines, and the 
safety and immunogenicity data generated in the HPV-001, HPV-003, and HPV-101 studies. In 
HPV-001 trial, the 6 mg dose was delivered intramuscularly (IM) followed by EP, which 


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showed trends toward higher response rates and magnitudes of IFN-γ ELISpot responses 
compared to the low (0.6 mg) and mid-dose (2 mg) cohorts without significant safety issues [9]. 
Imiquimod Cream, 5% is a licensed product intended to be used in this study concomitantly 
with the investigational product and device. Imiquimod Cream, 5% will be centrally sourced, 
supplied in single-use packets (24 per box), each of which contains 250 mg of the cream, 
equivalent to 12.5 mg of imiquimod. 
1.1.2. 
Statistical Analysis Plan Objectives 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data in order to answer the study objective(s). Populations for analysis, data handling 
rules, statistical methods, and formats for data presentation are provided. The statistical analyses 
and summary tabulations described in this SAP will provide the basis for the results sections of 
the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 
1.1.3. 
Study Objectives 
1.1.3.1. 
Primary Objective 
The primary objective is to determine the efficacy of 4 doses of VGX-3100, alone or in 
combination with imiquimod, with respect to combined histopathologic regression of vulvar 
HSIL and virologic clearance of HPV-16/18 in vulvar tissue. 
1.1.3.2. 
Secondary Objectives 
The secondary objectives include the following: 
• To evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP with 
CELLECTRA™ 2000, alone or in combination with imiquimod 
• To determine the efficacy of 4 doses of VGX-3100, alone or in combination with 
imiquimod, as measured by histologic regression of vulvar HSIL 
• To determine the efficacy of 4 doses of VGX-3100, alone or in combination with 
imiquimod, as measured by virologic clearance of HPV-16/18 in vulvar tissue 
• To determine the efficacy of 4 doses of VGX-3100, alone or in combination with 
imiquimod, as measured by histologic regression of vulvar HSIL to normal tissue 
• To determine the efficacy of 4 doses of VGX-3100, alone or in combination with 
imiquimod, as measured by non-progression of vulvar HSIL to vulvar cancer as 
determined by histology 
• To determine the efficacy of VGX-3100, alone or in combination with imiquimod, as 
measured by reduction in the surface area of the qualifying vulvar lesion(s) 
• To describe the cellular immune response of VGX-3100 administered alone or in 
combination with imiquimod, post dose 4 
• To determine the efficacy of four doses of VGX-3100 alone or in combination with 
imiquimod with respect to histopathologic regression of vulvar HSIL or virologic 
clearance of HPV-16/18 in vulvar tissue 


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1.1.3.3. 
Exploratory Objectives 
The exploratory objectives include the following: 
• To describe the efficacy of VGX-3100, administered alone or in combination with 
imiquimod, at Week 74 and/or Week 96 as measured by reduction in the surface area of 
the qualifying vulvar lesion(s), in subjects without a complete lesion resolution at 
Week 48 
• To describe the long term efficacy of VGX-3100, alone or in combination with prior 
imiquimod, as measured by histologic regression of vulvar HSIL 
• To describe the long term efficacy of VGX-3100, alone or in combination with prior 
imiquimod, as measured by virologic clearance of HPV-16/18 
• To evaluate tissue immune responses to VGX-3100, and VGX-3100 with imiquimod, as 
measured in vulvar tissue samples 
• To describe virologic clearance of HPV-16/18 from non-vulvar anatomic locations 
• To describe association of microRNA (miRNA) profile, previous vulvoscopy, and HPV 
testing results with Week 48 histologic regression 
• To describe patient reported outcomes (PRO) for subjects treated with VGX-3100 and 
VGX-3100 with imiquimod 
• To describe the humoral and cellular immune response of VGX-3100 administered alone 
or in combination with imiquimod, post dose 3, post dose 4, and after additional dosing 
• To determine the long term efficacy of VGX-3100 alone or in combination with 
imiquimod with respect to histopathologic regression of vulvar HSIL or virologic 
clearance of HPV-16/18 in vulvar tissue 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
HPV-201 is a Phase 2, randomized, open-label efficacy study of VGX-3100 (DNA plasmids 
encoding E6 and E7 proteins of HPV types 16 and 18) administered by IM injection followed 
by EP delivered with CELLECTRA™ 2000 alone or in combination with imiquimod in adult 
women with histologically confirmed vulvar HSIL associated with HPV-16/18. Approximately 
36 subjects will be enrolled. Twenty-four subjects will receive VGX-3100 alone and 12 subjects 
will receive VGX-3100 and topical imiquimod treatment. 
To be eligible for the study, subjects must sign consent to participate and have a vulvar punch 
biopsy/biopsies of approximately 4 mm with lesion remaining, and photographs of the 
acetowhite vulvar lesion(s) at the time of screening. In the case of multifocal disease, the 
2 lesions that potentially contain the most advanced disease, as judged by the Investigator, 
should be chosen for biopsy using vulvoscopy and documented using standardized high-
resolution photography with a digital single-lens reflex (SLR) camera on the case report form 
(CRF). Biopsy slides will be sent to a PAC for evaluation prior to enrollment. In order to be 
eligible for enrollment, the PAC must assign the diagnosis of vulvar HSIL based on the biopsy 
sample(s). Subjects must also have a vulvar specimen test positive for HPV genotype 16 and/or 
18 to be eligible for participation in the study. 


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All eligible subjects who consent to participate in the study will receive at least 4 doses of 6 mg 
of VGX-3100 administered by IM injection followed by EP. Subjects randomized to the VGX-
3100 with imiquimod arm will apply imiquimod 5% cream to the vulvar lesion beginning in the 
evening on Day 0, and will continue to apply treatment 3 times per week for 20 weeks 
(inclusive of administration in the evening of VGX-3100 dosing). 
Subjects will be placed into the following subgroups depending on status of biopsies performed 
at Week 48, Week 74, and Week 96: 
• Subgroup A: Subjects having no HSIL and no visible lesions 
• Subgroup B: Subjects having no HSIL but with a visible lesion 
• Subgroup C: Subjects having HSIL with >25% and <100% lesion area reduction from 
baseline 
• Subgroup D: Subjects having HSIL with 0-25% lesion area reduction from baseline  
• Subgroup E: Subjects having HSIL and any increase in lesion area from baseline or 
worsening to cancer 
Subjects in Subgroups C and D may receive a fifth and possibly a sixth dose at Week 52 and 
Week 78, respectively. 
To assess quality of life and related impacts on subjects, PRO instruments will be provided and 
will include the Short Form Health Survey version 2 (SF-36v2™), the EQ-5D-5L (EuroQol 
Research Foundation), WOMAN-PRO (WOMen with vulvAr Neoplasia) Clinical Trial 
Version 2.0, and 2 additional PRO questions assessing quality of life after surgery or biopsy. 
The total duration of the study is up to 10 weeks for the screening period and up to100 weeks 
for the treatment and follow-up periods. The study duration is reduced to 78 weeks for subjects 
that have not already completed the Week 78 visit. 
1.2.2. 
Randomization Methodology 
Subjects are randomized by Y-Prime, Inc. to VGX-3100 alone or VGX-3100 in combination 
with imiquimod in a 2:1 ratio using a central randomization algorithm. Randomization will be 
done in a stratified manner according to (a) recurrent disease at screening (0 vs. 1 or more 
recurrences), (b) multifocal disease (1 vs. 2 or more lesions at screening), (c) Body Mass Index 
(BMI) category (≤25 vs. >25 kg/m2), and (d) age category (<45 years vs. ≥45 years). 
1.2.3. 
Stopping Rules and Unblinding 
No blinding will be done for this study as the study is open-label. 
If any of the following situations occur then further enrollment and study treatments will be 
halted until a thorough review has been conducted by the Medical Monitor and Principal 
Investigator for the trial, the Data Safety Monitoring Board (DSMB), and the Institutional 
Review Board (IRB) / Ethics Committee (EC) (if applicable): 
• One-third or more subjects experience an adverse event of special interest (AESI) 
verified per protocol definition; 
• Any subject experiences a serious adverse event (SAE) (or potentially life-threatening 
adverse event [AE]) or death verified as related to study treatment; 


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• Three or more subjects experience the same Grade 3 or 4 unexpected AE, verified per 
protocol definition and assessed as related to study treatment; 
• In the event of 2 identical, unexpected, Grade 4 toxicities, verified per protocol 
definition and assessed as related to study treatment 
Upon conclusion, the Sponsor or designee will notify all Investigators and IRBs/EC (if required) 
regarding the outcome of any investigation stemming from a Study Pause. 
 


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1.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1-1. 
Table 1-1 
Schedule of Assessments 
Tests and Observations 
Screening  
(-10 wk to-1d) 
Day 0 
8-14 days post dose 1  
Phone Call 
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call 
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27 (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days) 
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days) 
Week 100 (± 14 days) 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History/Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medications (prior/concomitant) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Socio-behavioral assessment* 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
Inclusion/Exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical exam (PE)/assessment 1 
X 
X 
  
X 
  
X 
  
X 
X 
  
X 
X 
X 
X 
X 
X 
Vital signs 
X2 
X 
  
X 
  
X 
  
X 
X 
  
X 
X 
X 
X 
X 
X 
Screening safety (12 lead ECG, 
labs) 3 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Testing 4 
X 
X 
  
X 
  
X 
  
X 
X 
  
X 
X 
X 
X 
X 
X 
HIV Ab by ELISA 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood immunologic samples 
X5 
X5 
  
  
  
  
X5 
  
X6 
  
X5 
  
X5 
  
X5 
  
OP rinse, vaginal, and intra-anal 
swabs 
  
X 
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
Vulvar swabs 
  
X 
  
X 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  


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Tests and Observations 
Screening  
(-10 wk to-1d) 
Day 0 
8-14 days post dose 1  
Phone Call 
Week 4 (± 7 days) 
8-14 days post dose 2 
Phone Call 
Week 12 (± 7 days) 
Week 15 (± 7 days) 
Week 24 (± 7 days) 
Week 27 (± 7 days) 
Week 38 (± 7 days) 
Phone Call 
Week 48 (± 7 days) 
Week 52 (± 14 days) 
Week 74 (±14 days) 
Week 78 (± 14 days) 
Week 96 (± 14 days) 
Week 100 (± 14 days) 
Cervical colposcopy7 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Cervical cytology, ThinPrep® 8 
  
X 
  
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
Vulvoscopy 9 
X 
X 
  
X 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
Vulvar lesion standardized 
photography 10 
X 
X 
  
X 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
Biopsy 11 
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
Vulvar HPV genotyping 12 
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
Inject VGX-3100 +EP 12, 13 
  
X 
  
X 
  
X 
  
X 
  
  
  
X13 
  
X13 
  
  
Post treatment reaction 
assessment 
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
X 
  
  
Dispense imiquimod + distribute 
imiquimod dosing log 14 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
  
  
  
Review imiquimod dosing log 
and usage 
  
  
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
  
Distribute Participant Diary (PD) 
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
X 
  
  
Review PD 15 
  
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
X 
  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes 
(PROs) 16 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
 
 
*     Subjects completing the study before Week 100 will have the final socio-behavioral assessment done at their final discharge visit. This may be obtained by phone. 


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1  Full PE mandatory at screening and study discharge (Week 100 for subjects completing this visit before Amendment 5.0), otherwise targeted PE as determined by the 
Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE. PE will not be conducted on subjects completing the study with a Week 78 phone 
call. 
2  Screening vital signs must include a measured height and weight and calculated BMI (Bodyweight in kilograms divided by height in meters squared). Weight will be measured 
at all dosing visits. Vital signs will not be collected on subjects completing the study with a Week 78 phone call. 
3  Screening 12-lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), creatinine (Cr), glucose, ALT, CPK and urinalysis performed within 45 
days prior to first dose administration.  
4  Negative spot urine pregnancy test is required at screening and prior to each study treatment, vulvoscopy and biopsy/surgical excision.  
5  At least 34 mL (4 x 8.5 mL yellow (ACD) tubes) whole blood and 4 mL serum per time point. At least 68 mL whole blood and 8 mL serum should be collected prior to first 
dose. One additional 8.5 mL yellow (ACD) tube to be collected at Day 0, Week 15 and 48 for microRNA analysis.  
6  At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 27.  
7    Cervical colposcopy will be performed once at Day 0, and once at Week 96. For subjects completing the study at Week 78, the repeat cervical colposcopy will be performed at 
Week 74 or the discharge visit. 
8  HPV genotyping and Pap smears are performed on the same ThinPrep® cervical specimen.  
9  An additional visit may be scheduled to perform vulvoscopy if worsening of disease is suspected. Biopsies should not be performed at any visit other than at entry (Screening), 
Week 48, Week 74 and Week 96 for subjects in Subgroups C and D prior to Amendment 5.0 unless the Investigator suspects invasive cancer. All biopsy samples and/or excision 
samples obtained prior to or at the subjects final discharge visit (if not a phone visit) must be sent to the PAC for review.  
10  Photography of the acetowhite stained qualifying lesion(s) must be performed prior to and after biopsy, and at all vulvoscopy examinations. If a pre-biopsy digital photograph is 
not available for a historical biopsy sample at screening, a post biopsy photo will be sufficient. Additionally, standardized high resolution digital photographic imaging should be 
obtained during examinations of the vagina if lesions are identified, for documentation.  
11  Tissue specimen from all excised tissue obtained prior to or at the subjects in-person discharge visit must be reviewed by the PAC and will be sent to the central laboratory for 
HPV testing. All lesions will be biopsied at Week 48, 74, and 96 (as applicable), per Amendment 5.0. 
12  HPV genotyping is performed on vulvar tissue specimen using a PCR based assay.  
13  Potential dosing, post-treatment assessment, and distribution of the Participant Diary at Week 52 and Week 78 is applicable for partial responders only. Partial responders who 
reach Week 78 after Amendment 5.0 will not be offered a 6th dose. 
14  Subjects will take home imiquimod plus an imiquimod dosing log to document their use of imiquimod. Administration of imiquimod begins on Day 0.  
15  A phone call will be used to review the Participant Diary (PD) with subject within 8-14 days following dose 1 and 2. The patient will be expected to bring the PD to the next 
visit for review.  
16  PRO measures (SF-36v2™, EQ-5D-5L, WOMAN-PRO) plus 2 additional questions will be assessed as described in protocol Section 6.8. 
 


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1.2.5. 
Efficacy, Immunology, and Safety Parameters 
1.2.5.1. 
Efficacy Parameters 
The primary efficacy endpoint is the combined response outcome of histopathologic regression 
of vulvar HSIL and virologic clearance of HPV-16/18 in vulvar tissue at Week 48. 
The secondary efficacy endpoints include the following: 
• Histopathological regression is defined as no histologic evidence of vulvar HSIL at 
Week 48. 
• Virologic clearance is defined as no evidence of HPV-16/18 at Week 48 in vulvar tissue 
samples. 
• Proportion of subjects with no histologic evidence of vulvar HSIL or no evidence of 
HPV-16/18 at Week 48 in vulvar tissue samples (i.e. collected via biopsy or excisional 
treatment). 
• Proportion of subjects with no evidence of vulvar HSIL, no evidence of vulvar LSIL 
(VIN1), and no evidence of condyloma on histology (i.e. biopsies or excisional 
treatment) at the Week 48 visit. 
• Proportion of subjects with no progression of vulvar HSIL to vulvar cancer from 
baseline to Week 48 visit. 
• Percent reduction in the cumulative surface area of qualifying acetowhite vulvar 
lesion(s) as determined by the quantitative analysis of standardized pre-biopsy 
photographic imaging of qualifying lesion(s) at Week 48 compared to baseline. Results 
will be classified as: 
o No clinically significant lesion resolution (reduction in lesion area of 0-25%), 
o Partial lesion area resolution (>25% and <100% reduction), 
o Complete lesion resolution (no visible lesion). 
Exploratory efficacy endpoints include the following: 
• Percent reduction in the cumulative surface area of the acetowhite vulvar lesion(s) as 
determined by the quantitative analysis of standardized pre-biopsy photographic imaging 
of qualifying lesion(s) at Week 74 and/or Week 96 compared to baseline. Results will be 
classified as: no clinically significant lesion resolution (reduction in lesion area of 0-
25%), partial lesion area resolution (>25% and <100% reduction) and complete lesion 
resolution (no visible lesion).    
• Proportion of subjects with no evidence of vulvar HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 74 for subjects who receive 5 doses of VGX3100 and at 
Week 96 for subjects who receive 6 doses of VGX-3100. 
• Virologic clearance in vulvar tissue samples at Week 74 and/or Week 96 compared to 
baseline. 
• Virologic clearance from non-vulvar anatomic locations without surgical intervention at 
Week 48 compared to baseline. 


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• The relationship of microRNA (miRNA) profile (Day 0, Week 15, and Week 48), 
previous vulvoscopy, and HPV testing results (vulvar swab and vulvar tissue) with Week 
48 histologic regression of vulvar HSIL. 
• Proportion of subjects at Week 74 and 96 with no histologic evidence of vulvar HSIL or 
no evidence of HPV-16/18 in vulvar tissue samples (i.e. collected via biopsy or 
excisional treatment). 
To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be provided and will include the Short Form Health Survey version 2 (SF-
36v2™) (Optum), the EQ-5D-5L (EuroQol Research Foundation), WOMAN-PRO (WOMen 
with vulvAr Neoplasia) Clinical Trial Version 2.0, and 2 additional PRO questions assessing 
quality of life after surgery or biopsy. The PRO instruments are described below. 
• WOMAN-PRO - is a 31 item self-completed patient reported outcome measure designed 
to assess both physical and psychosocial impacts of VIN.  
• SF-36v2 – generically measures functional health and well-being, for physical and 
mental health. The questionnaire consists of 36 items covering 8 domains (Physical 
functioning, Role limitations due to physical problems, Bodily pain, General health, 
Vitality, Social functioning, Role limitations due to emotional problems, and Mental 
health). 
• EQ-5D-5L – generically measures activities and general health status and consists of 6 
items covering 6 domains (Mobility, Self-care, Usual activity, Pain/discomfort, 
Anxiety/depression, and Global health status). 
1.2.5.2. 
Immunology Parameters 
The secondary immunology endpoint is the Flow Cytometry response magnitudes at baseline 
and Week 27 visits. 
Exploratory immunology endpoints include the following: 
• Assessment of pro-inflammatory and immunosuppressive elements in vulvar tissue, 
which may include visualization of PD-L1, Granulysin, perforin, CD137, CD103, and 
possibly other relevant markers. 
• Levels of serum anti-HPV-16 and antiHPV-18 antibody concentrations at baseline, 
Weeks 15, 27, 48, 74, and 96 visits. 
• Interferon-γ ELISpot response magnitudes at baseline and Weeks 15, 27, 48, 74 and 96 
visits. 
• Immunohistochemistry biomarker results including but not limited to, CD8+ and 
FoxP3+ infiltrating cells as well as assessment of cell death via Cleaved Caspase 3 
assessment. 
1.2.5.3. 
Safety Parameters 
Safety evaluations performed during the study include physical examinations, measurement of 
vital signs, and monitoring of AEs, injection site reactions, pain, and concomitant medications. 
Secondary safety endpoints include the following:  


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• Local and systemic events for 7 days following each dose as noted in the Participant 
Diary 
• All adverse events including SAEs, AESIs, SUSARs, UADEs, and other unexpected 
AEs for the duration of the study (through Week 100 visit) 
Treatment-emergent adverse events (TEAEs) are collected throughout study. All TEAEs that 
occur within 7, 14, or 28 days following each injection will be summarized separately. 


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2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of 
the data: 
• Modified Intention-to-Treat (mITT) Population: All subjects who receive at least 1 dose 
of VGX-3100 + EP and who have the analysis endpoint of interest. Subjects in this 
sample will be grouped to treatment arms as randomized. 
• Per-protocol (PP) Population: All subjects who receive at least 4 doses of VGX-3100 + 
EP, have no protocol violations, and who have the analysis endpoint of interest. Subjects 
in this sample will be grouped to treatment arms as randomized. Subjects excluded from 
the PP population will be identified and documented prior to locking of the study 
database. 
• Safety Population: All subjects who receive at least 1 dose of VGX-3100 (with or 
without EP). Subjects will be analyzed as to the treatment they received. 
The mITT population is the primary population for the analysis of efficacy parameters. The PP 
population will be considered supportive of the corresponding mITT population for the analysis 
of efficacy. The Safety population is the primary population for the analysis of safety endpoints. 
2.2. 
Protocol Violations 
At the discretion of the Sponsor, protocol violations, as determined by a review of the data prior 
to locking of the study database and the conduct of statistical analyses, will result in the removal 
of a subject’s data from the PP population. The Sponsor or designee will be responsible for 
producing the final protocol violation file (formatted as a Microsoft Excel file), in collaboration 
with Veristat and the data monitoring group as applicable; this file will include a description of 
the protocol violation which warrant exclusion from the PP population. This file will be 
finalized prior to hard database lock. 
All protocol violations will be presented in a data listing. 
Relevant Output 
Listing 16.2.2.2 
Protocol Violations 


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Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
The study will enroll 36 subjects randomized to receive either 6 mg VGX-3100 or 6 mg 
VGX-3100 plus imiquimod, IM followed by EP in a 2:1 ratio. This sample size provides 80% 
power to declare each arm superior to historical control with a 1-sided 0.025 type 1 error level 
for each hypothesis, assuming the true proportion of subjects who achieve the primary endpoint 
is 20% and 28% for the respective treatment arms and 2% for the historical control, and that 
90% of subjects in each treatment group are evaluable at Week 48 from randomization. 
3.2. 
General Methods 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of study 
medication (Day 0) which is designated as Rel Day 1. The preceding day is Rel Day -1, the day 
before that is Rel Day -2, etc. There is no Rel Day 0. 
All output will be incorporated into Microsoft Word or Excel files, or Adobe Acrobat PDF files, 
sorted and labeled according to the International Conference on Harmonisation (ICH) 
recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, immunogenicity, 
and safety parameters. For categorical variables, summary tabulations of the number and 
percentage of subjects within each category of the parameter will be presented. For continuous 
variables, the number of subjects, mean, median, standard deviation (SD), minimum, and 
maximum values will be presented. Summarizations will be presented by treatment grouping 
and overall as applicable. 
Formal statistical hypothesis testing will be performed on the primary endpoint for each 
treatment group compared to historical control separately at a 1-sided, 0.025 level of 
significance. Summary statistics will be presented, as well as 2-sided 95% confidence intervals 
(CIs) on selected efficacy and safety parameters, as described in the sections below. 
3.3. 
Computing Environment 
All statistical analyses will be performed using SAS statistical software Version 9.3 or higher, 
unless otherwise noted. Adverse events will be coded using the current Medical Dictionary for 
Regulatory Activities (MedDRA), starting with Version 20.0. 
3.4. 
Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug. 
3.5. 
Methods of Pooling Data 
Data will be pooled across study sites. 
3.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 


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Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
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3.7. 
Multiple Comparisons/Multiplicity 
No adjustments for multiple testing will be implemented, as 2 one-sided tests will each utilize a 
type I error rate of 2.5% on testing the primary hypothesis. 
3.8. 
Subpopulations 
Certain subgroups will be analyzed separately at additional time points for effectiveness of 
additional doses and/or surgical treatments. 
• Subgroups A and B – Subjects with no HSIL at Week 48 will receive 4 doses. 
• Subgroups C and D – Subjects with HSIL at Week 48, who have a reduction in lesion 
size or no increase in lesion size from baseline, may receive a fifth dose of VGX-3100 
administered IM with EP at Week 52 per the judgment of the Investigator. Subjects with 
HSIL at Week 74 may receive a sixth dose of VGX-3100 administered IM with EP at 
Week 78 per the judgment of the Investigator. 
• Subgroup E – Subjects may receive surgical treatment per the judgment of the 
Investigator. 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who are withdrawn or discontinue from the study will not be replaced. 
3.10. 
Missing, Unused, and Spurious Data 
When tabulating AE data, partial dates will be handled as follows in order to determine 
treatment emergence. If any of the day, month, or year is missing, the onset date will be set to 
the earliest date that is consistent with any non-missing date information, unless the non-missing 
date information is the same as study treatment start. In this case, in order to conservatively 
report the event as treatment-emergent, the onset date will be assumed to be the date of start of 
treatment. A completely missing onset date will be coded as the day of start of treatment. 
A prior medication is defined as any medication that has a stop date before the start of the trial 
(prior to Dose #1 on Day 0). A concomitant medication is defined as any medication that has a 
stop date that is on or after the date of first dose of study drug. For prior and concomitant 
medications, partial start dates will not be imputed, as stop dates determine prior versus 
concomitant. Partial stop dates will be assumed to be the latest possible date consistent with the 
partial date. 
3.11. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the evaluation visit as recorded on the CRF even if the assessment is outside of the 
visit window. In data listings, the relative day of all dates will be presented. 
The efficacy time windows for histologic regression and virologic clearance are defined by 
samples obtained any time starting from 14 days prior to the protocol-specified target date of 
visit. 


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3.12. 
Interim Analyses 
For reasons of futility (early observational evidence of poor efficacy of VGX-3100), the study 
has the potential to be stopped by the DSMB at any time. However, no formal interim analyses 
are planned, and the study is not designed to be stopped early based on evidence of efficacy. 


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22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 24 of 38 
4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
Subject disposition will be tabulated by treatment group and overall, and will include the 
number screened, the number of screen failures, the number randomized (in total and by 
stratum), the number treated by the highest number of doses received, the number in each 
subject population for analysis, the number that completed all study treatments and follow-up 
visit, the number who withdrew prior to completing the study treatment, the number who 
withdrew prior to completing all follow-up visits, and reason(s) for withdrawal. Reasons for not 
participating in study will also be summarized. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. Consent and randomization, 
inclusion/exclusion criteria, and study populations will also be provided in listings. 
Relevant Output 
Table 14.1.1.1 
Subject Enrollment and Disposition 
Table 14.1.1.2 
Summary of Primary Reasons for Not Participating in Study  
Listing 16.2.1.1 
Study Completion Status 
Listing 16.2.1.2 
Consent and Randomization Information 
Listing 16.2.2.1 
Inclusion/Exclusion Criteria and Eligibility  
Listing 16.2.3.1 
Study Populations 
Listing 16.2.3.2 
Randomized Subjects Who Were Never Vaccinated 
Listing 16.2.3.3 
Subject Status Subgroups 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized and presented by treatment 
group and overall. Age, height, weight, and BMI will be summarized using descriptive statistics 
(number of subjects, mean, SD, median, minimum, and maximum). The number and percentage 
of subjects in each randomization stratum, ethnicity category, race category, and country also 
will be presented. Results at screening for VIN category, HPV type, years of education, and type 
of insurance will also be presented. 
Abnormal medical history will be summarized by term as collected on the electronic CRF. Prior 
vulvar disease, HPV diagnoses, and reproductive history will be presented in data listings as 
well as tobacco history and alcohol use. 
No formal statistical comparisons between groups will be performed for demographics, baseline 
data, or medical history data. Data for each subject will also be provided in data listings. 


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Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
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Relevant Output 
Table 14.1.2.1A 
Demographics and Baseline Characteristics (mITT/Safety Population) 
Listing 16.2.4.1 
Demographics and Baseline Disease Characteristics 
Listing 16.2.4.2 
Abnormal Medical History 
Listing 16.2.4.3 
Prior Vulvar Disease and HPV Diagnoses 
Listing 16.2.4.4 
Reproductive System History 
Listing 16.2.4.5 
Alcohol, Tobacco, and Recreational Drug Use 
4.3. 
Efficacy Evaluation 
Efficacy analyses will be conducted using the mITT population. Supportive analyses of efficacy 
will be based on the PP population. 
4.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the combined outcome of histologic regression of vulvar HSIL 
and virologic clearance of HPV-16/18 at Week 48. Histologic regression is defined as no 
histologic evidence of vulvar HSIL (normal tissue or vulvar LSIL (VIN 1) or condyloma) at 
Week 48. Virologic clearance is defined as clearance of HPV 16 or 18 at Week 48. A subject 
achieves the primary outcome (i.e., is a “responder”) if histologic regression and virologic 
clearance is observed at Week 48 and the subject did not receive any non-study related 
treatment for vulvar HSIL. A subject is a non-responder if there is histologic evidence of vulvar 
HSIL or vulvar carcinoma, or evidence of HPV-16/18, or subject received non-study related 
treatment for vulvar HSIL. 
Table 4-1: 
Definition of Responder and Non-Responder 
Responder 
Non-Responder 
• Subject with no histologic evidence of vulvar 
HSIL 
AND 
• Subject with no evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
AND 
• Subject did not receive any non-study related 
treatment for vulvar HSIL 
• Subject with histologic evidence of vulvar HSIL 
or vulvar carcinoma at evaluation 
OR 
• Subject with evidence of HPV-16 or HPV-18 in 
vulvar tissue at evaluation 
OR 
• Subject who received non-study related treatment 
for vulvar HSIL 
Note: The efficacy time frame is defined by samples obtained any time starting from 14 days prior to the protocol-specified 
target date of Week 48. The first such sample determines the histology endpoint. The most recent HPV clearance result 
prior to time of the histology sample within the time frame determines the HPV clearance endpoint. 
The number and percentage of subjects with response for the primary endpoint will be presented 
for each treatment group and compared to historical control separately. A 1-sided p-value and 
corresponding 2-sided 95% CI using Clopper-Pearson exact binomial methods will be presented 
for each comparison to prove superiority over historical control. Superiority of VGX-3100 alone 
or in combination with imiquimod will be declared if 1-sided p-value is <0.025 and the lower 
end of the CI is greater than 0.02. The primary efficacy will be analyzed separately based on 
qualifying lesions present at baseline and for all lesions regardless of presence at baseline. 


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Statistical Analysis Plan, Protocol HPV-201 
22 March 2021, Final Version 2.0 
 
CONFIDENTIAL 
Page 26 of 38 
Relevant Output 
Table 14.2.1.1A 
Primary Efficacy Analysis: Incidence of Histologic Regression and 
Virologic Clearance at Week 48 (mITT Population) 
Table 14.2.1.1B 
Primary Efficacy Analysis: Incidence of Histologic Regression and 
Virologic Clearance at Week 48 (PP Population) 
Listing 16.2.6.1 
Primary Efficacy Results 
4.3.2. 
Secondary and Exploratory Efficacy Endpoints 
Secondary and exploratory efficacy endpoints are supportive to the primary hypothesis. 
The following secondary and exploratory efficacy binary endpoints will be presented as 
percentage point estimates and exact Clopper-Pearson 95% CIs. Each of the following endpoints 
will be analyzed separately based on qualifying lesions present at baseline and for all lesions 
regardless of presence at baseline, unless otherwise noted. 
• Histologic regression of vulvar HSIL or virologic clearance of HPV-16/18 in vulvar 
tissue will be assessed at Weeks 74 and 96 by treatment group for all subjects and 
stratified by subjects who receive 4 or 5 doses (Week 74) and 4, 5, or 6 doses (Week 96).  
• Histologic regression of vulvar HSIL will be assessed at Week 48 by treatment group. 
• Virologic clearance of HPV-16/18 in vulvar tissue will be assessed at Week 48 by 
treatment group. 
• Histologic regression of vulvar HSIL will be assessed at Weeks 74 and 96 by treatment 
group for all subjects and stratified by subjects who receive 4 or 5 doses (Week 74) and 
4, 5, or 6 doses (Week 96).  
• Virologic clearance of HPV-16/18 in vulvar tissue will be assessed at Weeks 74 and 96 
by treatment group for all subjects and stratified by subjects who receive 4 or 5 doses 
(Week 74) and 4, 5, or 6 doses (Week 96).  
• Histologic regression of vulvar HSIL to normal tissue will be assessed at Week 48 by 
treatment group. Normal tissue is defined as having no evidence of vulvar HSIL, no 
evidence of LSIL (VIN1), and no evidence of condyloma. 
• Non-progression of vulvar HSIL to vulvar cancer will be investigated at Week 48 by 
treatment group. Progression is defined as advancement to carcinoma by histology 
according to the Pathology Adjudication Committee. 
• Virologic clearance of HPV-16/18 outside of the vulva will be assessed at Week 48 by 
treatment group (for qualifying lesions only) and be presented by anatomic location 
(cervical, intra anal, oral, and vaginal). 
• Histologic regression of vulvar HSIL or virologic clearance of HPV-16/18 in vulvar 
tissue will be assessed at Weeks 48, 74, and 96 by treatment group. 
Reduction in surface area of qualifying vulvar lesion(s) at Weeks 48, 74, and 96 will be assessed 
by treatment group and determined by quantitative analysis of standardized pre-biopsy 
photographic imaging. The mean percent change and associated 95% t-distribution based CI 
will be presented. Also, the percent reduction will be classified as no clinically significant lesion 


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22 March 2021, Final Version 2.0 
 
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resolution (reduction in lesion area of 0-25%), partial lesion area resolution (>25% and <100% 
reduction), and complete lesion resolution (no visible lesion). A lesion will be considered 
qualifying if it is confirmed to be HPV-16 and/or HPV-18 positive and have histologically 
confirmed vulvar HSIL by the PAC at screening. The percentage of subjects in each lesion 
category will be summarized by treatment group with point estimates and associated exact 
Clopper-Pearson 95% CIs. 
Regression/clearance endpoints will be summarized with the number and percentage of subjects 
meeting the endpoint separately by previous vulvoscopy results and by previous HPV test 
results. The relationship between the regression/clearance endpoints with miRNA profiles will 
be summarized with the median change from baseline in miRNA profiles by those who 
achieved versus not achieved the endpoint. 
By-subject listings will be provided for all efficacy-related parameters and results. 
Relevant Output 
Table 14.2.2.1A 
Incidence of Histologic Regression at Week 48 (mITT Population) 
Table 14.2.2.1B 
Incidence of Histologic Regression at Week 48 (PP Population) 
Table 14.2.2.2A 
Incidence of Vulvar Virologic Clearance at Week 48 (mITT Population) 
Table 14.2.2.2B 
Incidence of Vulvar Virologic Clearance at Week 48 (PP Population) 
Table 14.2.2.3A   
Incidence of Histologic Regression or Virologic Clearance at Week 48 
(mITT Population) 
Table 14.2.2.3B   
Incidence of Histologic Regression or Virologic Clearance at Week 48 
(PP Population) 
Table 14.2.2.4A 
Incidence of Histologic Regression to Normal at Week 48 (mITT 
Population) 
Table 14.2.2.4B 
Incidence of Histologic Regression to Normal at Week 48 (PP 
Population) 
Table 14.2.2.5A 
Incidence of Non-progression to Vulvar Cancer at Week 48 (mITT 
Population) 
Table 14.2.2.5B 
Incidence of Non-progression to Vulvar Cancer at Week 48 (PP 
Population) 
Table 14.2.2.6A 
Incidence of Virologic Clearance Outside of the Vulva at Week 48 (mITT 
Population) 
Table 14.2.2.6B 
Incidence of Virologic Clearance Outside of the Vulva at Week 48 (PP 
Population) 
Table 14.2.2.7A 
Incidence of Histologic Regression and Virologic Clearance at Week 74 
and Week 96 (mITT Population) 
Table 14.2.2.7B 
Incidence of Histologic Regression and Virologic Clearance at Week 74 
and Week 96 (PP Population) 
Table 14.2.2.8A 
Incidence of Histologic Regression at Week 74 and Week 96 (mITT 
Population)  
Table 14.2.2.8B 
Incidence of Histologic Regression at Week 74 and Week 96 (PP 
Population)  


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22 March 2021, Final Version 2.0 
 
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Table 14.2.2.9A 
Incidence of Vulvar Virologic Clearance at Week 74 and Week 96 (mITT 
Population)  
Table 14.2.2.9B 
Incidence of Vulvar Virologic Clearance at Week 74 and Week 96 (PP 
Population)  
Table 14.2.2.10A   
Incidence of Histologic Regression or Virologic Clearance at Week 48, 
Week 74, and Week 96 (mITT Population) 
Table 14.2.2.10B   
Incidence of Histologic Regression or Virologic Clearance at Week 48, 
Week 74, and Week 96 (PP Population) 
Table 14.2.2.11A 
Incidence of Histologic Regression and Virologic Clearance at Week 48 
by Previous Vulvoscopy Result (mITT Population) 
Table 14.2.2.11B 
Incidence of Histologic Regression and Virologic Clearance at Week 48 
by Previous Vulvoscopy Result (PP Population) 
Table 14.2.2.12A 
Incidence of Histologic Regression and Virologic Clearance at Week 48 
by Previous HPV Test Results (mITT Population) 
Table 14.2.2.12B 
Incidence of Histologic Regression and Virologic Clearance at Week 48 
by Previous HPV Test Results (PP Population) 
Table 14.2.2.13A 
Incidence of Histologic Regression and Virologic Clearance at Week 48 
by Previous miRNA Profile (mITT Population)  
Table 14.2.2.13B 
Incidence of Histologic Regression and Virologic Clearance at Week 48 
by Previous miRNA Profile (PP Population)  
Table 14.2.2.14A 
Incidence of Histologic Regression at Week 48 by Previous Vulvoscopy 
Result (mITT Population) 
Table 14.2.2.14B 
Incidence of Histologic Regression at Week 48 by Previous Vulvoscopy 
Result (PP Population) 
Table 14.2.2.15A 
Incidence of Histologic Regression at Week 48 by Previous HPV Test 
Results (mITT Population) 
Table 14.2.2.15B 
Incidence of Histologic Regression at Week 48 by Previous HPV Test 
Results (PP Population) 
Table 14.2.2.16A 
Incidence of Histologic Regression at Week 48 by Previous miRNA 
Profile (mITT Population)  
Table 14.2.2.16B 
Incidence of Histologic Regression at Week 48 by Previous miRNA 
Profile (PP Population)  
Table 14.2.2.17A 
Incidence of Virologic Clearance at Week 48 by Previous Vulvoscopy 
Result (mITT Population) 
Table 14.2.2.17B 
Incidence of Virologic Clearance at Week 48 by Previous Vulvoscopy 
Result (PP Population) 
Table 14.2.2.18A 
Incidence of Virologic Clearance at Week 48 by Previous HPV Test 
Results (mITT Population) 
Table 14.2.2.18B 
Incidence of Virologic Clearance at Week 48 by Previous HPV Test 
Results (PP Population) 


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22 March 2021, Final Version 2.0 
 
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Table 14.2.2.19A 
Incidence of Virologic Clearance at Week 48 by Previous miRNA Profile 
(mITT Population)  
Table 14.2.2.19B 
Incidence of Virologic Clearance at Week 48 by Previous miRNA Profile 
(PP Population)  
Table 14.2.2.20A 
Change in Surface Area of Qualifying Vulvar Lesion(s) (mITT 
Population) 
Table 14.2.2.20B 
Change in Surface Area of Qualifying Vulvar Lesion(s) (PP Population) 
Listing 16.2.6.2A 
HPV Testing Results: FFPE Vulvar Tissue Samples 
Listing 16.2.6.2B 
HPV Testing Results: Cervical ThinPrep and Swab Samples 
Listing 16.2.6.3 
Cervical Colposcopy and Biopsy Results 
Listing 16.2.6.4A 
Vulvoscopy and Biopsy Results  
Listing 16.2.6.5 
Photographic Lesion Results 
Listing 16.2.6.6 
miRNA Profiles by Visit 
4.3.3. 
Patient-Reported Outcomes 
PRO endpoints will be obtained at Day 0 prior to first dose, Weeks 4, 12, 24 after dosing, and at 
Weeks 15, 27, 48, 52, 74, and Weeks 96, and 100 as applicable. 
For the SF-36 results, scores and changes from baseline for the 8 subscales (Physical 
Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role 
Emotional and Mental Health) as well as the Physical Component Summary (PCS) and Mental 
Component Summary (MCS) will be summarized using medians and associated exact non-
parametric 95% CIs by treatment group. 
For the EQ-5D-5L results, the assessment of 5 health categories (1-5 scales) and overall health 
score, “Your Health Today”, (1-100 scale) will be summarized; the scores and changes from 
baseline will be summarized using medians and associated exact non-parametric 95% CIs, by 
treatment group. 
For the WOMAN-PRO results, 31 self-reported items assessing physical and psychosocial 
impacts will be summarized. Scores and change from baseline will be summarized for the group 
of 15 wound-related domain items and the group of 5 difficulties in daily life domain items, the 
group of 11 psychosocial domain items, and each of the 31 individual items. Medians and 
associated exact non-parametric 95% CIs will be constructed, by treatment group.  
For the 2 additional Global PRO questions assessing quality of life after surgery or biopsy, the 
time outcome will be summarized with a median and associated exact non-parametric 95% CI, 
and the binary yes/no outcomes will be summarized with a proportion and associated exact 
Clopper-Pearson 95% CI, by treatment group. 
All PRO data will be presented by study visit in data listings. 
Relevant Output 
Table 14.2.3.1 
Summary of SF-36 Outcomes by Visit (mITT Population) 
Table 14.2.3.2 
Summary of EQ-5D-5L Outcomes by Visit (mITT Population) 
 
Table 14.2.3.3 
Summary of WOMAN-PRO Outcomes by Visit (mITT Population) 
Table 14.2.3.4 
Summary of Global PRO Outcomes at Week 52 (mITT Population) 


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22 March 2021, Final Version 2.0 
 
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Listing 16.2.9.5 
Patient Reported Outcomes: SF-36 Results 
Listing 16.2.9.6 
Patient Reported Outcomes: EQ-5D-5L Results 
Listing 16.2.9.7 
Patient Reported Outcomes: WOMAN-PRO Results 
Listing 16.2.9.8 
Global PRO Results 
4.3.4. 
Immunology Endpoints 
The following immunology endpoints will be presented in tabulations: 
• ELISpot results will be presented by treatment group and scheduled visit, and increase 
from baseline will be analyzed using an exact non-parametric 95% CI on the median at 
each time point after baseline (Weeks 15, 27, 48, 74, and 96). 
• HPV-16 and HPV-18 E7 specific ELISA results will be presented by treatment group 
and scheduled visit and analyzed using an exact non-parametric 95% CI on the median 
at each time point after baseline (Weeks 15, 27, 48, 74, and 96). 
• Increase from baseline in frequency of VGX-3100 specific CD8+/CD137+ PBMCs that 
are Perforin+ will be presented by treatment group and will be analyzed using an exact 
non-parametric 95% CI on the median. 
• Change from baseline in pro-inflammatory and immunosuppressive elements in vulvar 
tissue, which may include visualization of PD-L1, Granulysin, perforin, CD137, CD103, 
and possibly other relevant markers, will be presented by treatment group and will be 
analyzed using a t-distribution based 95% CI on the mean. 
All immunology data will be presented by study visit in data listings. 
Relevant Output 
Table 14.2.4.1A 
ELISpot Results by Treatment Group and Scheduled Visit (mITT 
Population)  
Table 14.2.4.1B 
ELISpot Results by Treatment Group and Scheduled Visit (PP 
Population)  
Table 14.2.4.2A 
HPV-16 and HPV-18 E7 Specific ELISA Results by Treatment Group 
and Scheduled Visit (mITT Population) 
Table 14.2.4.2B 
HPV-16 and HPV-18 E7 Specific ELISA Results by Treatment Group 
and Scheduled Visit (PP Population) 
Table 14.2.4.3A 
Increase from Baseline in Frequency of VGX-3100 Specific 
CD8+/CD137+ PBMCs that are Perforin+ by Treatment Group (mITT 
Population) 
Table 14.2.4.3B 
Increase from Baseline in Frequency of VGX-3100 Specific 
CD8+/CD137+ PBMCs that are Perforin+ by Treatment Group (PP 
Population) 
Table 14.2.4.4A 
Change from Baseline in Pro-inflammatory and Immunosuppressive 
Elements in Vulvar Tissue by Treatment Group and Scheduled Visit 
(mITT Population) 


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Table 14.2.4.4B 
Change from Baseline in Pro-inflammatory and Immunosuppressive 
Elements in Vulvar Tissue by Treatment Group and Scheduled Visit (PP 
Population) 
Listing 16.2.6.7 
Immunologic Assay Collection 
Listing 16.2.6.8A 
Immunologic Results: ELISA and ELISpot 
Listing 16.2.6.8B 
Immunologic Results: Flow Cytometry 
Listing 16.2.6.8C 
Immunologic Results: Pro-inflammatory and Immunosuppressive 
Elements in Vulvar Tissue 
4.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population and will be presented based on 
actual treatment received. 
4.4.1. 
Study Drug Exposure 
Study drug exposure will be tabulated by the number of doses received. The number and 
percentage of subjects will be reported by treatment group and overall. 
Compliance will be measured by the following parameters: incorrect treatment received, 
unsuccessful EP, the location of the EP treatment, the size of EP array, and whether or not a 
guide was used. 
Dosing information for each subject will be presented in a data listing. 
Relevant Output 
Table 14.3.5.1 
Study Drug Exposure (Safety Population) 
Listing 16.2.5.1 
Study Drug Administration 
Listing 16.2.5.2 
Electroporation Administration 
Listing 16.2.5.3 
Electroporation Issue Reports 
Listing 16.2.5.4 
Electroporation Guide Use 
4.4.2. 
Adverse Events 
All AEs will be coded using the most current version of the MedDRA coding system and 
displayed in tables and data listings using system organ class (SOC) and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined per protocol as any AE with onset after the administration 
of study medication through the end of the study (i.e., study discharge). 
An AESI is defined as an AE deemed related to VGX-3100 delivered with CELLECTRA™ 
2000 that requires expedited communication from the site to the Sponsor and meets any of the 
following criteria per the Toxicity Grade for Healthy Adults: 
• Grade 3 or greater persistent administration site erythema, and/or induration recorded 
≥2 hours immediately after study treatment; 


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• Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after study treatment; 
• Grade 3 or greater fever; 
• Grade 3 or greater systemic symptoms, including generalized pruritus. 
Separate summaries of AEs will be presented by treatment group and overall for events with an 
onset within the first 28, 14, and 7 days after injection and overall. The summary will include 
the number and percentage of subjects with any treatment-emergent AE (TEAE), with any 
TEAE assessed by the Investigator as related to treatment, with any AESI, with any TEAE by 
Common Terminology Criteria for Adverse Events (CTCAE v4.03) grade, with any SAE, with 
any pre-treatment AE, with any AE leading to discontinuation of treatment, and with any AE 
leading to death. 
In these tabulations, each subject will contribute only once (i.e., the most related occurrence or 
the most intense occurrence) to each of the incidences in the analysis, regardless of the number 
of episodes. In addition to the number of subjects that experienced at least 1 of the events, the 
total number of events observed across subjects will also be reported. 
Summary tables by SOC and preferred term will be produced for the following, presented by 
treatment group: 
• All TEAEs 
• All TEAEs by most recent injection 
• All TEAEs by severity grade 
• All TEAE assessed as at least possibly related to treatment by the Investigator (i.e., 
treatment-related) 
• All TEAEs with onset within 7 days of an injection 
• All TEAEs with onset within 7 days by severity grade 
• All treatment-related TEAEs with onset within 7 days of an injection 
• All TEAEs with onset within 14 days of an injection 
• All TEAEs with onset within 14 days of an injection by severity grade 
• All treatment-related TEAEs with onset within 14 days of an injection 
• All TEAEs with onset within 28 days of an injection 
• All TEAEs with onset within 28 days of an injection by severity grade 
• All treatment-related TEAEs with onset within 28 days of an injection 
For each tabulation, TEAEs are summarized by proportions of subjects; therefore, in any 
tabulation, a subject contributes only once to the count for a given TEAE (SOC or preferred 
term), irrespective of the number of episodes of a particular AE term reported. Injection site 
reactions are included in the TEAE summaries. 
The frequency of subjects with preferred term events with onset within 7, 14, or 28 days 
separately will be summarized with percentages and exact Clopper-Pearson 95% CIs. All AEs 
occurring on-study will be listed in subject data listings. By-subject listings also will be 


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provided for the following: AEs leading to death, SAEs, AEs with severity ≥ Grade 3, AEs 
leading to discontinuation of treatment, and AESIs. 
Relevant Output 
Table 14.3.1.1A 
Overall Summary of Adverse Events (Safety Population) 
Table 14.3.1.1B 
Overall Summary of Treatment-Emergent Adverse Events with Onset 
within 7 Days of an Injection (Safety Population) 
Table 14.3.1.1C 
Overall Summary of Treatment-Emergent Adverse Events with Onset 
within 14 Days of an Injection (Safety Population) 
Table 14.3.1.1D 
Overall Summary of Treatment-Emergent Adverse Events with Onset 
within 28 Days of an Injection (Safety Population) 
Table 14.3.1.2A 
Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term (Safety Population) 
Table 14.3.1.2B 
Treatment-Emergent Adverse Events with Onset within 7 Days of an 
Injection by MedDRA System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.2C 
Treatment-Emergent Adverse Events with Onset within 14 Days of an 
Injection by MedDRA System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.2D 
Treatment-Emergent Adverse Events with Onset within 28 Days of an 
Injection by MedDRA System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.3A 
Treatment-Emergent Adverse Events by Most Recent Injection, 
MedDRA System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.3B 
Treatment-Emergent Adverse Events with Onset within 7 Days of Each 
Injection by Most Recent Injection, MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3C 
Treatment-Emergent Adverse Events with Onset within 14 Days of Each 
Injection by Most Recent Injection, MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.3D 
Treatment-Emergent Adverse Events with Onset within 28 Days of Each 
Injection by Most Recent Injection, MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.4A 
Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term, and Severity Grade (Safety Population) 
Table 14.3.1.4B 
Treatment-Emergent Adverse Events with Onset within 7 Days of an 
Injection by MedDRA System Organ Class, Preferred Term, and Severity 
Grade (Safety Population) 
Table 14.3.1.4C 
Treatment-Emergent Adverse Events with Onset within 14 Days of an 
Injection by MedDRA System Organ Class, Preferred Term, and Severity 
Grade (Safety Population) 


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Table 14.3.1.4D 
Treatment-Emergent Adverse Events with Onset within 28 Days of an 
Injection by MedDRA System Organ Class, Preferred Term, and Severity 
Grade (Safety Population) 
Table 14.3.1.5A 
Treatment-Related Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.5B 
Treatment-Related Adverse Events with Onset within 7 Days of an 
Injection by MedDRA System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.5C 
Treatment-Related Treatment-Emergent Adverse Events with Onset 
within 14 Days of an Injection by MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.5D 
Treatment-Related Treatment-Emergent Adverse Events with Onset 
within 28 Days of an Injection by MedDRA System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.2.1 
Listing of Adverse Events Leading to Death (Safety Population) 
Table 14.3.2.2 
Listing of Serious Adverse Events (Safety Population) 
 
Table 14.3.2.3 
Listing of Adverse Events with CTCAE Toxicity ≥ Grade 3 (Safety 
Population) 
Table 14.3.2.4 
Listing of Adverse Events Leading to Discontinuation of Treatment 
(Safety Population) 
Table 14.3.2.5 
Listing of Adverse Events of Special Interest (Safety Population) 
Listing 16.2.7.1 
Adverse Events by Subject, MedDRA Preferred Term, and Verbatim 
Term 
Listing 16.2.7.2 
Adverse Events by MedDRA System Organ Class/Preferred Term and 
Subject 
Listing 16.2.7.3 
Glossary of Adverse Events 
4.4.3. 
Laboratory Data 
Clinical laboratory values will be expressed in International System (SI) units. 
Clinical laboratory data will be collected at screening. All laboratory data will be provided in 
by-subject data listings, including hematology, clinical chemistry, creatinine phosphokinase, 
urinalysis, and pregnancy testing assessments. 
Relevant Output 
Listing 16.2.8.1 
Laboratory Results: Hematology 
Listing 16.2.8.2 
Laboratory Results: Serum Chemistry 
Listing 16.2.8.3 
Laboratory Results: Urinalysis  
Listing 16.2.8.4 
Laboratory Results: Creatine Phosphokinase 
Listing 16.2.8.6 
Laboratory Results: Pregnancy  


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4.4.4. 
Vital Signs and Physical Examination 
The actual value and change from baseline to each on-study evaluation will be summarized for 
vital signs. 
Physical examination results at each on-study evaluation will be summarized. 
All physical examination findings and vital sign measurement will be presented in by-subject 
data listings. 
Relevant Output 
Table 14.3.5.2 
Summary of Actual Value and Change from Baseline for Vital Signs by 
Scheduled Visit (Safety Population) 
Table 14.3.5.3 
Physical Examination Results by Scheduled Visit (Safety Population) 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
Physical Examination Findings 
4.4.5. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at screening for all subjects and results 
will be provided in a by-subject data listing. The ECG results include ventricular rate and PR, 
QRS, QT, QTcB (calculated by the Bazett correction formula), ST Segment, and T-wave. QTcB 
will be calculated using the formula QT/√𝑅𝑅𝑅𝑅. The RR interval will be derived as 60 divided by 
the ventricular rate. All abnormal results and clinical significance will be flagged within listing. 
Relevant Output 
Listing 16.2.9.3 
12-Lead Electrocardiogram Results 
4.4.6. 
Prior and Concomitant Medications 
Concomitant medications include all medications taken or medical procedures performed with a 
stop date that is on or after the date of first dose of study drug. The number and percentage of 
subjects with medications at anatomic therapeutic class (ATC) Class Level 3 and Preferred 
Term levels will be reported by treatment group and overall. Prior and concomitant medications 
will be presented separately. 
The use of concomitant medications, including medications used for management of anxiety or 
pain due to the EP procedure, will be included in a by-subject data listings. 
Relevant Output 
Table 14.3.5.4 
Prior Medications (Safety Population) 
Table 14.3.5.5 
Concomitant Medications (Safety Population) 
Listing 16.2.9.4A 
Prior Medications 
Listing 16.2.9.4B 
Concomitant Medications 


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5. 
CHANGES TO PLANNED ANALYSES 
As of this date, there have been no changes between the protocol-defined statistical analyses and 
those presented in this SAP. 
 


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6. 
REFERENCES 
 
1  
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé S. 
Human Papillomavirus and Related Diseases in USA. ICO Information Centre on HPV and 
Cancer (HPV Information Centre), Summary Report 30 June 2017. 2017. 
2  
Bruni L B-RL, Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé S. 
Human Papillomavirus and Related Diseases in Europe. ICO Information Centre on HPV and 
Cancer (HPV Information Centre), Summary Report 30 June 2017. 2017. 
3  
National Cancer Institute S, Epidemiology, and End Results Program (SEER) Stat Fact Sheets: 
Vulvar Cancer. 2016. 
4  
Hartwig S, St Guily JL, Dominiak-Felden G, Alemany L, de Sanjose S. Estimation of the overall 
burden of cancers, precancerous lesions, and genital warts attributable to 9-valent HPV vaccine 
types in women and men in Europe. Infect Agent Cancer 2017,12:19. 
5  
Howlader N NA, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer 
Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD 2015. 
6  
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, and 
immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-2088. 
7  
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
8  
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and Biophysical 
Research Communications 1999,261:377-380. 
9  
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy against 
HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med 
2012,4:155ra138. 


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7. 
STATISTICAL OUTPUT 
7.1. 
List of Statistical Output to be Generated 
The lists of statistical output are provided in separate documents for statistical tables and data 
listings. 
7.2. 
Statistical Table Shells 
Statistical table shells are provided in a separate document. 
7.3. 
Data Listing Shells 
Data listing shells are provided in a separate document.