A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 Related Anal or Anal/Peri-Anal, High Grade Squamous Intraepithelial Lesion (HSIL), (AIN2, AIN3, PAIN2, PAIN3) in Individuals That Are Seronegative for Human Immunodeficiency Virus (HIV)-1/2
Phase: PHASE2
Conditions: Anal Neoplasm
Sponsor: Inovio Pharmaceuticals

Official Title: 
NCT Number: 
NCT03499795
Document Dates:
Protocol Version 3.0: 22 January 2020 
Protocol Version 2.0: 15 May 2019 
Protocol Version 1.1: 08 November 2017 
Protocol Version 1.0: 15 September 2017
A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 
Related Anal or Anal/Peri-Anal, High Grade Squamous Intraepithelial Lesion 
(HSIL), (AIN2, AIN3, PAIN2, PAIN3) in Individuals That Are Seronegative for 
Human Immunodeficiency Virus (HIV)-1/2

HPV-203 
A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 
related Anal or Anal/Peri-anal, High grade squamous intraepithelial lesion (HSIL), 
(AIN2, AIN3, PAIN2, PAIN3) in individuals that are seronegative for Human 
Immunodeficiency Virus (HIV)-1/2 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND #:  13683
Protocol Version:  1.0 
Protocol Version Date:  15Sep2017 

V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
M e di c al M o nit or A p pr o v al P a g e 
Dr u g: 
S p o n s or: 
M e di c al M o nit or: 
A p pr o v al Si g n at ur e: 
, P h . D. 
 
l n o vi o P h ar m a c e uti c al s 
V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s , I n c. 
6 6 0 W. G er m a nt o w n Pi k e , S uit e 1 1 0 
Pl y m o ut h M e eti n g, P A 1 9 4 6 2 
, M. D .. P h. D . 
 
l n o vi o P h ar m a c e uti c al s , I n c. 
D at e 
C O N FI D E N TI A L 
H P V- 2 0 3 
Cli ni c al Pr ot o c ol 
T h e i nf or m ati o n i n t hi s d o c u m e nt i s c o n si d er e d pri vil e g e d a n d c o nfi d e nti al b y l n o vi o 
P h ar m a c e uti c al s I n c. (I N O VI O) a n d m a y n ot b e di s cl o s e d t o ot h er s e x c e pt t o t h e e xt e nt 
n e c e s s ar y t o o bt ai n I n stit uti o n al R e vi e w B o ar d/ Et hi c s c o m mitt e e a p pr o v al a n d i nf or m e d 
c o n s e nt, or a s r e q uir e d b y l o c al r e g ul at or y a ut h oriti e s. P er s o n s t o w h o m t hi s i nf or m ati o n 
i s di s cl o s e d m u st b e i nf or m e d t h at t hi s i nf or m ati o n i s pri vil e g e d a n d c o nfi d e nti al a n d t h at 
it s h o ul d n ot b e f urt h er di s cl o s e d wit h o ut 
t h e writt e n 
p er mi s si o n of I N O VI O. A n y 
s u p pl e m e nt al i nf or m ati o n a d d e d t o t hi s d o c u m e nt i s al s o c o nfi d e nti al a n d pr o pri et ar y 
i nf or m ati o n of I N O VI O a n d m u st b e k e pt i n c o nfi d e n c e i n t h e s a m e m a n n er a s t h e c o nt e nt s 
of t hi s d o c u m e nt. 
Pr ot o c ol V er si o n D at e: 
1 5 S e p 2 0 1 7 
C O N FI D E N T J A L 
P a g e 2 of 8 1 
Pr ot o c ol V er si o n: 1. 0 
P P D
P P D
P P D
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P P D

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 3 of 82 
 
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 (IRB/IEC) 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 International Conference on Harmonization (ICH)/Good Clinical Practice (GCP) and 
International Organization for Standardization (ISO) guidelines, local legal and regulatory 
requirements, and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
<Insert Principal Investigator Printed Name> 
 
Date (dd/Mmm/yyyy) 
 
 
 
 
 
 
 
Site Number: _____________________________________________ 
 
 
Site Name: _______________________________________________ 
 
 

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VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 8 of 83 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 related Anal 
or Anal/Peri-anal High-Grade Squamous Intraepithelial Lesions, HSIL (AIN2, AIN3, PAIN2, 
PAIN3) in individuals that are seronegative for Human Immunodeficiency Virus (HIV)-1/2 
Protocol Number: HPV-203 
 
Trial Phase: 2a 
 
Estimated Number of Trial Centers and Countries/Regions: Approximately 5 study 
centers located in North America 
 
Formulation: VGX-3100 
 
Trial Design: Multi-center, single-arm, open-label phase 2 study 
  
Criteria for Evaluation: To provide a treatment to regress anal or anal/peri-anal HSIL and 
clear the related HPV-16 and/or HPV-18 (HPV16/18) in individuals that are seronegative for 
HIV-1/2. 
 
Research Hypothesis: VGX-3100 followed by electroporation (EP) administered to adults 
with histologically confirmed anal or anal/peri-anal HSIL1, (AIN22, AIN33, PAIN24, PAIN35) 
associated with HPV-16 and/or HPV-18 will result in a higher proportion with 
histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence of anal 
or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than historical controls.  
Dose of VGX-3100: 6 mg (1mL) 
Administration: Intramuscular injection followed by EP 
VGX-3100 Dosing Schedule: Day 0, Week 4 and Week 12 with one additional dose given 
to partial responders at Week 40 
Study Duration: 88 Weeks 
Primary Objective: Determine the efficacy of 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and virologic clearance 
of HPV-16 and/or HPV-18. 
Primary Endpoint: Proportion of subjects with no histologic evidence of anal or anal/peri-
anal HSIL6 on histology (i.e., collected via biopsy or excisional treatment)7 and no evidence 
of HPV-16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue. 
1 High-grade Squamous Intraepithelial Lesion 
2 Grade 2 Anal Intraepithelial Neoplasia 
3 Grade 3 Anal Intraepithelial Neoplasia             
4 Grade 2 Peri-anal Intraepithelial Neoplasia 
5 Grade 3 Peri-anal Intraepithelial Neoplasia 
6  No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
7 A treatment responder is defined as a subject with no histologic evidence of anal or anal/peri-anal HSIL and no evidence of 
HPV-16 or HPV-18 in anal lesion tissue and who did not receive non-study treatment of curative intent of intra-anal and/or 
peri-anal lesions. A treatment non-responder is defined as a subject with histologic evidence of anal or anal/peri-anal HSIL, 
adenocarcinoma-in-situ (AIS), anal or anal/peri-anal carcinoma or a subject with evidence of HPV-16/18 in anal lesion tissue 
or a subject who received non-study treatment of curative intent of intra-anal and/or peri-anal lesions. 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 9 of 83 
 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary Card (PDC). 
 
1b. All adverse events including SAEs, 
UADEs, and other unexpected AEs 
for the duration of the study (through 
the Week 88 visit) 
2. Determine the efficacy of three doses 
of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL 
2. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
HSIL8 on histology (e.g. biopsies or 
excisional treatment) at the Week 36 
visit 
3. Determine the efficacy of VGX-3100 as 
measured by virologic clearance of 
HPV-16 and/or HPV-18 by testing from 
lesion tissue 
3. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-189 
from intra-anal and/or peri-anal tissue 
by type specific HPV testing at the 
Week 36 visit 
4. Determine the efficacy of VGX-3100 as 
measured by virologic clearance of 
HPV-16 and/or HPV-18 by intra-anal 
tissue swab testing 
4. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-18 
from intra-anal swab by specific HPV 
testing at the Weeks 36, 64, and 88 
visits 
5. Determine the efficacy of three doses 
of VGX-3100 as measured by complete 
histopathologic regression of anal or 
anal/peri-anal HSIL to normal tissue 
5. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
Low grade squamous intraepithelial 
lesion (LSIL) or HSIL (i.e. no 
evidence of AIN2, AIN3, PAIN2, 
PAIN3) on histology (i.e. biopsies or 
excisional treatment) at the Week 36 
visit 
6. Determine the efficacy of three doses 
of VGX-3100 as measured by 
histopathologic non-progression of 
anal or anal/peri-anal HSIL  
6. Proportion of subjects with no 
progression10 of anal or anal/peri-
anal HSIL to carcinoma from 
baseline to histology (i.e. biopsies or 
excisional treatment) at the Week 36 
visit 
7. Describe the efficacy of VGX-3100 for 
partial responders, as measured by 
reduction in the number of intra-anal 
and/or peri-anal lesion(s), as applicable 
and the reduction in size of peri-anal 
lesion(s) if present, and for whom the 
disease has not progressed according 
to Investigator judgment in subjects who 
did not have anal or anal/peri-anal HSIL 
lesion resolution at Week 36 
7. Percent reduction in the number of 
intra-anal and/or peri-anal lesion(s), 
as determined by the Investigator at 
Weeks 36, 64, and 88 compared to 
baseline. For all peri-anal lesion(s), 
digital photos will be analyzed with a 
computer program to assess the 
percent reduction in the cumulative 
surface area of the peri-anal lesion(s) 
as determined by the quantitative 
analysis of standardized pre-biopsy 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 10 of 83 
photographic imaging at Weeks 36, 
64, and 88 compared to the post-
biopsy photographic image of the 
previous biopsy visit. 
8. Determine the humoral and cellular 
immune response following dose 3 and 
additional time points compared to 
baseline 
8a. Levels of serum anti-HPV-16 and 
anti-HPV-18 antibody concentrations 
at baseline and the Weeks 15, 36, 
64, and 88 visits 
 
8b. Interferon-γ ELISpot response spot 
forming units (SFU) at baseline and 
the Weeks 15, 36, 64, and 88 visits 
 
8c. Flow Cytometry response magnitude 
at baseline and Week 15 visit 
8 No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
9 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
10 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication Committee.  
 
 
 
 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 11 of 83 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of more than 3 
doses of VGX-3100 with respect to 
combined histopathologic regression of 
anal or anal/peri-anal HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
1.  Proportion of subjects with no histologic 
evidence of anal or anal/peri-anal HSIL 
on histology (i.e. collected via biopsy or 
excisional treatment) and no evidence of 
HPV-16/18 at Week 64 by testing from 
intra-anal and/or peri-anal lesion tissue 
2. Describe the efficacy of more than 3 
doses of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL 
2.   Proportion of subjects with no evidence 
of anal or anal/peri-anal HSIL on histology 
(i.e. biopsies or excisional treatment) at 
Week 64 for subjects who receive 4 
doses of VGX-3100 
3. Describe the efficacy of more than 3 
doses of VGX-3100, as measured by 
virologic clearance of HPV-16 and/or 
HPV-18 
3.   Proportion of subjects with no HPV-16/18 
at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue for subjects 
who receive 4 doses of VGX-3100 
4. Evaluate tissue immune responses to 
VGX-3100 in intra-anal and/or peri-anal 
samples 
4.   Assessment of immunologic markers (e.g. 
CD8+ and FoxP3+ infiltrating cells). 
Additional assessments may include 
Granulysin, Perforin, CD137, CD103, and 
PD-L1 in intra-anal and/or peri-anal tissue 
as sample allows 
5. Describe the clearance of HPV-16 and/or 
HPV-18 infection from non-anal anatomic 
locations 
5.  Proportion of subjects who have cleared 
HPV-16 and/or HPV-18 on specimens 
from non-anal anatomic locations as 
applicable based upon gender (i.e. 
oropharynx, cervical, vaginal, and penile 
at Week 36 visit) 
6. Evaluate the effect of Human Leukocyte 
Antigen (HLA) type on efficacy 
6.   HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of 
anal or anal/peri-anal HSIL at the Week 
36 visit 
7. Describe the association of microRNA 
(miRNA) profile, previous anoscopy, 
cytology and HPV testing results with 
Week 36 histologic regression 
7.   HRA, cytology, and HPV test results and 
miRNA profile (baseline and at the Weeks 
15 and 36) in conjunction with histologic 
regression of anal or anal/peri-anal HSIL 
at the Week 36 visit 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 12 of 83 
8. Describe patient reported outcomes 
(PRO) for subjects treated with VGX-3100 
8.   Patient reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and following 
each dose, and at Weeks 36, 64, and 88. 
There will be an additional PRO 
assessment at Week 40 if a subject 
receives a 4th dose. 
 
 

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VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 16 of 83 
Given that HPV infection persistence is a critical factor in the clinical progression of HPV-
associated anal or anal/peri-anal HSIL and also based upon the findings of the secondary 
objective of the HPV-003 CIN2/3 proof of concept study, the responder definition for the HPV-
203 primary endpoint determination requires both histological regression of anal or anal/peri-
anal HSIL and clearance of HPV-16 and/or HPV-18 [1]. 
 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic assessment 
of intra-anal tissue, utilizing HRA with biopsies. All intra-anal and/or peri-anal lesion(s) of 
adequate size (≥4mm) will be biopsied at Screening. Once the PAC confirms HSIL at 
Screening, the Week 36 and 64 biopsies will be obtained from all HSIL site(s) confirmed by 
the PAC at Screening, unless the Investigator suspects disease progression. Tissue samples 
will be analyzed for evidence of histopathologic regression. Clearance of HPV-16 and/or 
HPV-18 will be determined by type specific HPV PCR on intra-anal and/or peri-anal tissue 
performed at Screening and Weeks 36 and 64 when applicable. 
 
Intra-anal and/or peri-anal swabs will be collected at Screening, Day 0, and at Weeks 4, 15, 
28, 36, 64 and 88 as a less invasive measure for exploratory purposes to determine the 
presence of HPV-16 and/or -18 as well as other high risk HPV types. Similarly, vaginal, 
cervical (female subjects), penile (male subjects), and oropharyngeal (OP) rinse samples will 
be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess systemic virologic 
response to treatment. 
 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction in 
intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size from 
baseline (Subgroup C), the Investigator will have the option to administer a 4th dose of VGX-
3100 at Week 40 and the subject will continue on the study with HRA and biopsy at Week 64. 
Alternatively, the Investigator may choose to treat the subject with standard of care treatment 
(i.e. electrocautery, ablation, surgical excision), and the subject will continue on the study 
without further biopsy. 
 
Immunogenicity Assessment: Humoral and cell mediated immune responses to VGX-3100 
may be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, 64, and 88. Intra-anal and/or peri-anal tissue samples may 
also be analyzed for evidence of elevated immune responses at Week 36 as compared to 
baseline (Screening). 
 
Virologic Assessment: Intra-anal and/or peri-anal swabs will be obtained to characterize 
HPV infection at Screening, Day 0, and Weeks 4, 15, 28, 36, 64 and 88 by PCR™. Likewise, 
PCR-based assessment of histological samples will occur at Screening and Weeks 36 and 
64. 
 
For testing of non-anal sites, vaginal, cervical (female subjects), penile (male subjects), and 
oropharyngeal (OP) samples (all subjects) will be obtained to characterize HPV infection at 
Day 0, and at Weeks 4,15, 28, 36, 64 and 88. 
 
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, 
then unstained slides and/or the relevant paraffin blocks may be evaluated for immune 
analysis. Whenever possible, these studies may be performed on tissue sections from the 
diagnostic Screening biopsy (pre-dose) and from tissue obtained post-dose(s) (Week 36). 
 

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VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 18 of 83 
 
 
 
Study Population: 
Inclusion: 
1. Must understand, agree and be able to comply with the requirements of the protocol 
and be able to provide voluntary consent to participate and sign an Informed Consent 
Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2 within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16 and/or HPV-18 infection at Screening by 
PCR from HSIL specimen; 
5. Anal tissue specimens/slides provided to the Study Pathology Adjudication 
Committee (PAC) for diagnosis must be collected within 10 weeks of first dose of 
VGX-3100; 
6. At least one anal or anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
a. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) should 
not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology collection 
procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
a. Post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level 
>40mlU/mL; 
b. Surgically sterile due to absence of ovaries or due to bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
c. Subject agreement to avoid pregnancy for one month after last dose (Week 
12 or Week 40); 
d. Women of Child Bearing Potential (WOCBP) are willing to use a 
contraceptive method with a failure rate of less than 1% per year when used 
consistently and correctly from Screening until one month following the last 
dose of investigational product (Week 12 or Week 40). The following are 
acceptable methods: 
i. Hormonal contraception: either combined progestin-alone including 
oral contraceptive, 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. Men who would father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, for 
the duration of study participation and one month after completion of VGX-3100 
administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 19 of 83 
 
 
Exclusion: 
1. Untreated micro invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care for VAIN; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing medical 
care for VIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care for CIN; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing medical 
care for PIN; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument; 
7. Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; 
8. Inability to have completed and satisfactory high resolution anoscopic exams (HRAs) 
as defined by full visualization of the anus, entire anal canal from the 
squamocolumnar junction at the border of the distal rectum, anal transformation zone, 
distal canal, anal verge, perianus;  
9. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
Screening; 
10. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
11. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 30 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; 
12. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) or oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 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. Prior chemotherapy within 1 year; 
f. History of solid organ or bone marrow transplantation; 
13. History of previous therapeutic HPV vaccination (however, licensed prophylactic HPV 
vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
14. Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-3100 
dose; 
15. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of 
any VGX-3100 dose; 
16. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
17. 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 
the study results (e.g. chronic renal failure, angina, myocardial ischemia or 
infarctation, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 20 of 83 
 
 
18. Treatment for non-anogenital malignancy within 2 years of Screening, with the   
exception of superficial skin cancers that only require local excision; 
19. 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; 
20. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
21. 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; 
22. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
23. Prior major surgery within 4 weeks of Day 0; 
24. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent form (participating in an observational 
study is permitted); 
25. 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 on the ipsilateral side (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); 
26. Any illness or condition that in the opinion of the Investigator may affect the safety of 
the subject or evaluation of any study product; 
27. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 personnel; 
d. Study-related staff or family members of study-related staff 
 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15Sep2017 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 21 of 83 
TRIAL SCHEDULE OF EVENTS 
 
Table 3: Schedule of Events 
 
 
 
1 Subject eligibility will be reconfirmed at every visit. 
 
Study Action 
Screen  (-10 wk. to -1d) 
Day 0 
8-14 days post dose 1 Phone Call 
Week 4 (± 4 days) 
8-14 days post dose 2 Phone Call 
Week 12 (± 4 days) 
Week 15 (± 1 Week) 
Week 28 (± 1 Week)  
Week 36 (± 1 Week) 
Week 40 (± 1 Week) 
8-14 days post dose 4 Phone Call 
Week 64 (± 2 Weeks) 
Week 88 (± 2 Weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
X 
 
 
Xo 
X 
Inclusion/Exclusion criteria1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
Xb 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Screening 
safety 
(12 
lead 
ECG, 
laboratories) c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d   
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xe 
 
Xf 
 
 
Xe 
Xe 
HLA testing g  
X 
Oropharyngeal (OP) rinse 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Vaginal, cervical, and penile swab 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Intra-anal and/or peri-anal swab 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Digital 
Anal 
Rectal 
Examination 
DARE h 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
High Resolution Anoscopy (HRA) i 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Lesion photography j 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Biopsy k  
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Inject VGX-3100 +EPl   
 
X 
 
X 
 
X 
 
 
 
Xl 
 
 
 
Post treatment reaction assessment 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Distribute Participant Diary Card (PDC) 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Review PDC m 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Patient Reported Outcomes (PROs) 
(SF-36v2™) (EQ-5D-5L) n 
 
Xp 
X 
X 
X 
X 
X 
 
X 
X 
Xq 
X 
X 

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a Full Physical exam (PE) mandatory at Screening and study discharge (Week 88), 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 body mass 
index (BMI) (Bodyweight in kilograms divided by height in meters squared). Weight will be 
collected at all dosing visits. 
c Screening 12-lead Electrocardiogram (ECG), complete blood count (CBC), serum electrolytes, 
blood urea nitrogen (BUN), creatine (Cr), glucose, alanine aminotransferase (ALT), and 
Creatine Phosphokinase (CPK) performed within 30 days prior to first dose administration. 
d Negative spot urine pregnancy test is required for female subjects at Screening, prior to each 
study treatment, high-resolution anoscopy (HRA), and biopsy/surgical excision; the pregnancy 
test at Week 40 would only be needed for subjects who receive an additional dose. 
e At least 42.5 mL (5 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 36. 
g Human Leukocyte Antigen (HLA) testing will be performed once from an existing Peripheral 
Blood Mononuclear Cells (PBMC) sample. 
h Digital Anal Rectal Examinations (DARE) are to be performed once cytology has been 
collected and prior to HRA. 
i An additional visit may be scheduled to perform HRA if worsening of disease is suspected. 
Biopsies should not be performed at any visit other than at entry (Screening) and Weeks 36 and 
64 for Subgroup C unless the Investigator suspects invasive cancer. All biopsy samples and/or 
excision samples must be sent to the Pathology Adjudication Committee (PAC) for review. 
j Photography of intra-anal and/or peri-anal lesion(s) must be performed prior to and after 
biopsy, and at all HRA examinations. Photographs of intra-anal lesion(s) will be for 
documentation purposes only. Photographs of peri-anal lesion(s) will be analyzed with a 
computer program to assess the percent reduction in the cumulative surface area of the peri-
anal lesion(s) as determined by the quantitative analysis of standardized pre-biopsy 
photographic imaging at Weeks 36, 64, and 88 compared to the post-biopsy photographic 
image of the previous biopsy visit.  
k Tissue specimen and slides from all excised tissue lesion(s) that led to eligibility at study entry 
must be reviewed by the PAC and residual tissue from entry and Weeks 36 and 64 specimen(s) 
(paraffin blocks or unstained slides) should be sent to the central laboratory for immune analysis 
and Human Papillomavirus (HPV) testing.  
l Potential dosing at Week 40 is applicable for partial responders only.  
m A phone call will be used to review the Participant Diary Card (PDC) with subject within 8-14 
days following doses 1 and 2. The patient will be expected to bring the PDC to the next visit for 
review. Subjects who receive an additional 4th dose will have a phone call 8-14 days post dose 
4 where the PDC will be reviewed.  
n Patient-reported outcome (PRO) measures (SF-36v2™ and the EQ-5D-5L), plus two 
additional "global" questions will be assessed as described in Section 6.13. 
o This socio-behavioral assessment will only apply to those subjects in Subgroup C who receive 
a 4th dose of investigational product. 

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p PROs must be administered prior to first dose of study drug.  
q PROs will only be for subjects who received a 4th dose of study drug. 
 

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1.0 
INTRODUCTION 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized 
primarily in the ano-genital area and aero-digestive tract, in both men and women. 
Human Papillomavirus 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). In the United States (US), approximately 14 million new genital HPV infections 
occur annually, and approximately half of these infections are with a high-risk HPV type 
(HR-HPV) and thus can cause cancer [2]. In U.S. adults through age 59 years, about 
25% of men and 20% of women have genital HR-HPV infection [3]. Human 
Papillomavirus causes more cancers than any other virus. In U.S. archival tissues of 
cancers diagnosed from 1993 to 2005, HPV Deoxyribonucleic Acid (DNA) was detected 
in 68.8% of vulvar, 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of 
oropharyngeal (OP), 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) [4]. An average of over 
30,000 cases per year of HPV-attributable cancer were diagnosed during the period 
2008 through 2012 in the U.S. [5]. Human Papillomavirus-16 and HPV-18 are the most 
significant among high-risk types since they are responsible for most HPV-caused 
cancers [4].  
With regard to anal cancer, about 95% of cases are caused by HPV, and most of those 
cases are caused by HPV-16 [6, 7]; with some by HPV-18 and perhaps other HPV 
genotypes [2]. An estimated 8,200 new cases of anal cancer in the US are diagnosed 
each year (for year 2017), with an estimated 1,100 deaths annually due to this cancer 
[8]. In Canada, the latest available data is for year 2013, during which 580 new cases of 
anal cancer were diagnosed and 144 persons died due to anal cancer [9]. 
The precursor lesion to HPV-associated anal cancer historically was known as anal 
high-grade dysplasia or intraepithelial neoplasia. In 2012, the Lower Anogenital 
Squamous Terminology (LAST) Standardization Project for HPV-associated lesions 
applied the term HSIL to encompass high grade dysplasia [10]. Among HPV-associated 
anal HSIL cases in the US, about 55% to 80% are associated with HPV-16/18, and 
worldwide about 80% of cases are associated with HPV-16/18 [7, 11, 12]. 
Left untreated, anal HSIL may progress to cancer. Spontaneous regression of these 
lesions may occur, but the available data indicate that such regression is in the minority 
of cases. For example, published results of a small observational study of anal HSIL in 
men who have sex with men (MSM) in Australia found spontaneous regression occurred 
in 29% of those HIV-negative after more than one year of follow-up time, with an even 
lower regression rate in those who were HIV-positive. That study also found that the 
majority (71%) of patients who regressed only did so to anal low-grade SIL (Low grade 
squamous intraepithelial lesion [LSIL]), with the remainder to normal tissue [13]. In an 
ongoing larger observational study of gay and bisexual men – the Study of the 
Prevention of Anal Cancer (SPANC) [14] -- also comprised of patients HIV-negative and 
HIV-positive (though with medically well-controlled CD4 cell counts), preliminary 
published data show that 55% of patients with anal HSIL, regardless of HIV status, had 
their HSIL persist to at least 12 months and HPV-16 was significantly associated with 
persistence as compared to other HPV genotypes (Relative Risk of 1.5) [15].  
 

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Spontaneous regression data from that study are not yet published, but preliminary data 
show spontaneous regression of only about 20% by one year of follow-up. Further, many 
of those patients who regressed later recurred to HSIL, suggesting that HSIL in some 
cases may be merely regressing to a level below the detection limit but is still present 
[16]. Other published data from a sub-study of that larger study indicate that HPV-16 E6-
specific T-cell responses may be associated with recent anal HSIL regression (Pexact = 
0.065) [17]. That finding provides further plausibility, in addition to other data 
summarized later in this protocol, that VGX-3100 plus electroporation treatment could 
cause anal HSIL regression. 
Anal HPV infection spontaneous clearance in non-immunocompromised adults can 
occur, but such data are generally unavailable for persons who have anal HSIL. 
Nevertheless, high-risk HPV (HR-HPV) clearance by one year ranges from 56% to 78%, 
varying by gender and sexual preference etc., as found in large, prospective studies [18-
20] with some wider variation in clearance rates for HPV-16 and HPV-18 specifically in 
those studies. 
Collectively, the aforementioned anal HSIL regression and HPV clearance data 
comprise in part the historical control data that the results of the present trial will be 
compared to. 
1.1.1 
VGX-3100 
VGX-3100 contains plasmids that target 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 (IP) designed as a non-surgical 
treatment of HPV-16/18-related anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, and 
PAIN3) via an immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was Water for Injection (WFI) with 1% w/w poly-L-
glutamate (WFI/LGS) that required frozen storage. This frozen formulation has been 
administered to more than 250 subjects in Phase 1 and 2 clinical trials. A buffered 
formulation of VGX-3100 was developed using a saline sodium citrate (SSC) solution, 
which is stored non-frozen (5°C). This non-frozen formulation of VGX-3100 was 
administered to 117 subjects in a Phase 1 clinical trial, HPV-101 in which subjects were 
randomized 1:1 to receive the non-frozen or frozen formulation of VGX-3100. In study 
HPV-101, healthy adults received three 6 mg IM doses of VGX-3100 in the frozen or 
non-frozen formulations followed by EP with the CELLECTRA™ 5Pdevice. The non-
frozen formulation was found to be non-inferior to the frozen formulation based upon a 2-
fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the plasmids 
per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ enzyme-linked immunospot (ELIspot) assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, 
placebo-controlled Phase 2b study of VGX-3100 (frozen formulation) followed by EP in 
the treatment of high grade cervical dysplasia, cervical HSIL associated with HPV-16/18 
[1]. The Phase 2b study, HPV-003, enrolled 169 subjects with high grade cervical 
dysplasia from seven countries and one US Territory (Australia, Canada, Estonia, 
Republic of Georgia, India, South Africa, US and Puerto Rico). Subjects were 
randomized in a 3:1 ratio to treatment with VGX-3100 or placebo, respectively. All 

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subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to 
repeat cervical biopsy or Loop Electrical Excision Procedure (LEEP) of the cervix at 
Week 36 to assess efficacy defined as regression of high grade Cervical Intraepithelial 
Neoplasia (CIN) by histopathology. The primary endpoint was histopathologic regression 
of cervical lesions (CIN2 or CIN3) to Grade 1 Cervical Intraepithelial Neoplasia (CIN1) or 
less at the Week 36 visit. A secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less. The 
proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol (PP) and modified Intent 
to Treat (mITT) analyses. Robust T-cell activity was detected in VGX-3100 recipients 
compared to placebo recipients. VGX-3100 was generally safe and well tolerated when 
administered intramuscularly with electroporation. 
1.1.2 
ELECTROPORATION 
CELLECTRA® 2000 &  CELLECTRA™ 5PSP are both electroporation (EP) devices 
developed by INOVIO. Electroporation with CELLECTRA™5PSP is a physical method of 
tissue transfection whereby the generation of short, controlled electrical pulses creates a 
localized electrical field at the injection site which increases cell membrane permeability 
and improves the transfection of DNA and subsequent immunogenicity [21, 22]. EP is 
believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced immunogenicity by 10 to 100 fold [23, 24]. 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 [21]. The CELLECTRA™ device developed by INOVIO is used for 
investigational purposes to administer plasmid-based DNA, in both prophylactic and 
therapeutic settings. Following successful proof-of-concept studies in animals, INOVIO 
has optimized both pulse pattern and voltage to increase transfection efficiency, and has 
demonstrated that the device helps to elicit favorable immunogenicity in several species 
(e.g., mice, pigs, and rhesus macaques) [22, 23]. 
A next generation device, CELLECTRA™ 5PSP, was created to address ergonomic 
functionality and automate the delivery of VGX-3100 and EP. The technology differences 
between the CELLECTRA® 2000 and CELLECTRA™ 5PSP design do not affect the 
intended mechanism of EP on the activity of VGX-3100 and will not present any new 
risks. The device design change does not affect the indications for use, operating 
principle, energy type, or sterilization specifications. The CELLECTRA™ 5PSP has been 
approved for investigational use in the U.S. with VGX-3100 and is being used in a Phase 
3 clinical study HPV-301, titled "A Prospective, Randomized, Double-blind, Placebo-
Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly (IM) followed by 
Electroporation with CELLECTRA™ 5PSP for the Treatment of HPV-16/18 related HSIL 
of the Cervix". Together, VGX-3100 and the CELLECTRA™ device represent an 
integrated product designed as a non-surgical treatment for HPV-16/18-related cervical 
HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Inovio Pharmaceuticals Inc. device experience demonstrates that delivery of its 
proprietary electroporation pulses into muscle immediately following injection of DNA 
plasmids (including VGX-3100) is well-tolerated in humans and no significant safety 
issues have been identified [1, 22, 24]. For further information concerning the 
CELLECTRA™ 5PSP device please refer to the User Manual and the Investigator's 
Brochure. 

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1.1.3 
DOSE RATIONALE 
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 the 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. 
This dose-trend was consistent with prior expectation, a feature of the finding that 
suggests it is a true effect rather than random variation. Adverse events (AEs) from 
previous human studies with VGX-3100 and closely related DNA plasmid products have 
been limited to injection site pain from the injection and electroporation procedure, which 
were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in HPV-003, 
Phase 2b study. The results obtained in the phase HPV-003 suggest that the 6 mg dose 
was efficacious with an acceptable safety profile, therefore the 6 mg dose will also be 
evaluated in this Phase 2 trial [1]. 
1.2 
POTENTIAL BENEFITS 
Currently accepted surgical treatments are associated with a high recurrence rate, 
>50%. The current surgical approaches also have risks inherent with any surgical 
procedure including anesthesia, post-operative bleeding, infection, or damage to 
surrounding structures such as the anus. This study has been designed to provide non-
surgical treatment with an aim of regression of the anal or anal/peri-anal HSIL and thus 
avoiding the need for surgical excision, infrared coagulation, electrocautery and laser 
therapy. In the absence of complete resolution of intra-anal and/or peri-anal lesions, 
there would still be potential benefit from a partial response, which would reduce or 
minimize the need for excisional or ablative treatment modalities. 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. Consequently, there is the potential to reduce the risk 
of recurrence of anal or anal/peri-anal HSIL. 
1.3 
POTENTIAL RISKS 
Risks associated with VGX-3100 for the treatment of anal or anal/peri-anal HSIL are 
injection site reactions related to the IM injection and/or electroporation. Based on the 
phase 1 and 2 clinical experience with VGX-3100 with healthy volunteers and in women 
with cervical HSIL, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at 
most. 
A potential risk is the delay of surgical intervention of the high grade anal dysplasia and 
possible missed diagnosis of an occult early invasive cancer for the VGX-3100 non-
responders, who do not spontaneously regress. Although professional guidelines 
typically advocate excisional therapy for adults with HSIL, scientific data indicates that 
the rate of progression from pre-invasive to invasive cervical disease is slow, typically 
thought to take several years [10]. The risk of a missed diagnosis of an occult early 
invasive cancer exists for all current treatment modalities including surgical and ablative 
therapies. To mitigate these potential risks the study design includes numerous 
safeguards to detect disease progression or the presence of an undiagnosed occult 

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early invasive cancer. These include, careful selection of immunocompetent patients, 
thorough screening and baseline evaluation, frequent High-resolution anoscopy (HRA) 
and high-risk HPV testing throughout the trial. Investigators will be comprised of 
experienced physicians, who will have the discretion to obtain biopsies at any point if 
disease progression is suspected. 
An independent Data and Safety Monitoring Board (DSMB) will also advise the Sponsor 
if it appears that the frequency of regression is unacceptably low. These measures 
should minimize the risk of progression of the HSIL and the risk of harboring an 
undiagnosed occult early invasive cancer.  
In the HPV-003 study of women with cervical HSIL, the percentage of subjects with 
micro-invasive cancer found in larger surgical excision samples in subjects who had no 
evidence of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is 
consistent with and even lower than the 6.7% that has been reported under standard of 
care settings [18]. 
For further information concerning the risks associated with VGX-3100 and the 
CELLECTRA™5PSP device please refer to the Investigator's Brochure. 
2.0 
PURPOSE AND HYPOTHESIS 
2.1 
PURPOSE 
To provide a treatment to potentially regress and clear HPV-16/18 related anal or 
anal/peri-anal HSIL in individuals that are seronegative for HIV-1/2. 
2.2 
HYPOTHESIS 
VGX-3100 followed by electroporation (EP) administered to adults with histologically 
confirmed anal or anal/peri-anal high-grade squamous intraepithelial lesions, HSIL, 
(AIN2, AIN3, PAIN2, PAIN3) associated with HPV-16/18 will result in a higher proportion 
with histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence 
of anal or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than 
historical controls. 
3.0 
TRIAL DESIGN AND ENDPOINTS 
HPV -203 is a Phase 2, 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 
in adult men and women who are HIV negative with histologically confirmed anal or 
anal/peri-anal HSIL associated with HPV-16 and/or 18. Approximately 24 subjects will 
receive at least 3 doses of VGX-3100. Each dose of VGX-3100 will be administered in a 
1 mL volume IM followed immediately by EP. As shown in Figure 1, study subjects will 
receive at least 3 doses of VGX-3100 depending upon their disposition with regard to 
histologic and lesion area changes during the trial. The first dose will be administered on 
Day 0, the second at Week 4, and the third at Week 12. Partial response to VGX-3100 
may still be of medical importance by being able to limit the extent of surgery necessary. 
For partial responders at Week 36, a fourth dose may be administered at Week 40. All 
subjects are scheduled to be followed to Week 88.  
To be eligible for the study, subjects must consent to participate and agree to the 
collection of anal lesion tissue samples for anal cytology and genotyping, a Digital Anal 
Rectal Examination (DARE), blood samples for immunologic and Human Leukocyte 

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Antigen (HLA) assessments, HRA and HRA guided biopsies. All intra-anal and/or peri-
anal lesion(s) of adequate size (≥ 4 mm) will be biopsied at Screening. 
Biopsy slides 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 anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the 
biopsy sample(s). Once the PAC confirms HSIL at Screening, the Week 36 and 64 
biopsies will be obtained from all HSIL site(s) confirmed by the PAC at Screening, unless 
the Investigator suspects disease progression. Subjects must also have intra-anal and/or 
peri-anal lesion tissue 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 administered and will include the Short Form Health Survey 
version 2 (SF-36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional 
PRO questions assessing quality of life after surgery or biopsy. 
3.1 
PRIMARY OBJECTIVE(S) 
Determine the efficacy of 3 doses of VGX-3100 with respect to combined histopathologic 
regression of anal or anal/peri-anal HSIL and virologic clearance of HPV-16/18 
3.2 
PRIMARY ENDPOINT(S) 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal HSIL on 
histology (i.e., collected via biopsy or excisional treatment) and no evidence of HPV-
16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue 
3.3 
SECONDARY OBJECTIVE(S) 
 
Evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP 
 
Determine the efficacy of three doses of VGX-3100 as measured by histologic 
regression of anal or anal/peri-anal HSIL 
 
Determine the efficacy of VGX-3100 as measured by virologic clearance of 
HPV-16/18 by testing from lesion tissue 
 
Determine the efficacy of VGX-3100 as measured by virologic clearance of 
HPV-16/18 by intra-anal tissue swab testing 
 
Determine the efficacy of three doses of VGX-3100 as measured by complete 
histopathologic regression of anal or anal/peri-anal HSIL to normal tissue 
 
Determine the efficacy of three doses of VGX-3100 as measured by 
histopathologic non-progression of anal or anal/peri-anal HSIL 
 
Describe the efficacy of VGX-3100 for partial responders, as measured by 
reduction in the number of intra-anal and/or peri-anal lesion(s), as applicable and 
the reduction in the size of peri-anal lesion(s), if present, and for whom the 
disease has not progressed according to Investigator judgment in subjects who 
did not have anal or anal/peri-anal HSIL lesion resolution at Week 36 
 
Determine the humoral and cellular immune response following administration of 
VGX-3100 at post dose 3, and after additional dosing compared to baseline 

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3.4 
ASSOCIATED SECONDARY ENDPOINT(S) 
 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary Card (PDC) 
 
All AEs including Serious Adverse Events (SAES), unanticipated (serious) 
adverse device effect (UADE), and other unexpected AEs for the duration of the 
study (through the Week 88 visit) 
 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (e.g. biopsies or excisional treatment) at the Week 36 visit 
 
Proportion of subjects with no evidence of HPV-16/18 from intra-anal and/or 
peri-anal tissue by type specific HPV testing at the Week 36 visit 
 
Proportion of subjects with no evidence of HPV-16/18 from intra-anal swab by 
specific HPV testing at the Weeks 36, 64, and 88 visits 
 
Proportion of subjects with no evidence of anal or anal/peri-anal LSIL or HSIL 
(i.e. no evidence of AIN2, AIN3, PAIN2, and PAIN3) on histology (i.e. biopsies or 
excisional treatment) at the Week 36 
 
Proportion of subjects with no progression of anal or anal/peri-anal HSIL to 
carcinoma from baseline on histology (i.e. biopsies or excisional treatment) at the 
Week 36 visit 
 
Percent reduction in the number of intra-anal and/or peri-anal lesion(s) and the 
size of peri-anal lesion(s) if present, as determined by the Investigator at Weeks 
36, 64, and 88 compared to baseline. For all peri-anal lesion(s), digital photos will 
be analyzed with a computer program to assess the percent reduction in the 
cumulative surface area of the peri-anal lesion(s) as determined by the 
quantitative analysis of standardized pre-biopsy photographic imaging at Weeks 
36, 64, and 88 compared to the post-biopsy photographic imaging of the previous 
biopsy visit 
 
Levels of serum anti-HPV-16 and anti-HPV-18 antibody (Ab) concentrations at 
baseline and the Weeks 15, 36, 64, 88 visits 
 
Interferon- γ ELISpot response magnitudes at baseline, and the Weeks 15, 36, 
64, and 88 visits 
 
Flow Cytometry response magnitudes at baseline and Week 15 visits 
3.5 
EXPLORATORY OBJECTIVE(S) 
 
Describe the efficacy of more than 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and 
virologic clearance of HPV-16/18 
 
Describe the efficacy of more than 3 doses of VGX-3100, as measured by 
histologic regression of anal or anal/peri-anal HSIL 
 
Describe the efficacy of more than 3 doses of VGX-3100, as measured by 
virologic clearance of HPV-16/18 
 
Evaluate tissue immune responses to VGX-3100 in intra-anal and/or peri-anal 
samples 
 
Describe the clearance of HPV-16/18 infection from non-anal anatomic locations 

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 
Evaluate the effect of HLA type on efficacy 
 
Describe the association of microRNA (miRNA) profile, previous anoscopy, 
cytology and HPV testing results with Week 36 histologic regression 
 
Describe PRO for subjects treated with VGX-3100 
3.6 
ASSOCIATED EXPLORATORY ENDPOINT(S) 
 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal 
HSIL on histology (i.e. collected via biopsy or excisional treatment) and no 
evidence of HPV-16/18 at Week 64 by testing from intra-anal and/or peri-anal 
lesion tissue 
 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (i.e. biopsies or excisional treatment) at Week 64 for subjects who 
receive 4 doses of VGX-3100 
 
Proportion of subjects with no HPV-16/18 at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue for subjects who receive 4 doses of VGX-3100 
 
Assessment of immunologic markers (e.g. CD8+ and FoxP3+ infiltrating cells). 
Additional assessments may include Granulysin, Perforin, CD137, CD103 and 
PD-L1 in intra-anal and/or peri-anal tissue as sample allows. 
 
Proportion of subjects who have cleared HPV-16/18 on specimens from non-
anal anatomic locations as applicable based upon gender (i.e. oropharynx, 
cervical, vaginal, and penile at Week 36 visit) 
 
HLA (per-locus and per-allele basis) in conjunction with histologic regression of 
anal or anal/peri-anal HSIL at Week 36 visit 
 
HRA, cytology, and HPV test results and miRNA profile (baseline and at Weeks 
15, 28, and 36) in conjunction with histologic regression of anal or anal/peri-anal 
HSIL at the Week 36 visit 
 
Patient reported outcome endpoints will be obtained prior to first dose (Day 0), on 
the day of and following each dose, and at Weeks 36, 64, and 88. There will be 
an additional PRO assessment at Week 40 if a subject receives a 4th dose. 
3.7 
EFFICACY ASSESSMENT 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesions of 
adequate size (≥4mm). Visible lesions observed during HRA should be large enough to 
biopsy, but the biopsy (typically 4mm) should not remove the entire lesion in order to 
allow for continued lesion measurement while on the study.  
Given that HPV infection persistence is a critical factor in the clinical progression of 
HPV-associated anal or anal/peri-anal HSIL and also based upon the findings of the 
secondary objective of the HPV-003 CIN2/3 proof of concept study, the responder 
definition for the HPV-203 primary endpoint determination requires both histological 
regression of anal or anal/peri-anal HSIL and clearance of HPV-16 and HPV-18 [1]. 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic 
assessment of intra-anal and/or peri-anal tissue obtained from biopsies. All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥4mm) will be biopsied at Screening. Once 
the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be obtained from 

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all HSIL site(s) confirmed by the PAC at Screening, unless the Investigator suspects 
disease progression. Tissue will be analyzed for evidence of histopathologic regression. 
Clearance of HPV-16/18 will be determined by type specific HPV polymerase chain 
reaction (PCR) on intra-anal and/or peri-anal tissue performed at Screening and Weeks 
36 and 64 when applicable. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0 (prior to dosing) 
and Weeks 4, 15, 28, 36, 64 and 88 as a less invasive measure for exploratory purposes 
to determine the presence of HPV-16 and/or -18 as well as other high risk HPV types. 
Similarly, vaginal, cervical (female subjects), penile (male subjects) and OP rinse 
samples (all subjects) will be obtained at Day 0 (prior to dosing), and at Weeks 4, 15, 28, 
36, 64, and 88 to assess systemic virologic response to treatment. 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction 
in intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size 
from baseline (Subgroup C), the Investigator will have the option to administer a 4th 
dose of VGX-3100 at Week 40 and the subject will continue on the study with HRA and 
biopsy at Week 64, i.e. the second efficacy checkpoint. Alternatively, the Investigator 
may choose to treat the subject with standard of care treatment (i.e. electrocautery, 
ablation, surgical excision), and the subject will continue on the study without further 
biopsy unless it is part of the standard of care. All tissue samples obtained from biopsies 
or removed per standard of care will be sent to the PAC for review. 
3.8 
SAFETY ASSESSMENT 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the 
PDC. 
2) All AEs including SAEs, UADEs, and other unexpected AEs for the duration of the 
study. 
All subjects will be followed for 88 weeks. 
Data Safety & Monitoring Board (DSMB): An independent 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, PI for the trial, and the DSMB. 
 
If any SAE (or potentially life-threatening AEs) 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 AEs, 
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. 

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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, 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. 
3.9 
IMMUNOGENICITY ASSESSMENT 
Humoral and cell mediated immune responses in response to VGX-3100 treatment may 
be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, and 88. Intra-anal and/or peri-anal tissue samples may 
also be analyzed for evidence of elevated immune responses at Week 36 as compared 
to baseline (Screening). 
4.0 
TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
1. Must understand, agree and be able to comply with the requirements of the 
protocol and be able to provide voluntary consent to participate and sign an 
Informed Consent Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2 within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by PCR from 
HSIL specimen; 
5. Anal tissue specimen/slides provided to the Study PAC for diagnosis must be 
collected within 10 weeks of first dose of VGX-3100; 
6. At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
i. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) 
should not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology 
collection procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
i. Post-menopausal as defined by spontaneous amenorrhea for more than 
12 months or spontaneous amenorrhea for 6-12 months with follicle-
stimulating hormone (FSH) level >40mlU/mL; 
ii. Surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
iii. Subject agreement to avoid pregnancy one month after last dose of IP 
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iv. Women of Childbearing 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 one month following 
the last dose of IP (Week 12 or Week 40). The following are acceptable 
methods: 
1. 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); 
2. Abstinence from penile-vaginal intercourse when this is the 
subject's preferred and usual lifestyle; 
3. Intrauterine device or intrauterine system; 
4. 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. Men who could father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, 
for the duration of study participation and one month after completion of VGX-
3100 administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 
4.2 
EXCLUSION CRITERIA 
1. Untreated micro invasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care for VAIN; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing 
medical care for VIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not 
undergoing medical care for CIN; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing 
medical care for PIN; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy 
instrument; 
7. Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; 
8. Inability to have complete and satisfactory high resolution anoscopic exams 
(HRAs) as defined by full visualization of the anus, entire anal canal from the 
squamocolumnar junction at the border of the distal rectum, anal transformation 
zone, distal canal, anal verge, perianus; 
9. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
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10. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
11. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 30 days prior 
to Day 0 or less than Grade 1 but deemed clinically significant by the 
Investigator; 
12. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or 
clinically diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) of oral or parenteral glucocorticoids at a dose of 
≥20 mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 
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 Tumor Necrosis Factor 
(TNF)-α inhibitors (e.g. infliximab, adalmumab or etanercept); 
e. Prior chemotherapy within 1 year; 
f. History of solid organ or bone marrow transplantation; 
13. History of previous therapeutic HPV vaccination (however, licensed prophylactic 
HPV vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
14. Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-
3100 dose; 
15. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 
weeks of any VGX-3100 dose; 
16. Significant acute or chronic medical illness that could be negatively impacted by 
the electroporation treated as deemed by the Investigator; 
17. 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 (e.g. chronic renal failure, angina, myocardial ischemia or 
infarction, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 
18. Treatment for non-anogenital malignancy within 2 years of Screening, with the 
exception of superficial skin cancers that only require local excision; 
19. Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of a 
study dose;  
20. History of seizures unless seizure free to 5 years with the use of one or fewer 
antiepileptic agents; 
21. 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; 

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22. Resting heart rate <50 beats per minute (bpm) (unless attributable to athletic 
conditioning) or >100 bpm at Screening or Day 0; 
23. Prior major surgery within 4 weeks of Day 0; 
24. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing the ICF (participation in an observational study is 
permitted); 
25. 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-defibrilator or pacemaker on the ipsilateral side (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); 
26. 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; 
27. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 (involuntary 
incarcerated) for treatment of either a psychiatric or physical (i.e. 
infectious disease) illness; 
c. Active military service personnel; 
d. Study-related staff or family members of study-related staff 
4.3 
DISCONTINUATION/WITHDRAWAL OF TRIAL SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION FROM THE STUDY 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from further treatment with VGX-3100. Subjects will not receive further 
doses of VGX-3100 followed by 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 VGX-3100/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
4.3.2 
CRITERIA FOR WITHDRAWAL FROM STUDY 
Subjects who become ineligible to continue on the study based on no longer meeting the 
inclusion criteria should be discontinued from study treatment and managed per routine 
standard of care but should continue on the study without further biopsy.  
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 

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should also counsel the subject on the importance of maintaining the assigned visit 
schedule for follow-up and treatment of anal or anal/peri-anal HSIL, 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 the subject 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 they 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 3). At 
a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 88). A subject will be considered 
to have completed the study when he/she completes all scheduled study treatments and 
follow-up visits. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or trial coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the trial or 
is withdrawn from the trial prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation. 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. 
4.3.4 
REASONS 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 of a subject, (including manner of death if known) 
 
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 
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Investigator must consult the Medical Monitor before withdrawing a subject from 
participation in the study. 

Protocol Deviation: 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.

Other: The subject was terminated for a reason other than those listed above,
such as the termination of the study by the Sponsor.
If more than 10% of subjects who receive study treatment and discontinue prior to Week 
36, primary endpoint procedures, then supplementation of study subjects will be 
considered. 
5.0 
TRIAL TREATMENT 
5.1 
INVESTIGATIONAL BIOLOGIC PRODUCT  
The IP to be used in this trial is described in Table 4. The IP will be presented in a clear 
glass cartridge and injected intramuscularly. 
Table 4: Investigational Biologic Product 
5.2 
CELLECTRA™ 5PSP DEVICE DESCRIPTION: 
VGX-3100 will be delivered using the CELLECTRA™5PSP device. The device 
consists of five (5) main components (see Figure 3).  

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Figure 3: CELLECTRA™5PSP Base Station with Handset 
 
 
 
Base Station 
The base station communicates instructions, alerts, and error messages to the user through a 
touch screen graphical user interface (GUI). It also accepts data inputs from the user, e.g., 
patient identification code, height, and weight; it communicates with the handset; provides 
energy access for the system through connection with standard wall electrical power supply 
sources (100-220V, ~0.5Amp, 50-60Hz); and serves as a docking and recharging station for the 
handset.   
Handset 
The handset facilitates delivery of the needles for injection and electroporation into the muscle 
tissue and executes the treatment sequence (drug injection, impedance check, and 
electroporation pulses). It has a display screen and speakers for user feedback and an 
embedded processor for running the system software that controls and measures all of the 
elements of the handset. The handset is powered by a custom, rechargeable battery pack that 
has its own safety circuit and is compliant to International Ethics Committee (IEC) 62133 and UL 
2054. The handset is designed with three independent fail-safes to minimize the risk of electrical 
shock, short, or fire. 
Array 
The array is a single-use, sterile, disposable component constructed of commonly-used medical 
plastics and metals, with 5 fixed, stainless-steel electrodes (needles) and 1 IM injection needle. 
The needles are covered by a plastic shroud that retracts as the needles are inserted into the 
patient, then returns to the starting position as the needles are removed and locks out to prevent 
accidental needle sticks. The opposite end of the array accepts the drug cartridge, which is 
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(indicated by an audible 'click'). When properly inserted, the septum is punctured and the 
cartridge cannot be removed. The 5PSP Array features no software. 
The base station and handset with the 5PSP Array are illustrated in  
Figure 3. 
5.3 
TREATMENT REGIMEN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the 
HPV-003 study, therefore all eligible subjects who consent to participate in the HPV-203 
study will receive the same three 6 mg doses of VGX-3100 administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment will 
be administered on Day 0, the second at Week 4, and the third at Week 12.  A fourth 
dose may be administered at Week 40. 
The first study treatment will be given as soon as possible following confirmation of anal 
or anal/peri-anal HSIL diagnosis and HPV-16/18 status but no more than 10 weeks 
following collection of the subject's biopsy specimen used for diagnosis by the PAC 
during Screening, concurrent with the positive testing for HPV-16/18. 
5.4 
PACKAGING AND HANDLING 
Each cartridge will be labeled with a single-panel label and then individually packaged 
within a pouch that will contain an additional, single-panel label with tear-off. The VGX-
3100 label will include, at minimum, the following information in Table 5. 
 
Table 5: Example of Packaging and Label Information 
Cartridges 
(primary container) 
Pouches 
(secondary packaging) 
 
 
 
 
LABEL 
 
VGX-3100 
Insert cap end 
Sponsor name 
IM administration 
Investigational Use Only 
LABEL BODY 
Study ID 
VGX-3100 
Single-use cartridge containing 1 mL 
IM administration via CELLECTRA™ 5PSP 
Store at 2-8°C, expiration date 
Caution Statement 
Sponsor name and address 
LABEL TEAR OFF 
Study ID 
VGX-3100 
Patient ID: _________ 
Date: (DD-MMM-YYYY): __________ 
 
Must be used by (time): _________ 
 
 
 

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See Figure 4 below for example of CELLECTRA™ 5PSP device component labels. 
 
Figure 4: Examples of Device Labels (Base, Handset, Array, Outer Box) 
 
Base Station Label 
 
Handset Label 
 
 

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5PSP Array Label 
 
 
Outer Box Packaging Label 
 
 
 
 
 
 
 
 
 
5.5 
HANDLING AND STORAGE OF IP AND DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure 
location according to the instructions in the User Manual. The CELLECTRA™ 5PSP 
device and its components must be stored between the temperature ranges 55.4°F-
91.4°F and relative humidity ranges of 30-70%. The Sponsor should be notified of any 
deviations from this recommended storage condition. 
Unless otherwise specified, IP will be shipped in a refrigerated condition with a 
temperature monitoring device. If the temperature monitoring device records 
temperatures outside the pre-specified range for any product, the Sponsor, or its 
designee should be contacted immediately.  
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 
°C (36-46 °F) storage, in a secure area, according to local regulations. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. The Sponsor should be notified of any deviations from 
this recommended storage condition. Inovio Pharmaceuticals Inc. will be responsible for 
assuring the quality of the IP is adequate for the duration of the trial. For the specific 

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temperature guidelines for storing, please refer to the CELLECTRA™ 5PSP User 
Manual. 
5.6 
PREPARATION AND DISPENSING 
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. 
When a subject is eligible, remove the pouch from the refrigerator and allow to reach 
room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. 
The pouch must not be discarded until: 
1. Administration is completed and 
2. All pertinent information from the pouch label has been documented in source. 
The product must be used within 4 hours of removal from the refrigerator. If VGX-3100 is 
not used within this timeframe it must be discarded after reconciliation. 
5.7 
USE OF CELLECTRA™5PSP DEVICE 
The instructions for use of the CELLECTRA™ 5PSP are located in the CELLECTRA™ 
5PSP User Manual. Users of the CELLECTRA™ 5PSP device must successfully 
complete training before using the device. Training will include review of the entire 
device user manual as well as hands-on training. After training on the proper use of the 
CELLECTRA™ 5PSP device, the intended users at each site will be required to 
demonstrate their competency in its use to INOVIO personnel or its designee. An 
instructional video has been prepared for review by site personnel on an as needed 
basis. Refer to the User Manual for further instruction. 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 
DRUG AND DEVICE ACCOUNTABILITY 
5.8.1 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of IP 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; 
 
Date and initials of person responsible for each IP 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; 

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 
Amount destroyed at study site, if applicable 
5.8.2 
CELLECTRA™ 5PSP DEVICE ACCOUNTABILITY 
The site is responsible for maintaining the device. The device must have full traceability 
from receipt of the products through the subject use, and the return of the device. The 
site must document acknowledgement of receipt and then notify INOVIO upon receipt of 
the device. This includes the content shipped and condition of the items upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 5PSP Base Station & Handset serial number, 5PSP Array lot 
number and the study drug lot number. The used Array attachment must be disposed of 
in accordance with institutional policy regarding disposal of sharp needles/instruments. 
5.9 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT AND CELLECTRA™ 5PSP 
DEVICE  
5.9.1 
RETURN OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at the site 
per the institutions policy or returned to INOVIO or its designee, if the site cannot destroy 
the unused IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps 
container at site. Do not attempt to remove the cartridge from the array once it has been 
used.  
It is the Investigator's responsibility to arrange for the 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. 
The unused IP can only be destroyed after being inspected and reconciled by the 
responsible INOVIO personal or designated Study Monitor. 
If IP is returned to INOVIO, or its designee, it must be accompanied by the appropriate 
documentation. Returned supplies should be in the original containers. Empty containers 
should not be returned to INOVIO. The return of unused IP(s) should be arranged with 
the responsible INOVIO personnel and/or Clinical Monitor. 
5.9.2 
RETURN OF CELLECTRA™ 5PSP DEVICE  
Upon completion or termination of the study, all investigational devices and unused 
components (Base, Station, Handset, and 5PSP Arrays) must be returned to INOVIO. 
All device components returned to INOVIO must be accompanied by the appropriate 
return documentation. Returned supplies should be in the original containers. The return 
of all device components identified above should be arranged by the responsible Study 
Monitor. 
If any component is to be destroyed on site, it is the Investigator's responsibility to 
ensure that arrangements have been made for the disposal. 
 
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 
Ensure that proper procedures for disposal have been established and followed 
according to applicable local regulations, guidelines and institutional procedures, 
 
Appropriate records of the disposal have been documented. 
6.0 
TRIAL PROCEDURES AND SCHEDULE 
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 3). 
A subject will be required to provide informed consent for the 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. Immediate safety concerns will be 
dealt with as deemed necessary by the Investigator. Adherence to the study design 
requirements, as outlined in the Schedule of Events (Table 3) are essential and required 
for study conduct. Subject eligibility should be reconfirmed at every study visit. 
6.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any trial related procedures being 
performed. The informed consent documentation must be in accordance with applicable 
regulations and GCP. Qualified trial personnel will meet with prospective trial subjects, 
explain the trial, and provide them with an ICF that describes the Screening tests, 
eligibility criteria for entering the trial, trial treatments and follow-up procedures, in a 
language understandable to the subject. Explanation of the trial includes, but is not 
limited to, trial objectives, potential benefits and risks, discomforts/inconveniences, and 
the subject's rights and responsibilities. The subject or subject's legally acceptable 
representative is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject or subject's legally acceptable 
representative. The qualified trial 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. 
6.2 
BEFORE TREATMENT PROCEDURES 
Subjects who consent to participate will have biopsy slides or paraffin-embedded tissue 
block(s) from a previous biopsy and/or newly collected intra-anal and/or peri-anal biopsy 
tissue samples (formalin fixed tissue) sent to the central pathology lab for review by the 
PAC. 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 the PAC with HSIL 
consensus diagnosis), until the date of first study treatment (i.e. Day 0).  
For those individuals diagnosed with anal or anal/peri-anal 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.  
At Screening, subjects must have a diagnosis of histologic anal or anal/peri-anal HSIL 
confirmed by the PAC and intra-anal and/or peri-anal specimen test positive for HPV-
16/18 by PCR to be eligible for participation in the study (provided the subject also 

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meets other eligibility criteria). Subjects whose intra-anal and/or peri-anal specimens 
also test positive for other HPV genotypes are not excluded as long as they have a 
positive result for HPV-16/18.  
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. 
6.2.1 
SCREENING EVALUATIONS 
The following evaluations/actions, unless noted, will be performed within 10 weeks and 
up to 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. Some of these evaluations/actions will be performed 
again later in the trial (see later text and the Schedule of Events Table 3 for more detail). 
 
Signed ICF 
 
Medical history/demographics, including history of prior anal or anal/peri-anal 
HSIL 
 
Socio-Behavioral Assessment; including smoking history, exposure to second-
hand smoke, alcohol intake history, recreational drug use and contraceptive use 
 
Prior concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Complete Physical Examination 
 
Vital signs (including oral temperature, respiratory rate, blood pressure and heart 
rate), height, weight and body mass index (BMI) measurements 
 
12-lead ECG (within 30 days prior to Day 0) 
 
Baseline laboratory evaluations (including complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatine (Cr), glucose, alanine 
aminotransferase [ALT], and creatine phosphokinase [CPK]) (to be performed 
within 30 days prior to Day 0) 
 
Urine pregnancy test 
 
Serology (HIV Ab) within 30 days prior to Day 0 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
Digital Anal Rectal Examination (DARE) 
 
High Resolution Anoscopy (HRA) 
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (slides from all excised tissue must be reviewed by the PAC). 
 
Whole blood (at least 68 mL) and serum (at least 8 mL) for baseline immunology 
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6.3 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will receive study treatment. Visit dates 
and windows must be calculated from Day 0. 
6.3.1 
DAY 0 
The following study evaluations will be performed at Day 0 (unless noted) prior to 
the first study treatment: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swabs 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcome (SF-36v2™ and EQ-5D-5L) (may be performed at Day 
-1 or on Day 0, again provided it is done prior to the first study treatment) 
 
Study treatment administration 
The following evaluations will be performed on Day 0 after study treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute Participant Diary Card (PDC) 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during the phone call: 
 
Review Day 0 of PDC (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
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6.3.3 
WEEK 4 (± 4 DAYS) 
The following study evaluations will be performed at Week 4 prior to study 
treatment: 
 
Reconfirm subject eligibility 
 
Concomitant mediation review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient report outcomes (SF-36v2™ and EQ-5D-5L) 
 
Collect PDC for dose 1 
 
Study treatment administration 
The following study evaluations will be performed at Week 4 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during the phone call: 
 
Review of PDC for dose 2 (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.5 
WEEK 12 (± 4 DAYS) 
The following study evaluations will be performed at Week 12 prior to study 
treatment: 
 
Reconfirm subject eligibility 

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 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Collect and review PDC for dose 2 
 
Study treatment administration 
The following study evaluations will be performed at Week 12 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.6 
WEEK 15 (± 1 WEEK) 
The following study evaluations will be performed at Week 15: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.3.7 
WEEK 28 (± 1 WEEK) 
The following study evaluations will be performed at Week 28: 
 
Reconfirm subject eligibility 

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 
Concomitant medical review 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
6.3.8 
WEEK 36 (± 1 WEEK) 
The following study evaluations will be performed at Week 36: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical and penile swabs 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA 
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (paraffin blocks or unstained slides) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
 
 
 

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6.3.9 
WEEK 40 (± 1 WEEK) 
The following study evaluations will be performed at Week 40: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Study treatment administration 
 
Based on biopsy results collected at Week 36 and Investigator judgment, a 4th 
dose may be given at this visit 
**Please remember to download EP data from CELLECTRA™ 5PSP device within 
24-48 hours of study treatment.** 
The following study evaluations will be performed at the Week 40 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment; 
 
Distribute PDC 
 
Patient reported outcomes-only the two "global" questions for this visit 
6.3.10 8-14 DAYS POST DOSE 4 PHONE CALL (FOR SUBJECTS WHO RECEIVED A 4TH DOSE) 
The following information will be evaluated during the phone call: 
 
Review PDC for dose 4 (after reviewing the PDC 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) 
6.3.11 WEEK 64 (± 2 WEEKS) 
The following study evaluations will be performed at Week 64: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment (only for subjects who received a 4th dose at Week 
40) 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical and penile swab 

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 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (paraffin blocks or unstained slides) for subjects who received a 4th dose 
at Week 40 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.3.12 WEEK 88 (± 2 WEEKS) 
The following study evaluations will be performed at Week 88: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment 
 
Targeted Physical assessment 
 
Urine pregnancy test 
 
Vital signs 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swabs 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.4 
TRIAL PROCEDURES 
6.5 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number 
(SID), which identifies the subject for all trial-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., ANUS01001). Once 
assigned, SIDs cannot be reused for any reason. Information regarding the SID and 
screen date will be documented on a screening and enrollment log/system and in the 
eCRF. 

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6.6 
DEMOGRAPHICS 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
 
Age 
 
Gender 
 
Race/ethnicity 
 
Dominant hand/arm 
6.7 
SAFETY EVALUATIONS 
6.7.1 
PHYSICAL EXAM 
A full Physical exam (PE) will be conducted during Screening and study discharge 
(Week 88). 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, and a DARE.   
A targeted physical assessment will be performed at other visits as determined by the 
Investigator or directed per subject complaints. 
6.7.2 
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 prior to measurement 
 
Respiration rate 
 
Heart rate 
 
Oral temperature measured with an automated thermometer 
6.7.3 
HEIGHT AND WEIGHT 
Weight and height will be collected at all dosing visits in order to calculate the BMI. 
6.7.4 
MEDICAL HISTORY 
Medical history, including history of prior anal or anal/peri-anal dysplasia and 
gynecologic history will be obtained at Screening. For females, previous history of 
treatment for VIN, CIN and/or VAIN will be collected. All relevant past and present 
conditions, as well as prior surgical procedures at least 6 months prior to enrollment will 
be recorded for the main body systems.  
6.7.5 
SOCIO-BEHAVIORAL ASSESSMENTS 
Socio-Behavioral Assessment, including self-reporting of the following: smoking history, 
history of exposure to second-hand smoke, alcohol intake history, recreational drug use 
history, history of contraceptive use and type of contraceptive if known, reproductive 
history, sexual preference and sexual practices history, and pregnancy history will be 
obtained at Screening.  

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At Weeks 36, 64, and 88, a socio-behavioral assessment will be performed again to 
document any changes from Screening and/or other time periods. 
6.7.6 
LABORATORY EVALUATIONS 
At Screening, blood samples will be taken to be tested for serum chemistry and 
hematology. 
Complete Blood Count: 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
Serum Chemistry: 
 
Glucose 
 
Blood urea nitrogen 
 
Creatine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase 
6.7.7 
PREGNANCY TESTING 
For women of reproductive potential, a negative spot urine pregnancy test is required at 
Screening, and prior to each study treatment, HRA, DARE and surgical excision or 
biopsy. 
6.7.8 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for at least 10 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. 
6.7.9 
PARTICIPANT DIARY CARD (PDC) 
Subjects will be provided and trained on a PDC and will be asked to record the following 
the evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59pm) 
 
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 PDC will be reviewed with the subject by the study staff at the 8-14 days 
post dose phone calls and at the next in-person visits. 
The study staff will review the PDC 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. 
Any PDC entry determined to meet the criteria for a Grade 1 or higher AEs should be 
documented as an AE unless deemed part of the subject's ongoing medical history. If 
the PDC entry does not meet the criteria of a Grade 1 or higher AE as per the CTCAE 
guidelines, clinical judgment can be used to determine whether the entry should be 
recorded as an AE and documented accordingly in the site's source. For cases where 
the PDC entry and final AE reporting (i.e. grading) do not agree, the reasoning should be 
recorded in the source documents. 
6.8 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive at least three doses of VGX-3100 (6 mg DNA/dose) in a volume of 
1 mL by IM injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 5PSP.  A fourth dose is optional for 
those assessed to be partial responders at the Week 36 efficacy assessment. 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. EP may not be performed in the 
same arm adjacent to an implantable medical device (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal). The timing of the initial dose will 
be designated Day 0 with the subsequent doses scheduled for administration at Weeks 
4, 12, and at Week 40 (for Subgroup C only). Please refer to the Investigator's Brochure 
for further information. 
6.9 
MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
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, and Weeks 4 and/or Week 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 should be added to the concomitant medications. 
6.10 ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening and will be performed for inclusion into the 
study as listed in the Schedule of Events (Table 3). 

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6.11 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
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 PDC which will be reviewed with study 
personnel 8 – 14 days after doses 1 and 2, Week 15, and 8-14 days after dose 4 (if 
applicable).  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any AEs, 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 AEs will be captured from the time of the informed consent to study 
discharge. These events will be recorded on the subject's Case Report Form (CRF). 
6.12 ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale in Table 6. 
 
Table 6: Grading Scale for Injection Site Reactions 
 
6.13 ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, PRO instruments will be 
administered. The following PRO questionnaires will be used: 

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 
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) [25]. 
SF-36v2™ will be administered at the following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4  
 
8-14 days post dose 2 
 
Weeks 12, 15, 36, 40 
 
8-14 days post dose 4 
 
Weeks 64, 88 
 
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) [26, 27] and will be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4  
 
8-14 days post dose 2 
 
Weeks 12, 15, 36, 40 
 
8-14 days post dose 4 
 
Weeks 64, 88 
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.    
 
Additional Global PRO Questions- regarding quality of life after surgery or biopsy. 
These two questions will be administered at Week 40 only. 
6.14 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, 36, 64 and 88. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual. 
A standardized binding enzyme-linked immunosorbent assay (ELISA) may be performed 
to measure the anti–HPV-16/18 Ab response induced by VGX-3100. 
Peripheral Blood Mononuclear Cells 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. 

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Profiling of miRNA may occur via the use of either sera or plasma obtained at Screening, 
Day 0 and Weeks 15 and 36.  Assessment of Day 0 samples alone will explore 
predictive algorithms for response to treatment with VGX-3100 prior to dosing. 
Assessment of Week 15 samples may 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. 
6.15 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 immune analysis. Assessment of markers may include, but are not 
limited to, CD8+ and FoxP3+ infiltrating cells as well as Granulysin, Perforin, CD137, 
CD103 and PD-L1 in intra-anal and/or peri-anal tissue as sample allows. Markers listed 
here may change as new relevant information becomes available. 
6.16 HUMAN LEUKOCYTE ANTIGEN TYPING 
Human Leukocyte Antigen 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 
Major Histocompatibility Complex (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. 
6.17 ANAL AND/OR PERI-ANAL HPV TESTING 
All intra-anal and/or peri-anal lesions of adequate size (≥4 mm) will be biopsied at 
Screening. Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will 
be obtained from all HSIL sites(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression.  
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching to eliminate potential interference with the results of HPV testing. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0, and at Weeks 4, 
15, 28, 36, 64, and 88 using ThinPrep™. An HPV PCR test will be performed on the 
ThinPrep™ specimens at Screening, and Weeks 36 and 64 when applicable. At each of 
these visits, a recent history will be collected via self-report.   
6.18 HPV TESTING FROM OTHER ANATOMICAL SITE (NON-ANAL) 
Vaginal, cervical (female subjects), penile (male subjects), and OP rinse samples (all 
subjects) will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess 
virologic clearance at non-anal sites. All samples will be read in a central laboratory. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching or vaginal and anal lubricants/medication for a period of 24 hours prior to 
collection of samples to eliminate potential interference with the results of HPV testing. 

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6.19 ANAL PHOTOGRAPHS AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of anal or anal/peri-
anal HSIL confirmed by the PAC at Screening. Subjects will undergo HRA at Screening, 
Day 0, and at Weeks 4, 15, 28, 36, 64, and 88 to identify all intra-anal lesion(s). All intra-
anal and/or peri-anal lesion(s) of adequate size (≥4 mm) will be biopsied at Screening. 
Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be 
obtained from all HSIL site(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. 
Photography of all intra-anal and/or peri-anal lesion(s) must be performed prior to and 
after biopsy, and at all HRA examinations. Photographs of intra-anal lesion(s) will be for 
documentation purposes only. For all peri-anal lesion(s), digital photographs will be 
analyzed with a computer program to assess the percent reduction in the cumulative 
surface area of the peri-anal lesion(s) as determined by the quantitative analysis of 
standardized pre-biopsy photographic imaging at Weeks 36, 64, and 88 compared to the 
post-biopsy photographic image of the previous biopsy visit. 
If the intra-anal and/or peri-anal tissue sample(s) result suggests progression to cancer, 
the Investigator may schedule an ad hoc visit to perform HRA and possible biopsy if 
clinically indicated. 
6.20 UNSCHEDULED BIOPSIES 
In the event an unscheduled biopsy is performed prior to the Week 36 visit, the subject 
will be classified as a non-responder in the efficacy analyses. The subject will 
discontinue further study treatment and continue in the study for safety follow-up visits. 
The subject will be managed according to standard of care and the Investigator's 
judgment based on the results of the histological diagnosis from the unscheduled biopsy. 
All biopsy samples/excised tissue (including standard of care) will be sent to the central 
pathology lab for review by the PAC.   
6.21 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the 
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 the 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. 
The following medications and treatments are prohibited: 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent; use of inhaled, otic, nasal, topical, 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; 

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 
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, live vaccine; 
 
Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that 
affects blood clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study 
treatment, biopsy or excisional procedure. 
The decision to administer a prohibited medication/treatment is done with the safety of 
the study participant as the primary consideration. When possible, the Sponsor should 
be notified before the prohibited medication/treatment is administered. All medications 
should be recorded in the appropriate sections of the subject's eCRF. 
6.22 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, including illicit 
drugs, taken to the Investigator and/or other study personnel. To remain in the study, 
illicit drugs should not be taken. 
Subjects should refrain from becoming pregnant until one month following the last dose 
of IP 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. 
Subjects should abstain from sexual activity and refrain from the use of douching and 
vaginal and anal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples. 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
As a requirement for inclusion in the HPV-203 study, Investigators will only be chosen if 
they are experienced in the management of anal cancer, and are experienced in 
performing HRA.  
HPV-203 Investigators are instructed to perform additional, ad hoc HRA exams and 
biopsies if they suspect potential disease progression. Subjects that undergo an 
unscheduled biopsy will be classified as a non-responder in the efficacy analyses. These 
additional measures should minimize the risk of progression of anal or anal/peri-anal 
HSIL and the risk of harboring an undiagnosed occult early invasive anal or anal/peri-
anal cancer. The frequency of close monitoring by experienced Investigators should 
minimize the risk of cancer progression during the study and the additional measures 
are beyond what is expected in standard of care. 
7.2 
ADVERSE EVENTS (AES) 
An 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 AEs only if they worsen after starting study treatment. 
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and reported on an AE CRF, including the event's seriousness, severity, action taken, 
and relationship to IP. Adverse Events 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. 
Adverse Events 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 increased 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); 
 
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. 
Adverse Events 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 ICF 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. 
7.3 
SERIOUS ADVERSE EVENTS 
A 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 
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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 (ER) or at home, 2) blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or 3) the development of drug dependency or drug 
abuse.  
Classification of Serious Adverse Events: 
 
Death is an outcome of an AE, and not an SAE in and of 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 7.15. 
7.4 
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 AE is at least a reasonable possibility; i.e., there is evidence to 
suggest a causal relationship between the product and the AEs. An AE or ADR is 
considered unexpected if it is not listed in the applicable product information 
(Investigator's Brochure, protocol, or user manual) or is not listed at the specificity or 
severity which is consistent with the risk information provided. The Sponsor will assess 
each serious ADR report for expectedness, to determine if it is a serious unexpected 
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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 serious 
expected AEs, the identification of a significant hazard to the patient population, or a 
major safety finding from a study conducted in animals.   
7.5 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of SAE that requires expedited reporting on 
the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 
hours. Sponsor will assess each device related SAE to determine if anticipated based on 
prior identification within the investigational plan. 
7.6 
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 or SAEs with respect to the 
following levels of severity as per CTCAE v 4.03 for applicable patient populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4) 
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. 
7.7 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS 
A causally related AE is one judged to have a reasonable causal relationship to the 
administration to either or both IP and/or the CELLECTRA™ 5PSP device. The 
Investigator will assess causal relationship of the AE separately to each of the 
investigational drugs and also the investigational device. The reasonable causal 
relationship means that there are facts (evidence) or arguments to suggest a causal 
relationship. An AE may also be assessed as not related to either or both IP and/or 
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(e.g., medical history, concomitant medications), administers the IP, and monitors the 
subject's response to the IP, the Investigator is responsible for reporting AEs and judging 
the relationship between the administration of the IP and EP and a subsequent AE. The 
Investigator is aware of the 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 Study Subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the IP and/or the device 
indicating "yes" or "no" accordingly. Causality should be assessed by the Investigator as 
related to drug or related to device or related to both drug and device (i.e. indiscernible) 
by the following criteria: 
 
Yes- there is a reasonable possibility that administration of the Study Treatment 
(drug or device or both drug and device) contributed to the event; 
 
No- there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or EP; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event. 
7.8 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK) independent of the underlying medical 
condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation or deemed clinically significant by the Investigator must be recorded as 
an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., ECG, x-rays, and vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or 
SAE) as described in Sections 7.2 and 7.3. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory result 
(e.g., decreased hemoglobin). 
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 

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 
Has accompanying or inducing symptoms or signs 
 
Is judged by the Investigator as clinically significant 
Severity is assessed as detailed in Section 7.6. 
Grade is an essential element of these criteria. Each CTCAE grading term in the current 
version is a unique representation of a specific event used for medical documentation 
and scientific analysis and is a single Medical Dictionary for Regulatory Activities 
(MedDRA) Lowest Level Term (LLT). 
Investigators are asked to take the CTCAE grading criteria into account when assessing 
if a laboratory abnormality qualifies as a laboratory AE. Their clinical judgment ultimately 
determines not only the severity of the event but also whether the abnormality in 
question is "clinically significant (CS)" or "NCS." CTCAE v. 4.03 grading criteria can be 
used as a reference when making this determination. It is the responsibility of the 
Investigators to ensure all AEs are accurately reported and graded. 
7.9 
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 
probably or possibly related to the study treatment, he/she should promptly document 
and report the event to the Sponsor. 
7.10 PROCEDURES FOR DOCUMENTING PREGNANCY DURING THE TRIAL 
Subjects who are pregnant or expect to become pregnant during the course of the study 
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 treatments with the IP. A 
Pregnancy Form will be completed by the Investigator and submitted to the Sponsor 
within 24 hours after learning of the pregnancy. Site personnel will submit the Pregnancy 
Form to the Sponsor or its designee by fax or email, as described in Section 7.15. 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 IP. 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 Screening procedure 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 Sponsor. 
Male subjects will be instructed through the Informed Consent Form to immediately 
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period. A Pregnancy Form will be completed by the Investigator and submitted to the 
Sponsor within 24 hours after learning of the pregnancy. Attempts will be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
subject exposed to IP. The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Pregnancy 
Form with additional information on the course and outcome of the pregnancy. An 
Investigator who is contacted by the male subject or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
7.11 METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time 
when informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. The subject's response to questions about his/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. 
7.12 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 AEs classified by system organ class (SOC), preferred term, 
severity, and relationship to study treatment; 
 
Changes in safety laboratory parameters (e.g., hematology and serum 
chemistry); 
 
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. 
7.12.1 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with Cellectra™ 5PSP that require expedited communication from 
the Site to the Sponsor and meet any of the following criteria: 

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 
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 
Sites will inform the Sponsor via method described in Section 7.15 within 24 hours to 
discuss whether further dosing for the particular subject should continue. 
7.13 ADVERSE EVENT REPORTING 
To assure the safety of the participants, information about all AEs (see Section 7.2), 
whether volunteered by the subject, discovered by the 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. 
7.14 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited AEs will be collected throughout the study and recorded in 
the Electronic Data Capture (EDC) system. The Study Report will analyze and 
summarize all AEs throughout the study. Emphasis will be placed on the following: 
1. Certain AEs of interest will be solicited during the 7 days following each 
administration of Study Treatment and summarized separately 
2. Unsolicited AEs will be collected and summarized for the entire study period 
7.15 TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS AND AESIS 
The reporting period for SAEs (without regard to causality or relationship) and AESIs is 
comprised of the period following the signing of the ICF through Week 88. Each AE will 
be assessed to determine whether it meets seriousness criteria. If the AE is considered 
serious, the Investigator will complete the SAE/AESI Report form 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 EC 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 7.5 (UADE) in line with relevant legislation. All investigators will 
receive a safety letter notifying them of relevant SUSAR reports. The Investigator should 
notify the IRB/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 

V G X- 3 1 0 0  
H P V -2 0 3  
I n o vi o P h ar m a c e uti c al s, I n c. 
Cli ni c al Pr ot o c ol  
Pr ot o c ol V er si o n D at e:  1 5 S e p 2 0 1 7  
C O N FI D E N TI A L  
Pr ot o c ol V er si o n: 1. 0  
P a g e 6 8  of 8 3  
e v e nt r el at e d t o pri or St u d y Tr e at m e nt, t h e I n v e sti g at or will r e p ort it t o t h e S p o n s or or t h e 
a p pr o pri at e d e si g n e e. 
S P O N S O R C O N T A C T I N F O R M A TI O N 
M E DI C A L M O NI T O R: 
, M. D., P h. D. 
E M AI L: 
 
S A E R E P O R TI N G I N F O R M A TI O N 
E M AI L: s af et y.i n o vi o @ a p c erl s. c o m  
S A F E T Y F A X: 
 
S A F E T Y P H O N E: 
 
T h e pr ef err e d m et h o d f or pr o vi di n g S A E f or m s or S A E s u p p orti n g d o c u m e nt s t o t h e 
S p o n s or or d e si g n e e i s a n att a c h m e nt t o a n e- m ail m e s s a g e, t o t h e e m ail a d dr e s s a s 
i n di c at e d a b o v e. A n y S A E s u p p orti n g d o c u m e nt s pr o vi d e d b y f a c si mil e ( F a x) ar e t o 
i n cl u d e a c o v er s h e et t h at i d e ntifi e s t h e r e p ort er n a m e a n d c o nt a ct i nf or m ati o n of t h e 
st u d y sit e. 
All s u p p orti n g d o c u m e nt s f or S A E r e p ort s, i n cl u di n g m e di c al r e c or d s a n d di a g n o sti c t e st 
r e s ult s, will i n cl u d e r ef er e n c e t o t h e st u d y s u bj e ct n u m b er. T h e st u d y sit e will r e d a ct all 
ot h er p ati e nt i d e ntif yi n g i nf or m ati o n pr e s e nt o n S A E s u p p orti n g d o c u m e nt s pri or t o 
s e n di n g t h e r e p ort t o t h e S p o n s or.  
I n a d diti o n t o pr o vi di n g t h e S A E r e p ort t o t h e S p o n s or or d e si g n e e wit hi n 2 4 h o ur s of 
b e c o mi n g a w ar e of t h e e v e nt, t h e A E t h at i s s eri o u s m u st b e r e c or d e d i n t h e A E s e C R F. 
T h e e ntr y i nt o t h e e C R F i s r e q uir e d t o b e d o n e a s s o o n a s p o s si bl e. 
T h e I n v e sti g at or will s u p pl y t h e S p o n s or a n d t h e I R B wit h m or e i nf or m ati o n a s it 
b e c o m e s a v ail a bl e a n d a n y a d diti o n al r e q u e st e d i nf or m ati o n. T h e ori gi n al S A E f or m 
m u st b e k e pt at t h e st u d y sit e. T h e S p o n s or or it s r e pr e s e nt ati v e will b e r e s p o n si bl e f or 
d et er mi ni n g a n d i n t ur n, r e p orti n g S A E s t o r e g ul at or y a ut h oriti e s a c c or di n g t o t h e 
a p pli c a bl e r e g ul at or y r e q uir e m e nt s. 
W h e n r e c or di n g t h e S A E f or m, c orr e ct m e di c al t er mi n ol o g y/ c o n c e pt s ar e t o b e u s e d a n d 
t h e u s e of a b br e vi ati o n s a n d c oll o q ui ali s m s ar e t o b e a v oi d e d. 
S eri o u s A d v er s e E v e nt s m u st b e f oll o w e d b y t h e I n v e sti g at or u ntil r e s ol uti o n, e v e n if t hi s 
e xt e n d s b e y o n d t h e st u d y-r e p orti n g p eri o d. R e s ol uti o n of a n S A E i s d efi n e d a s t h e r et ur n 
t o b a s eli n e st at u s or st a bili z ati o n of t h e c o n diti o n wit h t h e e x p e ct ati o n t h at it will r e m ai n 
c hr o ni c. 
I n t h e e v e nt of d e at h, if a n a ut o p s y i s p erf or m e d, a c o p y of t h e r e p ort will b e s e nt t o t h e 
S p o n s or. 
I n t h e e v e nt of a pr e g n a n c y, t h e I n v e sti g at or will s u b mit a Pr e g n a n c y F or m t o t h e 
S p o n s or or d e si g n e e t o t h e s af et y e m ail a d dr e s s or f a x n u m b er wit hi n 2 4 h o ur s of 
l e ar ni n g of t h e pr e g n a n c y. 
P P D
P P D
P P D
P P D

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7.16 NOTIFICATIONS 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 7.4 and 7.16). 
7.17 REPORTING OF CELLECTRA™5PSP DEVICE RELATED COMPLAINTS OR 
DEFICIENCIES 
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 within 24 hours of becoming aware of the event per Sections 7.2 and 7.3. 
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. The error reporting or complaint form provided must be completed and 
emailed to the Sponsor at clinicalcomplaint@inovio.com. 
Additional instructions on complaint reporting to be provided separately. 
7.18 TRIAL DISCONTINUATION 
Inovio Pharmaceuticals Inc. reserves the right to discontinue the trial 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. Additionally, the trial may be 
discontinued at any time by an IRB, INOVIO, the FDA or other government agencies as 
part of their duties to ensure that research subjects are protected.  
Should the trial be terminated and/or the site closed for any reason, all investigational 
drugs & devices must be returned to INOVIO or its representative. The PI should ensure 
their site file documents are complete prior to archiving, and provide copies of any 
requested documents to INOVIO for its Trial Master File (TMF). 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 

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8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by INOVIO or its representative. 
This is a single-arm, multi-center, open-label clinical trial of VGX-3100 in subjects with a 
diagnosis of AIN2, AIN3, PAIN2, or PAIN3 associated with HPV types 16 and/or 18. The 
study's primary endpoint is binary: regression of AIN/PAIN HSIL and viral clearance of 
HPV-16/18 based on tissue collected at Week 36. The primary hypothesis is that the 
treatment will result in regression of HSIL and clearance. Secondary efficacy analyses 
pertain to regression, clearance of HPV-16/18 infection, complete regression, 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, clearance among non-anal 
anatomic locations, and effect of HLA type on efficacy and association of miRNA profile, 
anoscopy, cytology, and virology with efficacy. Other exploratory analyses pertain to 
tissue immunological measures and PRO. 
8.3 
STATISTICAL HYPOTHESES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15.  There are no other formal hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations are: 
 
The modified intention to treat (mITT) population includes all subjects who 
receive at least one dose of Study Treatment. 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 Treatment and have no protocol violations. 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 locking of the study database. 
 
The safety analysis set includes all subjects who receive at least one does of 
Study Treatment. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 
PRIMARY ANALYSES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.05 and the corresponding lower bound of the one-sided 
95% CI exceeds 0.15. 
For the analysis, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week. 

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8.5.2 
SECONDARY ANALYSES 
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
the same as for the primary endpoint. 
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
in surface area and the mean percent change in number of lesions and associated 95% 
t-distribution based confidence intervals. 
Post-baseline ELISA titers will be summarized with geometric mean and associated 95% 
CIs. Post-baseline increases in ELISPOT and Flow responses will be summarized with 
tobit-based means and 95% CIs. Valid samples for statistical analysis purposes will be 
those collected within 14 days of the specified visits. Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.5.3 
SAFETY ANALYSES 
All AEs will be summarized among the safety population by frequency. These 
frequencies will be presented overall and separately by dose, and will depict overall, by 
SOC 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 AE data will be based on events occurring within 28 days 
following 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 following any dose and 
regardless of when they occurred. 
For safety laboratory results, 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. 
Baseline is defined as the last measurement prior to the first treatment administration. 
8.5.4 
DISPOSITION 
Disposition will be summarized 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. 
8.5.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables for the mITT population. 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system for the mITT population. 
Prior medications are those that were used and stopped before the start of the trial (prior 
to Day 0). Partial stop dates of prior medications will be assumed to be the latest 

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possible date consistent with the partial date. Data for all prior medications will be 
summarized with percentages for the mITT population. 
8.5.6 
INTERIM ANALYSES 
No formal interim analyses will be performed for this study. For reasons of futility (early 
evidence of poor efficacy of VGX-3100) or safety issues, the DSMB could recommend 
stopping enrollment at any time. The type I error will not be adjusted for possible early 
stopping due to futility. 
8.5.7 
MULTIPLICITY 
Not applicable, there is one hypothesis that will be tested. 
8.5.8 
MISSING VALUES 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. 
No other missing data will be imputed or replaced. 
8.5.9 
EXPLORATORY ANALYSES 
The exploratory efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
the same as for the primary endpoint. 
Other analyses will examine the relationship between the primary efficacy endpoint and 
a) HLA results, b) miRNA results, c) HRA results, d) cytology results, and e) HPV 
results. Relationships will be examined with contingency tables and/or logistic regression 
models which model the primary endpoint versus these results as regressor variables. 
The change in tissue immune response magnitude will be summarized with means and 
associated t-distribution based 95% CIs. 
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. 
8.6 
SAMPLE SIZE/POWER 
A sample of 24 subjects provides ~80% power to declare superiority over historical 
control, assuming the true proportion of subjects who achieve the primary endpoint is 
40% for the treatment arm versus 15% for the historical control, and that 90% are 
evaluable at Week 36 from 1st dose. 
8.7 
RANDOMIZATION AND BLINDING 
This is an open-label trial, and therefore, site personnel, individual subjects and INOVIO 
or its representative trial personnel will be aware of the treatment allocations for this trial. 
Randomization does not apply. 

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9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
GCP, and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., ICF, 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/EC include the following: 
 
Submit progress reports to the IRB/EC as required, and request re-review and 
approval of the trial at least once a year during the conduct of the trial. 
 
Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects. 
 
Notify the IRB/EC immediately if the Sponsor notifies the Investigator about any 
reportable safety events. 
 
Obtain approval from the IRB/EC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements, as required. 
 
Submit reports on, and reviews of, the trial and its progress to the IRB/EC at 
intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
 
Maintain a file of trial-related information (refer to trial files) that include all 
correspondence with the IRB/EC. 
 
Notify the IRB/EC when the trial is completed (i.e. after the last visit of the final 
trial subject). 
 
After trial completion (within three (3) months is recommended) provide the 
IRB/EC with a final report on the trial. 
9.3 
IBC APPROVAL AND REPORTING 
Investigator will ensure responsibilities relevant to Institutional Biosafety Committee 
(IBC) approval and reporting if applicable per local regulations. 
9.4 
OFFICE OF BIOTECHNOLOGY ACTIVITIES 
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., 
National Institutes of Health [NIH] Office of Biotechnology Activities [OBA]) governing 
research that involves recombinant or synthetic nucleic acid. 
 

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9.5 
PROTECTION OF HUMAN SUBJECTS 
9.5.1 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to enrollment into the 
trial, 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 
(Section 6.1). 
9.5.2 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This trial 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 trial 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 
should be provided to Sponsor. 
9.5.3 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.5.4 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURE REGULATIONS (21CRF 
PART 11) 
When applicable, this trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.5.5 
COMPLIANCE WITH PROTOCOL 
Subjects will be provided with Investigator emergency contact information and advised to 
report all AEs. While every effort should be made to avoid protocol deviation (PD), 
should a deviation be discovered, Sponsor must be informed immediately. Any PD 
impacting subject safety must be reported to the Medical Monitor immediately. 
9.5.6 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without prior review and documented approval/favorable opinion from the Sponsor and 
IRB/EC of a protocol amendment, except where necessary to eliminate immediate 
hazards to trial subjects. While every effort should be made to avoid PD, should a 
deviation be discovered, Sponsor must be informed immediately. Any PD impacting 
Subject safety must be reported to the Medical Monitor immediately. 
10.0 DATA COLLECTION, MONITORING, AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the trial 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 trial Sponsor, the governing health 

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authorities or the FDA, if they inspect the trial 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 trial, 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 (HIPAA)]. 
Information about trial subjects will be kept confidential and managed in accordance with 
the requirements of the HIPAA of 1996. 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 trial 
 
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 
In the event that a subject revokes authorization to collect or use PHI, the Sponsor 
retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect vital status, at a minimum, (i.e., 
that the subject is alive) at the end of their scheduled trial period. 
11.0 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. The 
Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspections by providing direct access to source data/documents related to 
this trial. 
11.1 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
Case Report Form will be provided for each subject. Subjects must not be identified by 
name on any CRFs. Subjects will be identified with an SID. 
It is the Investigator's responsibility to retain trial essential documents for at least two (2) 
years after the last approval of a marketing application in their country and until there are 
no pending or contemplated marketing applications in their country or at least two (2) 

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years have elapsed since the formal discontinuation of clinical development of the IP. 
This retention period may be superseded by country requirements. The Sponsor will 
inform the Investigator/institution as to when these documents are no longer needed to 
be retained. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY AND QUALITY MONITORING 
An independent DSMB will provide safety oversight. The DSMB will be scheduled to 
meet quarterly. 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 there appears to be a regression with VGX-
3100.However, no formal interim analysis will be performed. 
12.2 PATHOLOGY ADJUDICATION COMMITTEE 
All anal 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 four pathologists in separate locations. Each specimen will be read by two 
pathologists independently in a blinded fashion. If the two pathologists agree the reading 
will be considered the clinical disease status for the subject. If the readings of the first 
two pathologists are discordant, the third pathologist will review the discordant slide(s) 
independently and if there is agreement among any of the three readings, it will stand as 
the clinical disease status for that subject. If there is no agreement after the third review, 
the most severe diagnosis would be deemed the final diagnosis. 
12.3 CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced Clinical 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 trial. 
 
The Clinical Monitor will address and document the following trial conduct 
activities and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution 
trip report. Report any significant unresolved problems immediately to the 
Sponsor. 

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o Remind the Investigator as necessary of the obligation to immediately 
report all SAE and provide subsequent follow-up report of the final 
outcome to the IRB. 
o Throughout the trial, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, 
original, and accurate (ALCOA). 
o Assure that the trial facilities continue to be acceptable. 
o Compare the trial CRFs with source documents to assure that the data 
are accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and 
reconciliation of records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded 
properly for testing per laboratory manual requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13.0 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 at 
least 60 days prior to submission for publication. The Sponsor will have 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) will 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 US Patent and 
Trademark Office and/or foreign patent office(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14.0 LIST OF ABBREVIATIONS 
Ab 
Antibody 
ADR 
Adverse Drug Reaction 
AEs 
Adverse events 
AESI 
Adverse Event of Special Interest 
AIN 
Anal Intraepithelial Neoplasia 
AIS 
Adenocarcinoma-in-situ 
ALT 
Alanine Aminotransferase 
BMI 
Body Mass Index 
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CIN 
Cervical Intraepithelial Neoplasia 
CIN1 
Grade 1 Cervical Intraepithelial Neoplasia 
CIOMS-I 
Council for International Organizations of Medical Sciences 
Cr 
Creatine 
CRF 
Case Report Form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CPK 
Creatine Phosphokinase 
DARE 
Digital Anal Rectal Examination 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELIspot 
Enzyme-linked Immunospot Assay 
EP 
Electroporation with CELLECTRA™5PSP  
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
gbm 
gay and bisexual men 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRA 
High-resolution Anoscopy 
HR-HPV 
High-risk HPV Type 
HSIL 
High Grade Squamous Intraepithelial Lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
International Ethics Committee 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
Investigational New Drug 

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INOVIO 
Inovio Pharmaceuticals, Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRB/IEC 
Institutional Review Board or Independent Ethics Committee 
ISO 
International Organization for Standardization 
LAST 
Lower Anogenital Squamous Terminology 
LSIL 
Low Grade Squamous Intraepithelial Lesion 
miRNA 
MicroRNA 
mITT 
Modified Intent to Treat 
MSM 
men who have sex with men 
NCS 
Not Clinically Significant 
OBA 
Office of Biotechnology Activities 
OP 
Ororpharyngeal  
PAIN 
Peri-anal Intraepithelial Neoplasia 
PAM 
Protocol Administrative Memo or Letter 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PIN 
Penile Intraepithelial Neoplasia 
PP 
Per Protocol 
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PE 
Physical Exam 
PRO 
Patient-reported Outcome 
SAEs 
Serious Adverse Events 
SF-36v2™ 
36-Item Short Form Health Survey 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPANC 
Study of the Prevention of Anal Cancer 
SSC 
Saline Sodium Citrate 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated (Serious) Adverse Device Effect 
US 
United States 
VAIN 
Vaginal Intraepithelial Neoplasia 
VIN 
Vulvar Intraepithelial Neoplasia 
WFI 
Water for Injection 
WOCBP 
Women of Childbearing Potential 
 
 
 
 

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15.0  REFERENCES 
1. 
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. 
2. 
Humans IWGotEoCRt. Biological agents. Volume 100 B. A review of human carcinogens. 
IARC Monogr Eval Carcinog Risks Hum 2012,100:1-441. 
3. 
McQuillan G, Kruszon-Moran D, Markowitz LE, Unger ER, Paulose-Ram R. Prevalence 
of HPV in Adults Aged 18-69: United States, 2011-2014. NCHS Data Brief 2017:1-8. 
4. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United 
States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
5. 
Viens LJ, Henley SJ, Watson M, Markowitz LE, Thomas CC, Thompson TD, et al. Human 
Papillomavirus-Associated Cancers - United States, 2008-2012. MMWR Morb Mortal 
Wkly Rep 2016,65:661-666. 
6. 
National Cancer Institute. Fact Sheet: HPV and Cancer. In; 2015. 
7. 
Bruni L, Barrionuevo-Rosas L, Alberto G, Serrano B, Mena M, Gomez D, et al. Human 
Papillomavirus and Related Diseases Report in USA. In: ICO Information Centre on HPV 
and Cancer (HPV Information Centre); 2017. 
8. 
National Cancer Institute SEER Program. Cancer Stat Facts: Anal Cancer. In; 2017. 
9. 
Canadian Cancer Society. Anal Cancer Statistics. In; 2017. 
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. 
Sahasrabuddhe VV, Castle PE, Follansbee S, Borgonovo S, Tokugawa D, Schwartz LM, 
et al. Human papillomavirus genotype attribution and estimation of preventable fraction of 
anal intraepithelial neoplasia cases among HIV-infected men who have sex with men. J 
Infect Dis 2013,207:392-401. 
12. 
Alemany L, Saunier M, Alvarado-Cabrero I, Quiros B, Salmeron J, Shin HR, et al. Human 
papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J 
Cancer 2015,136:98-107. 
13. 
Tong WW, Jin F, McHugh LC, Maher T, Sinclair B, Grulich AE, et al. Progression to and 
spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-
infected and uninfected men. AIDS 2013,27:2233-2243. 
14. 
Machalek DA, Grulich AE, Hillman RJ, Jin F, Templeton DJ, Tabrizi SN, et al. The Study 
of the Prevention of Anal Cancer (SPANC): design and methods of a three-year 
prospective cohort study. BMC Public Health 2013,13:946. 
15. 
Grulich A, Jin F, Poynten IM, Templeton D, Law C, Cornall A, et al. Predictors of 12-month 
persistent high-grade squamous intraepithelial lesions (hsil) in gay and bisexual men 
(gbm): data from the SPANC study. . In: 31st International Papillomavirus Conference 
(HPV2017). Cape Town, South Africa; 2017. 
16. 
Hillman R. Oral comments during a panel discussion. In: 16th World Congress of the 
International Federation of Cervical Pathology and Colposcopy (IFCPC). Orlando, Florida; 
2017. 
17. 
Tong WW, Shepherd K, Garland S, Meagher A, Templeton DJ, Fairley CK, et al. Human 
papillomavirus 16-specific T-cell responses and spontaneous regression of anal high-
grade squamous intraepithelial lesions. J Infect Dis 2015,211:405-415. 
18. 
Dona MG, Vescio MF, Latini A, Giglio A, Moretto D, Frasca M, et al. Anal human 
papillomavirus in HIV-uninfected men who have sex with men: incidence and clearance 

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rates, duration of infection, and risk factors. Clin Microbiol Infect 2016,22:1004 e1001-
1004 e1007. 
19. 
Shvetsov YB, Hernandez BY, McDuffie K, Wilkens LR, Zhu X, Ning L, et al. Duration and 
clearance of anal human papillomavirus (HPV) infection among women: the Hawaii HPV 
cohort study. Clin Infect Dis 2009,48:536-546. 
20. 
Nyitray AG, Carvalho da Silva RJ, Baggio ML, Smith D, Abrahamsen M, Papenfuss M, et 
al. Six-month incidence, persistence, and factors associated with persistence of anal 
human papillomavirus in men: the HPV in men study. J Infect Dis 2011,204:1711-1722. 
21. 
Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine 
delivery and potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
22. 
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. 
23. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation 
increases in vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
24. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of 
intramuscular and intradermal delivery by CELLECTRA((R)) adaptive constant current 
electroporation device in healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
25. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
26. 
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. 
27. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics 1993,4:353-365. 
 
 
 

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16.0 APPENDICES

 
 
 
 
 
 
 
 
 
 
 
 
HPV-203 
 
A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 
related Anal or Anal/Peri-anal, High grade squamous intraepithelial lesion (HSIL), 
(AIN2, AIN3, PAIN2, PAIN3) in individuals that are seronegative for Human 
Immunodeficiency Virus (HIV)-1/2 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #:  13683 
 
Protocol Version:  1.1 
Protocol Version Date:  08Nov2017 
 
 
 
 
 

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Page 2 of 85 
SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 1.0 dated 15 September 2017 
to Version 1.1 dated 08 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. Associated secondary endpoint #7 currently states: ‘Percent reduction in the 
number of intra-anal and/or peri-anal lesion(s) as determined by the Investigator 
at Weeks 36, 64, and 88 compared to baseline. For all peri-anal lesion(s), digital 
photos will be analyzed with a computer program to assess the percent reduction 
in the cumulative surface area of the peri-anal lesion(s) as determined by the 
quantitative analysis of standardized pre-biopsy photographic imaging at Week 
36, 64, and 88 compared to the post-biopsy photographic image of the previous 
biopsy visit. The new associated secondary endpoint #7 will read as follows and 
has been updated to reflect this throughout the protocol: Percent reduction in the 
number of intra-anal and/or peri-anal lesion(s) as determined by the Investigator 
at Weeks 36, 64, and 88 compared to baseline. For all peri-anal lesion(s), digital 
photos will be analyzed with a computer program to assess the percent reduction 
in the cumulative surface area of the peri-anal lesion(s) as determined by the 
quantitative analysis of standardized pre-biopsy photographic imaging of 
qualifying lesion(s) at Weeks 36, 64, and 88 compared to baseline. 
2. The definition of baseline photographic imaging has been provided and is defined 
as follows: photographs obtained pre-biopsy at Screening, or post biopsy at 
Screening (for subjects with historical biopsy tissue). 
3. The definition of qualifying lesion(s) has been added and the definition is as 
follows: an intra-anal and/or peri-anal lesion which is confirmed to be HPV-16 
and/or HPV-18 positive and have histologically confirmed anal or anal/peri-anal 
HSIL by the Pathology Adjudication Committee (PAC). 
4. Exclusion criteria numbers 2, 3, 4, and 5: Subjects who are under the care of a 
health provider for their biopsy-proven VAIN, AIN, CIN, or PIN but may not be 
receiving treatment are eligible for this trial. There criteria were modified in 
consideration of subjects who are under medical surveillance by their healthcare 
provider. 
5. Exclusion criteria #11: 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 and ECG results within 45 days prior to Day 0 to determine eligibility. 
6. Per Table 3 Schedule of Events for blood immunologic samples: Subjects will 
have 34 ml of whole blood and 4 ml of serum drawn per time point. At Screening 
and Day 0, a total of at least 68 ml of whole blood and 8 ml of serum will be 
collected. Additionally, the current protocol (15 Sep 2017) indicates that at Week 

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36, subjects will have at least 51 ml of whole blood and 4 ml of serum drawn. 
This time point is incorrect and has been moved to Week 15. At Week 15, 
subjects will have at least 51 ml of whole blood and 4 ml serum drawn. This 
change is due to immunologic markers and for the purpose of expected 
responses at these designated time points.  
7. Section 6.2 Before Treatment Procedures indicates that subjects who consent to 
participate will have biopsy slides or paraffin-embedded tissue block(s) from a 
previous biopsy visit and/or newly collected intra-anal and/or peri-anal biopsy 
tissue samples (formalin fixed tissue) sent to the central pathology lab for review 
by the PAC. This language has been updated to say: Subjects who consent to 
participate must have paraffin-embedded tissue block(s) from a previous biopsy 
visit and/or newly collected intra-anal and/or peri-anal biopsy tissue samples 
(formalin fixed tissue) sent to the central pathology lab for review by the PAC. 
8. Section 7.12.1 Adverse Events of Special Interest: the following sentence was 
added: As per the Toxicity Grade for Healthy Adults, the most severe grade for 
that particular event is to be documented in the CRFs. 
9. Section 12.2 Pathology Adjudication Committee: This section has been updated 
to remove procedural content from the protocol and allow individuals to reference 
the PAC Charter document. 
10. The ICF blood sample amount has been updated to reflect the new amount 
drawn throughout the study which will be about 221ml.  
 
 

V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
M e di c al M o nit or A p pr o v al P a g e 
Dr u g: 
S p o n s or: 
M e di c al M o nit or: 
A p pr o v al Si g n at ur e: 
l n o vi o P h ar m a c e uti c al s 
V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
6 6 0 W. G er m a nt o w n Pi k e, S uit e 1 1 0 
Pl y m o ut h M e eti n g, P A 1 9 4 6 2 
, M. D., P h. D. 
 
l n o vi o P h ar m a c e uti c al s, I n c. 
D at e 
C O N FI D E N TI A L 
H P V- 2 0 3 
Cli ni c al Pr ot o c ol 
T h e i nf or m ati o n i n t hi s d o c u m e nt i s c o n si d er e d pri vil e g e d a n d c o nfi d e nti al b y l n o vi o 
P h ar m a c e uti c al s I n c. (I N O VI O) a n d m a y n ot b e di s cl o s e d t o ot h er s e x c e pt t o t h e e xt e nt 
n e c e s s ar y t o o bt ai n I n stit uti o n al R e vi e w B o ar d/ Et hi c s c o m mitt e e a p pr o v al a n d i nf or m e d 
c o n s e nt, or a s r e q uir e d b y l o c al r e g ul at or y a ut h oriti e s. P er s o n s t o w h o m t hi s i nf or m ati o n 
i s di s cl o s e d m u st b e i nf or m e d t h at t hi s i nf or m ati o n i s pri vil e g e d a n d c o nfi d e nti al a n d t h at 
it s h o ul d n ot b e f urt h er di s cl o s e d wit h o ut 
t h e writt e n 
p er mi s si o n of I N O VI O. A n y 
s u p pl e m e nt al i nf or m ati o n a d d e d t o t hi s d o c u m e nt  i s al s o c o nfi d e nti al a n d pr o pri et ar y 
i nf or m ati o n of I N O VI O a n d m u st b e k e pt i n c o nfi d e n c e i n t h e s a m e m a n n er a s t h e c o nt e nt s 
of t hi s d o c u m e nt. 
Pr ot o c ol V er si o n D at e: 0 8 N o v 2 0 1 7 
C O N FI D E N TI A L 
P a g e 4 of 8 6 
Pr ot o c ol V er si o n : 1. 1 
P P D
P P D
P P D
P P D
P P D

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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 (IRB/IEC) 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 International Conference on Harmonization (ICH)/Good Clinical Practice (GCP) and 
International Organization for Standardization (ISO) guidelines, local legal and regulatory 
requirements, and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
<Insert Principal Investigator Printed Name> 
 
Date (dd/Mmm/yyyy) 
 
 
 
 
 
 
 
Site Number: _____________________________________________ 
 
 
Site Name: _______________________________________________ 
 
 

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TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ...................................................... 5 
CLINICAL PROTOCOL SYNOPSIS ............................................................................ 10 
TRIAL SCHEDULE OF EVENTS ................................................................................ 23 
1.0 
INTRODUCTION ........................................................................................... 26 
1.1 
Background and Scientific Rationale ....................................................................26 
1.1.1 
VGX-3100 ........................................................................................................................ 27 
1.1.2 
Electroporation .............................................................................................................. 28 
1.1.3 
Dose Rationale............................................................................................................... 29 
1.2 
Potential Benefits ....................................................................................................29 
1.3 
Potential Risks ........................................................................................................29 
2.0 
PURPOSE AND HYPOTHESIS ....................................................................... 30 
2.1 
Purpose ...................................................................................................................30 
2.2 
Hypothesis ...............................................................................................................30 
3.0 
TRIAL DESIGN AND ENDPOINTS .................................................................. 30 
3.1 
Primary Objective(s) ...............................................................................................31 
3.2 
Primary Endpoint(s) ................................................................................................31 
3.3 
Secondary Objective(s) ..........................................................................................31 
3.4 
Associated Secondary Endpoint(s) .......................................................................32 
3.5 
Exploratory Objective(s) .........................................................................................32 
3.6 
Associated Exploratory Endpoint(s) ......................................................................33 
3.7 
Efficacy Assessment ..............................................................................................33 
3.8 
Safety Assessment .................................................................................................34 
3.9 
Immunogenicity Assessment .................................................................................35 
4.0 
TRIAL POPULATION .................................................................................... 35 
4.1 
Inclusion Criteria .....................................................................................................35 
4.2 
Exclusion Criteria ....................................................................................................36 
4.3 
Discontinuation/Withdrawal of Trial Subjects .......................................................38 
4.3.1 
Criteria for Discontinuation from the Study ............................................................... 38 
4.3.2 
Criteria for Withdrawal from Study .............................................................................. 38 
4.3.3 
Sponsor Notification of Discontinuation/Withdrawal ................................................ 39 
4.3.4 
Reasons for Discontinuation/Withdrawal ................................................................... 39 
5.0 
TRIAL TREATMENT ..................................................................................... 40 
5.1 
Investigational Biologic Product ............................................................................40 
5.2 
Cellectra™ 5PSP Device Description: ...................................................................40 
5.3 
Treatment Regimen .................................................................................................42 
5.4 
Packaging and Handling .........................................................................................42 
5.5 
Handling and Storage of IP and Device .................................................................44 

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5.6 
Preparation and Dispensing ...................................................................................45 
5.7 
Use of Cellectra™5PSP Device ..............................................................................45 
5.8 
Drug and Device Accountability ............................................................................45 
5.8.1 
Investigational Product Accountability ....................................................................... 45 
5.8.2 
Cellectra™ 5PSP Device Accountability ..................................................................... 46 
5.9 
Return and Destruction of Investigational Product and Cellectra™ 5PSP Device
 ..................................................................................................................................46 
5.9.1 
Return of Investigational Product................................................................................ 46 
5.9.2 
Return of Cellectra™ 5PSP Device .............................................................................. 46 
6.0 
TRIAL PROCEDURES AND SCHEDULE .......................................................... 47 
6.1 
Informed Consent ...................................................................................................47 
6.2 
Before Treatment Procedures ................................................................................47 
6.2.1 
Screening Evaluations .................................................................................................. 48 
6.3 
During Treatment Procedures by Visit ..................................................................49 
6.3.1 
Day 0 ............................................................................................................................... 49 
6.3.2 
8-14 Days Post Dose 1 Phone Call .............................................................................. 49 
6.3.3 
Week 4 (± 4 Days) .......................................................................................................... 50 
6.3.4 
8-14 Days Post Dose 2 Phone Call .............................................................................. 50 
6.3.5 
Week 12 (± 4 Days) ........................................................................................................ 50 
6.3.6 
Week 15 (± 1 Week) ....................................................................................................... 51 
6.3.7 
Week 28 (± 1 Week) ....................................................................................................... 51 
6.3.8 
Week 36 (± 1 Week) ....................................................................................................... 52 
6.3.9 
Week 40 (± 1 Week) ....................................................................................................... 53 
6.3.10 8-14 Days Post Dose 4 Phone Call (for subjects who received a 4th dose) ............. 53 
6.3.11 Week 64 (± 2 Weeks) ..................................................................................................... 53 
6.3.12 Week 88 (± 2 Weeks) ..................................................................................................... 54 
6.4 
Trial Procedures ......................................................................................................54 
6.5 
Assignment of Subject Identification Numbers ....................................................54 
6.6 
Demographics .........................................................................................................55 
6.7 
Safety Evaluations ..................................................................................................55 
6.7.1 
Physical Exam ............................................................................................................... 55 
6.7.2 
Vital Signs ...................................................................................................................... 55 
6.7.3 
Height and Weight ......................................................................................................... 55 
6.7.4 
Medical History .............................................................................................................. 55 
6.7.5 
Socio-Behavioral Assessments ................................................................................... 55 
6.7.6 
Laboratory Evaluations ................................................................................................ 56 
6.7.7 
Pregnancy Testing ........................................................................................................ 56 
6.7.8 
ECG ................................................................................................................................. 56 
6.7.9 
Participant Diary Card (PDC) ........................................................................................ 56 
6.8 
Injection and Electroporation (EP) .........................................................................57 
6.9 
Management of Anxiety and Pain due to Electroporation (EP) Procedures .......57 
6.10 Assessment of Laboratory Abnormalities .............................................................57 
6.11 Assessment of Clinical Trial Adverse Events (AEs) .............................................58 

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Clinical Protocol 
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6.12 Assessment of Injection Site Reactions ................................................................58 
6.13 Assessment of Patient Reported Outcomes .........................................................58 
6.14 Peripheral Blood Immunogenicity Assessments ..................................................59 
6.15 Tissue Immunogenicity Assessment .....................................................................60 
6.16 Human Leukocyte Antigen Typing .........................................................................60 
6.17 Anal and/or Peri-anal HPV Testing.........................................................................60 
6.18 HPV Testing from other Anatomical Site (Non-anal) ............................................60 
6.19 Anal Photographs and Biopsies ............................................................................61 
6.20 Unscheduled Biopsies ............................................................................................61 
6.21 Concomitant Medications/Treatments ...................................................................61 
6.22 Restrictions .............................................................................................................62 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ........................... 62 
7.1 
Safety Parameters ...................................................................................................62 
7.2 
Adverse Events (AEs) .............................................................................................62 
7.3 
Serious Adverse Events .........................................................................................63 
7.4 
Unexpected Adverse Drug Reactions and Expedited Reporting .........................64 
7.5 
Unanticipated (Serious) Adverse Device Effect ....................................................65 
7.6 
Assessing Severity (Intensity) ...............................................................................65 
7.7 
Causal Relationship of Clinical Material to Adverse Events ................................65 
7.8 
Abnormal Laboratory Value ...................................................................................66 
7.9 
Post-Trial Reporting Requirements .......................................................................67 
7.10 Procedures for Documenting Pregnancy During the Trial ...................................67 
7.11 Methods and Timing of Collection of Safety Data ................................................68 
7.12 Safety and Toxicity Management ...........................................................................68 
7.12.1 Adverse Events of Special Interest ............................................................................. 68 
7.13 Adverse Event Reporting .......................................................................................69 
7.14 Trial Reporting Period of Adverse Events .............................................................69 
7.15 Trial Reporting Period of Serious Adverse Events and AESIs ............................69 
7.16 Notifications of Serious Adverse Events ...............................................................71 
7.17 Reporting of CELLECTRA™5PSP Device Related Complaints or Deficiencies .71 
7.18 Trial Discontinuation ..............................................................................................71 
8.0 
STATISTICAL CONSIDERATIONS .................................................................. 72 
8.1 
Statistical and Analytical Plan ................................................................................72 
8.2 
General Considerations ..........................................................................................72 
8.3 
Statistical Hypotheses ............................................................................................72 
8.4 
Analytical Populations ............................................................................................72 
8.5 
Description of Statistical Methods .........................................................................72 
8.5.1 
Primary Analyses .......................................................................................................... 72 
8.5.2 
Secondary Analyses ..................................................................................................... 73 
8.5.3 
Safety Analyses ............................................................................................................. 73 
8.5.4 
Disposition ..................................................................................................................... 73 

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8.5.5 
Demographic and Other Baseline Characteristics .................................................... 74 
8.5.6 
Interim Analyses ............................................................................................................ 74 
8.5.7 
Multiplicity ...................................................................................................................... 74 
8.5.8 
Missing Values............................................................................................................... 74 
8.5.9 
Exploratory Analyses .................................................................................................... 74 
8.6 
Sample Size/Power .................................................................................................75 
8.7 
Randomization and Blinding ..................................................................................75 
9.0 
ETHICS ...................................................................................................... 75 
9.1 
Investigator and Sponsor Responsibilities ...........................................................75 
9.2 
Institutional Review Board or Ethics Committee ..................................................75 
9.3 
IBC Approval and Reporting ..................................................................................76 
9.4 
Office of Biotechnology Activities .........................................................................76 
9.5 
Protection of Human Subjects ...............................................................................76 
9.5.1 
Compliance with Informed Consent Regulations ...................................................... 76 
9.5.2 
Compliance with IRB/EC Requirements ..................................................................... 76 
9.5.3 
Compliance with Good Clinical Practice .................................................................... 76 
9.5.4 
Compliance with Electronic Records/Signature Regulations (21CRF Part 11) ...... 76 
9.5.5 
Compliance with Protocol ............................................................................................ 76 
9.5.6 
Changes to the Protocol ............................................................................................... 76 
10.0 
DATA COLLECTION, MONITORING, AND REPORTING .................................... 77 
10.1 Confidentiality and Privacy ....................................................................................77 
11.0 
SOURCE DOCUMENTS ................................................................................ 77 
11.1 Records Retention ..................................................................................................78 
12.0 
SAFETY AND QUALITY MONITORING ............................................................ 78 
12.1 Safety and Quality Monitoring ................................................................................78 
12.2 Pathology Adjudication Committee .......................................................................78 
12.3 Clinical Monitoring ..................................................................................................78 
13.0 
PUBLICATION POLICY ................................................................................. 80 
14.0 
LIST OF ABBREVIATIONS ............................................................................ 81 
15.0 
REFERENCES ............................................................................................. 83 
16.0 
APPENDICES .............................................................................................. 85 
 
 
 
 
 

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CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 related Anal 
or Anal/Peri-anal High-Grade Squamous Intraepithelial Lesions, HSIL (AIN2, AIN3, PAIN2, 
PAIN3) in individuals that are seronegative for Human Immunodeficiency Virus (HIV)-1/2 
Protocol Number: HPV-203 
 
Trial Phase: 2a 
 
Estimated Number of Trial Centers and Countries/Regions: Approximately 5 study 
centers located in North America 
 
Formulation: VGX-3100 
 
Trial Design: Multi-center, single-arm, open-label phase 2 study 
  
Criteria for Evaluation: To provide a treatment to regress anal or anal/peri-anal HSIL and 
clear the related HPV-16 and/or HPV-18 (HPV16/18) in individuals that are seronegative for 
HIV-1/2. 
 
Research Hypothesis: VGX-3100 followed by electroporation (EP) administered to adults 
with histologically confirmed anal or anal/peri-anal HSIL1, (AIN22, AIN33, PAIN24, PAIN35) 
associated with HPV-16 and/or HPV-18 will result in a higher proportion with 
histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence of anal 
or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than historical controls.  
Dose of VGX-3100: 6 mg (1mL) 
Administration: Intramuscular injection followed by EP 
VGX-3100 Dosing Schedule: Day 0, Week 4 and Week 12 with one additional dose given 
to partial responders at Week 40 
Study Duration: 88 Weeks 
Primary Objective: Determine the efficacy of 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and virologic clearance 
of HPV-16 and/or HPV-18. 
Primary Endpoint: Proportion of subjects with no histologic evidence of anal or anal/peri-
anal HSIL6 on histology (i.e., collected via biopsy or excisional treatment)7 and no evidence 
of HPV-16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue. 
1 High-grade Squamous Intraepithelial Lesion 
2 Grade 2 Anal Intraepithelial Neoplasia 
3 Grade 3 Anal Intraepithelial Neoplasia             
4 Grade 2 Peri-anal Intraepithelial Neoplasia 
5 Grade 3 Peri-anal Intraepithelial Neoplasia 
6  No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
7 A treatment responder is defined as a subject with no histologic evidence of anal or anal/peri-anal HSIL and no evidence of 
HPV-16 or HPV-18 in anal lesion tissue and who did not receive any non-study treatment of curative intent of intra-anal and/or 
peri-anal lesions. A treatment non-responder is defined as a subject with histologic evidence of anal or anal/peri-anal HSIL, 
adenocarcinoma-in-situ (AIS), anal or anal/peri-anal carcinoma or a subject with evidence of HPV-16/18 in anal lesion tissue 
or a subject who received non-study treatment of curative intent of intra-anal and/or peri-anal lesions. 

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Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary Card (PDC). 
 
1b. All adverse events including SAEs, 
UADEs, and other unexpected AEs 
for the duration of the study (through 
the Week 88 visit) 
2. Determine the efficacy of three doses 
of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL 
2. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
HSIL8 on histology (e.g. biopsies or 
excisional treatment) at the Week 36 
visit 
3. Determine the efficacy of VGX-3100 as 
measured by virologic clearance of 
HPV-16 and/or HPV-18 by testing from 
lesion tissue 
3. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-189 
from intra-anal and/or peri-anal tissue 
by type specific HPV testing at the 
Week 36 visit 
4. Determine the efficacy of VGX-3100 as 
measured by virologic clearance of 
HPV-16 and/or HPV-18 by intra-anal 
tissue swab testing 
4. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-18 
from intra-anal swab by specific HPV 
testing at the Weeks 36, 64, and 88 
visits 
5. Determine the efficacy of three doses 
of VGX-3100 as measured by complete 
histopathologic regression of anal or 
anal/peri-anal HSIL to normal tissue 
5. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
Low grade squamous intraepithelial 
lesion (LSIL) or HSIL (i.e. no 
evidence of AIN2, AIN3, PAIN2, 
PAIN3) on histology (i.e. biopsies or 
excisional treatment) at the Week 36 
visit 
6. Determine the efficacy of three doses 
of VGX-3100 as measured by 
histopathologic non-progression of 
anal or anal/peri-anal HSIL  
6. Proportion of subjects with no 
progression10 of anal or anal/peri-
anal HSIL to carcinoma from 
baseline to histology (i.e. biopsies or 
excisional treatment) at the Week 36 
visit 
7. Describe the efficacy of VGX-3100 for 
partial responders, as measured by 
reduction in the number of intra-anal 
and/or peri-anal lesion(s), as applicable 
and the reduction in size of peri-anal 
lesion(s) if present, and for whom the 
disease has not progressed according 
to Investigator judgment in subjects who 
did not have anal or anal/peri-anal HSIL 
lesion resolution at Week 36 
7. Percent reduction in the number of 
intra-anal and/or peri-anal lesion(s), 
as determined by the Investigator at 
Weeks 36, 64, and 88 compared to 
baseline11. For all peri-anal lesion(s), 
digital photos will be analyzed with a 
computer program to assess the 
percent reduction in the cumulative 
surface area of the peri-anal lesion(s) 
as determined by the quantitative 
analysis of standardized pre-biopsy 

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photographic imaging of qualifying 
lesion(s)12 at Weeks 36, 64, and 88 
compared to baseline11. 
8. Determine the humoral and cellular 
immune response following dose 3 and 
additional time points compared to 
baseline 
8a. Levels of serum anti-HPV-16 and 
anti-HPV-18 antibody concentrations 
at baseline and the Weeks 15, 36, 
64, and 88 visits 
 
8b. Interferon-γ ELISpot response spot 
forming units (SFU) at baseline and 
the Weeks 15, 36, 64, and 88 visits 
 
8c. Flow Cytometry response magnitude 
at baseline and Week 15 visit 
8 No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
9 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
10 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication Committee.  
11 Baseline photographic imaging is defined as photographs obtained pre-biopsy at Screening, or post biopsy at Screening (for 
subjects with historical biopsy tissue). 
12 An intra-anal and/or peri-anal lesion which is confirmed to be HPV-16 and/or HPV-18 positive and have histologically 
confirmed anal or anal/peri-anal HSIL by the Pathology Adjudication Committee (PAC). 
 
 
 
 

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Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of more than 3 
doses of VGX-3100 with respect to 
combined histopathologic regression of 
anal or anal/peri-anal HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
1.  Proportion of subjects with no histologic 
evidence of anal or anal/peri-anal HSIL 
on histology (i.e. collected via biopsy or 
excisional treatment) and no evidence of 
HPV-16/18 at Week 64 by testing from 
intra-anal and/or peri-anal lesion tissue 
2. Describe the efficacy of more than 3 
doses of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL 
2.   Proportion of subjects with no evidence 
of anal or anal/peri-anal HSIL on histology 
(i.e. biopsies or excisional treatment) at 
Week 64 for subjects who receive 4 
doses of VGX-3100 
3. Describe the efficacy of more than 3 
doses of VGX-3100, as measured by 
virologic clearance of HPV-16 and/or 
HPV-18 
3.   Proportion of subjects with no HPV-16/18 
at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue for subjects 
who receive 4 doses of VGX-3100 
4. Evaluate tissue immune responses to 
VGX-3100 in intra-anal and/or peri-anal 
samples 
4.   Assessment of proinflammatory and 
immunosuppressive elements in tissue, 
where feasibile.13 
5. Describe the clearance of HPV-16 and/or 
HPV-18 infection from non-anal anatomic 
locations 
5.  Proportion of subjects who have cleared 
HPV-16 and/or HPV-18 on specimens 
from non-anal anatomic locations as 
applicable based upon gender (i.e. 
oropharynx, cervical, vaginal, and penile 
at Week 36 visit) 
6. Evaluate the effect of Human Leukocyte 
Antigen (HLA) type on efficacy 
6.   HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of 
anal or anal/peri-anal HSIL at the Week 
36 visit 
7. Describe the association of microRNA 
(miRNA) profile, previous anoscopy, 
cytology and HPV testing results with 
Week 36 histologic regression 
7.   HRA, cytology, and HPV test results and 
miRNA profile (baseline and at the Weeks 
15 and 36) in conjunction with histologic 
regression of anal or anal/peri-anal HSIL 
at the Week 36 visit 
8. Describe patient reported outcomes 
(PRO) for subjects treated with VGX-3100 
8.   Patient reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and following 
each dose, and at Weeks 36, 64, and 88. 

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There will be an additional PRO 
assessment at Week 40 if a subject 
receives a 4th dose. 
13Additonal assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possible other relevant 
markers identified in the literature as sample allows. 
 

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HPV-203 
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Study Design: 
 
HPV-203 is a Phase 2, 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 in adult 
men and women who are HIV negative with histologically confirmed anal or anal/peri-anal 
HSIL associated with HPV-16 and/or HPV-18. 
 
Approximately 24 subjects will receive at least 3 doses of VGX-3100. Each dose of VGX-
3100 will be administered in a 1 mL volume IM followed immediately by EP. As shown in 
Figure 1, study subjects will receive at least 3 doses of VGX-3100 depending upon their 
disposition with regard to histologic and lesion area changes during the trial. The first dose 
will be administered on Day 0, the second at Week 4, and the third at Week 12. Partial 
response to VGX-3100 may still be of medical importance by being able to limit the extent of 
surgery necessary. For partial responders at Week 36, a fourth dose may be administered at 
Week 40.  
 
All subjects are scheduled to be followed to Week 88. 
 
Figure 1: HPV-203 Study Visit Schedule 
 
 
 
 
Biopsy slides 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 anal or 
anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the biopsy sample(s). All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥ 4mm) will be biopsied at Screening. Subjects 
must also have intra-anal and/or peri-anal lesion(s) tissue test positive for HPV genotype 16 
and/or 18 to be eligible for participation in the study. 
 
 
 
 

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To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be administered and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional PRO questions 
assessing quality of life after surgery or biopsy. 
 
Visualization of the lesion and digital anal rectal examination (DARE) alone are insufficient 
evidence to confirm disease regression. Disease regression will be primarily based on 
histopathologic assessment at Week 36 and additionally assessed at Week 64. Subjects will 
be monitored during the course of the study by DARE and HRA. Intra-anal lesion(s) will be 
assessed at Screening, Day 0, and at Weeks 4, 15, 28, 36, 64 and 88 using HRA. 
Standardized high resolution digital imaging will be used to assess the percent reduction in 
the cumulative surface area of the peri-anal lesion(s) as determined by the quantitative 
analysis of standardized  pre-biopsy photographic imaging of qualifying lesion(s) at Weeks 
36, 64, and 88 compared to baseline.. 
 
The decision process following the results of the Week 36 biopsy are described below in 
Figure 2 and are as follows: At Week 36, the subject will undergo repeat intra-anal and/or 
peri-anal punch biopsies of all HSIL lesions confirmed by the PAC at Screening of adequate 
size (≥ 4mm). (See Table 1 for Minimally Required Biopsy Procedures). If after evaluation of 
the biopsy tissue(s) by the PAC there is no evidence of HSIL (defined by Subgroups A or B), 
the subject will continue to Week 64 for HRA and undergo biopsies of the same areas (HSIL 
lesions) as the baseline biopsies. 
 
 
Figure 2: Decision process at Week 40 
 
 
 
 
 

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Table 1: Minimally Required Procedure at each Biopsy Visit 
 
Pre-biopsy High Resolution Anoscopy 
Finding 
Minimally required procedure 
 
No lesion 
Punch biopsy and photography; biopsy 
should be collected from within the 
approximate original boundaries of the 
study entry HSIL as proximal as possible to 
the original biopsy site which was 
previously determined to be HSIL by the 
PAC. 
 
Single lesion (which was also present at 
baseline) 
Punch biopsy and photography; biopsy 
should be collected within the boundaries of 
the original lesion and from the area most 
suspicious for advanced disease within the 
lesion by clinical exam. 
 
Multiple lesions 
Punch biopsies and photography; biopsy 
should be collected from the same lesions 
diagnosed as HSIL from study entry and 
from the area most suspicious for advanced 
disease within the lesion by clinical exam. 
 
If HSIL is diagnosed in any Week 36 biopsy, but there is a reduction in the number of intra-
anal and/or peri-anal lesion(s), reduction in peri-anal lesion(s) size or no change in peri-anal 
lesion(s) size from baseline (defined by Subgroup C), the Investigator has the option to 
administer a 4th dose of VGX-3100 at Week 40, and the subject will continue on the study to 
have HRA and biopsy at Week 64, i.e. the second efficacy checkpoint. Alternatively, the 
Investigator may instead choose to treat the subject with standard of care treatment (i.e. 
electrocautery, ablation, surgical excision), and the subject will continue on the study without 
further biopsy unless it is part of standard of care. 
 
In the event of worsening anal or anal/peri-anal HSIL at any time during the trial (defined as 
any increase in lesion(s) area from baseline or worsening of anal or anal/peri-anal HSIL to 
cancer), the subject may receive standard of care treatment (i.e. electrocautery, ablation, 
surgical excision) per the Investigator's judgment but will continue on the study through Week 
88 with HRA, but without further biopsy unless it is part of the standard of care. 
 
If there is histologic progression to carcinoma, subjects will receive surgical treatment, and be 
discontinued from study treatment but will continue through Week 88 with HRA, but without 
further biopsy unless it is part of the standard of care. The event will be reported as an SAE 
per Section 7.3. If wide excision is required, the sample(s) obtained will be sent to the PAC 
for evaluation. 
 
Efficacy Assessment: 
 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesion(s) of adequate 
size (≥4mm). Visible lesion(s) observed during HRA should be large enough to biopsy, but the 
biopsy (typically 4mm) should not remove the entire lesion in order to allow for continued 
lesion measurement while on the study. 

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Inovio Pharmaceuticals, Inc. 
 
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Given that HPV infection persistence is a critical factor in the clinical progression of HPV-
associated anal or anal/peri-anal HSIL and also based upon the findings of the secondary 
objective of the HPV-003 CIN2/3 proof of concept study, the responder definition for the HPV-
203 primary endpoint determination requires both histological regression of anal or anal/peri-
anal HSIL and clearance of HPV-16 and/or HPV-18 [1]. 
 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic assessment 
of intra-anal tissue, utilizing HRA with biopsies. All intra-anal and/or peri-anal lesion(s) of 
adequate size (≥4mm) will be biopsied at Screening. Once the PAC confirms HSIL at 
Screening, the Week 36 and 64 biopsies will be obtained from all HSIL site(s) confirmed by 
the PAC at Screening, unless the Investigator suspects disease progression. Tissue samples 
will be analyzed for evidence of histopathologic regression. Clearance of HPV-16 and/or 
HPV-18 will be determined using the type specific HPV PCR test SPF10 on intra-anal and/or 
peri-anal tissue performed at Screening and Weeks 36 and 64 when applicable. 
 
Intra-anal and/or peri-anal swabs will be collected at Screening, Day 0, and at Weeks 4, 15, 
28, 36, 64 and 88 as a less invasive measure for exploratory purposes to determine the 
presence of HPV-16 and/or -18 as well as other high risk HPV types using Cobas HPV 
testing. Similarly, vaginal, cervical (female subjects), penile (male subjects), and 
oropharyngeal (OP) rinse samples will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, 
and 88 to assess systemic virologic response to treatment. 
 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction in 
intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size from 
baseline (Subgroup C), the Investigator will have the option to administer a 4th dose of VGX-
3100 at Week 40 and the subject will continue on the study with HRA and biopsy at Week 64. 
Alternatively, the Investigator may choose to treat the subject with standard of care treatment 
(i.e. electrocautery, ablation, surgical excision), and the subject will continue on the study 
without further biopsy. 
 
Immunogenicity Assessment: Humoral and cell mediated immune responses to VGX-3100 
may be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, 64, and 88. Intra-anal and/or peri-anal tissue samples may 
also be analyzed for evidence of proinflammatory and immunosuppressive elements at Week 
36 as compared to baseline (Screening), where feasible. 
 
Virologic Assessment: Intra-anal and/or peri-anal swabs will be obtained to characterize 
HPV infection at Screening, Day 0, and Weeks 4, 15, 28, 36, 64 and 88 by PCR™ Cobas. 
Likewise, PCR-based assessment of histological samples will occur at Screening and Weeks 
36 and 64. 
 
For testing of non-anal sites, vaginal, cervical (female subjects), penile (male subjects), and 
oropharyngeal (OP) samples (all subjects) will be obtained to characterize HPV infection at 
Day 0, and at Weeks 4,15, 28, 36, 64 and 88. 
 
 
HLA haplotyping: A PBMC sample from any sample collected during the study will be tested 
to explore the relationship between subject HLA haplotypes and regression. 
 
 

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HPV-203 
Inovio Pharmaceuticals, Inc. 
 
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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 Card (PCD). 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the 
duration of the study. 
 
All subjects will be followed to Week 88. 
 
Data Safety & Monitoring Board (DSMB): An independent 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. Refer to Section 3.8 for stopping rule criteria. 
 
Definition of Responder and Non-Responder for Primary Endpoint: 
 
Responder and non-responder definitions (Table 2) take into account both histopathologic 
regression of anal or anal/peri-anal HSIL and virologic (HPV-16/18) clearance as measured 
by intra-anal and/or peri-anal tissue since HPV persistence is an important factor in the 
clinical progression of HSIL. Any case of histologically confirmed progression from HPV-16/18 
positive anal or anal/peri-anal HSIL to carcinoma is considered a non-responder. 
 
Table 2: Definition of Responder and Non-Responder for Primary Endpoint 
 
Responder 
Non-Responder 
 
 
No histologic evidence of anal or anal/peri-
anal HSIL 
 
AND 
 
Negative PCR for HPV-16 or HPV-18 in 
anal lesion tissue  
 
 
AND 
 
No non-study treatment of curative intent of 
intra-anal and/or peri-anal lesions 
 
 
 
 
 
 
Histologic evidence of anal or anal/peri-anal  
HSIL, anal Adenocarcinoma-in-situ (AIS), 
anal or anal/peri-anal carcinoma 
 
OR 
 
PCR positive for HPV-16 or HPV-18 in anal 
lesion tissue  
 
 
OR 
 
Any non-study treatment of curative intent of 
intra-anal and/or peri-anal lesions 
 

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Study Population: 
Inclusion: 
1. Must understand, agree and be able to comply with the requirements of the protocol 
and be able to provide voluntary consent to participate and sign an Informed Consent 
Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2 within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16 and/or HPV-18 infection at Screening by 
PCR from HSIL specimen; 
5. Anal tissue specimens/slides provided to the Study Pathology Adjudication 
Committee (PAC) for diagnosis must be collected within 10 weeks of first dose of 
VGX-3100; 
6. At least one anal or anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
a. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) should 
not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology collection 
procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
a. Post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level 
>40mlU/mL; 
b. Surgically sterile due to absence of ovaries or due to bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
c. Subject agreement to avoid pregnancy for one month after last dose (Week 
12 or Week 40); 
d. Women of Child Bearing Potential (WOCBP) are willing to use a 
contraceptive method with a failure rate of less than 1% per year when used 
consistently and correctly from Screening until one month following the last 
dose of investigational product (Week 12 or Week 40). The following are 
acceptable methods: 
i. Hormonal contraception: either combined progestin-alone including 
oral contraceptive, 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. Men who would father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, for 
the duration of study participation and one month after completion of VGX-3100 
administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
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Exclusion: 
1. Untreated micro invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAIN; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing medical 
care and/or treatment for VIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CIN; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing medical 
care and/or treatment for PIN; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument; 
7. Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; 
8. Inability to have completed and satisfactory high resolution anoscopic exams (HRAs) 
as defined by full visualization of the anus, entire anal canal from the 
squamocolumnar junction at the border of the distal rectum, anal transformation zone, 
distal canal, anal verge, perianus;  
9. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
Screening; 
10. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
11. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 45 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; 
12. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) or oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 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. Prior chemotherapy within 1 year; 
f. History of solid organ or bone marrow transplantation; 
13. History of previous therapeutic HPV vaccination (however, licensed prophylactic HPV 
vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
14. Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-3100 
dose; 
15. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of 
any VGX-3100 dose; 
16. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
17. 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 
the study results (e.g. chronic renal failure, angina, myocardial ischemia or 
infarctation, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
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18. Treatment for non-anogenital malignancy within 2 years of Screening, with the   
exception of superficial skin cancers that only require local excision; 
19. 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; 
20. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
21. 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; 
22. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
23. Prior major surgery within 4 weeks of Day 0; 
24. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent form (participating in an observational 
study is permitted); 
25. 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 on the ipsilateral side (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); 
26. Any illness or condition that in the opinion of the Investigator may affect the safety of 
the subject or evaluation of any study product; 
27. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 personnel; 
d. Study-related staff or family members of study-related staff 
 

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TRIAL SCHEDULE OF EVENTS 
 
Table 3: Schedule of Events 
 
 
 
1 Subject eligibility will be reconfirmed at every visit. 
 
Study Action 
Screen  (-10 wk. to -1d) 
Day 0 
8-14 days post dose 1 Phone Call 
Week 4 (± 4 days) 
8-14 days post dose 2 Phone Call 
Week 12 (± 4 days) 
Week 15 (± 1 Week) 
Week 28 (± 1 Week)  
Week 36 (± 1 Week) 
Week 40 (± 1 Week) 
8-14 days post dose 4 Phone Call 
Week 64 (± 2 Weeks) 
Week 88 (± 2 Weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
X 
 
 
Xo 
X 
Inclusion/Exclusion criteria1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
Xb 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Screening 
safety 
(12 
lead 
ECG, 
laboratories) c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d   
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xf 
 
Xe 
 
 
Xe 
Xe 
HLA testing g  
X 
Oropharyngeal (OP) rinse 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Vaginal, cervical, and penile swab 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Intra-anal and/or peri-anal swab 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Digital 
Anal 
Rectal 
Examination 
DARE h 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
High Resolution Anoscopy (HRA) i 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Lesion photography j 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Biopsy k  
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Inject VGX-3100 +EPl   
 
X 
 
X 
 
X 
 
 
 
Xl 
 
 
 
Post treatment reaction assessment 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Distribute Participant Diary Card (PDC) 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Review PDC m 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Patient Reported Outcomes (PROs) 
(SF-36v2™) (EQ-5D-5L) n 
 
Xp 
X 
X 
X 
X 
X 
 
X 
X 
Xq 
X 
X 

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a Full Physical exam (PE) mandatory at Screening and study discharge (Week 88), 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 body mass 
index (BMI) (Bodyweight in kilograms divided by height in meters squared). Weight will be 
collected at all dosing visits. 
c Screening 12-lead Electrocardiogram (ECG), complete blood count (CBC), serum electrolytes, 
blood urea nitrogen (BUN), creatinine (Cr), glucose, alanine aminotransferase (ALT), and 
Creatine Phosphokinase (CPK) performed within 45 days prior to first dose administration. 
d Negative spot urine pregnancy test is required for female subjects at Screening, prior to each 
study treatment, high-resolution anoscopy (HRA), and biopsy/surgical excision; the pregnancy 
test at Week 40 would only be needed for subjects who receive an additional dose. 
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 15. 
g Human Leukocyte Antigen (HLA) testing will be performed once from an existing Peripheral 
Blood Mononuclear Cells (PBMC) sample. 
h Digital Anal Rectal Examinations (DARE) are to be performed once cytology has been 
collected and prior to HRA. 
i An additional visit may be scheduled to perform HRA if worsening of disease is suspected. 
Biopsies should not be performed at any visit other than at entry (Screening) and Weeks 36 and 
64 for Subgroup C unless the Investigator suspects invasive cancer. All biopsy samples and/or 
excision samples must be sent to the Pathology Adjudication Committee (PAC) for review. 
j Photography of qualifying  lesion(s) must be performed prior to and after biopsy, and at all HRA 
examinations. If a pre-biopsy digital photograph is not available for a historical biopsy sample at 
Screening, a post biopsy photo will be sufficient. Photographs of intra-anal lesion(s) will be for 
documentation purposes only. Photographs of peri-anal lesion(s) will be analyzed with a 
computer program to assess the percent reduction in the cumulative surface area of the peri-
anal lesion(s) as determined by the quantitative analysis of standardized pre-biopsy 
photographic imaging of qualifying lesion(s) at Weeks 36, 64, and 88 compared to baseline.  
k Tissue specimen and slides from all excised tissue lesion(s) that led to eligibility at study entry 
must be reviewed by the PAC and residual tissue from entry and Weeks 36 and 64 specimen(s) 
(paraffin blocks) must be sent to the central laboratory for immune analysis and Human 
Papillomavirus (HPV) testing.  
l Potential dosing at Week 40 is applicable for partial responders only.  
m A phone call will be used to review the Participant Diary Card (PDC) with subject within 8-14 
days following doses 1 and 2. The patient will be expected to bring the PDC to the next visit for 
review. Subjects who receive an additional 4th dose will have a phone call 8-14 days post dose 
4 where the PDC will be reviewed.  
n Patient-reported outcome (PRO) measures (SF-36v2™ and the EQ-5D-5L), plus two 
additional "global" questions will be assessed as described in Section 6.13. 
o This socio-behavioral assessment will only apply to those subjects in Subgroup C who receive 
a 4th dose of investigational product. 

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p PROs must be administered prior to first dose of study drug.  
q PROs will only be for subjects who received a 4th dose of study drug. 
 

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1.0 
INTRODUCTION 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized 
primarily in the ano-genital area and aero-digestive tract, in both men and women. 
Human Papillomavirus 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). In the United States (US), approximately 14 million new genital HPV infections 
occur annually, and approximately half of these infections are with a high-risk HPV type 
(HR-HPV) and thus can cause cancer [2]. In U.S. adults through age 59 years, about 
25% of men and 20% of women have genital HR-HPV infection [3]. Human 
Papillomavirus causes more cancers than any other virus. In U.S. archival tissues of 
cancers diagnosed from 1993 to 2005, HPV Deoxyribonucleic Acid (DNA) was detected 
in 68.8% of vulvar, 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of 
oropharyngeal (OP), 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) [4]. An average of over 
30,000 cases per year of HPV-attributable cancer were diagnosed during the period 
2008 through 2012 in the U.S. [5]. Human Papillomavirus-16 and HPV-18 are the most 
significant among high-risk types since they are responsible for most HPV-caused 
cancers [4].  
With regard to anal cancer, about 95% of cases are caused by HPV, and most of those 
cases are caused by HPV-16 [6, 7]; with some by HPV-18 and perhaps other HPV 
genotypes [2]. An estimated 8,200 new cases of anal cancer in the US are diagnosed 
each year (for year 2017), with an estimated 1,100 deaths annually due to this cancer 
[8]. In Canada, the latest available data is for year 2013, during which 580 new cases of 
anal cancer were diagnosed and 144 persons died due to anal cancer [9]. 
The precursor lesion to HPV-associated anal cancer historically was known as anal 
high-grade dysplasia or intraepithelial neoplasia. In 2012, the Lower Anogenital 
Squamous Terminology (LAST) Standardization Project for HPV-associated lesions 
applied the term HSIL to encompass high grade dysplasia [10]. Among HPV-associated 
anal HSIL cases in the US, about 55% to 80% are associated with HPV-16/18, and 
worldwide about 80% of cases are associated with HPV-16/18 [7, 11, 12]. 
Left untreated, anal HSIL may progress to cancer. Spontaneous regression of these 
lesions may occur, but the available data indicate that such regression is in the minority 
of cases. For example, published results of a small observational study of anal HSIL in 
men who have sex with men (MSM) in Australia found spontaneous regression occurred 
in 29% of those HIV-negative after more than one year of follow-up time, with an even 
lower regression rate in those who were HIV-positive. That study also found that the 
majority (71%) of patients who regressed only did so to anal low-grade SIL (Low grade 
squamous intraepithelial lesion [LSIL]), with the remainder to normal tissue [13]. In an 
ongoing larger observational study of gay and bisexual men – the Study of the 
Prevention of Anal Cancer (SPANC) [14] -- also comprised of patients HIV-negative and 
HIV-positive (though with medically well-controlled CD4 cell counts), preliminary 
published data show that 55% of patients with anal HSIL, regardless of HIV status, had 
their HSIL persist to at least 12 months and HPV-16 was significantly associated with 
persistence as compared to other HPV genotypes (Relative Risk of 1.5) [15].  
 

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Spontaneous regression data from that study are not yet published, but preliminary data 
show spontaneous regression of only about 20% by one year of follow-up. Further, many 
of those patients who regressed later recurred to HSIL, suggesting that HSIL in some 
cases may be merely regressing to a level below the detection limit but is still present 
[16]. Other published data from a sub-study of that larger study indicate that HPV-16 E6-
specific T-cell responses may be associated with recent anal HSIL regression (Pexact = 
0.065) [17]. That finding provides further plausibility, in addition to other data 
summarized later in this protocol, that VGX-3100 plus electroporation treatment could 
cause anal HSIL regression. 
Anal HPV infection spontaneous clearance in non-immunocompromised adults can 
occur, but such data are generally unavailable for persons who have anal HSIL. 
Nevertheless, high-risk HPV (HR-HPV) clearance by one year ranges from 56% to 78%, 
varying by gender and sexual preference etc., as found in large, prospective studies [18-
20] with some wider variation in clearance rates for HPV-16 and HPV-18 specifically in 
those studies. 
Collectively, the aforementioned anal HSIL regression and HPV clearance data 
comprise in part the historical control data that the results of the present trial will be 
compared to. 
1.1.1 
VGX-3100 
VGX-3100 contains plasmids that target 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 (IP) designed as a non-surgical 
treatment of HPV-16/18-related anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, and 
PAIN3) via an immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was Water for Injection (WFI) with 1% w/w poly-L-
glutamate (WFI/LGS) that required frozen storage. This frozen formulation has been 
administered to more than 250 subjects in Phase 1 and 2 clinical trials. A buffered 
formulation of VGX-3100 was developed using a saline sodium citrate (SSC) solution, 
which is stored non-frozen (5°C). This non-frozen formulation of VGX-3100 was 
administered to 117 subjects in a Phase 1 clinical trial, HPV-101 in which subjects were 
randomized 1:1 to receive the non-frozen or frozen formulation of VGX-3100. In study 
HPV-101, healthy adults received three 6 mg IM doses of VGX-3100 in the frozen or 
non-frozen formulations followed by EP with the CELLECTRA™ 5Pdevice. The non-
frozen formulation was found to be non-inferior to the frozen formulation based upon a 2-
fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the plasmids 
per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ enzyme-linked immunospot (ELIspot) assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, 
placebo-controlled Phase 2b study of VGX-3100 (frozen formulation) followed by EP in 
the treatment of high grade cervical dysplasia, cervical HSIL associated with HPV-16/18 
[1]. The Phase 2b study, HPV-003, enrolled 169 subjects with high grade cervical 
dysplasia from seven countries and one US Territory (Australia, Canada, Estonia, 
Republic of Georgia, India, South Africa, US and Puerto Rico). Subjects were 
randomized in a 3:1 ratio to treatment with VGX-3100 or placebo, respectively. All 

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subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to 
repeat cervical biopsy or Loop Electrical Excision Procedure (LEEP) of the cervix at 
Week 36 to assess efficacy defined as regression of high grade Cervical Intraepithelial 
Neoplasia (CIN) by histopathology. The primary endpoint was histopathologic regression 
of cervical lesions (CIN2 or CIN3) to Grade 1 Cervical Intraepithelial Neoplasia (CIN1) or 
less at the Week 36 visit. A secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less. The 
proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol (PP) and modified Intent 
to Treat (mITT) analyses. Robust T-cell activity was detected in VGX-3100 recipients 
compared to placebo recipients. VGX-3100 was generally safe and well tolerated when 
administered intramuscularly with electroporation. 
1.1.2 
ELECTROPORATION 
CELLECTRA® 2000 & CELLECTRA™ 5PSP are both electroporation (EP) devices 
developed by INOVIO. Electroporation with CELLECTRA™5PSP is a physical method of 
tissue transfection whereby the generation of short, controlled electrical pulses creates a 
localized electrical field at the injection site which increases cell membrane permeability 
and improves the transfection of DNA and subsequent immunogenicity [21, 22]. EP is 
believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced immunogenicity by 10 to 100 fold [23, 24]. 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 [21]. The CELLECTRA™ device developed by INOVIO is used for 
investigational purposes to administer plasmid-based DNA, in both prophylactic and 
therapeutic settings. Following successful proof-of-concept studies in animals, INOVIO 
has optimized both pulse pattern and voltage to increase transfection efficiency, and has 
demonstrated that the device helps to elicit favorable immunogenicity in several species 
(e.g., mice, pigs, and rhesus macaques) [22, 23]. 
A next generation device, CELLECTRA™ 5PSP, was created to address ergonomic 
functionality and automate the delivery of VGX-3100 and EP. The technology differences 
between the CELLECTRA® 2000 and CELLECTRA™ 5PSP design do not affect the 
intended mechanism of EP on the activity of VGX-3100 and will not present any new 
risks. The device design change does not affect the indications for use, operating 
principle, energy type, or sterilization specifications. The CELLECTRA™ 5PSP has been 
approved for investigational use in the U.S. with VGX-3100 and is being used in a Phase 
3 clinical study HPV-301, titled "A Prospective, Randomized, Double-blind, Placebo-
Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly (IM) followed by 
Electroporation with CELLECTRA™ 5PSP for the Treatment of HPV-16/18 related HSIL 
of the Cervix". Together, VGX-3100 and the CELLECTRA™ device represent an 
integrated product designed as a non-surgical treatment for HPV-16/18-related cervical 
HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Inovio Pharmaceuticals Inc. device experience demonstrates that delivery of its 
proprietary electroporation pulses into muscle immediately following injection of DNA 
plasmids (including VGX-3100) is well-tolerated in humans and no significant safety 
issues have been identified [1, 22, 24]. For further information concerning the 
CELLECTRA™ 5PSP device please refer to the User Manual and the Investigator's 
Brochure. 

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1.1.3 
DOSE RATIONALE 
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 the 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. 
This dose-trend was consistent with prior expectation, a feature of the finding that 
suggests it is a true effect rather than random variation. Adverse events (AEs) from 
previous human studies with VGX-3100 and closely related DNA plasmid products have 
been limited to injection site pain from the injection and electroporation procedure, which 
were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in HPV-003, 
Phase 2b study. The results obtained in the phase HPV-003 suggest that the 6 mg dose 
was efficacious with an acceptable safety profile, therefore the 6 mg dose will also be 
evaluated in this Phase 2 trial [1]. 
1.2 
POTENTIAL BENEFITS 
Currently accepted surgical treatments are associated with a high recurrence rate, 
>50%. The current surgical approaches also have risks inherent with any surgical 
procedure including anesthesia, post-operative bleeding, infection, or damage to 
surrounding structures such as the anus. This study has been designed to provide non-
surgical treatment with an aim of regression of the anal or anal/peri-anal HSIL and thus 
avoiding the need for surgical excision, infrared coagulation, electrocautery and laser 
therapy. In the absence of complete resolution of intra-anal and/or peri-anal lesions, 
there would still be potential benefit from a partial response, which would reduce or 
minimize the need for excisional or ablative treatment modalities. 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. Consequently, there is the potential to reduce the risk 
of recurrence of anal or anal/peri-anal HSIL. 
1.3 
POTENTIAL RISKS 
Risks associated with VGX-3100 for the treatment of anal or anal/peri-anal HSIL are 
injection site reactions related to the IM injection and/or electroporation. Based on the 
phase 1 and 2 clinical experience with VGX-3100 with healthy volunteers and in women 
with cervical HSIL, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at 
most. 
A potential risk is the delay of surgical intervention of the high grade anal dysplasia and 
possible missed diagnosis of an occult early invasive cancer for the VGX-3100 non-
responders, who do not spontaneously regress. Although professional guidelines 
typically advocate excisional therapy for adults with HSIL, scientific data indicates that 
the rate of progression from pre-invasive to invasive cervical disease is slow, typically 
thought to take several years [10]. The risk of a missed diagnosis of an occult early 
invasive cancer exists for all current treatment modalities including surgical and ablative 
therapies. To mitigate these potential risks the study design includes numerous 
safeguards to detect disease progression or the presence of an undiagnosed occult 

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early invasive cancer. These include, careful selection of immunocompetent patients, 
thorough screening and baseline evaluation, frequent High-resolution anoscopy (HRA) 
and high-risk HPV testing throughout the trial. Investigators will be comprised of 
experienced physicians, who will have the discretion to obtain biopsies at any point if 
disease progression is suspected. 
An independent Data and Safety Monitoring Board (DSMB) will also advise the Sponsor 
if it appears that the frequency of regression is unacceptably low. These measures 
should minimize the risk of progression of the HSIL and the risk of harboring an 
undiagnosed occult early invasive cancer.  
In the HPV-003 study of women with cervical HSIL, the percentage of subjects with 
micro-invasive cancer found in larger surgical excision samples in subjects who had no 
evidence of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is 
consistent with and even lower than the 6.7% that has been reported under standard of 
care settings [18]. 
For further information concerning the risks associated with VGX-3100 and the 
CELLECTRA™5PSP device please refer to the Investigator's Brochure. 
2.0 
PURPOSE AND HYPOTHESIS 
2.1 
PURPOSE 
To provide a treatment to potentially regress and clear HPV-16/18 related anal or 
anal/peri-anal HSIL in individuals that are seronegative for HIV-1/2. 
2.2 
HYPOTHESIS 
VGX-3100 followed by electroporation (EP) administered to adults with histologically 
confirmed anal or anal/peri-anal high-grade squamous intraepithelial lesions, HSIL, 
(AIN2, AIN3, PAIN2, PAIN3) associated with HPV-16/18 will result in a higher proportion 
with histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence 
of anal or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than 
historical controls. 
3.0 
TRIAL DESIGN AND ENDPOINTS 
HPV-203 is a Phase 2, 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 
in adult men and women who are HIV negative with histologically confirmed anal or 
anal/peri-anal HSIL associated with HPV-16 and/or 18. Approximately 24 subjects will 
receive at least 3 doses of VGX-3100. Each dose of VGX-3100 will be administered in a 
1 mL volume IM followed immediately by EP. As shown in Figure 1, study subjects will 
receive at least 3 doses of VGX-3100 depending upon their disposition with regard to 
histologic and lesion area changes during the trial. The first dose will be administered on 
Day 0, the second at Week 4, and the third at Week 12. Partial response to VGX-3100 
may still be of medical importance by being able to limit the extent of surgery necessary. 
For partial responders at Week 36, a fourth dose may be administered at Week 40. All 
subjects are scheduled to be followed to Week 88.  
To be eligible for the study, subjects must consent to participate and agree to the 
collection of anal lesion tissue samples for anal cytology and genotyping, a Digital Anal 
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Antigen (HLA) assessments, HRA and HRA guided biopsies. All intra-anal and/or peri-
anal lesion(s) of adequate size (≥ 4mm) will be biopsied at Screening. 
Biopsy slides 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 anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the 
biopsy sample(s). Once the PAC confirms HSIL at Screening, the Week 36 and 64 
biopsies will be obtained from all HSIL site(s) confirmed by the PAC at Screening, unless 
the Investigator suspects disease progression. Subjects must also have intra-anal and/or 
peri-anal lesion tissue 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 administered and will include the Short Form Health Survey 
version 2 (SF-36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional 
PRO questions assessing quality of life after surgery or biopsy. 
3.1 
PRIMARY OBJECTIVE(S) 
Determine the efficacy of 3 doses of VGX-3100 with respect to combined histopathologic 
regression of anal or anal/peri-anal HSIL and virologic clearance of HPV-16/18 
3.2 
PRIMARY ENDPOINT(S) 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal HSIL on 
histology (i.e., collected via biopsy or excisional treatment) and no evidence of HPV-
16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue 
3.3 
SECONDARY OBJECTIVE(S) 
 
Evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP 
 
Determine the efficacy of three doses of VGX-3100 as measured by histologic 
regression of anal or anal/peri-anal HSIL 
 
Determine the efficacy of VGX-3100 as measured by virologic clearance of 
HPV-16/18 by testing from lesion tissue 
 
Determine the efficacy of VGX-3100 as measured by virologic clearance of 
HPV-16/18 by intra-anal tissue swab testing 
 
Determine the efficacy of three doses of VGX-3100 as measured by complete 
histopathologic regression of anal or anal/peri-anal HSIL to normal tissue 
 
Determine the efficacy of three doses of VGX-3100 as measured by 
histopathologic non-progression of anal or anal/peri-anal HSIL 
 
Describe the efficacy of VGX-3100 for partial responders, as measured by 
reduction in the number of intra-anal and/or peri-anal lesion(s), as applicable and 
the reduction in the size of peri-anal lesion(s), if present, and for whom the 
disease has not progressed according to Investigator judgment in subjects who 
did not have anal or anal/peri-anal HSIL lesion resolution at Week 36 
 
Determine the humoral and cellular immune response following administration of 
VGX-3100 at post dose 3, and after additional dosing compared to baseline 

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3.4 
ASSOCIATED SECONDARY ENDPOINT(S) 
 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary Card (PDC) 
 
All AEs including Serious Adverse Events (SAES), unanticipated (serious) 
adverse device effect (UADE), and other unexpected AEs for the duration of the 
study (through the Week 88 visit) 
 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (e.g. biopsies or excisional treatment) at the Week 36 visit 
 
Proportion of subjects with no evidence of HPV-16/18 from intra-anal and/or 
peri-anal tissue by type specific HPV testing at the Week 36 visit 
 
Proportion of subjects with no evidence of HPV-16/18 from intra-anal swab by 
specific HPV testing at the Weeks 36, 64, and 88 visits 
 
Proportion of subjects with no evidence of anal or anal/peri-anal LSIL or HSIL 
(i.e. no evidence of AIN2, AIN3, PAIN2, and PAIN3) on histology (i.e. biopsies or 
excisional treatment) at the Week 36 
 
Proportion of subjects with no progression of anal or anal/peri-anal HSIL to 
carcinoma from baseline on histology (i.e. biopsies or excisional treatment) at the 
Week 36 visit 
 
Percent reduction in the number of intra-anal and/or peri-anal lesion(s) and the 
size of peri-anal lesion(s) if present, as determined by the Investigator at Weeks 
36, 64, and 88 compared to baseline. For all peri-anal lesion(s), digital photos will 
be analyzed with a computer program to assess the percent reduction in the 
cumulative surface area of the peri-anal lesion(s) as determined by the 
quantitative analysis of standardized pre-biopsy photographic imaging of the 
qualifying lesions at Weeks 36, 64, and 88 compared to baseline 
 
Levels of serum anti-HPV-16 and anti-HPV-18 antibody (Ab) concentrations at 
baseline and the Weeks 15, 36, 64, 88 visits 
 
Interferon- γ ELISpot response magnitudes at baseline, and the Weeks 15, 36, 
64, and 88 visits 
 
Flow Cytometry response magnitudes at baseline and Week 15 visits 
3.5 
EXPLORATORY OBJECTIVE(S) 
 
Describe the efficacy of more than 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and 
virologic clearance of HPV-16/18 
 
Describe the efficacy of more than 3 doses of VGX-3100, as measured by 
histologic regression of anal or anal/peri-anal HSIL 
 
Describe the efficacy of more than 3 doses of VGX-3100, as measured by 
virologic clearance of HPV-16/18 
 
Evaluate tissue immune responses to VGX-3100 in intra-anal and/or peri-anal 
samples 
 
Describe the clearance of HPV-16/18 infection from non-anal anatomic locations 

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 
Evaluate the effect of HLA type on efficacy 
 
Describe the association of microRNA (miRNA) profile, previous anoscopy, 
cytology and HPV testing results with Week 36 histologic regression 
 
Describe PRO for subjects treated with VGX-3100 
3.6 
ASSOCIATED EXPLORATORY ENDPOINT(S) 
 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal 
HSIL on histology (i.e. collected via biopsy or excisional treatment) and no 
evidence of HPV-16/18 at Week 64 by testing from intra-anal and/or peri-anal 
lesion tissue 
 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (i.e. biopsies or excisional treatment) at Week 64 for subjects who 
receive 4 doses of VGX-3100 
 
Proportion of subjects with no HPV-16/18 at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue for subjects who receive 4 doses of VGX-3100 
 
Assessment of proinflammatory and immunosuppressive elements in tissue, 
where feasible.  
 
Proportion of subjects who have cleared HPV-16/18 on specimens from non-
anal anatomic locations as applicable based upon gender (i.e. oropharynx, 
cervical, vaginal, and penile at Week 36 visit) 
 
HLA (per-locus and per-allele basis) in conjunction with histologic regression of 
anal or anal/peri-anal HSIL at Week 36 visit 
 
HRA, cytology, and HPV test results and miRNA profile (baseline and at Weeks 
15, 28, and 36) in conjunction with histologic regression of anal or anal/peri-anal 
HSIL at the Week 36 visit 
 
Patient reported outcome endpoints will be obtained prior to first dose (Day 0), on 
the day of and following each dose, and at Weeks 36, 64, and 88. There will be 
an additional PRO assessment at Week 40 if a subject receives a 4th dose. 
3.7 
EFFICACY ASSESSMENT 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesions of 
adequate size (≥4mm). Visible lesions observed during HRA should be large enough to 
biopsy, but the biopsy (typically 4mm) should not remove the entire lesion in order to 
allow for continued lesion measurement while on the study.  
Given that HPV infection persistence is a critical factor in the clinical progression of 
HPV-associated anal or anal/peri-anal HSIL and also based upon the findings of the 
secondary objective of the HPV-003 CIN2/3 proof of concept study, the responder 
definition for the HPV-203 primary endpoint determination requires both histological 
regression of anal or anal/peri-anal HSIL and clearance of HPV-16 and HPV-18 [1]. 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic 
assessment of intra-anal and/or peri-anal tissue obtained from biopsies. All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥4mm) will be biopsied at Screening. Once 
the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be obtained from 
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disease progression. Tissue will be analyzed for evidence of histopathologic regression. 
Clearance of HPV-16/18 will be determined using the by type specific HPV polymerase 
chain reaction (PCR) test SPF10 on intra-anal and/or peri-anal tissue performed at 
Screening and Weeks 36 and 64 when applicable. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0 (prior to dosing) 
and Weeks 4, 15, 28, 36, 64 and 88 as a less invasive measure for exploratory purposes 
to determine the presence of HPV-16 and/or -18 as well as other high risk HPV types 
using Cobas HPV testing. Similarly, vaginal, cervical (female subjects), penile (male 
subjects) and OP rinse samples (all subjects) will be obtained at Day 0 (prior to dosing), 
and at Weeks 4, 15, 28, 36, 64, and 88 to assess systemic virologic response to 
treatment. 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction 
in intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size 
from baseline (Subgroup C), the Investigator will have the option to administer a 4th 
dose of VGX-3100 at Week 40 and the subject will continue on the study with HRA and 
biopsy at Week 64, i.e. the second efficacy checkpoint. Alternatively, the Investigator 
may choose to treat the subject with standard of care treatment (i.e. electrocautery, 
ablation, surgical excision), and the subject will continue on the study without further 
biopsy unless it is part of the standard of care. All tissue samples obtained from biopsies 
or removed per standard of care will be sent to the PAC for review. 
3.8 
SAFETY ASSESSMENT 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the 
PDC. 
2) All AEs including SAEs, UADEs, and other unexpected AEs for the duration of the 
study. 
All subjects will be followed for 88 weeks. 
Data Safety & Monitoring Board (DSMB): An independent 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, PI for the trial, and the DSMB. 
 
If any SAE (or potentially life-threatening AEs) 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 AEs, 
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. 

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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, 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. 
3.9 
IMMUNOGENICITY ASSESSMENT 
Humoral and cell mediated immune responses in response to VGX-3100 treatment may 
be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, and 88. Intra-anal and/or peri-anal tissue samples may 
also be analyzed for evidence of proinflammatory and immunosuppressive elements at 
Week 36 as compared to baseline (Screening), where feasible. 
4.0 
TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
1. Must understand, agree and be able to comply with the requirements of the 
protocol and be able to provide voluntary consent to participate and sign an 
Informed Consent Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2 within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by PCR from 
HSIL specimen; 
5. Anal tissue specimen/slides provided to the Study PAC for diagnosis must be 
collected within 10 weeks of first dose of VGX-3100; 
6. At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
i. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) 
should not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology 
collection procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
i. Post-menopausal as defined by spontaneous amenorrhea for more than 
12 months or spontaneous amenorrhea for 6-12 months with follicle-
stimulating hormone (FSH) level >40mlU/mL; 
ii. Surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
iii. Subject agreement to avoid pregnancy one month after last dose of IP 
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iv. Women of Childbearing 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 one month following 
the last dose of IP (Week 12 or Week 40). The following are acceptable 
methods: 
1. 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); 
2. Abstinence from penile-vaginal intercourse when this is the 
subject's preferred and usual lifestyle; 
3. Intrauterine device or intrauterine system; 
4. 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. Men who could father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, 
for the duration of study participation and one month after completion of VGX-
3100 administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 
4.2 
EXCLUSION CRITERIA 
1. Untreated micro invasive or invasive cancer; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAIN; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing 
medical care and/or treatment for VIN; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not 
undergoing medical care and/or treatment for CIN; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing 
medical care and/or treatment for PIN; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy 
instrument; 
7. Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; 
8. Inability to have complete and satisfactory high resolution anoscopic exams 
(HRAs) as defined by full visualization of the anus, entire anal canal from the 
squamocolumnar junction at the border of the distal rectum, anal transformation 
zone, distal canal, anal verge, perianus; 
9. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
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10. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
11. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 45 days prior 
to Day 0 or less than Grade 1 but deemed clinically significant by the 
Investigator; 
12. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or 
clinically diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) of oral or parenteral glucocorticoids at a dose of 
≥20 mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 
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 Tumor Necrosis Factor 
(TNF)-α inhibitors (e.g. infliximab, adalmumab or etanercept); 
e. Prior chemotherapy within 1 year; 
f. History of solid organ or bone marrow transplantation; 
13. History of previous therapeutic HPV vaccination (however, licensed prophylactic 
HPV vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
14. Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-
3100 dose; 
15. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 
weeks of any VGX-3100 dose; 
16. Significant acute or chronic medical illness that could be negatively impacted by 
the electroporation treated as deemed by the Investigator; 
17. 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 (e.g. chronic renal failure, angina, myocardial ischemia or 
infarction, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 
18. Treatment for non-anogenital malignancy within 2 years of Screening, with the 
exception of superficial skin cancers that only require local excision; 
19. Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of a 
study dose;  
20. History of seizures unless seizure free to 5 years with the use of one or fewer 
antiepileptic agents; 
21. 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; 

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22. Resting heart rate <50 beats per minute (bpm) (unless attributable to athletic 
conditioning) or >100 bpm at Screening or Day 0; 
23. Prior major surgery within 4 weeks of Day 0; 
24. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing the ICF (participation in an observational study is 
permitted); 
25. 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-defibrilator or pacemaker on the ipsilateral side (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); 
26. 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; 
27. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 (involuntary 
incarcerated) for treatment of either a psychiatric or physical (i.e. 
infectious disease) illness; 
c. Active military service personnel; 
d. Study-related staff or family members of study-related staff 
4.3 
DISCONTINUATION/WITHDRAWAL OF TRIAL SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION FROM THE STUDY 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from further treatment with VGX-3100. Subjects will not receive further 
doses of VGX-3100 followed by 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 VGX-3100/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
4.3.2 
CRITERIA FOR WITHDRAWAL FROM STUDY 
Subjects who become ineligible to continue on the study based on no longer meeting the 
inclusion criteria should be discontinued from study treatment and managed per routine 
standard of care but should continue on the study without further biopsy.  
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 

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should also counsel the subject on the importance of maintaining the assigned visit 
schedule for follow-up and treatment of anal or anal/peri-anal HSIL, 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 the subject 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 they 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 3). At 
a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 88). A subject will be considered 
to have completed the study when he/she completes all scheduled study treatments and 
follow-up visits. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or trial coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the trial or 
is withdrawn from the trial prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation. 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. 
4.3.4 
REASONS 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 of a subject, (including manner of death if known) 
 
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 
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Investigator must consult the Medical Monitor before withdrawing a subject from 
participation in the study. 
 
Protocol Deviation: 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. 
 
Other: The subject was terminated for a reason other than those listed above, 
such as the termination of the study by the Sponsor. 
If more than 10% of subjects who receive study treatment and discontinue prior to Week 
36, primary endpoint procedures, then supplementation of study subjects will be 
considered. 
 
5.0 
TRIAL TREATMENT 
5.1 
INVESTIGATIONAL BIOLOGIC PRODUCT  
The IP to be used in this trial is described in Table 4. The IP will be presented in a clear 
glass cartridge and injected intramuscularly. 
Table 4: Investigational Biologic Product 
 
 
5.2 
CELLECTRA™ 5PSP DEVICE DESCRIPTION: 
VGX-3100 will be delivered using the CELLECTRA™5PSP device. The device consists 
of five (5) main components (see  
Figure 3). 
 
 
 
 
 
 
 
 
 

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Figure 3: CELLECTRA™5PSP Base Station with Handset 
 
 
 
Base Station 
The base station communicates instructions, alerts, and error messages to the user through a 
touch screen graphical user interface (GUI). It also accepts data inputs from the user, e.g., 
patient identification code, height, and weight; it communicates with the handset; provides 
energy access for the system through connection with standard wall electrical power supply 
sources (100-220V, ~0.5Amp, 50-60Hz); and serves as a docking and recharging station for the 
handset.   
Handset 
The handset facilitates delivery of the needles for injection and electroporation into the muscle 
tissue and executes the treatment sequence (drug injection, impedance check, and 
electroporation pulses). It has a display screen and speakers for user feedback and an 
embedded processor for running the system software that controls and measures all of the 
elements of the handset. The handset is powered by a custom, rechargeable battery pack that 
has its own safety circuit and is compliant to International Ethics Committee (IEC) 62133 and UL 
2054. The handset is designed with three independent fail-safes to minimize the risk of electrical 
shock, short, or fire. 
Array 
The array is a single-use, sterile, disposable component constructed of commonly-used medical 
plastics and metals, with 5 fixed, stainless-steel electrodes (needles) and 1 IM injection needle. 
The needles are covered by a plastic shroud that retracts as the needles are inserted into the 
patient, then returns to the starting position as the needles are removed and locks out to prevent 
accidental needle sticks. The opposite end of the array accepts the drug cartridge, which is 
inserted cap-end-first until the bottom of the cartridge is flush with the opening of the array 

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(indicated by an audible 'click'). When properly inserted, the septum is punctured and the 
cartridge cannot be removed. The 5PSP Array features no software. 
The base station and handset with the 5PSP Array are illustrated in  
Figure 3. 
5.3 
TREATMENT REGIMEN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the 
HPV-003 study, therefore all eligible subjects who consent to participate in the HPV-203 
study will receive the same three 6 mg doses of VGX-3100 administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment will 
be administered on Day 0, the second at Week 4, and the third at Week 12.  A fourth 
dose may be administered at Week 40. 
The first study treatment will be given as soon as possible following confirmation of anal 
or anal/peri-anal HSIL diagnosis and HPV-16/18 status but no more than 10 weeks 
following collection of the subject's biopsy specimen used for diagnosis by the PAC 
during Screening, concurrent with the positive testing for HPV-16/18. 
5.4 
PACKAGING AND HANDLING 
Each cartridge will be labeled with a single-panel label and then individually packaged 
within a pouch that will contain an additional, single-panel label with tear-off. The VGX-
3100 label will include, at minimum, the following information in Table 5. 
 
Table 5: Example of Packaging and Label Information 
Cartridges 
(primary container) 
Pouches 
(secondary packaging) 
 
 
 
 
LABEL 
 
VGX-3100 
Insert cap end 
Sponsor name 
IM administration 
Investigational Use Only 
LABEL BODY 
Study ID 
VGX-3100 
Single-use cartridge containing 1 mL 
IM administration via CELLECTRA™ 5PSP 
Store at 2-8°C, expiration date 
Caution Statement 
Sponsor name and address 
LABEL TEAR OFF 
Study ID 
VGX-3100 
Patient ID: _________ 
Date: (DD-MMM-YYYY): __________ 
 
Must be used by (time): _________ 
 
 
 

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See Figure 4 below for example of CELLECTRA™ 5PSP device component labels. 
 
Figure 4: Examples of Device Labels (Base, Handset, Array, Outer Box) 
 
Base Station Label 
 
Handset Label 
 
 

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5PSP Array Label 
 
 
Outer Box Packaging Label 
 
 
 
 
 
 
 
 
 
5.5 
HANDLING AND STORAGE OF IP AND DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure 
location according to the instructions in the User Manual. The CELLECTRA™ 5PSP 
device and its components must be stored between the temperature ranges 55.4°F-
91.4°F and relative humidity ranges of 30-70%. The Sponsor should be notified of any 
deviations from this recommended storage condition. 
Unless otherwise specified, IP will be shipped in a refrigerated condition with a 
temperature monitoring device. If the temperature monitoring device records 
temperatures outside the pre-specified range for any product, the Sponsor, or its 
designee should be contacted immediately.  
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 
°C (36-46 °F) storage, in a secure area, according to local regulations. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. The Sponsor should be notified of any deviations from 
this recommended storage condition. Inovio Pharmaceuticals Inc. will be responsible for 
assuring the quality of the IP is adequate for the duration of the trial. For the specific 

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temperature guidelines for storing, please refer to the CELLECTRA™ 5PSP User 
Manual. 
5.6 
PREPARATION AND DISPENSING 
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. 
When a subject is eligible, remove the pouch from the refrigerator and allow to reach 
room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. 
The pouch must not be discarded until: 
1. Administration is completed and 
2. All pertinent information from the pouch label has been documented in source. 
The product must be used within 4 hours of removal from the refrigerator. If VGX-3100 is 
not used within this timeframe it must be discarded after reconciliation. 
5.7 
USE OF CELLECTRA™5PSP DEVICE 
The instructions for use of the CELLECTRA™ 5PSP are located in the CELLECTRA™ 
5PSP User Manual. Users of the CELLECTRA™ 5PSP device must successfully 
complete training before using the device. Training will include review of the entire 
device user manual as well as hands-on training. After training on the proper use of the 
CELLECTRA™ 5PSP device, the intended users at each site will be required to 
demonstrate their competency in its use to INOVIO personnel or its designee. An 
instructional video has been prepared for review by site personnel on an as needed 
basis. Refer to the User Manual for further instruction. 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 
DRUG AND DEVICE ACCOUNTABILITY 
5.8.1 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of IP 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; 
 
Date and initials of person responsible for each IP 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; 

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 
Amount destroyed at study site, if applicable 
5.8.2 
CELLECTRA™ 5PSP DEVICE ACCOUNTABILITY 
The site is responsible for maintaining the device. The device must have full traceability 
from receipt of the products through the subject use, and the return of the device. The 
site must document acknowledgement of receipt and then notify INOVIO upon receipt of 
the device. This includes the content shipped and condition of the items upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 5PSP Base Station & Handset serial number, 5PSP Array lot 
number and the study drug lot number. The used Array attachment must be disposed of 
in accordance with institutional policy regarding disposal of sharp needles/instruments. 
5.9 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT AND CELLECTRA™ 5PSP 
DEVICE  
5.9.1 
RETURN OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at the site 
per the institutions policy or returned to INOVIO or its designee, if the site cannot destroy 
the unused IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps 
container at site. Do not attempt to remove the cartridge from the array once it has been 
used.  
It is the Investigator's responsibility to arrange for the 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. 
The unused IP can only be destroyed after being inspected and reconciled by the 
responsible INOVIO personal or designated Study Monitor. 
If IP is returned to INOVIO, or its designee, it must be accompanied by the appropriate 
documentation. Returned supplies should be in the original containers. Empty containers 
should not be returned to INOVIO. The return of unused IP(s) should be arranged with 
the responsible INOVIO personnel and/or Clinical Monitor. 
5.9.2 
RETURN OF CELLECTRA™ 5PSP DEVICE  
Upon completion or termination of the study, all investigational devices and unused 
components (Base, Station, Handset, and 5PSP Arrays) must be returned to INOVIO. 
All device components returned to INOVIO must be accompanied by the appropriate 
return documentation. Returned supplies should be in the original containers. The return 
of all device components identified above should be arranged by the responsible Study 
Monitor. 
If any component is to be destroyed on site, it is the Investigator's responsibility to 
ensure that arrangements have been made for the disposal. 
 
Written authorization must be granted by INOVIO, or its designee of the disposal, 

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 
Ensure that proper procedures for disposal have been established and followed 
according to applicable local regulations, guidelines and institutional procedures, 
 
Appropriate records of the disposal have been documented. 
6.0 
TRIAL PROCEDURES AND SCHEDULE 
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 3). 
A subject will be required to provide informed consent for the 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. Immediate safety concerns will be 
dealt with as deemed necessary by the Investigator. Adherence to the study design 
requirements, as outlined in the Schedule of Events (Table 3) are essential and required 
for study conduct. Subject eligibility should be reconfirmed at every study visit. 
6.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any trial related procedures being 
performed. The informed consent documentation must be in accordance with applicable 
regulations and GCP. Qualified trial personnel will meet with prospective trial subjects, 
explain the trial, and provide them with an ICF that describes the Screening tests, 
eligibility criteria for entering the trial, trial treatments and follow-up procedures, in a 
language understandable to the subject. Explanation of the trial includes, but is not 
limited to, trial objectives, potential benefits and risks, discomforts/inconveniences, and 
the subject's rights and responsibilities. The subject or subject's legally acceptable 
representative is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject or subject's legally acceptable 
representative. The qualified trial 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. 
6.2 
BEFORE TREATMENT PROCEDURES 
Subjects who consent to participate must have paraffin-embedded tissue block(s) from a 
previous biopsy and/or newly collected intra-anal and/or peri-anal biopsy tissue samples 
(formalin fixed tissue) sent to the central pathology lab for review by the PAC. 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 the PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).  
For those individuals diagnosed with anal or anal/peri-anal 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.  
At Screening, subjects must have a diagnosis of histologic anal or anal/peri-anal HSIL 
confirmed by the PAC and intra-anal and/or peri-anal specimen test positive for HPV-
16/18 by PCR to be eligible for participation in the study (provided the subject also 

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meets other eligibility criteria). Subjects whose intra-anal and/or peri-anal specimens 
also test positive for other HPV genotypes are not excluded as long as they have a 
positive result for HPV-16/18.  
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. 
6.2.1 
SCREENING EVALUATIONS 
The following evaluations/actions, unless noted, will be performed within 10 weeks and 
up to Day 0 – except for the safety laboratory collections/assessments, which must be 
performed within 45 days prior to Day 0. All Screening assessment values must be 
reviewed prior to study treatment. Some of these evaluations/actions will be performed 
again later in the trial (see later text and the Schedule of Events Table 3 for more detail). 
 
Signed ICF 
 
Medical history/demographics, including history of prior anal or anal/peri-anal 
HSIL 
 
Socio-Behavioral Assessment; including smoking history, exposure to second-
hand smoke, alcohol intake history, recreational drug use and contraceptive use 
 
Prior concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Complete Physical Examination 
 
Vital signs (including oral temperature, respiratory rate, blood pressure and heart 
rate), height, weight and body mass index (BMI) measurements 
 
12-lead ECG (within 45 days prior to Day 0) 
 
Baseline laboratory evaluations (including complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine (Cr), glucose, alanine 
aminotransferase [ALT], and creatine phosphokinase [CPK]) (to be performed 
within 45 days prior to Day 0) 
 
Urine pregnancy test 
 
Serology (HIV Ab) within 30 days prior to Day 0 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
Digital Anal Rectal Examination (DARE) 
 
High Resolution Anoscopy (HRA) 
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (slides from all excised tissue must be reviewed by the PAC). 
 
Whole blood (at least 68 mL) and serum (at least 8 mL) for baseline immunology 
including miRNA profile 

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6.3 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will receive study treatment. Visit dates 
and windows must be calculated from Day 0. 
6.3.1 
DAY 0 
The following study evaluations will be performed at Day 0 (unless noted) prior to 
the first study treatment: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swabs 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcome (SF-36v2™ and EQ-5D-5L) (may be performed at Day 
-1 or on Day 0, again provided it is done prior to the first study treatment) 
 
Study treatment administration 
The following evaluations will be performed on Day 0 after study treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute Participant Diary Card (PDC) 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during the phone call: 
 
Review Day 0 of PDC (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
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6.3.3 
WEEK 4 (± 4 DAYS) 
The following study evaluations will be performed at Week 4 prior to study 
treatment: 
 
Reconfirm subject eligibility 
 
Concomitant mediation review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient report outcomes (SF-36v2™ and EQ-5D-5L) 
 
Collect PDC for dose 1 
 
Study treatment administration 
The following study evaluations will be performed at Week 4 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during the phone call: 
 
Review of PDC for dose 2 (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.5 
WEEK 12 (± 4 DAYS) 
The following study evaluations will be performed at Week 12 prior to study 
treatment: 
 
Reconfirm subject eligibility 

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 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Collect and review PDC for dose 2 
 
Study treatment administration 
The following study evaluations will be performed at Week 12 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.6 
WEEK 15 (± 1 WEEK) 
The following study evaluations will be performed at Week 15: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.3.7 
WEEK 28 (± 1 WEEK) 
The following study evaluations will be performed at Week 28: 
 
Reconfirm subject eligibility 

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 
Concomitant medical review 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
6.3.8 
WEEK 36 (± 1 WEEK) 
The following study evaluations will be performed at Week 36: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical and penile swabs 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA 
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (paraffin blocks) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
 
 
 

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6.3.9 
WEEK 40 (± 1 WEEK) 
The following study evaluations will be performed at Week 40: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Study treatment administration 
 
Based on biopsy results collected at Week 36 and Investigator judgment, a 4th 
dose may be given at this visit 
**Please remember to download EP data from CELLECTRA™ 5PSP device within 
24-48 hours of study treatment.** 
The following study evaluations will be performed at the Week 40 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment; 
 
Distribute PDC 
 
Patient reported outcomes-only the two "global" questions for this visit 
6.3.10 8-14 DAYS POST DOSE 4 PHONE CALL (FOR SUBJECTS WHO RECEIVED A 4TH DOSE) 
The following information will be evaluated during the phone call: 
 
Review PDC for dose 4 (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.11 WEEK 64 (± 2 WEEKS) 
The following study evaluations will be performed at Week 64: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment (only for subjects who received a 4th dose at Week 
40) 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 

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 
Vaginal, cervical and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (paraffin blocks)  
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L)  
6.3.12 WEEK 88 (± 2 WEEKS) 
The following study evaluations will be performed at Week 88: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment 
 
Targeted Physical assessment 
 
Urine pregnancy test 
 
Vital signs 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swabs 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.4 
TRIAL PROCEDURES 
6.5 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number 
(SID), which identifies the subject for all trial-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., ANUS01001). Once 
assigned, SIDs cannot be reused for any reason. Information regarding the SID and 
screen date will be documented on a screening and enrollment log/system and in the 
eCRF. 

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6.6 
DEMOGRAPHICS 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
 
Age 
 
Gender 
 
Race/ethnicity 
 
Dominant hand/arm 
6.7 
SAFETY EVALUATIONS 
6.7.1 
PHYSICAL EXAM 
A full Physical exam (PE) will be conducted during Screening and study discharge 
(Week 88). 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, and a DARE. 
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. 
6.7.2 
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 prior to measurement 
 
Respiration rate 
 
Heart rate 
 
Oral temperature measured with an automated thermometer 
6.7.3 
HEIGHT AND WEIGHT 
Weight and height will be collected at all dosing visits in order to calculate the BMI. 
6.7.4 
MEDICAL HISTORY 
Medical history, including history of prior anal or anal/peri-anal dysplasia and 
gynecologic history will be obtained at Screening. For females, previous history of 
treatment for VIN, CIN and/or VAIN will be collected. All relevant past and present 
conditions, as well as prior surgical procedures at least 6 months prior to enrollment will 
be recorded for the main body systems.  
6.7.5 
SOCIO-BEHAVIORAL ASSESSMENTS 
Socio-Behavioral Assessment, including self-reporting of the following: smoking history, 
history of exposure to second-hand smoke, alcohol intake history, recreational drug use 
history, history of contraceptive use and type of contraceptive if known, reproductive 
history, sexual preference and sexual practices history, and pregnancy history will be 
obtained at Screening.  

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At Weeks 36, 64, and 88, a socio-behavioral assessment will be performed again to 
document any changes from Screening and/or other time periods. 
6.7.6 
LABORATORY EVALUATIONS 
At Screening, blood samples will be taken to be tested for serum chemistry and 
hematology. 
Complete Blood Count: 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
Serum Chemistry: 
 
Glucose 
 
Blood urea nitrogen 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase 
6.7.7 
PREGNANCY TESTING 
For women of reproductive potential, a negative spot urine pregnancy test is required at 
Screening, and prior to each study treatment, HRA, DARE and surgical excision or 
biopsy. 
6.7.8 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for at least 10 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. 
6.7.9 
PARTICIPANT DIARY CARD (PDC) 
Subjects will be provided and trained on a PDC and will be asked to record the following 
the evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
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The completed PDC will be reviewed with the subject by the study staff at the 8-14 days 
post dose phone calls and at the next in-person visits. 
The study staff will review the PDC 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. 
Any PDC entry determined to meet the criteria for a Grade 1 or higher AEs should be 
documented as an AE unless deemed part of the subject's ongoing medical history. If 
the PDC entry does not meet the criteria of a Grade 1 or higher AE as per the CTCAE 
guidelines, clinical judgment can be used to determine whether the entry should be 
recorded as an AE and documented accordingly in the site's source. For cases where 
the PDC entry and final AE reporting (i.e. grading) do not agree, the reasoning should be 
recorded in the source documents. 
6.8 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive at least three doses of VGX-3100 (6 mg DNA/dose) in a volume of 
1 mL by IM injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 5PSP.  A fourth dose is optional for 
those assessed to be partial responders at the Week 36 efficacy assessment. 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. EP may not be performed in the 
same arm adjacent to an implantable medical device (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal). The timing of the initial dose will 
be designated Day 0 with the subsequent doses scheduled for administration at Weeks 
4, 12, and at Week 40 (for Subgroup C only). Please refer to the Investigator's Brochure 
for further information. 
6.9 
MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
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, and Weeks 4 and/or Week 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 should be added to the concomitant medications. 
6.10 ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening and will be performed for inclusion into the 
study as listed in the Schedule of Events (Table 3). 

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6.11 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
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 PDC which will be reviewed with study 
personnel 8 – 14 days after doses 1 and 2, Week 15, and 8-14 days after dose 4 (if 
applicable).  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any AEs, 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 AEs will be captured from the time of the informed consent to study 
discharge. These events will be recorded on the subject's Case Report Form (CRF). 
6.12 ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale in Table 6. 
 
Table 6: Grading Scale for Injection Site Reactions 
 
6.13 ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, PRO instruments will be 
administered. The following PRO questionnaires will be used: 

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 
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) [25]. 
SF-36v2™ will be administered at the following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4  
 
8-14 days post dose 2 
 
Weeks 12, 15, 36, 40 
 
8-14 days post dose 4* (only for those who received a 4th dose) 
 
Weeks 64, 88 
 
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) [26, 27] and will be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4  
 
8-14 days post dose 2 
 
Weeks 12, 15, 36, 40 
 
8-14 days post dose 4* (only for those who received a 4th dose) 
 
Weeks 64, 88 
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.    
 
Additional Global PRO Questions- regarding quality of life after surgery or biopsy. 
These two questions will be administered at Week 40 only. 
6.14 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, 36, 64 and 88. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual. 
A standardized binding enzyme-linked immunosorbent assay (ELISA) may be performed 
to measure the anti–HPV-16/18 Ab response induced by VGX-3100. 
Peripheral Blood Mononuclear Cells 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 
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Profiling of miRNA may occur via the use of either sera or plasma obtained at Screening, 
Day 0 and Weeks 15 and 36.  Assessment of Day 0 samples alone will explore 
predictive algorithms for response to treatment with VGX-3100 prior to dosing. 
Assessment of Week 15 samples may 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. 
6.15 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then the relevant paraffin blocks may be collected for the assessment of 
proinflammatory and immunosuppressive elements. . Assessment of markers may 
include, but are not limited to, CD8+ and FoxP3+ infiltrating cells as well as Granulysin, 
Perforin, CD137, CD103 and PD-L1 in intra-anal and/or peri-anal tissue as sample 
allows. Markers listed here may change as new relevant information becomes available. 
6.16 HUMAN LEUKOCYTE ANTIGEN TYPING 
Human Leukocyte Antigen 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 
Major Histocompatibility Complex (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. 
6.17 ANAL AND/OR PERI-ANAL HPV TESTING 
All intra-anal and/or peri-anal lesions of adequate size (≥4 mm) will be biopsied at 
Screening. Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will 
be obtained from all HSIL sites(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. Intra-anal and/or peri-anal swabs will 
undergo HPV testing using a PCR based assay, SPF10. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching to eliminate potential interference with the results of HPV testing. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0, and at Weeks 4, 
15, 28, 36, 64, and 88 in ThinPrep™ collection media. The HPV Cobas test will be 
performed on the ThinPrep™ specimens at Screening, and Weeks 36 and 64 when 
applicable. Anal cytology will be performed on intra-anal samples. At each of these 
visits, a recent history will be collected via self-report.   
6.18 HPV TESTING FROM OTHER ANATOMICAL SITE (NON-ANAL) 
Vaginal, cervical (female subjects), penile (male subjects), and OP rinse samples (all 
subjects) will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess 
virologic clearance at non-anal sites using a PCR based HPV assay, SPF10. All 
samples will be read in a central laboratory. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching or vaginal and anal lubricants/medication for a period of 24 hours prior to 
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6.19 ANAL PHOTOGRAPHS AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of anal or anal/peri-
anal HSIL confirmed by the PAC at Screening. Subjects will undergo HRA at Screening, 
Day 0, and at Weeks 4, 15, 28, 36, 64, and 88 to identify all intra-anal lesion(s). All intra-
anal and/or peri-anal lesion(s) of adequate size (≥4 mm) will be biopsied at Screening. 
Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be 
obtained from all HSIL site(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. 
Photography of all qualifying intra-anal and/or peri-anal lesion(s) must be performed 
prior to and after biopsy, and at all HRA examinations. If a pre-biopsy digital photograph 
is not available for a historical biopsy sample at Screening, a post biopsy photo will be 
sufficient. Photographs of intra-anal lesion(s) will be for documentation purposes only. 
For all peri-anal lesion(s), digital photographs will be analyzed with a computer program 
to assess the percent reduction in the cumulative surface area of the peri-anal lesion(s) 
as determined by the quantitative analysis of standardized pre-biopsy photographic 
imaging of qualifying lesion(s) at Weeks 36, 64, and 88 compared to baseline.  
If the intra-anal and/or peri-anal tissue sample(s) result suggests progression to cancer, 
the Investigator may schedule an ad hoc visit to perform HRA and possible biopsy if 
clinically indicated. 
6.20 UNSCHEDULED BIOPSIES 
In the event an unscheduled biopsy is performed prior to the Week 36 visit, the subject 
will be classified as a non-responder in the efficacy analyses. The subject will 
discontinue further study treatment and continue in the study for safety follow-up visits. 
The subject will be managed according to standard of care and the Investigator's 
judgment based on the results of the histological diagnosis from the unscheduled biopsy. 
All biopsy samples/excised tissue (including standard of care) will be sent to the central 
pathology lab for review by the PAC.   
6.21 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the 
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 the 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. 
The following medications and treatments are prohibited: 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent; use of inhaled, otic, nasal, topical, and ophthalmic 
corticosteroids are allowed; 
 
Disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, 
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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, live vaccine; 
 
Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that 
affects blood clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study 
treatment, biopsy or excisional procedure. 
The decision to administer a prohibited medication/treatment is done with the safety of 
the study participant as the primary consideration. When possible, the Sponsor should 
be notified before the prohibited medication/treatment is administered. All medications 
should be recorded in the appropriate sections of the subject's eCRF. 
6.22 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, including illicit 
drugs, taken to the Investigator and/or other study personnel. To remain in the study, 
illicit drugs should not be taken. 
Subjects should refrain from becoming pregnant until one month following the last dose 
of IP 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. 
Subjects should abstain from sexual activity and refrain from the use of douching and 
vaginal and anal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples. 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
As a requirement for inclusion in the HPV-203 study, Investigators will only be chosen if 
they are experienced in the management of anal cancer, and are experienced in 
performing HRA.  
HPV-203 Investigators are instructed to perform additional, ad hoc HRA exams and 
biopsies if they suspect potential disease progression. Subjects that undergo an 
unscheduled biopsy will be classified as a non-responder in the efficacy analyses. These 
additional measures should minimize the risk of progression of anal or anal/peri-anal 
HSIL and the risk of harboring an undiagnosed occult early invasive anal or anal/peri-
anal cancer. The frequency of close monitoring by experienced Investigators should 
minimize the risk of cancer progression during the study and the additional measures 
are beyond what is expected in standard of care. 
7.2 
ADVERSE EVENTS (AES) 
An 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 

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drug will be considered AEs 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 IP. Adverse Events 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. 
Adverse Events 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 increased 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); 
 
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. 
Adverse Events 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 ICF 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. 
7.3 
SERIOUS ADVERSE EVENTS 
A 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 

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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 (ER) or at home, 2) blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or 3) the development of drug dependency or drug 
abuse.  
Classification of Serious Adverse Events: 
 
Death is an outcome of an AE, and not an SAE in and of 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 7.15. 
7.4 
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 AE is at least a reasonable possibility; i.e., there is evidence to 
suggest a causal relationship between the product and the AEs. An AE or ADR is 
considered unexpected if it is not listed in the applicable product information 
(Investigator's Brochure, protocol, or user manual) or is not listed at the specificity or 
severity which is consistent with the risk information provided. The Sponsor will assess 
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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 serious 
expected AEs, the identification of a significant hazard to the patient population, or a 
major safety finding from a study conducted in animals.   
7.5 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of SAE that requires expedited reporting on 
the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 
hours. Sponsor will assess each device related SAE to determine if anticipated based on 
prior identification within the investigational plan. 
7.6 
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 or SAEs with respect to the 
following levels of severity as per CTCAE v 4.03 for applicable patient populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4) 
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. 
7.7 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS 
A causally related AE is one judged to have a reasonable causal relationship to the 
administration to either or both IP and/or the CELLECTRA™ 5PSP device. The 
Investigator will assess causal relationship of the AE separately to each of the 
investigational drugs and also the investigational device. The reasonable causal 
relationship means that there are facts (evidence) or arguments to suggest a causal 
relationship. An AE may also be assessed as not related to either or both IP and/or 

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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 AEs and judging 
the relationship between the administration of the IP and EP 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 Study Subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the IP and/or the device 
indicating "yes" or "no" accordingly. Causality should be assessed by the Investigator as 
related to drug or related to device or related to both drug and device (i.e. indiscernible) 
by the following criteria: 
 
Yes- there is a reasonable possibility that administration of the Study Treatment 
(drug or device or both drug and device) contributed to the event; 
 
No- there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or EP; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event. 
7.8 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK) independent of the underlying medical 
condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation or deemed clinically significant by the Investigator must be recorded as 
an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., ECG, x-rays, and vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or 
SAE) as described in Sections 7.2 and 7.3. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory result 
(e.g., decreased hemoglobin). 
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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 
Has accompanying or inducing symptoms or signs 
 
Is judged by the Investigator as clinically significant 
Severity is assessed as detailed in Section 7.6. 
Grade is an essential element of these criteria. Each CTCAE grading term in the current 
version is a unique representation of a specific event used for medical documentation 
and scientific analysis and is a single Medical Dictionary for Regulatory Activities 
(MedDRA) Lowest Level Term (LLT). 
Investigators are asked to take the CTCAE grading criteria into account when assessing 
if a laboratory abnormality qualifies as a laboratory AE. Their clinical judgment ultimately 
determines not only the severity of the event but also whether the abnormality in 
question is "clinically significant (CS)" or "NCS." CTCAE v. 4.03 grading criteria can be 
used as a reference when making this determination. It is the responsibility of the 
Investigators to ensure all AEs are accurately reported and graded. 
7.9 
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 
probably or possibly related to the study treatment, he/she should promptly document 
and report the event to the Sponsor. 
7.10 PROCEDURES FOR DOCUMENTING PREGNANCY DURING THE TRIAL 
Subjects who are pregnant or expect to become pregnant during the course of the study 
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 treatments with the IP. A 
Pregnancy Form will be completed by the Investigator and submitted to the Sponsor 
within 24 hours after learning of the pregnancy. Site personnel will submit the Pregnancy 
Form to the Sponsor or its designee by fax or email, as described in Section 7.15. 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 IP. 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 Screening procedure 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 Sponsor. 
Male subjects will be instructed through the Informed Consent Form to immediately 
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period. A Pregnancy Form will be completed by the Investigator and submitted to the 
Sponsor within 24 hours after learning of the pregnancy. Attempts will be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
subject exposed to IP. The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Pregnancy 
Form with additional information on the course and outcome of the pregnancy. An 
Investigator who is contacted by the male subject or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
7.11 METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time 
when informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. The subject's response to questions about his/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. 
7.12 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 AEs classified by system organ class (SOC), preferred term, 
severity, and relationship to study treatment; 
 
Changes in safety laboratory parameters (e.g., hematology and serum 
chemistry); 
 
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. 
7.12.1 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 5PSP that require expedited communication 
from the Site to the Sponsor and meet any of the following criteria: 

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 
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 via method described in Section 7.15 within 24 hours to 
discuss whether further dosing for the particular subject should continue. 
7.13 ADVERSE EVENT REPORTING 
To assure the safety of the participants, information about all AEs (see Section 7.2), 
whether volunteered by the subject, discovered by the 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. 
7.14 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited AEs will be collected throughout the study and recorded in 
the Electronic Data Capture (EDC) system. The Study Report will analyze and 
summarize all AEs throughout the study. Emphasis will be placed on the following: 
1. Certain AEs of interest will be solicited during the 7 days following each 
administration of Study Treatment and summarized separately 
2. Unsolicited AEs will be collected and summarized for the entire study period 
7.15 TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS AND AESIS 
The reporting period for SAEs (without regard to causality or relationship) and AESIs is 
comprised of the period following the signing of the ICF through Week 88. Each AE will 
be assessed to determine whether it meets seriousness criteria. If the AE is considered 
serious, the Investigator will complete the SAE/AESI Report form 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 EC 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 7.5 (UADE) in line with relevant legislation. All investigators will 
receive a safety letter notifying them of relevant SUSAR reports. The Investigator should 
notify the IRB/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 

V G X- 3 1 0 0  
H P V -2 0 3  
I n o vi o P h ar m a c e uti c al s, I n c. 
Cli ni c al Pr ot o c ol  
Pr ot o c ol V er si o n D at e:  0 8 N o v 2 0 1 7  
C O N FI D E N TI A L  
Pr ot o c ol V er si o n: 1. 1  
P a g e 7 0  of 8 5  
of a n S A E i n a st u d y s u bj e ct aft er t h e l a st s c h e d ul e d f oll o w- u p vi sit, a n d c o n si d er s t h e 
e v e nt r el at e d t o pri or St u d y Tr e at m e nt, t h e I n v e sti g at or will r e p ort it t o t h e S p o n s or or t h e 
a p pr o pri at e d e si g n e e. 
S P O N S O R C O N T A C T I N F O R M A TI O N 
M E DI C A L M O NI T O R: 
, M. D., P h. D. 
E M AI L: 
 
S A E R E P O R TI N G I N F O R M A TI O N 
E M AI L: s af et y.i n o vi o @ a p c erl s. c o m  
S A F E T Y F A X: 
 
S A F E T Y P H O N E: 
 
T h e pr ef err e d m et h o d f or pr o vi di n g S A E f or m s or S A E s u p p orti n g d o c u m e nt s t o t h e 
S p o n s or or d e si g n e e i s a n att a c h m e nt t o a n e- m ail m e s s a g e, t o t h e e m ail a d dr e s s a s 
i n di c at e d a b o v e. A n y S A E s u p p orti n g d o c u m e nt s pr o vi d e d b y f a c si mil e ( F a x) ar e t o 
i n cl u d e a c o v er s h e et t h at i d e ntifi e s t h e r e p ort er n a m e a n d c o nt a ct i nf or m ati o n of t h e 
st u d y sit e. 
All s u p p orti n g d o c u m e nt s f or S A E r e p ort s, i n cl u di n g m e di c al r e c or d s a n d di a g n o sti c t e st 
r e s ult s, will i n cl u d e r ef er e n c e t o t h e st u d y s u bj e ct n u m b er. T h e st u d y sit e will r e d a ct all 
ot h er p ati e nt i d e ntif yi n g i nf or m ati o n pr e s e nt o n S A E s u p p orti n g d o c u m e nt s pri or t o 
s e n di n g t h e r e p ort t o t h e S p o n s or.  
I n a d diti o n t o pr o vi di n g t h e S A E r e p ort t o t h e S p o n s or or d e si g n e e wit hi n 2 4 h o ur s of 
b e c o mi n g a w ar e of t h e e v e nt, t h e A E t h at i s s eri o u s m u st b e r e c or d e d i n t h e A E s e C R F. 
T h e e ntr y i nt o t h e e C R F i s r e q uir e d t o b e d o n e a s s o o n a s p o s si bl e. 
T h e I n v e sti g at or will s u p pl y t h e S p o n s or a n d t h e I R B wit h m or e i nf or m ati o n a s it 
b e c o m e s a v ail a bl e a n d a n y a d diti o n al r e q u e st e d i nf or m ati o n. T h e ori gi n al S A E f or m 
m u st b e k e pt at t h e st u d y sit e. T h e S p o n s or or it s r e pr e s e nt ati v e will b e r e s p o n si bl e f or 
d et er mi ni n g a n d i n t ur n, r e p orti n g S A E s t o r e g ul at or y a ut h oriti e s a c c or di n g t o t h e 
a p pli c a bl e r e g ul at or y r e q uir e m e nt s. 
W h e n r e c or di n g t h e S A E f or m, c orr e ct m e di c al t er mi n ol o g y/ c o n c e pt s ar e t o b e u s e d a n d 
t h e u s e of a b br e vi ati o n s a n d c oll o q ui ali s m s ar e t o b e a v oi d e d. 
S eri o u s A d v er s e E v e nt s m u st b e f oll o w e d b y t h e I n v e sti g at or u ntil r e s ol uti o n, e v e n if t hi s 
e xt e n d s b e y o n d t h e st u d y-r e p orti n g p eri o d. R e s ol uti o n of a n S A E i s d efi n e d a s t h e r et ur n 
t o b a s eli n e st at u s or st a bili z ati o n of t h e c o n diti o n wit h t h e e x p e ct ati o n t h at it will r e m ai n 
c hr o ni c. 
I n t h e e v e nt of d e at h, if a n a ut o p s y i s p erf or m e d, a c o p y of t h e r e p ort will b e s e nt t o t h e 
S p o n s or. 
P P D
P P D
P P D
P P D

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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. 
7.16 NOTIFICATIONS 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 7.4 and 7.16). 
7.17 REPORTING OF CELLECTRA™5PSP DEVICE RELATED COMPLAINTS OR 
DEFICIENCIES 
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 within 24 hours of becoming aware of the event per Sections 7.2 and 7.3. 
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. The error reporting or complaint form provided must be completed and 
emailed to the Sponsor at clinicalcomplaint@inovio.com. 
Additional instructions on complaint reporting to be provided separately. 
7.18 TRIAL DISCONTINUATION 
Inovio Pharmaceuticals Inc. reserves the right to discontinue the trial 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. Additionally, the trial may be 
discontinued at any time by an IRB, INOVIO, the FDA or other government agencies as 
part of their duties to ensure that research subjects are protected.  
Should the trial be terminated and/or the site closed for any reason, all investigational 
drugs & devices must be returned to INOVIO or its representative. The PI should ensure 
their site file documents are complete prior to archiving, and provide copies of any 
requested documents to INOVIO for its Trial Master File (TMF). 
 
 

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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by INOVIO or its representative. 
This is a single-arm, multi-center, open-label clinical trial of VGX-3100 in subjects with a 
diagnosis of AIN2, AIN3, PAIN2, or PAIN3 associated with HPV types 16 and/or 18. The 
study's primary endpoint is binary: regression of AIN/PAIN HSIL and viral clearance of 
HPV-16/18 based on tissue collected at Week 36. The primary hypothesis is that the 
treatment will result in regression of HSIL and clearance. Secondary efficacy analyses 
pertain to regression, clearance of HPV-16/18 infection, complete regression, 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, clearance among non-anal 
anatomic locations, and effect of HLA type on efficacy and association of miRNA profile, 
anoscopy, cytology, and virology with efficacy. Other exploratory analyses pertain to 
tissue immunological measures and PRO. 
8.3 
STATISTICAL HYPOTHESES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15.  There are no other formal hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations are: 
 
The modified intention to treat (mITT) population includes all subjects who 
receive at least one dose of Study Treatment. 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 Treatment and have no protocol violations. 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 locking of the study database. 
 
The safety analysis set includes all subjects who receive at least one does of 
Study Treatment. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 
PRIMARY ANALYSES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15. 

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A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.05 and the corresponding lower bound of the one-sided 
95% CI exceeds 0.15. 
For the analysis, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week. 
8.5.2 
SECONDARY ANALYSES 
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
the same as for the primary endpoint. 
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
in surface area and the mean percent change in number of lesions and associated 95% 
t-distribution based confidence intervals. 
Post-baseline ELISA titers will be summarized with geometric mean and associated 95% 
CIs. Post-baseline increases in ELISPOT and Flow responses will be summarized with 
tobit-based means and 95% CIs. Valid samples for statistical analysis purposes will be 
those collected within 14 days of the specified visits. Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.5.3 
SAFETY ANALYSES 
All AEs will be summarized among the safety population by frequency. These 
frequencies will be presented overall and separately by dose, and will depict overall, by 
SOC 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 AE data will be based on events occurring within 28 days 
following 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 following any dose and 
regardless of when they occurred. 
For safety laboratory results, 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. 
Baseline is defined as the last measurement prior to the first treatment administration. 
8.5.4 
DISPOSITION 
Disposition will be summarized 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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8.5.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables for the mITT population. 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system for the mITT population. 
Prior medications are those that were used and stopped before the start of the trial (prior 
to Day 0). Partial stop dates of prior medications will be assumed to be the latest 
possible date consistent with the partial date. Data for all prior medications will be 
summarized with percentages for the mITT population. 
8.5.6 
INTERIM ANALYSES 
No formal interim analyses will be performed for this study. For reasons of futility (early 
evidence of poor efficacy of VGX-3100) or safety issues, the DSMB could recommend 
stopping enrollment at any time. The type I error will not be adjusted for possible early 
stopping due to futility. 
8.5.7 
MULTIPLICITY 
Not applicable, there is one hypothesis that will be tested. 
8.5.8 
MISSING VALUES 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. 
No other missing data will be imputed or replaced. 
8.5.9 
EXPLORATORY ANALYSES 
The exploratory efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
the same as for the primary endpoint. 
Other analyses will examine the relationship between the primary efficacy endpoint and 
a) HLA results, b) miRNA results, c) HRA results, d) cytology results, and e) HPV 
results. Relationships will be examined with contingency tables and/or logistic regression 
models which model the primary endpoint versus these results as regressor variables. 
The change in tissue immune response magnitude will be summarized with means and 
associated t-distribution based 95% CIs. 
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. 

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8.6 
SAMPLE SIZE/POWER 
A sample of 24 subjects provides ~80% power to declare superiority over historical 
control, assuming the true proportion of subjects who achieve the primary endpoint is 
40% for the treatment arm versus 15% for the historical control, and that 90% are 
evaluable at Week 36 from 1st dose. 
8.7 
RANDOMIZATION AND BLINDING 
This is an open-label trial, and therefore, site personnel, individual subjects and INOVIO 
or its representative trial personnel will be aware of the treatment allocations for this trial. 
Randomization does not apply. 
9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
GCP, and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., ICF, 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/EC include the following: 
 
Submit progress reports to the IRB/EC as required, and request re-review and 
approval of the trial at least once a year during the conduct of the trial. 
 
Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects. 
 
Notify the IRB/EC immediately if the Sponsor notifies the Investigator about any 
reportable safety events. 
 
Obtain approval from the IRB/EC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements, as required. 
 
Submit reports on, and reviews of, the trial and its progress to the IRB/EC at 
intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
 
Maintain a file of trial-related information (refer to trial files) that include all 
correspondence with the IRB/EC. 
 
Notify the IRB/EC when the trial is completed (i.e. after the last visit of the final 
trial subject). 
 
After trial completion (within three (3) months is recommended) provide the 
IRB/EC with a final report on the trial. 

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9.3 
IBC APPROVAL AND REPORTING 
Investigator will ensure responsibilities relevant to Institutional Biosafety Committee 
(IBC) approval and reporting if applicable per local regulations. 
9.4 
OFFICE OF BIOTECHNOLOGY ACTIVITIES 
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., 
National Institutes of Health [NIH] Office of Biotechnology Activities [OBA]) governing 
research that involves recombinant or synthetic nucleic acid. 
9.5 
PROTECTION OF HUMAN SUBJECTS 
9.5.1 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to enrollment into the 
trial, 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 
(Section 6.1). 
9.5.2 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This trial 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 trial 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 
should be provided to Sponsor. 
9.5.3 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.5.4 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURE REGULATIONS (21CRF 
PART 11) 
When applicable, this trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.5.5 
COMPLIANCE WITH PROTOCOL 
Subjects will be provided with Investigator emergency contact information and advised to 
report all AEs. While every effort should be made to avoid protocol deviation (PD), 
should a deviation be discovered, Sponsor must be informed immediately. Any PD 
impacting subject safety must be reported to the Medical Monitor immediately. 
9.5.6 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without prior review and documented approval/favorable opinion from the Sponsor and 
IRB/EC of a protocol amendment, except where necessary to eliminate immediate 
hazards to trial subjects. While every effort should be made to avoid PD, should a 

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deviation be discovered, Sponsor must be informed immediately. Any PD impacting 
Subject safety must be reported to the Medical Monitor immediately. 
10.0 DATA COLLECTION, MONITORING, AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the trial 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 trial Sponsor, the governing health 
authorities or the FDA, if they inspect the trial 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 trial, 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 (HIPAA)]. 
Information about trial subjects will be kept confidential and managed in accordance with 
the requirements of the HIPAA of 1996. 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 trial 
 
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 
In the event that a subject revokes authorization to collect or use PHI, the Sponsor 
retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect vital status, at a minimum, (i.e., 
that the subject is alive) at the end of their scheduled trial period. 
11.0 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. The 
Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspections by providing direct access to source data/documents related to 
this trial. 

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11.1 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
Case Report Form will be provided for each subject. Subjects must not be identified by 
name on any CRFs. Subjects will be identified with an SID. 
It is the Investigator's responsibility to retain trial essential documents for at least two (2) 
years after the last approval of a marketing application in their country and until there are 
no pending or contemplated marketing applications in their country or at least two (2) 
years have elapsed since the formal discontinuation of clinical development of the IP. 
This retention period may be superseded by country requirements. The Sponsor will 
inform the Investigator/institution as to when these documents are no longer needed to 
be retained. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY AND QUALITY MONITORING 
An independent DSMB will provide safety oversight. The DSMB will be scheduled to 
meet quarterly. 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 there appears to be a regression with VGX-
3100.However, no formal interim analysis will be performed. 
12.2 PATHOLOGY ADJUDICATION COMMITTEE 
All anal 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 four pathologists in separate locations. Each specimen will be read by two 
pathologists independently in a blinded fashion. The logistics and details of the PAC are 
detailed in the PAC Charter. 
12.3 CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced Clinical 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 trial. 
 
The Clinical Monitor will address and document the following trial conduct 
activities and obligations: 

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o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution 
trip report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately 
report all SAE and provide subsequent follow-up report of the final 
outcome to the IRB. 
o Throughout the trial, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, 
original, and accurate (ALCOA). 
o Assure that the trial facilities continue to be acceptable. 
o Compare the trial CRFs with source documents to assure that the data 
are accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and 
reconciliation of records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded 
properly for testing per laboratory manual requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13.0 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 at 
least 60 days prior to submission for publication. The Sponsor will have 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) will 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 US Patent and 
Trademark Office and/or foreign patent office(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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14.0 LIST OF ABBREVIATIONS 
Ab 
Antibody 
ADR 
Adverse Drug Reaction 
AEs 
Adverse events 
AESI 
Adverse Event of Special Interest 
AIN 
Anal Intraepithelial Neoplasia 
AIS 
Adenocarcinoma-in-situ 
ALT 
Alanine Aminotransferase 
BMI 
Body Mass Index 
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CIN 
Cervical Intraepithelial Neoplasia 
CIN1 
Grade 1 Cervical Intraepithelial Neoplasia 
CIOMS-I 
Council for International Organizations of Medical Sciences 
Cr 
Creatinine 
CRF 
Case Report Form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CPK 
Creatine Phosphokinase 
DARE 
Digital Anal Rectal Examination 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELIspot 
Enzyme-linked Immunospot Assay 
EP 
Electroporation with CELLECTRA™5PSP  
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
gbm 
gay and bisexual men 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRA 
High-resolution Anoscopy 
HR-HPV 
High-risk HPV Type 
HSIL 
High Grade Squamous Intraepithelial Lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
International Ethics Committee 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
Investigational New Drug 

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INOVIO 
Inovio Pharmaceuticals, Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRB/IEC 
Institutional Review Board or Independent Ethics Committee 
ISO 
International Organization for Standardization 
LAST 
Lower Anogenital Squamous Terminology 
LSIL 
Low Grade Squamous Intraepithelial Lesion 
miRNA 
MicroRNA 
mITT 
Modified Intent to Treat 
MSM 
men who have sex with men 
NCS 
Not Clinically Significant 
OBA 
Office of Biotechnology Activities 
OP 
Ororpharyngeal  
PAIN 
Peri-anal Intraepithelial Neoplasia 
PAM 
Protocol Administrative Memo or Letter 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PIN 
Penile Intraepithelial Neoplasia 
PP 
Per Protocol 
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PE 
Physical Exam 
PRO 
Patient-reported Outcome 
SAEs 
Serious Adverse Events 
SF-36v2™ 
36-Item Short Form Health Survey 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPANC 
Study of the Prevention of Anal Cancer 
SSC 
Saline Sodium Citrate 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated (Serious) Adverse Device Effect 
US 
United States 
VAIN 
Vaginal Intraepithelial Neoplasia 
VIN 
Vulvar Intraepithelial Neoplasia 
WFI 
Water for Injection 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 

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15.0  REFERENCES 
1. 
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. 
2. 
Humans IWGotEoCRt. Biological agents. Volume 100 B. A review of human carcinogens. 
IARC Monogr Eval Carcinog Risks Hum 2012,100:1-441. 
3. 
McQuillan G, Kruszon-Moran D, Markowitz LE, Unger ER, Paulose-Ram R. Prevalence 
of HPV in Adults Aged 18-69: United States, 2011-2014. NCHS Data Brief 2017:1-8. 
4. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United 
States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
5. 
Viens LJ, Henley SJ, Watson M, Markowitz LE, Thomas CC, Thompson TD, et al. Human 
Papillomavirus-Associated Cancers - United States, 2008-2012. MMWR Morb Mortal 
Wkly Rep 2016,65:661-666. 
6. 
National Cancer Institute. Fact Sheet: HPV and Cancer. In; 2015. 
7. 
Bruni L, Barrionuevo-Rosas L, Alberto G, Serrano B, Mena M, Gomez D, et al. Human 
Papillomavirus and Related Diseases Report in USA. In: ICO Information Centre on HPV 
and Cancer (HPV Information Centre); 2017. 
8. 
National Cancer Institute SEER Program. Cancer Stat Facts: Anal Cancer. In; 2017. 
9. 
Canadian Cancer Society. Anal Cancer Statistics. In; 2017. 
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. 
Sahasrabuddhe VV, Castle PE, Follansbee S, Borgonovo S, Tokugawa D, Schwartz LM, 
et al. Human papillomavirus genotype attribution and estimation of preventable fraction of 
anal intraepithelial neoplasia cases among HIV-infected men who have sex with men. J 
Infect Dis 2013,207:392-401. 
12. 
Alemany L, Saunier M, Alvarado-Cabrero I, Quiros B, Salmeron J, Shin HR, et al. Human 
papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J 
Cancer 2015,136:98-107. 
13. 
Tong WW, Jin F, McHugh LC, Maher T, Sinclair B, Grulich AE, et al. Progression to and 
spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-
infected and uninfected men. AIDS 2013,27:2233-2243. 
14. 
Machalek DA, Grulich AE, Hillman RJ, Jin F, Templeton DJ, Tabrizi SN, et al. The Study 
of the Prevention of Anal Cancer (SPANC): design and methods of a three-year 
prospective cohort study. BMC Public Health 2013,13:946. 
15. 
Grulich A, Jin F, Poynten IM, Templeton D, Law C, Cornall A, et al. Predictors of 12-month 
persistent high-grade squamous intraepithelial lesions (hsil) in gay and bisexual men 
(gbm): data from the SPANC study. . In: 31st International Papillomavirus Conference 
(HPV2017). Cape Town, South Africa; 2017. 
16. 
Hillman R. Oral comments during a panel discussion. In: 16th World Congress of the 
International Federation of Cervical Pathology and Colposcopy (IFCPC). Orlando, Florida; 
2017. 
17. 
Tong WW, Shepherd K, Garland S, Meagher A, Templeton DJ, Fairley CK, et al. Human 
papillomavirus 16-specific T-cell responses and spontaneous regression of anal high-
grade squamous intraepithelial lesions. J Infect Dis 2015,211:405-415. 
18. 
Dona MG, Vescio MF, Latini A, Giglio A, Moretto D, Frasca M, et al. Anal human 
papillomavirus in HIV-uninfected men who have sex with men: incidence and clearance 

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rates, duration of infection, and risk factors. Clin Microbiol Infect 2016,22:1004 e1001-
1004 e1007. 
19. 
Shvetsov YB, Hernandez BY, McDuffie K, Wilkens LR, Zhu X, Ning L, et al. Duration and 
clearance of anal human papillomavirus (HPV) infection among women: the Hawaii HPV 
cohort study. Clin Infect Dis 2009,48:536-546. 
20. 
Nyitray AG, Carvalho da Silva RJ, Baggio ML, Smith D, Abrahamsen M, Papenfuss M, et 
al. Six-month incidence, persistence, and factors associated with persistence of anal 
human papillomavirus in men: the HPV in men study. J Infect Dis 2011,204:1711-1722. 
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Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine 
delivery and potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
22. 
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. 
23. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation 
increases in vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
24. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of 
intramuscular and intradermal delivery by CELLECTRA((R)) adaptive constant current 
electroporation device in healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
25. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
26. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
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27. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
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16.0 APPENDICES

HPV-203 
A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 
related Anal or Anal/Peri-anal, High grade squamous intraepithelial lesion (HSIL), 
(AIN2, AIN3, PAIN2, PAIN3) in individuals that are seronegative for Human 
Immunodeficiency Virus (HIV)-1/2 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND #:  13683 
Protocol Version:  2.0 
Protocol Version Date:  15May2019 

V G X -3 1 0 0  
H P V -2 0 3  
I n o vi o P h ar m a c e uti c al s, I n c. 
Cli ni c al Pr ot o c ol  
Pr ot o c ol V er si o n D at e:  1 5 M a y 2 0 1 9  
C O N FI D E N TI A L  
Pr ot o c ol V er si o n: 2. 0  
P a g e 2  of 8 5  
S U M M A R Y O F C H A N G E S  
T h e f oll o wi n g ar e a li st of pr ot o c ol c h a n g e s fr o m V er si o n 1. 1 d at e d 0 8  N o v e m b er 2 0 1 7  t o 
V er si o n  2. 0  d at e d 1 4 M a y  2 0 1 9 . All ot h er c h a n g e s ar e a d mi ni str ati v e a n d d o n ot si g nifi c a ntl y 
aff e ct t h e s af et y of s u bj e ct s, tri al s c o p e, or s ci e ntifi c q u alit y of t h e pr ot o c ol.  
1.
Eff e cti v e 0 5 J ul 2 0 1 8, t h e M e di c al M o nit or f or H P V -2 0 3  i s 
. T hi s h a s b e e n
pr e vi o u sl y a d dr e s s e d i n P A M  # 3 ( 2 5 J a n 2 0 1 9) a n d i s  n o w  i n c or p or at e d i nt o t hi s
a m e n d m e nt.  
 c o nt a ct i nf or m ati o n i s a s f oll o w s:
, M. D., P h. D. 
P h o n e:  
 
E m ail:  
 
2.
W e h a v e a d d e d cl arif yi n g l a n g u a g e t o t h e pri m ar y e n d p oi nt  t o i n di c at e o ur e n d p oint will
b e a s s e s s e d b a s e d o n q u alif yi n g l e si o n s  w hi c h i s d efi n e d i n t h e a p pli c a bl e f o ot n ot e.
3.
T h e l a n g u a g e fr o m Pr ot o c ol V er si o n 1. 1 i n di c at e s: F or all p eri -a n al l e si o n( s), di git al
p h ot o s will b e a n al y z e d wit h a c o m p ut er pr o gr a m t o a s s e s s t h e p er c e nt r e d u cti o n i n t h e
c u m ul ati v e s urf a c e ar e a of t h e p eri -a n al l e si o n( s) a s d et er mi n e d b y t h e q u a ntit ati v e
a n al y si s of st a n d ar di z e d pr e -bi o p s y p h ot o gr a p hi c i m a gi n g of q u alif yi n g l e si o n( s) at
W e e k s 3 6, 6 4, a n d 8 8 c o m p ar e d t o b a s eli n e. W e will n o  l o n g er b e u si n g a c o m p ut er
pr o gr a m t o d et er mi n e t h e p er c e nt r e d u cti o n i n c u m ul ati v e s urf a c e ar e a. T h er ef or e t h e
n e w l a n g u a g e i s a s f oll o w s: All q u alif yi n g p eri -a n al l e si o n( s) will b e a s s e s s e d u si n g t h e
r ul er pr o vi d e d. T h e r ul er s h o ul d b e pl a c e d i n t h e fi el d of vi si o n a n d s h o ul d b e
d o c u m e nt e d wit h p h ot o gr a p h y at S cr e e ni n g, D a y 0, a n d W e e k s 4, 1 5, 2 8, 3 6, 6 4 a n d 8 8.
T h e a p pli c a bl e o bj e cti v e ( s e c o n d ar y o bj e cti v e # 7), c orr e s p o n di n g e n d p oi nt r e m ai n s
u n c h a n g e d.  T hi s w a s pr e vi o u sl y cl arifi e d i n P A M # 1 ( 1 1 M a y 2 0 1 8)  a n d i s n o w
i n c or p or at e d i nt o t hi s a m e n d m e nt.
4.
W e h a v e i n cl u d e d i n str u cti o n s b a s e d o n t h e o ut c o m e of t h e W e e k 6 4 bi o p s y r e s ult s. If
H SI L r e m ai n s, t h e s u bj e ct will r e c ei v e st a n d ar d of c ar e tr e at m e nt a n d r e m ai n o n t h e
st u d y f or f oll o w u p  a n d s af et y  o nl y.
5.
H L A t y pi n g will n o l o n g er b e d o n e f or t hi s st u d y. H L A t y pi n g h a s b e e n r e m o v e d
t hr o u g h o ut t hi s pr ot o c ol a s w ell a s t h e i nf or m e d c o n s e nt f or m (I C F).
6.
E x cl u si o n crit eri a  #1 ( Pr ot o c ol V er si o n 1. 1, 0 8 N o v 2 0 1 7) st at e s t h at s u bj e ct s will b e
e x cl u d e d fr o m t h e st u d y if t h e y h a v e ‘ u ntr e at e d mi cr o i n v a si v e c a n c er’. T hi s crit eri o n  w a s
pr e vi o u sl y cl arifi e d i n P A M # 3 ( 2 5 J a n 2 0 1 9 ) a n d i n cl u d e s s u bj e ct s w h o h a v e mi cr os c o pi c
or gr o s s e vi d e n c e of i n v a si v e c a n c er, or t h e s u s pi ci o n of c a n c er i n a n y hi st o p at h ol o gi c
s p e ci m e n b y a n y p at h ol o gi st at s cr e e ni n g.
7.
F or e x cl u si o n crit eri a n u m b er s 2, 3, 4, a n d 5 ( Pr ot o c ol V er si o n 1. 1, 0 8 N o v 2 0 1 7) a
s u p er s cri pt h a s b e e n a d d e d t o cl arif y t h at if t h e st a n d ar d of c ar e i s o b s er v ati o n  t h e n t hi s
will n ot e x cl u d e a s u bj e ct fr o m p arti ci p ati n g.
8.
I n cl u si o n crit eri a # 3 w hi c h w a s pr e vi o u sl y cl arifi e d i n P A M  # 3 ( 2 9 J a n 2 0 1 9)  all o w s f or a n
HI V r a pi d t e st t o b e p erf or m e d  a s l o n g a s t h e f oll o wi n g i s a d h er e d t o:  1. T h e t e st i s a n
a nti g e n/ a nti b o d y i m m u n o a s s a y, 2. T h e t e st i s o nl y d o n e u si n g bl o o d, 3. T h e t e st m u st b e
p erf or m e d i n t h e offi c e a n d d o n e b y q u alifi e d st u d y st aff m e m b er s .
P P D
P P D
P P D
P P D

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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version Date:  15May2019 
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Protocol Version: 2.0 
 
Page 3 of 85 
9. Exclusion Criteria #11 in Protocol Version 1.1, 08Nov2017 indicates that subjects with 
‘the 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,’ will be 
excluded from the protocol. This criterion 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 Criterion #11, then the subject should no longer be 
excluded on the basis of this criterion. This has previously been clarified in PAM #1 
(18May2018) and is now incorporated into this amendment. 
10. Exclusion Criteria #14 in Protocol Version 1.1 reads: ‘Receipt of any non-study related 
non-live vaccine within 2 weeks of any VGX-3100 dose.’ The two week period applies to 
both before and after having received any VGX-3100 dose and therefore will now read: 
‘Receipt of any non-study related non-live vaccine within 2 weeks before or after having 
received any VGX-3100 dose.’ This will ensure subjects do not receive non-live vaccines 
after being dosed with VGX-3100 for 2 weeks. This has been previously clarified in PAM 
#5 (25Feb2019) and is now incorporated into this amendment. 
11. Exclusion Criteria #15 in Protocol Version 1.1 reads: ‘Receipt of any non-study related 
live vaccine (e.g. measles vaccine) within 4 weeks of any VGX-3100 dose.’ The 4 week 
period applies to both before and after having received any VGX-3100 dose: ‘Receipt of 
any non-study related live vaccine (e.g. measles vaccine) within 4 weeks before or after 
having received any VGX-3100 dose. This will ensure subjects do not receive live 
vaccines after being dosed with VGX-3100 for 4 weeks. This has been previously 
clarified in PAM #3 (25Jan2019) and is now incorporated into this amendment. 
12. Clarification of HRA at Screening: Protocol Version 1.1 allows for historical biopsy 
samples (i.e. blocks) to be sent to the study lab within the allowable window of 10 weeks 
from the date of collection until the date of first study treatment (Day 0). Since HRA must 
be performed in order to obtain the biopsies; if a historical biopsy is used with a 
corresponding historic HRA evaluation, then the HRA does not need to be repeated for 
Screening to determine eligibility as long as it is within the allowable window of 10 
weeks. This has been previously clarified in PAM #4 (19Feb2019) and is now 
incorporated into this amendment. 
13. Section 6.20 Unscheduled Biopsies: Protocol Version 1.1 states: in the event an 
unscheduled biopsy is performed prior to the Week 36 visit, the subject will be classified 
as a non-responder in the efficacy analyses. The subject will discontinue further study 
treatment and continue in the study for safety follow-up visits. This is inconsistent from 
the definition of responder and non-responder for primary endpoint in Table 2 where one 
of the criteria of non-responder is any non-study treatment of curative intent of intra-anal 
and/or peri-anal lesions. We have changed this section to state: ‘Unscheduled biopsies 
may be performed on new lesions or suspected progression of original lesions per the 
Investigator’s medical judgment during the study. The subject will be managed according 
to standard of care and the Investigator’s judgment based on the results of the 
histological diagnosis from the unscheduled biopsy. All biopsy samples/excised tissue 
(including standard of care) will be sent to the central pathology lab for review by the 
PAC.’ 

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Page 4 of 85 
14. Section 6.3.3: Patient Report Outcomes at the Week 4 Visit was previously clarified in
PAM #2 (19Jul2018) to indicate that the PROs will be completed after study treatment at
the Week 4 visit and after the Week 12 visit and are now incorporated into this
amendment.
15. Section 6.3.9 Patient Reported Outcomes at the Week 40 visit was previously clarified in
PAM #2 (18Jul2018) to indicate that a subject must complete the SF-36v2, the EQ-5D-
5L and the two additional ‘global’ questions at the Week 40 visit; this has been
incorporated into this amendment.
16. Section 6.3.12 previously clarified in PAM #2 (18Jul2018) states that a full physical
examination will occur at the Week 88 visit and is now incorporated into this amendment.
17. The last paragraph of Section 8.5.3 Safety Analyses has been removed because safety
labs are only performed at the screening visit, and therefore changes between the
baseline and other time points are not applicable. This was previously addressed in PAM
#3 (25Jan2019) and will now be incorporated into this amendment.

V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
M e di c al M o nit or A p pr o v al P a g e 
Dr u g: 
S p o n s or: 
M e di c al M o nit or: 
A p pr o v al Si g n at ur e: 
V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
6 6 0 W. G er m a nt o w n Pi k e, S uit e 1 1 0 
Pl y m o ut h M e eti n g, P A 1 9 4 6 2 
, M. D., P h. D. 
 
l n o vi o P h ar m a c e uti c al s, I n c. 
D at e 
 
l n o vi o P h ar m a c e uti c al s 
C O N FI D E N TI A L 
H P V- 2 0 3 
Cli ni c al Pr ot o c ol 
T h e i nf or m ati o n i n t hi s d o c u m e nt i s c o n si d er e d pri vil e g e d a n d c o nfi d e nti al b y l n o vi o 
P h ar m a c e uti c al s I n c. (I N O VI O) a n d m a y n ot b e di s cl o s e d t o ot h er s e x c e pt t o t h e e xt e nt 
n e c e s s ar y t o o bt ai n I n stit uti o n al R e vi e w B o ar d/ Et hi c s c o m mitt e e a p pr o v al a n d i nf or m e d 
c o n s e nt, or a s r e q uir e d b y l o c al r e g ul at or y a ut h oriti e s. P er s o n s t o w h o m t hi s i nf or m ati o n 
i s di s cl o s e d m u st b e i nf or m e d t h at t hi s i nf or m ati o n i s pri vil e g e d a n d c o nfi d e nti al a n d t h at 
it s h o ul d n ot b e f urt h er di s cl o s e d wit h o ut 
t h e writt e n 
p er mi s si o n of I N O VI O. A n y 
s u p pl e m e nt al i nf or m ati o n a d d e d t o t hi s d o c u m e nt i s al s o c o nfi d e nti al a n d pr o pri et ar y 
i nf or m ati o n of I N O VI O a n d m u st b e k e pt i n c o nfi d e n c e i n t h e s a m e m a n n er a s t h e c o nt e nt s 
of t hi s d o c u m e nt. 
Pr ot o c ol V er si o n D at e: 
1 5 M a y 2 0 1 9 
C O N FI D E N TI A L 
P a g e 5 of 8 5 
Pr ot o c ol V er si o n: 2. 0 
P P D
P P D
P P D
P P D
P P D
P P D

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Protocol Version Date:  15May2019 
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Protocol Version: 2.0 
 
Page 6 of 85 
 
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 (IRB/IEC) 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 International Conference on Harmonization (ICH)/Good Clinical Practice (GCP) and 
International Organization for Standardization (ISO) guidelines, local legal and regulatory 
requirements, and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
<Insert Principal Investigator Printed Name> 
 
Date (dd/Mmm/yyyy) 
 
 
 
 
 
 
 
Site Number: _____________________________________________ 
 
 
Site Name: _______________________________________________ 
 
 

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Protocol Version Date:  15May2019 
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Protocol Version: 2.0 
 
Page 7 of 85 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ...................................................... 6 
CLINICAL PROTOCOL SYNOPSIS ............................................................................ 11 
TRIAL SCHEDULE OF EVENTS ................................................................................ 23 
1.0 
INTRODUCTION ........................................................................................... 26 
1.1 
Background and Scientific Rationale ....................................................................26 
1.1.1 
VGX-3100 ........................................................................................................................ 27 
1.1.2 
Electroporation .............................................................................................................. 28 
1.1.3 
Dose Rationale............................................................................................................... 29 
1.2 
Potential Benefits ....................................................................................................29 
1.3 
Potential Risks ........................................................................................................29 
2.0 
PURPOSE AND HYPOTHESIS ....................................................................... 30 
2.1 
Purpose ...................................................................................................................30 
2.2 
Hypothesis ...............................................................................................................30 
3.0 
TRIAL DESIGN AND ENDPOINTS .................................................................. 30 
3.1 
Primary Objective(s) ...............................................................................................31 
3.2 
Primary Endpoint(s) ................................................................................................31 
3.3 
Secondary Objective(s) ..........................................................................................31 
3.4 
Associated Secondary Endpoint(s) .......................................................................32 
3.5 
Exploratory Objective(s) .........................................................................................32 
3.6 
Associated Exploratory Endpoint(s) ......................................................................33 
3.7 
Efficacy Assessment ..............................................................................................33 
3.8 
Safety Assessment .................................................................................................34 
3.9 
Immunogenicity Assessment .................................................................................35 
4.0 
TRIAL POPULATION .................................................................................... 35 
4.1 
Inclusion Criteria .....................................................................................................35 
4.2 
Exclusion Criteria ....................................................................................................37 
4.3 
Discontinuation/Withdrawal of Trial Subjects .......................................................40 
4.3.1 
Criteria for Discontinuation from the Study ............................................................... 40 
4.3.2 
Criteria for Withdrawal from Study .............................................................................. 40 
4.3.3 
Sponsor Notification of Discontinuation/Withdrawal ................................................ 40 
4.3.4 
Reasons for Discontinuation/Withdrawal ................................................................... 41 
5.0 
TRIAL TREATMENT ..................................................................................... 41 
5.1 
Investigational Biologic Product ............................................................................41 
5.2 
Cellectra™ 5PSP Device Description: ...................................................................42 
5.3 
Treatment Regimen .................................................................................................43 
5.4 
Packaging and Handling .........................................................................................43 
5.5 
Handling and Storage of IP and Device .................................................................45 

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5.6 
Preparation and Dispensing ...................................................................................45 
5.7 
Use of Cellectra™5PSP Device ..............................................................................46 
5.8 
Drug and Device Accountability ............................................................................46 
5.8.1 
Investigational Product Accountability ....................................................................... 46 
5.8.2 
Cellectra™ 5PSP Device Accountability ..................................................................... 47 
5.9 
Return and Destruction of Investigational Product and Cellectra™ 5PSP Device
 ..................................................................................................................................47 
5.9.1 
Return of Investigational Product................................................................................ 47 
5.9.2 
Return of Cellectra™ 5PSP Device .............................................................................. 47 
6.0 
TRIAL PROCEDURES AND SCHEDULE .......................................................... 48 
6.1 
Informed Consent ...................................................................................................48 
6.2 
Before Treatment Procedures ................................................................................48 
6.2.1 
Screening Evaluations .................................................................................................. 49 
6.3 
During Treatment Procedures by Visit ..................................................................50 
6.3.1 
Day 0 ............................................................................................................................... 50 
6.3.2 
8-14 Days Post Dose 1 Phone Call .............................................................................. 51 
6.3.3 
Week 4 (± 4 Days) .......................................................................................................... 51 
6.3.4 
8-14 Days Post Dose 2 Phone Call .............................................................................. 52 
6.3.5 
Week 12 (± 4 Days) ........................................................................................................ 52 
6.3.6 
Week 15 (± 1 Week) ....................................................................................................... 52 
6.3.7 
Week 28 (± 1 Week) ....................................................................................................... 53 
6.3.8 
Week 36 (± 1 Week) ....................................................................................................... 53 
6.3.9 
Week 40 (± 1 Week) ....................................................................................................... 54 
6.3.10 8-14 Days Post Dose 4 Phone Call (for subjects who received a 4th dose) ............. 54 
6.3.11 Week 64 (± 2 Weeks) ..................................................................................................... 55 
6.3.12 Week 88 (± 2 Weeks) ..................................................................................................... 55 
6.4 
Trial Procedures ......................................................................................................56 
6.5 
Assignment of Subject Identification Numbers ....................................................56 
6.6 
Demographics .........................................................................................................56 
6.7 
Safety Evaluations ..................................................................................................56 
6.7.1 
Physical Exam ............................................................................................................... 56 
6.7.2 
Vital Signs ...................................................................................................................... 56 
6.7.3 
Height and Weight ......................................................................................................... 57 
6.7.4 
Medical History .............................................................................................................. 57 
6.7.5 
Socio-Behavioral Assessments ................................................................................... 57 
6.7.6 
Laboratory Evaluations ................................................................................................ 57 
6.7.7 
Pregnancy Testing ........................................................................................................ 57 
6.7.8 
ECG ................................................................................................................................. 58 
6.7.9 
Participant Diary Card (PDC) ........................................................................................ 58 
6.8 
Injection and Electroporation (EP) .........................................................................58 
6.9 
Management of Anxiety and Pain due to Electroporation (EP) Procedures .......58 
6.10 Assessment of Laboratory Abnormalities .............................................................59 
6.11 Assessment of Clinical Trial Adverse Events (AEs) .............................................59 

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6.12 Assessment of Injection Site Reactions ................................................................59 
6.13 Assessment of Patient Reported Outcomes .........................................................60 
6.14 Peripheral Blood Immunogenicity Assessments ..................................................61 
6.15 Tissue Immunogenicity Assessment .....................................................................61 
6.16 Anal and/or Peri-anal HPV Testing.........................................................................62 
6.17 HPV Testing from other Anatomical Site (Non-anal) ............................................62 
6.18 Anal Photographs and Biopsies ............................................................................62 
6.19 Unscheduled Biopsies ............................................................................................62 
6.20 Concomitant Medications/Treatments ...................................................................63 
6.21 Restrictions .............................................................................................................63 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ........................... 64 
7.1 
Safety Parameters ...................................................................................................64 
7.2 
Adverse Events (AEs) .............................................................................................64 
7.3 
Serious Adverse Events .........................................................................................65 
7.4 
Unexpected Adverse Drug Reactions and Expedited Reporting .........................66 
7.5 
Unanticipated (Serious) Adverse Device Effect ....................................................66 
7.6 
Assessing Severity (Intensity) ...............................................................................67 
7.7 
Causal Relationship of Clinical Material to Adverse Events ................................67 
7.8 
Abnormal Laboratory Value ...................................................................................68 
7.9 
Post-Trial Reporting Requirements .......................................................................68 
7.10 Procedures for Documenting Pregnancy During the Trial ...................................69 
7.11 Methods and Timing of Collection of Safety Data ................................................69 
7.12 Safety and Toxicity Management ...........................................................................70 
7.12.1 Adverse Events of Special Interest ............................................................................. 70 
7.13 Adverse Event Reporting .......................................................................................70 
7.14 Trial Reporting Period of Adverse Events .............................................................70 
7.15 Trial Reporting Period of Serious Adverse Events and AESIs ............................71 
7.16 Notifications of Serious Adverse Events ...............................................................72 
7.17 Reporting of CELLECTRA™5PSP Device Related Complaints or Deficiencies .72 
7.18 Trial Discontinuation ..............................................................................................73 
8.0 
STATISTICAL CONSIDERATIONS .................................................................. 73 
8.1 
Statistical and Analytical Plan ................................................................................73 
8.2 
General Considerations ..........................................................................................73 
8.3 
Statistical Hypotheses ............................................................................................73 
8.4 
Analytical Populations ............................................................................................73 
8.5 
Description of Statistical Methods .........................................................................74 
8.5.1 
Primary Analyses .......................................................................................................... 74 
8.5.2 
Secondary Analyses ..................................................................................................... 74 
8.5.3 
Safety Analyses ............................................................................................................. 74 
8.5.4 
Disposition ..................................................................................................................... 75 
8.5.5 
Demographic and Other Baseline Characteristics .................................................... 75 

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8.5.6 
Interim Analyses ............................................................................................................ 75 
8.5.7 
Multiplicity ...................................................................................................................... 75 
8.5.8 
Missing Values............................................................................................................... 75 
8.5.9 
Exploratory Analyses .................................................................................................... 75 
8.6 
Sample Size/Power .................................................................................................76 
8.7 
Randomization and Blinding ..................................................................................76 
9.0 
ETHICS ...................................................................................................... 76 
9.1 
Investigator and Sponsor Responsibilities ...........................................................76 
9.2 
Institutional Review Board or Ethics Committee ..................................................76 
9.3 
IBC Approval and Reporting ..................................................................................77 
9.4 
Office of Biotechnology Activities .........................................................................77 
9.5 
Protection of Human Subjects ...............................................................................77 
9.5.1 
Compliance with Informed Consent Regulations ...................................................... 77 
9.5.2 
Compliance with IRB/EC Requirements ..................................................................... 77 
9.5.3 
Compliance with Good Clinical Practice .................................................................... 77 
9.5.4 
Compliance with Electronic Records/Signature Regulations (21CRF Part 11) ...... 77 
9.5.5 
Compliance with Protocol ............................................................................................ 77 
9.5.6 
Changes to the Protocol ............................................................................................... 78 
10.0 
DATA COLLECTION, MONITORING, AND REPORTING .................................... 78 
10.1 Confidentiality and Privacy ....................................................................................78 
11.0 
SOURCE DOCUMENTS ................................................................................ 78 
11.1 Records Retention ..................................................................................................79 
12.0 
SAFETY AND QUALITY MONITORING ............................................................ 79 
12.1 Safety and Quality Monitoring ................................................................................79 
12.2 Pathology Adjudication Committee .......................................................................79 
12.3 Clinical Monitoring ..................................................................................................79 
13.0 
PUBLICATION POLICY ................................................................................. 80 
14.0 
LIST OF ABBREVIATIONS ............................................................................ 81 
15.0 
REFERENCES ............................................................................................. 83 
16.0 
APPENDICES .............................................................................................. 85 
 
 
 
 
 

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Clinical Protocol 
Protocol Version Date:  15May2019 
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Protocol Version: 2.0 
 
Page 11 of 85 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 related Anal 
or Anal/Peri-anal High-Grade Squamous Intraepithelial Lesions, HSIL (AIN2, AIN3, PAIN2, 
PAIN3) in individuals that are seronegative for Human Immunodeficiency Virus (HIV)-1/2 
Protocol Number: HPV-203 
 
Trial Phase: 2a 
 
Estimated Number of Trial Centers and Countries/Regions: Approximately 3 study 
centers located in North America 
 
Formulation: VGX-3100 
 
Trial Design: Multi-center, single-arm, open-label phase 2 study 
  
Criteria for Evaluation: To provide a treatment to regress anal or anal/peri-anal HSIL and 
clear the related HPV-16 and/or HPV-18 (HPV16/18) in individuals that are seronegative for 
HIV-1/2. 
 
Research Hypothesis: VGX-3100 followed by electroporation (EP) administered to adults 
with histologically confirmed anal or anal/peri-anal HSIL1, (AIN22, AIN33, PAIN24, PAIN35) 
associated with HPV-16 and/or HPV-18 will result in a higher proportion with 
histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence of anal 
or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than historical controls.  
Dose of VGX-3100: 6 mg (1mL) 
Administration: Intramuscular injection followed by EP 
VGX-3100 Dosing Schedule: Day 0, Week 4 and Week 12 with one additional dose given 
to partial responders at Week 40 
Study Duration: 88 Weeks 
Primary Objective: Determine the efficacy of 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and virologic clearance 
of HPV-16 and/or HPV-18. 
Primary Endpoint: Proportion of subjects with no histologic evidence of anal or anal/peri-
anal HSIL6 on histology (i.e., collected via biopsy or excisional treatment)7 and no evidence 
of HPV-16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue qualifying lesions8. 
1 High-grade Squamous Intraepithelial Lesion 
2 Grade 2 Anal Intraepithelial Neoplasia 
3 Grade 3 Anal Intraepithelial Neoplasia             
4 Grade 2 Peri-anal Intraepithelial Neoplasia 
5 Grade 3 Peri-anal Intraepithelial Neoplasia 
6  No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
7  A treatment responder is defined as a subject with no histologic evidence of anal or anal/peri-anal HSIL and no evidence of 
HPV-16 or HPV-18 in anal lesion tissue and who did not receive any non-study treatment of curative intent of intra-anal 
and/or peri-anal lesions. A treatment non-responder is defined as a subject with histologic evidence of anal or anal/peri-anal 
HSIL, adenocarcinoma-in-situ (AIS), anal or anal/peri-anal carcinoma or a subject with evidence of HPV-16/18 in anal lesion 
tissue or a subject who received non-study treatment of curative intent of intra-anal and/or peri-anal lesions. 

VGX-3100 
 
HPV-203 
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Clinical Protocol 
Protocol Version Date:  15May2019 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 12 of 85 
8 An intra-anal and/or peri-anal lesion which is confirmed to be HPV-16 and/or HPV-18 positive and have histologically confirmed 
anal or anal/peri-anal HSIL by the Pathology Adjudication Committee (PAC). 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary Card (PDC). 
 
1b. All adverse events including SAEs, 
UADEs, and other unexpected AEs 
for the duration of the study (through 
the Week 88 visit) 
2. Determine the efficacy of three doses 
of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL 
2. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
HSIL9 on histology (e.g. biopsies or 
excisional treatment) at the Week 36 
visit 
3. Determine the efficacy of VGX-3100 as 
measured by virologic clearance of 
HPV-16 and/or HPV-18 by testing from 
lesion tissue 
3. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-
1810 from intra-anal and/or peri-anal 
tissue by type specific HPV testing at 
the Week 36 visit 
4. Determine the efficacy of VGX-3100 as 
measured by virologic clearance of 
HPV-16 and/or HPV-18 by intra-anal 
tissue swab testing 
4. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-18 
from intra-anal swab by specific HPV 
testing at the Weeks 36, 64, and 88 
visits 
5. Determine the efficacy of three doses 
of VGX-3100 as measured by complete 
histopathologic regression of anal or 
anal/peri-anal HSIL to normal tissue 
5. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
Low grade squamous intraepithelial 
lesion (LSIL) or HSIL (i.e. no 
evidence of AIN2, AIN3, PAIN2, 
PAIN3) on histology (i.e. biopsies or 
excisional treatment) at the Week 36 
visit 
6. Determine the efficacy of three doses 
of VGX-3100 as measured by 
histopathologic non-progression of 
anal or anal/peri-anal HSIL  
6. Proportion of subjects with no 
progression11 of anal or anal/peri-
anal HSIL to carcinoma from 
baseline12 to histology (i.e. biopsies 
or excisional treatment) at the Week 
36 visit 
7. Describe the efficacy of VGX-3100 for 
partial responders, as measured by 
reduction in the number of intra-anal 
and/or peri-anal lesion(s), as applicable 
and the reduction in size of peri-anal 
lesion(s) if present, and for whom the 
disease has not progressed according 
to Investigator judgment in subjects who 
did not have anal or anal/peri-anal HSIL 
lesion resolution at Week 36 
7. Percent reduction in the number of 
intra-anal and/or peri-anal lesion(s), 
and the reduction in size of peri-anal 
lesion(s) as determined by the 
Investigator at Weeks 36, 64, and 88 
compared to baseline12. 

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8. Determine the humoral and cellular 
immune response following dose 3 and 
additional time points compared to 
baseline 
8a. Levels of serum anti-HPV-16 and 
anti-HPV-18 antibody concentrations 
at baseline and the Weeks 15, 36, 
64, and 88 visits 
 
8b. Interferon-γ ELISpot response spot 
forming units (SFU) at baseline and 
the Weeks 15, 36, 64, and 88 visits 
 
8c. Flow Cytometry response magnitude 
at baseline and Week 15 visit 
  9 No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
10 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
11 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication Committee.  
12 Baseline photographic imaging is defined as photographs obtained pre-biopsy at Screening, or post biopsy at Screening (for      
subjects with historical biopsy tissue). 
 
 
 
 

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Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the efficacy of more than 3 
doses of VGX-3100 with respect to 
combined histopathologic regression of 
anal or anal/peri-anal HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
1.  Proportion of subjects with no histologic 
evidence of anal or anal/peri-anal HSIL 
on histology (i.e. collected via biopsy or 
excisional treatment) and no evidence of 
HPV-16/18 at Week 64 by testing from 
intra-anal and/or peri-anal lesion tissue 
2. Describe the efficacy of more than 3 
doses of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL 
2.   Proportion of subjects with no evidence 
of anal or anal/peri-anal HSIL on histology 
(i.e. biopsies or excisional treatment) at 
Week 64 for subjects who receive 4 
doses of VGX-3100 
3. Describe the efficacy of more than 3 
doses of VGX-3100, as measured by 
virologic clearance of HPV-16 and/or 
HPV-18 
3.   Proportion of subjects with no HPV-16/18 
at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue for subjects 
who receive 4 doses of VGX-3100 
4. Evaluate tissue immune responses to 
VGX-3100 in intra-anal and/or peri-anal 
samples 
4.   Assessment of proinflammatory and 
immunosuppressive elements in tissue, 
where feasibile13 
5. Describe the clearance of HPV-16 and/or 
HPV-18 infection from non-anal anatomic 
locations 
5.  Proportion of subjects who have cleared 
HPV-16 and/or HPV-18 on specimens 
from non-anal anatomic locations as 
applicable based upon gender (i.e. 
oropharynx, cervical, vaginal, and penile 
at Week 36 visit) 
6. Describe the association of microRNA 
(miRNA) profile, previous anoscopy, 
cytology and HPV testing results with 
Week 36 histologic regression 
6.   HRA, cytology, and HPV test results and 
miRNA profile (baseline and at the Weeks 
15 and 36) in conjunction with histologic 
regression of anal or anal/peri-anal HSIL 
at the Week 36 visit 
7. Describe patient reported outcomes 
(PRO) for subjects treated with VGX-3100 
7.   Patient reported outcome (PRO) 
endpoints will be obtained prior to first 
dose (Day 0), on the day of and following 
each dose, and at Weeks 36, 64, and 88. 
There will be an additional PRO 
assessment at Week 40 if a subject 
receives a 4th dose 
13Additonal assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possible other relevant 
markers identified in the literature as sample allows. 
 

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Study Design: 
 
HPV-203 is a Phase 2, 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 in adult 
men and women who are HIV negative with histologically confirmed anal or anal/peri-anal 
HSIL associated with HPV-16 and/or HPV-18. 
 
Approximately 24 subjects will receive at least 3 doses of VGX-3100. Each dose of VGX-
3100 will be administered in a 1 mL volume IM followed immediately by EP. As shown in 
Figure 1, study subjects will receive at least 3 doses of VGX-3100 depending upon their 
disposition with regard to histologic and lesion area changes during the trial. The first dose 
will be administered on Day 0, the second at Week 4, and the third at Week 12. Partial 
response to VGX-3100 may still be of medical importance by being able to limit the extent of 
surgery necessary. For partial responders at Week 36, a fourth dose may be administered at 
Week 40.  
 
All subjects are scheduled to be followed to Week 88. 
 
Figure 1: HPV-203 Study Visit Schedule 
 
 
 
 
Biopsy (ies) 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 anal or 
anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the biopsy sample(s). All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥ 4mm) will be biopsied at Screening. Subjects 
must also have intra-anal and/or peri-anal lesion(s) tissue test positive for HPV genotype 16 
and/or 18 to be eligible for participation in the study. 
 
 
 
 

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To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be administered and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional PRO questions 
assessing quality of life after surgery or biopsy. 
 
Visualization of the lesion and digital anal rectal examination (DARE) alone are insufficient 
evidence to confirm disease regression. Disease regression will be primarily based on 
histopathologic assessment at Week 36 and additionally assessed at Week 64. Subjects will 
be monitored during the course of the study by DARE and HRA. Intra-anal lesion(s) will be 
assessed at Screening, Day 0, and at Weeks 4, 15, 28, 36, 64 and 88 using HRA. All 
qualifying peri-anal lesion(s) will be assessed using the ruler provided. The ruler should be 
placed in the field of vision and should be documented with photography at Screening, Day 0, 
and Weeks 4, 15, 28, 36, 64, and 88. 
 
The decision process following the results of the Week 36 biopsy are described below in 
Figure 2 and are as follows: At Week 36, the subject will undergo repeat intra-anal and/or 
peri-anal punch biopsies of all HSIL lesions confirmed by the PAC at Screening of adequate 
size (≥ 4mm). (See  
 
Table 1 for Minimally Required Biopsy Procedures). If after evaluation of the biopsy tissue(s) 
by the PAC there is no evidence of HSIL (defined by Subgroups A or B), the subject will 
continue to Week 64 for HRA and undergo biopsies of the same areas (HSIL lesions) as the 
baseline biopsies. If HSIL remains based on the Week 64 biopsy results, the subject will 
receive standard of care and remain on the study for safety and follow up only. 
 
 
Figure 2: Decision process at Week 40 
 
 
 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  15May2019 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 17 of 85 
 
 
Table 1: Minimally Required Procedure at each Biopsy Visit 
 
Pre-biopsy High Resolution Anoscopy 
Finding 
Minimally required procedure 
 
No lesion 
Punch biopsy and photography; biopsy 
should be collected from within the 
approximate original boundaries of the 
study entry HSIL as proximal as possible to 
the original biopsy site which was 
previously determined to be HSIL by the 
PAC. 
 
Single lesion (which was also present at 
baseline) 
Punch biopsy and photography; biopsy 
should be collected within the boundaries of 
the original lesion and from the area most 
suspicious for advanced disease within the 
lesion by clinical exam. 
 
Multiple lesions 
Punch biopsies and photography; biopsy 
should be collected from the same lesions 
diagnosed as HSIL from study entry and 
from the area most suspicious for advanced 
disease within the lesion by clinical exam. 
 
If HSIL is diagnosed in any Week 36 biopsy, but there is a reduction in the number of intra-
anal and/or peri-anal lesion(s), reduction in peri-anal lesion(s) size or no change in peri-anal 
lesion(s) size from baseline (defined by Subgroup C), the Investigator has the option to 
administer a 4th dose of VGX-3100 at Week 40, and the subject will continue on the study to 
have HRA and biopsy at Week 64, i.e. the second efficacy checkpoint. Alternatively, the 
Investigator may instead choose to treat the subject with standard of care treatment (i.e. 
electrocautery, ablation, surgical excision), and the subject will continue on the study without 
further biopsy unless it is part of standard of care. 
 
In the event of worsening anal or anal/peri-anal HSIL at any time during the trial (defined as 
any increase in lesion(s) area from baseline or worsening of anal or anal/peri-anal HSIL to 
cancer), the subject may receive standard of care treatment (i.e. electrocautery, ablation, 
surgical excision) per the Investigator's judgment but will continue on the study through Week 
88 with HRA, but without further biopsy unless it is part of the standard of care. 
 
If there is histologic progression to carcinoma, subjects will receive surgical treatment, and be 
discontinued from study treatment but will continue through Week 88 with HRA, but without 
further biopsy unless it is part of the standard of care. The event will be reported as an SAE 
per Section 7.3. If wide excision is required, the sample(s) obtained will be sent to the PAC 
for evaluation. 
 
Efficacy Assessment: 
 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesion(s) of adequate 
size (≥ 4mm). Visible lesion(s) observed during HRA should be large enough to biopsy, but 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
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Protocol Version Date:  15May2019 
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Protocol Version: 2.0 
 
Page 18 of 85 
the biopsy (typically 4mm) should not remove the entire lesion in order to allow for continued 
lesion measurement while on the study. 
 
Given that HPV infection persistence is a critical factor in the clinical progression of HPV-
associated anal or anal/peri-anal HSIL and also based upon the findings of the secondary 
objective of the HPV-003 CIN2/3 proof of concept study, the responder definition for the HPV-
203 primary endpoint determination requires both histological regression of anal or anal/peri-
anal HSIL and clearance of HPV-16 and/or HPV-18 [1]. 
 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic assessment 
of intra-anal tissue, utilizing HRA with biopsies. All intra-anal and/or peri-anal lesion(s) of 
adequate size (≥4mm) will be biopsied at Screening. Once the PAC confirms HSIL at 
Screening, the Week 36 and 64 biopsies will be obtained from all HSIL site(s) confirmed by 
the PAC at Screening, unless the Investigator suspects disease progression. Tissue samples 
will be analyzed for evidence of histopathologic regression. Clearance of HPV-16 and/or 
HPV-18 will be determined using the type specific HPV PCR test on intra-anal and/or peri-
anal tissue performed at Screening and Weeks 36 and 64 when applicable. 
 
Intra-anal and/or peri-anal swabs will be collected at Screening, Day 0, and at Weeks 4, 15, 
28, 36, 64 and 88 as a less invasive measure for exploratory purposes to determine the 
presence of HPV-16 and/or -18 as well as other high risk HPV types using HPV testing. 
Similarly, vaginal, cervical (female subjects), penile (male subjects), and oropharyngeal (OP) 
rinse samples will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess 
systemic virologic response to treatment. 
 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction in 
intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size from 
baseline (Subgroup C), the Investigator will have the option to administer a 4th dose of VGX-
3100 at Week 40 and the subject will continue on the study with HRA and biopsy at Week 64. 
Alternatively, the Investigator may choose to treat the subject with standard of care treatment 
(i.e. electrocautery, ablation, surgical excision), and the subject will continue on the study 
without further biopsy. If HSIL remains based on the Week 64 biopsy results, the subject will 
receive standard of care and remain on the study for safety and follow up only. 
 
Immunogenicity Assessment: Humoral and cell mediated immune responses to VGX-3100 
may be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, 64, and 88. Intra-anal and/or peri-anal tissue samples may 
also be analyzed for evidence of proinflammatory and immunosuppressive elements at Week 
36 as compared to baseline (Screening), where feasible. 
 
Virologic Assessment: Intra-anal and/or peri-anal swabs will be obtained to characterize 
HPV infection at Screening, Day 0, and Weeks 4, 15, 28, 36, 64 and 88. Likewise, PCR-
based assessment of histological samples will occur at Screening and Weeks 36 and 64. 
 
For testing of non-anal sites, vaginal, cervical (female subjects), penile (male subjects), and 
oropharyngeal (OP) samples (all subjects) will be obtained to characterize HPV infection at 
Day 0, and at Weeks 4,15, 28, 36, 64 and 88. 
 
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 Card (PCD). 

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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version: 2.0 
 
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2) All adverse events including SAEs, UADEs, and other unexpected AEs for the 
duration of the study. 
 
All subjects will be followed to Week 88. 
 
Data Safety & Monitoring Board (DSMB): An independent 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. Refer to Section 3.8 for stopping rule criteria. 
 
Definition of Responder and Non-Responder for Primary Endpoint: 
 
Responder and non-responder definitions ( 
Table 2) take into account both histopathologic regression of anal or anal/peri-anal HSIL and 
virologic (HPV-16/18) clearance as measured by intra-anal and/or peri-anal tissue since HPV 
persistence is an important factor in the clinical progression of HSIL. Any case of 
histologically confirmed progression from HPV-16/18 positive anal or anal/peri-anal HSIL to 
carcinoma is considered a non-responder. 
 
Table 2: Definition of Responder and Non-Responder for Primary Endpoint 
 
Responder 
Non-Responder 
 
 
No histologic evidence of anal or anal/peri-
anal HSIL  
 
AND 
 
Negative PCR for HPV-16 or HPV-18 in 
anal lesion tissue  
 
 
AND 
 
No non-study treatment of curative intent of 
intra-anal and/or peri-anal lesions 
 
 
 
 
 
 
Histologic evidence of anal or anal/peri-anal  
HSIL, anal Adenocarcinoma-in-situ (AIS), 
anal or anal/peri-anal carcinoma 
 
OR 
 
PCR positive for HPV-16 or HPV-18 in anal 
lesion tissue  
 
 
OR 
 
Any non-study treatment of curative intent of 
intra-anal and/or peri-anal lesions 
 

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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 
and be able to provide voluntary consent to participate and sign an Informed Consent 
Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2a within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16 and/or HPV-18 infection at Screening by 
PCR from HSIL specimen; 
5. Anal tissue (blocks only) provided to the Study Pathology Adjudication Committee 
(PAC) for diagnosis must be collected within 10 weeks of first dose of VGX-3100; 
6. At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
a. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) should 
not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology collection 
procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
a. Post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level 
>40mlU/mL; 
b. Surgically sterile due to absence of ovaries or due to bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
c. Subject agreement to avoid pregnancy for one month after last dose (Week 12 
or Week 40); 
d. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive 
method with a failure rate of less than 1% per year when used consistently and 
correctly from Screening until one month following the last dose of 
investigational product (Week 12 or Week 40). The following are acceptable 
methods: 
i. Hormonal contraception: either combined progestin-alone including 
oral contraceptive, 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. Men who would father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, for 
the duration of study participation and one month after completion of VGX-3100 
administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 
a An HIV rapid test may be used given the following conditions are met: 1. The test is an antigen/antibody 
immunoassay, 2. The test is only done using blood, 3. The test must be performed in the office and done by qualified 
study staff members   

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Exclusion: 
1. Untreated micro invasive cancera; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAINb; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing medical 
care and/or treatment for VINb; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CINb; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing medical 
care and/or treatment for PINb; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument; 
7. Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; 
8. Inability to have complete and satisfactory high resolution anoscopic exams (HRAs) 
as defined by full visualization of the anus, entire anal canal from the 
squamocolumnar junction at the border of the distal rectum, anal transformation zone, 
distal canal, anal verge, perianus;  
9. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
Screening; 
10. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
11. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 45 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigatorc; 
12. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) or oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 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. Prior chemotherapy within 1 year; 
f. History of solid organ or bone marrow transplantation; 
13. History of previous therapeutic HPV vaccination (however, licensed prophylactic HPV 
vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
14. Receipt of any non-study related non-live vaccine within 2 weeks before or after any 
VGX-3100 dose; 
15. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks 
before or after any VGX-3100 dose; 
16. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
17. 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 
the study results (e.g. chronic renal failure, angina, myocardial ischemia or 
infarctation, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 
 
a This criterion includes subjects who have microscopic or gross evidence of invasive cancer, or the suspicion of cancer 
in any histopathologic specimen by any pathologist at screening. 
b When observation is the standard of care this will not exclude a subject from the study. 
c If the lab is redrawn and the result from the redrawn sample no longer meets this exclusion criteria, then the subject is 
not excluded on the basis of this criterion 
 

VGX-3100 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
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18. Treatment for non-anogenital malignancy within 2 years of Screening, with the   
exception of superficial skin cancers that only require local excision; 
19. 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; 
20. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
21. 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; 
22. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
23. Prior major surgery within 4 weeks of Day 0; 
24. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent form (participating in an observational 
study is permitted); 
25. 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 on the ipsilateral side (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); 
26. Any illness or condition that in the opinion of the Investigator may affect the safety of 
the subject or evaluation of any study product; 
27. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 personnel; 
d. Study-related staff or family members of study-related staff 
 

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TRIAL SCHEDULE OF EVENTS 
 
Table 3: Schedule of Events 
 
 
 
1 Subject eligibility will be reconfirmed at every visit. 
 
Study Action 
Screen  (-10 wk. to -1d) 
Day 0 
8-14 days post dose 1 Phone Call 
Week 4 (± 4 days) 
8-14 days post dose 2 Phone Call 
Week 12 (± 4 days) 
Week 15 (± 1 Week) 
Week 28 (± 1 Week)  
Week 36 (± 1 Week) 
Week 40 (± 1 Week) 
8-14 days post dose 4 Phone Call 
Week 64 (± 2 Weeks) 
Week 88 (± 2 Weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
X 
 
 
Xn 
X 
Inclusion/Exclusion criteria1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
Xb 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Screening safety (12 lead ECG, 
laboratories) c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d   
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xf 
 
Xe 
 
 
Xe 
Xe 
Oropharyngeal (OP) rinse 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Vaginal, cervical, and penile swab 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Intra-anal and/or peri-anal swab 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Digital Anal Rectal Examination 
DARE g 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
High Resolution Anoscopy (HRA) h 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Lesion photography i 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Biopsy j  
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Inject VGX-3100 +EPk   
 
X 
 
X 
 
X 
 
 
 
Xk 
 
 
 
Post 
treatment 
reaction 
assessment 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Distribute Participant Diary Card 
(PDC) 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Review PDC l 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Patient Reported Outcomes 
(PROs) (SF-36v2™) (EQ-5D-5L) m 
 
Xo 
X 
X 
X 
X 
X 
 
X 
X 
Xp 
X 
X 

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a Full Physical exam (PE) mandatory at Screening and study discharge (Week 88), 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 body mass 
index (BMI) (Bodyweight in kilograms divided by height in meters squared). Weight will be 
collected at all dosing visits. 
c Screening 12-lead Electrocardiogram (ECG), complete blood count (CBC), serum electrolytes, 
blood urea nitrogen (BUN), creatinine (Cr), glucose, alanine aminotransferase (ALT), and 
Creatine Phosphokinase (CPK) performed within 45 days prior to first dose administration. 
d Negative spot urine pregnancy test is required for female subjects at Screening, prior to each 
study treatment, high-resolution anoscopy (HRA), and biopsy/surgical excision; the pregnancy 
test at Week 40 would only be needed for subjects who receive an additional dose. 
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 15. 
g Digital Anal Rectal Examinations (DARE) are to be performed once cytology has been 
collected and prior to HRA. 
h An additional visit may be scheduled to perform HRA if worsening of disease is suspected. 
Biopsies should not be performed at any visit other than at entry (Screening) and Weeks 36 
and 64 for Subgroup C unless the Investigator suspects invasive cancer. All biopsy samples 
and/or excision samples must be sent to the Pathology Adjudication Committee (PAC) for 
review. 
i Photography of qualifying lesion(s) must be performed prior to and after biopsy, and at all HRA 
examinations. If a pre-biopsy digital photograph is not available for a historical biopsy sample 
at Screening, a post biopsy photo will be sufficient. Photographs of intra-anal lesion(s) will be 
for documentation purposes only. All qualifying peri-anal lesion(s) will be assessed using the 
ruler provided. The ruler should be placed in the field of vision and should be documented with 
photography at Screening, Day 0, and Weeks 4, 15, 28, 36, 64, and 88. 
j Tissue specimen (paraffin blocks) from all excised tissue lesion(s) that led to eligibility at study 
entry must be reviewed by the PAC and residual tissue from entry and Weeks 36 and 64 
specimen(s) (paraffin blocks) must be sent to the central laboratory for immune analysis and 
Human Papillomavirus (HPV) testing.  
k Potential dosing at Week 40 is applicable for partial responders only.  
l A phone call will be used to review the Participant Diary Card (PDC) with subject within 8-14 
days following doses 1 and 2. The subject will be expected to bring the PDC to the next visits 
for review. Subjects who receive an additional 4th dose will also have a phone call 8-14 days 
post dose 4 where the PDC will be reviewed. The subject should bring the PDC to the next 
visit.  
m Patient-reported outcome (PRO) measures (SF-36v2™ and the EQ-5D-5L), plus two 
additional "global" questions will be assessed as described in Section 6.13. 
n This socio-behavioral assessment will only apply to those subjects in Subgroup C who receive 
a 4th dose of investigational product. 
o PROs at this time point must be administered prior to first dose of study drug.  

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p PROs at this time point will only be for subjects who received a 4th dose of study drug. 

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1.0 
INTRODUCTION 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized 
primarily in the ano-genital area and aero-digestive tract, in both men and women. 
Human Papillomavirus 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). In the United States (US), approximately 14 million new genital HPV infections 
occur annually, and approximately half of these infections are with a high-risk HPV type 
(HR-HPV) and thus can cause cancer [2]. In U.S. adults through age 59 years, about 
25% of men and 20% of women have genital HR-HPV infection [3]. Human 
Papillomavirus causes more cancers than any other virus. In U.S. archival tissues of 
cancers diagnosed from 1993 to 2005, HPV Deoxyribonucleic Acid (DNA) was detected 
in 68.8% of vulvar, 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of 
oropharyngeal (OP), 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) [4]. An average of over 
30,000 cases per year of HPV-attributable cancer were diagnosed during the period 
2008 through 2012 in the U.S. [5]. Human Papillomavirus-16 and HPV-18 are the most 
significant among high-risk types since they are responsible for most HPV-caused 
cancers [4].  
With regard to anal cancer, about 95% of cases are caused by HPV, and most of those 
cases are caused by HPV-16 [6, 7]; with some by HPV-18 and perhaps other HPV 
genotypes [2]. An estimated 8,200 new cases of anal cancer in the US are diagnosed 
each year (for year 2017), with an estimated 1,100 deaths annually due to this cancer 
[8]. In Canada, the latest available data is for year 2013, during which 580 new cases of 
anal cancer were diagnosed and 144 persons died due to anal cancer [9]. 
The precursor lesion to HPV-associated anal cancer historically was known as anal 
high-grade dysplasia or intraepithelial neoplasia. In 2012, the Lower Anogenital 
Squamous Terminology (LAST) Standardization Project for HPV-associated lesions 
applied the term HSIL to encompass high grade dysplasia [10]. Among HPV-associated 
anal HSIL cases in the US, about 55% to 80% are associated with HPV-16/18, and 
worldwide about 80% of cases are associated with HPV-16/18 [7, 11, 12]. 
Left untreated, anal HSIL may progress to cancer. Spontaneous regression of these 
lesions may occur, but the available data indicate that such regression is in the minority 
of cases. For example, published results of a small observational study of anal HSIL in 
men who have sex with men (MSM) in Australia found spontaneous regression occurred 
in 29% of those HIV-negative after more than one year of follow-up time, with an even 
lower regression rate in those who were HIV-positive. That study also found that the 
majority (71%) of patients who regressed only did so to anal low-grade SIL (Low grade 
squamous intraepithelial lesion [LSIL]), with the remainder to normal tissue [13]. In an 
ongoing larger observational study of gay and bisexual men – the Study of the 
Prevention of Anal Cancer (SPANC) [14] -- also comprised of patients HIV-negative and 
HIV-positive (though with medically well-controlled CD4 cell counts), preliminary 
published data show that 55% of patients with anal HSIL, regardless of HIV status, had 
their HSIL persist to at least 12 months and HPV-16 was significantly associated with 
persistence as compared to other HPV genotypes (Relative Risk of 1.5) [15].  
 

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Spontaneous regression data from that study are not yet published, but preliminary data 
show spontaneous regression of only about 20% by one year of follow-up. Further, many 
of those patients who regressed later recurred to HSIL, suggesting that HSIL in some 
cases may be merely regressing to a level below the detection limit but is still present 
[16]. Other published data from a sub-study of that larger study indicate that HPV-16 E6-
specific T-cell responses may be associated with recent anal HSIL regression (Pexact = 
0.065) [17]. That finding provides further plausibility, in addition to other data 
summarized later in this protocol, that VGX-3100 plus electroporation treatment could 
cause anal HSIL regression. 
Anal HPV infection spontaneous clearance in non-immunocompromised adults can 
occur, but such data are generally unavailable for persons who have anal HSIL. 
Nevertheless, high-risk HPV (HR-HPV) clearance by one year ranges from 56% to 78%, 
varying by gender and sexual preference etc., as found in large, prospective studies [18-
20] with some wider variation in clearance rates for HPV-16 and HPV-18 specifically in 
those studies. 
Collectively, the aforementioned anal HSIL regression and HPV clearance data 
comprise in part the historical control data that the results of the present trial will be 
compared to. 
1.1.1 
VGX-3100 
VGX-3100 contains plasmids that target 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 (IP) designed as a non-surgical 
treatment of HPV-16/18-related anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, and 
PAIN3) via an immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was Water for Injection (WFI) with 1% w/w poly-L-
glutamate (WFI/LGS) that required frozen storage. This frozen formulation has been 
administered to more than 250 subjects in Phase 1 and 2 clinical trials. A buffered 
formulation of VGX-3100 was developed using a saline sodium citrate (SSC) solution, 
which is stored non-frozen (5°C). This non-frozen formulation of VGX-3100 was 
administered to 117 subjects in a Phase 1 clinical trial, HPV-101 in which subjects were 
randomized 1:1 to receive the non-frozen or frozen formulation of VGX-3100. In study 
HPV-101, healthy adults received three 6 mg IM doses of VGX-3100 in the frozen or 
non-frozen formulations followed by EP with the CELLECTRA™ 5Pdevice. The non-
frozen formulation was found to be non-inferior to the frozen formulation based upon a 2-
fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the plasmids 
per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ enzyme-linked immunospot (ELIspot) assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, 
placebo-controlled Phase 2b study of VGX-3100 (frozen formulation) followed by EP in 
the treatment of high grade cervical dysplasia, cervical HSIL associated with HPV-16/18 
[1]. The Phase 2b study, HPV-003, enrolled 169 subjects with high grade cervical 
dysplasia from seven countries and one US Territory (Australia, Canada, Estonia, 
Republic of Georgia, India, South Africa, US and Puerto Rico). Subjects were 
randomized in a 3:1 ratio to treatment with VGX-3100 or placebo, respectively. All 

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subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to 
repeat cervical biopsy or Loop Electrical Excision Procedure (LEEP) of the cervix at 
Week 36 to assess efficacy defined as regression of high grade Cervical Intraepithelial 
Neoplasia (CIN) by histopathology. The primary endpoint was histopathologic regression 
of cervical lesions (CIN2 or CIN3) to Grade 1 Cervical Intraepithelial Neoplasia (CIN1) or 
less at the Week 36 visit. A secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less. The 
proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol (PP) and modified Intent 
to Treat (mITT) analyses. Robust T-cell activity was detected in VGX-3100 recipients 
compared to placebo recipients. VGX-3100 was generally safe and well tolerated when 
administered intramuscularly with electroporation. 
1.1.2 
ELECTROPORATION 
CELLECTRA® 2000 & CELLECTRA™ 5PSP are both electroporation (EP) devices 
developed by INOVIO. Electroporation with CELLECTRA™5PSP is a physical method of 
tissue transfection whereby the generation of short, controlled electrical pulses creates a 
localized electrical field at the injection site which increases cell membrane permeability 
and improves the transfection of DNA and subsequent immunogenicity [21, 22]. EP is 
believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced immunogenicity by 10 to 100 fold [23, 24]. 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 [21]. The CELLECTRA™ device developed by INOVIO is used for 
investigational purposes to administer plasmid-based DNA, in both prophylactic and 
therapeutic settings. Following successful proof-of-concept studies in animals, INOVIO 
has optimized both pulse pattern and voltage to increase transfection efficiency, and has 
demonstrated that the device helps to elicit favorable immunogenicity in several species 
(e.g., mice, pigs, and rhesus macaques) [22, 23]. 
A next generation device, CELLECTRA™ 5PSP, was created to address ergonomic 
functionality and automate the delivery of VGX-3100 and EP. The technology differences 
between the CELLECTRA® 2000 and CELLECTRA™ 5PSP design do not affect the 
intended mechanism of EP on the activity of VGX-3100 and will not present any new 
risks. The device design change does not affect the indications for use, operating 
principle, energy type, or sterilization specifications. The CELLECTRA™ 5PSP has been 
approved for investigational use in the U.S. with VGX-3100 and is being used in a Phase 
3 clinical study HPV-301, titled "A Prospective, Randomized, Double-blind, Placebo-
Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly (IM) followed by 
Electroporation with CELLECTRA™ 5PSP for the Treatment of HPV-16/18 related HSIL 
of the Cervix". Together, VGX-3100 and the CELLECTRA™ device represent an 
integrated product designed as a non-surgical treatment for HPV-16/18-related cervical 
HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Inovio Pharmaceuticals Inc. device experience demonstrates that delivery of its 
proprietary electroporation pulses into muscle immediately following injection of DNA 
plasmids (including VGX-3100) is well-tolerated in humans and no significant safety 
issues have been identified [1, 22, 24]. For further information concerning the 
CELLECTRA™ 5PSP device please refer to the User Manual and the Investigator's 
Brochure. 

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1.1.3 
DOSE RATIONALE 
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 the 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. 
This dose-trend was consistent with prior expectation, a feature of the finding that 
suggests it is a true effect rather than random variation. Adverse events (AEs) from 
previous human studies with VGX-3100 and closely related DNA plasmid products have 
been limited to injection site pain from the injection and electroporation procedure, which 
were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in HPV-003, 
Phase 2b study. The results obtained in the phase HPV-003 suggest that the 6 mg dose 
was efficacious with an acceptable safety profile, therefore the 6 mg dose will also be 
evaluated in this Phase 2 trial [1]. 
1.2 
POTENTIAL BENEFITS 
Currently accepted surgical treatments are associated with a high recurrence rate, 
>50%. The current surgical approaches also have risks inherent with any surgical 
procedure including anesthesia, post-operative bleeding, infection, or damage to 
surrounding structures such as the anus. This study has been designed to provide non-
surgical treatment with an aim of regression of the anal or anal/peri-anal HSIL and thus 
avoiding the need for surgical excision, infrared coagulation, electrocautery and laser 
therapy. In the absence of complete resolution of intra-anal and/or peri-anal lesions, 
there would still be potential benefit from a partial response, which would reduce or 
minimize the need for excisional or ablative treatment modalities. 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. Consequently, there is the potential to reduce the risk 
of recurrence of anal or anal/peri-anal HSIL. 
1.3 
POTENTIAL RISKS 
Risks associated with VGX-3100 for the treatment of anal or anal/peri-anal HSIL are 
injection site reactions related to the IM injection and/or electroporation. Based on the 
phase 1 and 2 clinical experience with VGX-3100 with healthy volunteers and in women 
with cervical HSIL, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at 
most. 
A potential risk is the delay of surgical intervention of the high grade anal dysplasia and 
possible missed diagnosis of an occult early invasive cancer for the VGX-3100 non-
responders, who do not spontaneously regress. Although professional guidelines 
typically advocate excisional therapy for adults with HSIL, scientific data indicates that 
the rate of progression from pre-invasive to invasive cervical disease is slow, typically 
thought to take several years [10]. The risk of a missed diagnosis of an occult early 
invasive cancer exists for all current treatment modalities including surgical and ablative 
therapies. To mitigate these potential risks the study design includes numerous 
safeguards to detect disease progression or the presence of an undiagnosed occult 

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early invasive cancer. These include, careful selection of immunocompetent patients, 
thorough screening and baseline evaluation, frequent High-resolution anoscopy (HRA) 
and high-risk HPV testing throughout the trial. Investigators will be comprised of 
experienced physicians, who will have the discretion to obtain biopsies at any point if 
disease progression is suspected. 
An independent Data and Safety Monitoring Board (DSMB) will also advise the Sponsor 
if it appears that the frequency of regression is unacceptably low. These measures 
should minimize the risk of progression of the HSIL and the risk of harboring an 
undiagnosed occult early invasive cancer.  
In the HPV-003 study of women with cervical HSIL, the percentage of subjects with 
micro-invasive cancer found in larger surgical excision samples in subjects who had no 
evidence of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is 
consistent with and even lower than the 6.7% that has been reported under standard of 
care settings [18]. 
For further information concerning the risks associated with VGX-3100 and the 
CELLECTRA™5PSP device please refer to the Investigator's Brochure. 
2.0 
PURPOSE AND HYPOTHESIS 
2.1 
PURPOSE 
To provide a treatment to potentially regress and clear HPV-16/18 related anal or 
anal/peri-anal HSIL in individuals that are seronegative for HIV-1/2. 
2.2 
HYPOTHESIS 
VGX-3100 followed by electroporation (EP) administered to adults with histologically 
confirmed anal or anal/peri-anal high-grade squamous intraepithelial lesions, HSIL, 
(AIN2, AIN3, PAIN2, PAIN3) associated with HPV-16/18 will result in a higher proportion 
with histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence 
of anal or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than 
historical controls. 
3.0 
TRIAL DESIGN AND ENDPOINTS 
HPV-203 is a Phase 2, 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 
in adult men and women who are HIV negative with histologically confirmed anal or 
anal/peri-anal HSIL associated with HPV-16 and/or 18. Approximately 24 subjects will 
receive at least 3 doses of VGX-3100. Each dose of VGX-3100 will be administered in a 
1 mL volume IM followed immediately by EP. As shown in Figure 1, study subjects will 
receive at least 3 doses of VGX-3100 depending upon their disposition with regard to 
histologic and lesion area changes during the trial. The first dose will be administered on 
Day 0, the second at Week 4, and the third at Week 12. Partial response to VGX-3100 
may still be of medical importance by being able to limit the extent of surgery necessary. 
For partial responders at Week 36, a fourth dose may be administered at Week 40. All 
subjects are scheduled to be followed to Week 88.  
To be eligible for the study, subjects must consent to participate and agree to the 
collection of anal lesion tissue samples for anal cytology and genotyping, a Digital Anal 
Rectal Examination (DARE), blood samples for immunologic) assessments, HRA and 

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HRA guided biopsies. All intra-anal and/or peri-anal lesion(s) of adequate size (≥ 4mm) 
will be biopsied at Screening. 
Biopsy slides 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 anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the 
biopsy sample(s). Once the PAC confirms HSIL at Screening, the Week 36 and 64 
biopsies will be obtained from all HSIL site(s) confirmed by the PAC at Screening, unless 
the Investigator suspects disease progression. Subjects must also have intra-anal and/or 
peri-anal lesion tissue 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 administered and will include the Short Form Health Survey 
version 2 (SF-36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional 
PRO questions assessing quality of life after surgery or biopsy. 
3.1 
PRIMARY OBJECTIVE(S) 
Determine the efficacy of 3 doses of VGX-3100 with respect to combined histopathologic 
regression of anal or anal/peri-anal HSIL and virologic clearance of HPV-16/18 
3.2 
PRIMARY ENDPOINT(S) 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal HSIL on 
histology (i.e., collected via biopsy or excisional treatment) and no evidence of HPV-
16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue for qualifying lesions 
3.3 
SECONDARY OBJECTIVE(S) 
• 
Evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP 
• 
Determine the efficacy of three doses of VGX-3100 as measured by histologic 
regression of anal or anal/peri-anal HSIL 
• 
Determine the efficacy of VGX-3100 as measured by virologic clearance of 
HPV-16/18 by testing from lesion tissue 
• 
Determine the efficacy of VGX-3100 as measured by virologic clearance of 
HPV-16/18 by intra-anal tissue swab testing 
• 
Determine the efficacy of three doses of VGX-3100 as measured by complete 
histopathologic regression of anal or anal/peri-anal HSIL to normal tissue 
• 
Determine the efficacy of three doses of VGX-3100 as measured by 
histopathologic non-progression of anal or anal/peri-anal HSIL 
• 
Describe the efficacy of VGX-3100 for partial responders, as measured by 
reduction in the number of intra-anal and/or peri-anal lesion(s), as applicable and 
the reduction in the size of peri-anal lesion(s), if present, and for whom the 
disease has not progressed according to Investigator judgment in subjects who 
did not have anal or anal/peri-anal HSIL lesion resolution at Week 36 
• 
Determine the humoral and cellular immune response following administration of 
VGX-3100 at post dose 3, and after additional dosing compared to baseline 

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3.4 
ASSOCIATED SECONDARY ENDPOINT(S) 
• 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary Card (PDC) 
• 
All AEs including Serious Adverse Events (SAES), unanticipated (serious) 
adverse device effect (UADE), and other unexpected AEs for the duration of the 
study (through the Week 88 visit) 
• 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (e.g. biopsies or excisional treatment) at the Week 36 visit 
• 
Proportion of subjects with no evidence of HPV-16/18 from intra-anal and/or 
peri-anal tissue by type specific HPV testing at the Week 36 visit 
• 
Proportion of subjects with no evidence of HPV-16/18 from intra-anal swab by 
specific HPV testing at the Weeks 36, 64, and 88 visits 
• 
Proportion of subjects with no evidence of anal or anal/peri-anal LSIL or HSIL 
(i.e. no evidence of AIN2, AIN3, PAIN2, and PAIN3) on histology (i.e. biopsies or 
excisional treatment) at the Week 36 
• 
Proportion of subjects with no progression of anal or anal/peri-anal HSIL to 
carcinoma from baseline on histology (i.e. biopsies or excisional treatment) at the 
Week 36 visit 
• 
Percent reduction in the number of intra-anal and/or peri-anal lesion(s) and the 
size of peri-anal lesion(s) if present, as determined by the Investigator at Weeks 
36, 64, and 88 compared to baseline.. 
• 
Levels of serum anti-HPV-16 and anti-HPV-18 antibody (Ab) concentrations at 
baseline and the Weeks 15, 36, 64, 88 visits 
• 
Interferon- γ ELISpot response magnitudes at baseline, and the Weeks 15, 36, 
64, and 88 visits 
• 
Flow Cytometry response magnitudes at baseline and Week 15 visits 
3.5 
EXPLORATORY OBJECTIVE(S) 
• 
Describe the efficacy of more than 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and 
virologic clearance of HPV-16/18 
• 
Describe the efficacy of more than 3 doses of VGX-3100, as measured by 
histologic regression of anal or anal/peri-anal HSIL 
• 
Describe the efficacy of more than 3 doses of VGX-3100, as measured by 
virologic clearance of HPV-16/18 
• 
Evaluate tissue immune responses to VGX-3100 in intra-anal and/or peri-anal 
samples 
• 
Describe the clearance of HPV-16/18 infection from non-anal anatomic locations 
• 
Describe the association of microRNA (miRNA) profile, previous anoscopy, 
cytology and HPV testing results with Week 36 histologic regression 
• 
Describe PRO for subjects treated with VGX-3100 

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3.6 
ASSOCIATED EXPLORATORY ENDPOINT(S) 
• 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal 
HSIL on histology (i.e. collected via biopsy or excisional treatment) and no 
evidence of HPV-16/18 at Week 64 by testing from intra-anal and/or peri-anal 
lesion tissue 
• 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (i.e. biopsies or excisional treatment) at Week 64 for subjects who 
receive 4 doses of VGX-3100 
• 
Proportion of subjects with no HPV-16/18 at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue for subjects who receive 4 doses of VGX-3100 
• 
Assessment of proinflammatory and immunosuppressive elements in tissue, 
where feasible.  
• 
Proportion of subjects who have cleared HPV-16/18 on specimens from non-
anal anatomic locations as applicable based upon gender (i.e. oropharynx, 
cervical, vaginal, and penile at Week 36 visit) 
• 
HRA, cytology, and HPV test results and miRNA profile (baseline and at Weeks 
15, 28, and 36) in conjunction with histologic regression of anal or anal/peri-anal 
HSIL at the Week 36 visit 
• 
Patient reported outcome endpoints will be obtained prior to first dose (Day 0), on 
the day of and following each dose, and at Weeks 36, 64, and 88. There will be 
an additional PRO assessment at Week 40 if a subject receives a 4th dose. 
3.7 
EFFICACY ASSESSMENT 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesions of 
adequate size (≥ 4mm). Visible lesions observed during HRA should be large enough to 
biopsy, but the biopsy (typically 4mm) should not remove the entire lesion in order to 
allow for continued lesion measurement while on the study.  
Given that HPV infection persistence is a critical factor in the clinical progression of 
HPV-associated anal or anal/peri-anal HSIL and also based upon the findings of the 
secondary objective of the HPV-003 CIN2/3 proof of concept study, the responder 
definition for the HPV-203 primary endpoint determination requires both histological 
regression of anal or anal/peri-anal HSIL and clearance of HPV-16 and HPV-18 [1]. 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic 
assessment of intra-anal and/or peri-anal tissue obtained from biopsies. All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥ 4mm) will be biopsied at Screening. Once 
the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be obtained from 
all HSIL site(s) confirmed by the PAC at Screening, unless the Investigator suspects 
disease progression. Tissue will be analyzed for evidence of histopathologic regression. 
Clearance of HPV-16/18 will be determined using the by type specific HPV polymerase 
chain reaction (PCR) test on intra-anal and/or peri-anal tissue performed at Screening 
and Weeks 36 and 64 when applicable. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0 (prior to dosing) 
and Weeks 4, 15, 28, 36, 64 and 88 as a less invasive measure for exploratory purposes 
to determine the presence of HPV-16 and/or -18 as well as other high risk HPV types 
using HPV testing. Similarly, vaginal, cervical (female subjects), penile (male subjects) 

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and OP rinse samples (all subjects) will be obtained at Day 0 (prior to dosing), and at 
Weeks 4, 15, 28, 36, 64, and 88 to assess systemic virologic response to treatment. 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction 
in intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size 
from baseline (Subgroup C, Figure 2), the Investigator will have the option to administer 
a 4th dose of VGX-3100 at Week 40 and the subject will continue on the study with HRA 
and biopsy at Week 64, i.e. the second efficacy checkpoint. Alternatively, the 
Investigator may choose to treat the subject with standard of care treatment (i.e. 
electrocautery, ablation, surgical excision), and the subject will continue on the study 
without further biopsy unless it is part of the standard of care. If HSIL remains based on 
the Week 64 biopsy results, the subject will receive standard of care and remain on the 
study for safety and follow up only. All tissue samples obtained from biopsies or 
removed per standard of care will be sent to the PAC for review. 
3.8 
SAFETY ASSESSMENT 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the 
PDC. 
2) All AEs including SAEs, UADEs, and for the duration of the study. 
All subjects will be followed for 88 weeks. 
Data Safety & Monitoring Board (DSMB): An independent 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, PI for the trial, and the DSMB. 
• 
If any SAE (or potentially life-threatening AEs) 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 AEs, 
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. 

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3.9 
IMMUNOGENICITY ASSESSMENT 
Humoral and cell mediated immune responses in response to VGX-3100 treatment may 
be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, and 88. Intra-anal and/or peri-anal tissue samples may 
also be analyzed for evidence of proinflammatory and immunosuppressive elements at 
Week 36 as compared to baseline (Screening), where feasible. 
4.0 
TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
1. Must understand, agree and be able to comply with the requirements of the 
protocol and be able to provide voluntary consent to participate and sign an 
Informed Consent Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2a within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by PCR from 
HSIL specimen; 
5. Anal tissue (blocks only) provided to the Study PAC for diagnosis must be 
collected within 10 weeks of first dose of VGX-3100; 
6. At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
i. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) 
should not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology 
collection procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
i. Post-menopausal as defined by spontaneous amenorrhea for more than 
12 months or spontaneous amenorrhea for 6-12 months with follicle-
stimulating hormone (FSH) level >40mlU/mL; 
ii. Surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
iii. Subject agreement to avoid pregnancy one month after last dose of IP 
(Week 12 or Week 40); 
iv. Women of Childbearing 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 one month following 
the last dose of IP (Week 12 or Week 40). The following are acceptable 
methods: 
1. Hormonal contraception: either combined or progestin-alone 
including oral contraceptives, injectable, implants, vaginal ring, or 
percutaneous patches. Hormonal contraceptives must not be used 

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a An HIV rapid test may be used given the following conditions are met: 1. The test is an antigen/antibody 
immunoassay, 2. The test is only done using blood, 3. The test must be performed in the office and done by 
qualified study staff members   
in subjects with a history of hypercoagulability (e.g. deep vein 
thrombosis, pulmonary embolism); 
2. Abstinence from penile-vaginal intercourse when this is the 
subject's preferred and usual lifestyle; 
3. Intrauterine device or intrauterine system; 
4. 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. Men who could father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, 
for the duration of study participation and one month after completion of VGX-
3100 administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.2 
EXCLUSION CRITERIA 
1. Untreated micro invasive or invasive cancera; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAINb; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing 
medical care and/or treatment for VINb; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not 
undergoing medical care and/or treatment for CINb; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing 
medical care and/or treatment for PINb; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy 
instrument; 
7.   Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at 
Screening;8.Inability to have complete and satisfactory high resolution anoscopic 
exams (HRAs) as defined by full visualization of the anus, entire anal canal from 
the squamocolumnar junction at the border of the distal rectum, anal 
transformation zone, distal canal, anal verge, perianus; 
8. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
Screening; 
9. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
10. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 45 days prior 
to Day 0 or less than Grade 1 but deemed clinically significant by the 
Investigatorc; 
11. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or 
clinically diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) of oral or parenteral glucocorticoids at a dose of 
≥20 mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 
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 Tumor Necrosis Factor 
(TNF)-α inhibitors (e.g. infliximab, adalmumab or etanercept); 
e. Prior chemotherapy within 1 year; 
f. 
History of solid organ or bone marrow transplantation; 
12. History of previous therapeutic HPV vaccination (however, licensed prophylactic 
HPV vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 

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13. Receipt of any non-study related non-live vaccine within 2 weeks before or after 
any VGX-3100 dose; 
14. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 
weeks before or after any VGX-3100 dose; 
15. Significant acute or chronic medical illness that could be negatively impacted by 
the electroporation treated as deemed by the Investigator; 
16. 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 (e.g. chronic renal failure, angina, myocardial ischemia or 
infarction, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 
17. Treatment for non-anogenital malignancy within 2 years of Screening, with the 
exception of superficial skin cancers that only require local excision; 
18. Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of a 
study dose;  
19. History of seizures unless seizure free to 5 years with the use of one or fewer 
antiepileptic agents; 
20. 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; 
21. Resting heart rate <50 beats per minute (bpm) (unless attributable to athletic 
conditioning) or >100 bpm at Screening or Day 0; 
22. Prior major surgery within 4 weeks of Day 0; 
23. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing the ICF (participation in an observational study is 
permitted); 
24. 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-defibrilator or pacemaker on the ipsilateral side (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); 
25. 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; 
26. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) or alcohol use or dependence that, in the 
opinion of the Investigator, would interfere with adherence to study 
requirements; 

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b. Prisoner or subject who is compulsorily detained (involuntary incarcerated) 
for treatment of either a psychiatric or physical (i.e. infectious disease) 
illness; 
c. Active military service personnel; 
d. Study-related staff or family members of study-related staff 
a This criterion includes subjects who have microscopic or gross evidence of invasive cancer, or the suspicion of 
cancer in any histopathologic specimen by any pathologist at screening. 
b  When observation is the standard of care this will not exclude a subject from the study. 
                            c If the lab is redrawn and the result from the redrawn sample no longer meets this exclusion  criteria, then the 
subject is not excluded on the basis of this criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.3 
DISCONTINUATION/WITHDRAWAL OF TRIAL SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION FROM THE STUDY 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from further treatment with VGX-3100. Subjects will not receive further 
doses of VGX-3100 followed by 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 VGX-3100/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
4.3.2 
CRITERIA FOR WITHDRAWAL FROM STUDY 
Subjects who become ineligible to continue on the study based on no longer meeting the 
inclusion criteria should be discontinued from study treatment and managed per routine 
standard of care but should continue on the study without further biopsy.  
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 anal or anal/peri-anal HSIL, 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 the subject 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 they 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 3). At 
a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 88). A subject will be considered 
to have completed the study when he/she completes all scheduled study treatments and 
follow-up visits. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or trial coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the trial or 
is withdrawn from the trial prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation. 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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4.3.4 
REASONS 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 of a subject, (including manner of death if known) 
• 
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 subject. 
Investigator must consult the Medical Monitor before withdrawing a subject from 
participation in the study. 
• 
Protocol Deviation: 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. 
• 
Other: The subject was terminated for a reason other than those listed above, 
such as the termination of the study by the Sponsor. 
If more than 10% of subjects who receive study treatment and discontinue prior to Week 
36, primary endpoint procedures, then supplementation of study subjects will be 
considered. 
 
5.0 
TRIAL TREATMENT 
5.1 
INVESTIGATIONAL BIOLOGIC PRODUCT  
The IP to be used in this trial is described in Table 4. The IP will be presented in a clear 
glass cartridge and injected intramuscularly. 

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Table 4: Investigational Biologic Product 
5.2 
CELLECTRA™ 5PSP DEVICE DESCRIPTION: 
VGX-3100 will be delivered using the CELLECTRA™5PSP device. The device consists 
of five (5) main components (see Figure 3). 
Figure 3: CELLECTRA™ 5PSP Base Station with Handset 
 
 
Base Station 
The base station communicates instructions, alerts, and error messages to the user through a 
touch screen graphical user interface (GUI). It also accepts data inputs from the user, e.g., 
patient identification code, height, and weight; it communicates with the handset; provides 
energy access for the system through connection with standard wall electrical power supply 
sources (100-220V, ~0.5Amp, 50-60Hz); and serves as a docking and recharging station for the 
handset.   
Handset 
The handset facilitates delivery of the needles for injection and electroporation into the muscle 
tissue and executes the treatment sequence (drug injection, impedance check, and 
electroporation pulses). It has a display screen and speakers for user feedback and an 
embedded processor for running the system software that controls and measures all of the 
elements of the handset. The handset is powered by a custom, rechargeable battery pack that 
has its own safety circuit and is compliant to International Ethics Committee (IEC) 62133 and UL 
2054. The handset is designed with three independent fail-safes to minimize the risk of electrical 
shock, short, or fire. 

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Array 
The array is a single-use, sterile, disposable component constructed of commonly-used medical 
plastics and metals, with 5 fixed, stainless-steel electrodes (needles) and 1 IM injection needle. 
The needles are covered by a plastic shroud that retracts as the needles are inserted into the 
patient, then returns to the starting position as the needles are removed and locks out to prevent 
accidental needle sticks. The opposite end of the array accepts the drug cartridge, which is 
inserted cap-end-first until the bottom of the cartridge is flush with the opening of the array 
(indicated by an audible 'click'). When properly inserted, the septum is punctured and the 
cartridge cannot be removed. The 5PSP Array features no software. 
The base station and handset with the 5PSP Array are illustrated in Figure 3. 
5.3 
TREATMENT REGIMEN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the 
HPV-003 study, therefore all eligible subjects who consent to participate in the HPV-203 
study will receive the same three 6 mg doses of VGX-3100 administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment will 
be administered on Day 0, the second at Week 4, and the third at Week 12.  A fourth 
dose may be administered at Week 40. 
The first study treatment will be given as soon as possible following confirmation of anal 
or anal/peri-anal HSIL diagnosis and HPV-16/18 status but no more than 10 weeks 
following collection of the subject's biopsy specimen used for diagnosis by the PAC 
during Screening, concurrent with the positive testing for HPV-16/18. 
5.4 
PACKAGING AND HANDLING 
Each cartridge will be labeled with a single-panel label and then individually packaged 
within a pouch that will contain an additional, single-panel label with tear-off. The VGX-
3100 label will include, at minimum, the following information in Table 5. 
Table 5: Example of Packaging and Label Information 
Cartridges 
(primary container) 
Pouches 
(secondary packaging) 
 
 
 
 
LABEL 
 
VGX-3100 
Insert cap end 
Sponsor name 
IM administration 
Investigational Use Only 
LABEL BODY 
Study ID 
VGX-3100 
Single-use cartridge containing 1 mL 
IM administration via CELLECTRA™ 5PSP 
Store at 2-8°C, expiration date 
Caution Statement 
Sponsor name and address 
LABEL TEAR OFF 
Study ID 
VGX-3100 
Patient ID: _________ 
Date: (DD-MMM-YYYY): __________ 
 
Must be used by (time): _________ 

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See Figure 4 below for example of CELLECTRA™ 5PSP device component labels. 
 
Figure 4: Examples of Device Labels (Base, Handset, Array, Outer Box) 
 
Base Station Label 
 
 
Handset Label 
 
 

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5PSP Array Label 
 
 
Outer Box Packaging Label 
 
 
 
 
 
 
 
 
 
5.5 
HANDLING AND STORAGE OF IP AND DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure 
location according to the instructions in the User Manual. The CELLECTRA™ 5PSP 
device and its components must be stored between the temperature ranges 55.4°F-
91.4°F and relative humidity ranges of 30-70%. The Sponsor should be notified of any 
deviations from this recommended storage condition. For the specific temperature 
guidelines for storing, please refer to the CELLECTRA™ 5PSP User Manual. 
Unless otherwise specified, IP will be shipped in a refrigerated condition with a 
temperature monitoring device. If the temperature monitoring device records 
temperatures outside the pre-specified range for any product, the Sponsor, or its 
designee should be contacted immediately.  
5.6 
PREPARATION AND DISPENSING 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 
°C (36-46 °F) storage, in a secure area, according to local regulations. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. The Sponsor should be notified of any deviations from 

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this recommended storage condition. Inovio Pharmaceuticals Inc. will be responsible for 
assuring the quality of the IP is adequate for the duration of the trial. Preparation and 
Dispensing 
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. 
When a subject is eligible, remove the pouch from the refrigerator and allow to reach 
room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. 
The pouch must not be discarded until: 
1. Administration is completed and 
2. All pertinent information from the pouch label has been documented in source. 
The product must be used within 4 hours of removal from the refrigerator. If VGX-3100 is 
not used within this timeframe it must be discarded after reconciliation. 
5.7 
USE OF CELLECTRA™5PSP DEVICE 
The instructions for use of the CELLECTRA™ 5PSP are located in the CELLECTRA™ 
5PSP User Manual. Users of the CELLECTRA™ 5PSP device must successfully 
complete training before using the device. Training will include review of the entire 
device user manual as well as hands-on training. After training on the proper use of the 
CELLECTRA™ 5PSP device, the intended users at each site will be required to 
demonstrate their competency in its use to INOVIO personnel or its designee. An 
instructional video has been prepared for review by site personnel on an as needed 
basis. Refer to the User Manual for further instruction. 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 
DRUG AND DEVICE ACCOUNTABILITY 
5.8.1 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of IP 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; 
• 
Date and initials of person responsible for each IP 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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5.8.2 
CELLECTRA™ 5PSP DEVICE ACCOUNTABILITY 
The site is responsible for maintaining the device. The device must have full traceability 
from receipt of the products through the subject use, and the return of the device. The 
site must document acknowledgement of receipt and then notify INOVIO upon receipt of 
the device. This includes the content shipped and condition of the items upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 5PSP Base Station & Handset serial number, 5PSP Array lot 
number and the study drug lot number. The used Array attachment must be disposed of 
in accordance with institutional policy regarding disposal of sharp needles/instruments. 
5.9 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT AND CELLECTRA™ 5PSP 
DEVICE  
5.9.1 
RETURN OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at the site 
per the institutions policy or returned to INOVIO or its designee, if the site cannot destroy 
the unused IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps 
container at site. Do not attempt to remove the cartridge from the array once it has been 
used.  
It is the Investigator's responsibility to arrange for the 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. 
The unused IP can only be destroyed after being inspected and reconciled by the 
responsible INOVIO personal or designated Study Monitor. 
If IP is returned to INOVIO, or its designee, it must be accompanied by the appropriate 
documentation. Returned supplies should be in the original containers. Empty containers 
should not be returned to INOVIO. The return of unused IP(s) should be arranged with 
the responsible INOVIO personnel and/or Clinical Monitor. 
5.9.2 
RETURN OF CELLECTRA™ 5PSP DEVICE  
Upon completion or termination of the study, all investigational devices and unused 
components (Base, Station and Handset,) must be returned to INOVIO. Please contact 
an Inovio representative for specific instructions on the return of the device and 
components. Any unused or expired 5PSP Arrays should be destroyed on site per the 
site’s institutional policy. If a site’s policy does not allow for the destruction of the Arrays 
on site, please contact an Inovio representative for further instruction.  
All device components returned to INOVIO must be accompanied by the appropriate 
return documentation. Returned supplies should be in the original containers. The return 
of all device components identified above should be arranged by the responsible Study 
Monitor. 
If any component is to be destroyed on site, it is the Investigator's responsibility to 
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• 
Written authorization must be granted by INOVIO, or its designee of the disposal, 
• 
Ensure that proper procedures for disposal have been established and followed 
according to applicable local regulations, guidelines and institutional procedures, 
• 
Appropriate records of the disposal have been documented. 
6.0 
TRIAL PROCEDURES AND SCHEDULE 
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 3). 
A subject will be required to provide informed consent for the 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. Immediate safety concerns will be 
dealt with as deemed necessary by the Investigator. Adherence to the study design 
requirements, as outlined in the Schedule of Events (Table 3) are essential and required 
for study conduct. Subject eligibility should be reconfirmed at every study visit. 
6.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any trial related procedures being 
performed. The informed consent documentation must be in accordance with applicable 
regulations and GCP. Qualified trial personnel will meet with prospective trial subjects, 
explain the trial, and provide them with an ICF that describes the Screening tests, 
eligibility criteria for entering the trial, trial treatments and follow-up procedures, in a 
language understandable to the subject. Explanation of the trial includes, but is not 
limited to, trial objectives, potential benefits and risks, discomforts/inconveniences, and 
the subject's rights and responsibilities. The subject or subject's legally acceptable 
representative is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject or subject's legally acceptable 
representative. The qualified trial 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. 
6.2 
BEFORE TREATMENT PROCEDURES 
Subjects who consent to participate must have paraffin-embedded tissue block(s) from a 
previous biopsy (ies) and/or newly collected intra-anal and/or peri-anal biopsy tissue 
samples (formalin fixed tissue) sent to the central pathology lab for review by the PAC. 
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 the PAC with HSIL 
consensus diagnosis), until the date of first study treatment (i.e. Day 0).  
For those individuals diagnosed with anal or anal/peri-anal 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, biopsy samples should be collected 
from all intra-anal and/or peri-anal lesions of adequate size during Screening  following 
the consent of the subject. The 10 week Screening window begins upon collection of the 
biopsy sample(s) that will be evaluated by the PAC.  
At Screening, subjects must have a diagnosis of histologic anal or anal/peri-anal HSIL 
confirmed by the PAC and intra-anal and/or peri-anal specimen test positive for HPV-

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16/18 by PCR to be eligible for participation in the study (provided the subject also 
meets other eligibility criteria). Subjects whose intra-anal and/or peri-anal specimens 
also test positive for other HPV genotypes are not excluded as long as they have a 
positive result for HPV-16/18.  
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. 
6.2.1 
SCREENING EVALUATIONS 
The following evaluations/actions, unless noted, will be performed within 10 weeks and 
up to Day 0 – except for the HIV test which must be performed within 30 days prior to 
Day 0 and 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. Some of these evaluations/actions will be performed 
again later in the trial (see later text and the Schedule of Events Table 3 for more detail). 
• 
Signed ICF 
• 
Medical history/demographics, including history of prior anal or anal/peri-anal 
HSIL 
• 
Socio-Behavioral Assessment; including smoking history, exposure to second-
hand smoke, alcohol intake history, recreational drug use and contraceptive use 
• 
Prior concomitant medications review 
• 
Determination of eligibility per inclusion/exclusion criteria 
• 
Complete Physical Examination 
• 
Vital signs (including oral temperature, respiratory rate, blood pressure and heart 
rate), height, weight and body mass index (BMI) measurements 
• 
12-lead ECG (within 45 days prior to Day 0) 
• 
Baseline laboratory evaluations (including complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine (Cr), glucose, alanine 
aminotransferase [ALT], and creatine phosphokinase [CPK]) (to be performed 
within 45 days prior to Day 0) 
• 
Urine pregnancy test 
• 
Serology (HIV Ab) within 30 days prior to Day 0 
• 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
Digital Anal Rectal Examination (DARE) 
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
High Resolution Anoscopy (HRA) with Biopsy (tissue must be reviewed by the 
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o If a historical biopsy is used with a corresponding HRA evaluation, then 
the HRA does not need to be repeated for Screening to determine 
eligibility as long as it is within the allowable window of 10 weeks.  
• 
Whole blood (at least 68 mL) and serum (at least 8 mL) for baseline immunology 
including miRNA profile must be collected before dosing on Day 0 
o It is acceptable to collect the blood as follows: 
 
Screening: obtain 34 ml of whole blood and 4 ml of serum 
 
Day 0: obtain 34 ml of whole blood and 4 ml of serum prior to 
dosing 
6.3 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will receive study treatment. Visit dates 
and windows must be calculated from Day 0. 
6.3.1 
DAY 0 
The following study evaluations will be performed at Day 0 (unless noted) prior to 
the first study treatment: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Targeted Physical assessment 
• 
Vital signs including weight 
• 
Urine pregnancy test 
• 
Whole blood and serum for immunology including miRNA profile (if whole blood 
and serum were not collected at Screening, then 68 ml of whole blood and 8 ml 
of serum should be drawn at this time point prior to dosing) 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical, and penile swabs 
• 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 
• 
HRA  
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
Patient reported outcome (SF-36v2™ and EQ-5D-5L) (may be performed at Day 
-1 or on Day 0, again provided it is done prior to the first study treatment) 
• 
Study treatment administration 
The following evaluations will be performed on Day 0 after study treatment: 
• 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
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• 
Distribute Participant Diary Card (PDC) 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during the phone call: 
• 
Review Day 0 of PDC (after reviewing the PDC 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) 
• 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.3 
WEEK 4 (± 4 DAYS) 
The following study evaluations will be performed at Week 4 prior to study 
treatment: 
• 
Reconfirm subject eligibility 
• 
Concomitant mediation review 
• 
Targeted Physical assessment 
• 
Vital signs including weight 
• 
Urine pregnancy test 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical, and penile swab 
• 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 
• 
HRA  
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
Collect and review PDC for dose 1 
• 
Study treatment administration 
The following study evaluations will be performed at Week 4 post treatment: 
• 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
• 
Distribute PDC 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) **Please remember to 
download EP data from the CELLECTRA™ 5PSP device within 24-48 hours of 
study treatment.** 
 

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6.3.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during the phone call: 
• 
Review of PDC for dose 2 (after reviewing the PDC 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) 
• 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.5 
WEEK 12 (± 4 DAYS) 
The following study evaluations will be performed at Week 12 prior to study 
treatment: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Targeted Physical assessment 
• 
Vital signs including weight 
• 
Urine pregnancy test 
• 
Collect and review PDC for dose 2 
• 
Study treatment administration 
The following study evaluations will be performed at Week 12 post treatment: 
• 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
• 
Distribute PDC 
• 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L)  
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
within 24-48 hours of study treatment.** 
6.3.6 
WEEK 15 (± 1 WEEK) 
The following study evaluations will be performed at Week 15: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Targeted Physical assessment 
• 
Vital signs 
• 
Urine pregnancy test 
• 
Whole blood and serum for immunology including miRNA 
o 51 ml of whole blood and 4 ml serum should be drawn at this time point 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical, and penile swab 

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• 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 
• 
HRA  
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.3.7 
WEEK 28 (± 1 WEEK) 
The following study evaluations will be performed at Week 28: 
• 
Reconfirm subject eligibility 
• 
Concomitant medical review 
• 
Targeted Physical assessment 
• 
Vital signs 
• 
Urine pregnancy test 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical, and penile swab 
• 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 
• 
HRA  
• 
Lesion photography (intra-anal and/or peri-anal) 
6.3.8 
WEEK 36 (± 1 WEEK) 
The following study evaluations will be performed at Week 36: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Socio-behavioral assessment 
• 
Targeted Physical assessment 
• 
Vital signs 
• 
Urine pregnancy test 
• 
Serology (HIV Ab) 
• 
Whole blood and serum for immunology including miRNA profile 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical and penile swabs 

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• 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 
• 
HRA 
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
Biopsy (paraffin blocks) 
• 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
 
6.3.9 
WEEK 40 (± 1 WEEK) 
The following study evaluations will be performed at Week 40: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Targeted Physical assessment 
• 
Vital signs including weight 
• 
Urine pregnancy test  
• 
Study treatment administration 
• 
Based on biopsy results collected at Week 36 and Investigator judgment, a 4th 
dose may be given at this visit 
**Please remember to download EP data from CELLECTRA™ 5PSP device within 
24-48 hours of study treatment.** 
The following study evaluations will be performed at the Week 40 post treatment: 
• 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
• 
Distribute PDC 
• 
Patient reported outcomes:- the two "global" questions and SF-36v2™ and EQ-
5D-5L 
6.3.10 8-14 DAYS POST DOSE 4 PHONE CALL (FOR SUBJECTS WHO RECEIVED A 4TH DOSE) 
The following information will be evaluated during the phone call: 
• 
Review PDC for dose 4 (after reviewing the PDC 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) 
• 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
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6.3.11 WEEK 64 (± 2 WEEKS) 
The following study evaluations will be performed at Week 64: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Socio-behavioral assessment (only for subjects who received a 4th dose at Week 
40) 
• 
Targeted Physical assessment 
• 
Vital signs 
• 
Urine pregnancy test 
• 
Whole blood and serum for immunology including miRNA profile 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical and penile swab 
• 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 
• 
HRA  
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
Biopsy (paraffin blocks)  
• 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L)  
6.3.12 WEEK 88 (± 2 WEEKS) 
The following study evaluations will be performed at Week 88: 
• 
Reconfirm subject eligibility 
• 
Concomitant medication review 
• 
Socio-behavioral assessment 
• 
Full Physical assessment 
• 
Urine pregnancy test 
• 
Vital signs 
• 
Whole blood and serum for immunology including miRNA profile 
• 
Oropharyngeal rinse 
• 
Vaginal, cervical, and penile swabs 
• 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 
DARE 

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• 
HRA  
• 
Lesion photography (intra-anal and/or peri-anal) 
• 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.4 
TRIAL PROCEDURES 
6.5 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number 
(SID), which identifies the subject for all trial-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., ANUS01001). Once 
assigned, SIDs cannot be reused for any reason. Information regarding the SID and 
screen date will be documented on a screening and enrollment log/system and in the 
eCRF. 
6.6 
DEMOGRAPHICS 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
• 
Age 
• 
Gender 
• 
Race/ethnicity 
• 
Dominant hand/arm 
6.7 
SAFETY EVALUATIONS 
6.7.1 
PHYSICAL EXAM 
A full Physical exam (PE) will be conducted during Screening and study discharge 
(Week 88). 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, and a DARE. 
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. 
6.7.2 
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 prior to measurement 
• 
Respiration rate 
• 
Heart rate 
• 
Oral temperature measured with an automated thermometer 
 

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6.7.3 
HEIGHT AND WEIGHT 
Weight and height will be collected at all dosing visits in order to calculate the BMI. 
6.7.4 
MEDICAL HISTORY 
Medical history, including history of prior anal or anal/peri-anal dysplasia and 
gynecologic history will be obtained at Screening. For females, previous history of 
treatment for VIN, CIN and/or VAIN will be collected. All relevant past and present 
conditions, as well as prior surgical procedures at least 6 months prior to enrollment will 
be recorded for the main body systems.  
6.7.5 
SOCIO-BEHAVIORAL ASSESSMENTS 
Socio-Behavioral Assessment, including self-reporting of the following: smoking history, 
history of exposure to second-hand smoke, alcohol intake history, recreational drug use 
history, history of contraceptive use and type of contraceptive if known, reproductive 
history, sexual preference and sexual practices history, and pregnancy history will be 
obtained at Screening.  
At Weeks 36, 64 (only for subjects who receive a 4th dose), and 88, a socio-behavioral 
assessment will be performed to document any changes from Screening and/or other 
time periods. 
6.7.6 
LABORATORY EVALUATIONS 
At Screening, blood samples will be taken to be tested for serum chemistry and 
hematology. 
Complete Blood Count: 
• 
White blood cell (WBC) count with differential 
• 
Red blood cell (RBC) count 
• 
Hemoglobin, Hematocrit 
• 
Platelet count 
Serum Chemistry: 
• 
Glucose 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
• 
Creatine Phosphokinase 
6.7.7 
PREGNANCY TESTING 
For women of reproductive potential, a negative spot urine pregnancy test is required at 
Screening, and prior to each study treatment, HRA, DARE and surgical excision or 
biopsy. 
 
 

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6.7.8 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for at least 10 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. 
6.7.9 
PARTICIPANT DIARY CARD (PDC) 
Subjects will be provided and trained on a PDC and will be asked to record the following 
the evening of study treatment through Day 6: 
• 
Oral temperature and time taken (before 11:59pm) 
• 
General symptoms of feeling unwell 
• 
Pain and itching at injection site 
• 
Measure redness, swelling, bruising at injection site 
• 
Medications taken 
The completed PDC will be reviewed with the subject by the study staff at the 8-14 days 
post dose phone calls and at the next in-person visits. 
The study staff will review the PDC 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. 
Any PDC entry determined to meet the criteria for a Grade 1 or higher AEs should be 
documented as an AE unless deemed part of the subject's ongoing medical history. If 
the PDC entry does not meet the criteria of a Grade 1 or higher AE as per the CTCAE 
guidelines, clinical judgment can be used to determine whether the entry should be 
recorded as an AE and documented accordingly in the site's source. For cases where 
the PDC entry and final AE reporting (i.e. grading) do not agree, the reasoning should be 
recorded in the source documents. 
6.8 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive at least three doses of VGX-3100 (6 mg DNA/dose) in a volume of 
1 mL by IM injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 5PSP.  A fourth dose is optional for 
those assessed to be partial responders at the Week 36 efficacy assessment. 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. EP may not be performed in the 
same arm adjacent to an implantable medical device (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal). The timing of the initial dose will 
be designated Day 0 with the subsequent doses scheduled for administration at Weeks 
4, 12, and at Week 40 (for Subgroup C, Figure 2 only). Please refer to the Investigator's 
Brochure for further information. 
6.9 
MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
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, and Weeks 4 and/or Week 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 should be added to the concomitant medications. 
6.10 ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening and will be performed for inclusion into the 
study as listed in the Schedule of Events (Table 3). 
6.11 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
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 PDC which will be reviewed with study 
personnel 8 – 14 days after doses 1 and 2, Week 15, and 8-14 days after dose 4 (if 
applicable).  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any AEs, 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 AEs will be captured from the time of the informed consent to study 
discharge. These events will be recorded on the subject's Case Report Form (CRF). 
6.12 ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale in Table 6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 6: Grading Scale for Injection Site Reactions 
 
6.13 ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, PRO instruments will be 
administered. The following PRO questionnaires will be used: 
• 
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) [25]. 
SF-36v2™ will be administered at the following time points:  
• 
Day 0 (before the first study treatment) 
• 
8-14 days post dose 1 
• 
Week 4 (post dose 2) 
• 
8-14 days post dose 2 
• 
Weeks 12 (post dose 3), 15, 36, 40 
• 
8-14 days post dose 4* (only for those who received a 4th dose) 
• 
Weeks 64, 88 
• 
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) [26, 27] and will be administered as described below: 
• 
Day 0 (before the first study treatment) 

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• 
8-14 days post dose 1 
• 
Week 4 (post dose 2) 
• 
8-14 days post dose 2 
• 
Weeks 12 (post dose 3), 15, 36, 40 
• 
8-14 days post dose 4* (only for those who received a 4th dose) 
• 
Weeks 64, 88 
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.    
• 
Additional Global PRO Questions- regarding quality of life after surgery or biopsy. 
These two questions will be administered at Week 40 only. 
6.14 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, 36, 64 and 88. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual. 
A standardized binding enzyme-linked immunosorbent assay (ELISA) may be performed 
to measure the anti–HPV-16/18 Ab response induced by VGX-3100. 
Peripheral Blood Mononuclear Cells 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 may occur via the use of either sera or plasma obtained at Screening, 
Day 0 and Weeks 15 and 36.  Assessment of Day 0 samples alone will explore 
predictive algorithms for response to treatment with VGX-3100 prior to dosing. 
Assessment of Week 15 samples may 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. 
6.15 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then the relevant paraffin blocks may be collected for the assessment of 
proinflammatory and immunosuppressive elements. . Assessment of markers may 
include, but are not limited to, CD8+ and FoxP3+ infiltrating cells as well as Granulysin, 
Perforin, CD137, CD103 and PD-L1 in intra-anal and/or peri-anal tissue as sample 
allows. Markers listed here may change as new relevant information becomes available. 

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6.16 ANAL AND/OR PERI-ANAL HPV TESTING 
All intra-anal and/or peri-anal lesions of adequate size (≥4 mm) will be biopsied at 
Screening. Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will 
be obtained from all HSIL sites(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. Intra-anal and/or peri-anal swabs will 
undergo HPV testing using a PCR based assay, SPF10. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching to eliminate potential interference with the results of HPV testing. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0, and at Weeks 4, 
15, 28, 36, 64, and 88 in ThinPrep™ collection media. The HPV Cobas test will be 
performed on the ThinPrep™ specimens at Screening, and Weeks 36 and 64 when 
applicable. Anal cytology will be performed on intra-anal samples. At each of these 
visits, a recent history will be collected via self-report.   
6.17 HPV TESTING FROM OTHER ANATOMICAL SITE (NON-ANAL) 
Vaginal, cervical (female subjects), penile (male subjects), and OP rinse samples (all 
subjects) will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess 
virologic clearance at non-anal sites using a PCR based HPV assay. All samples will be 
read in a central laboratory. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching or vaginal and anal lubricants/medication for a period of 24 hours prior to 
collection of samples to eliminate potential interference with the results of HPV testing. 
6.18 ANAL PHOTOGRAPHS AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of anal or anal/peri-
anal HSIL confirmed by the PAC at Screening. Subjects will undergo HRA at Screening, 
Day 0, and at Weeks 4, 15, 28, 36, 64, and 88 to identify all intra-anal lesion(s). All intra-
anal and/or peri-anal lesion(s) of adequate size (≥4 mm) will be biopsied at Screening. 
Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be 
obtained from all HSIL site(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. Investigators should follow Table 1: Minimally 
Required Procedure at each Biopsy Visit for the Weeks 36 and 64 biopsies. 
Photography of all qualifying intra-anal and/or peri-anal lesion(s) must be performed 
prior to and after biopsy, and at all HRA examinations. If a pre-biopsy digital photograph 
is not available for a historical biopsy sample at Screening, a post biopsy photo will be 
sufficient. Photographs of intra-anal lesion(s) will be for documentation purposes only. 
All qualifying peri-anal lesion(s) will be assessed using the ruler provided. The ruler 
should be placed in the field of vision and should be documented with photography at 
Screening, Day 0, and Weeks 4, 15, 28, 36, 64, and 88. 
If the intra-anal and/or peri-anal tissue sample(s) result suggests progression to cancer, 
the Investigator may schedule an ad hoc visit to perform HRA and possible biopsy if 
clinically indicated. 
6.19 UNSCHEDULED BIOPSIES 
Unscheduled biopsies may be performed on new lesions or suspected progression of 
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be managed according to standard of care and the Investigator’s judgment based on the 
results of the histological diagnosis from the unscheduled biopsy. All biopsy 
samples/excised tissue (including standard of care) will be sent to the central pathology 
lab for review by the PAC.  
6.20 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the 
Screening biopsy date of eligible subjects must be recorded on the eCRF. Actual or 
estimated start and stop dates must be provided. Medical procedures performed within 8 
weeks prior to the 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 eCRFs. 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 eCRF. 
The following medications and treatments are prohibited: 
• 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent; use of inhaled, otic, nasal, topical, 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, live vaccine; 
• 
Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that 
affects blood clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study 
treatment, biopsy or excisional procedure. 
The decision to administer a prohibited medication/treatment is done with the safety of 
the study participant as the primary consideration. When possible, the Sponsor should 
be notified before the prohibited medication/treatment is administered. All medications 
should be recorded in the appropriate sections of the subject's eCRF. 
6.21 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, including illicit 
drugs, taken to the Investigator and/or other study personnel. To remain in the study, 
illicit drugs should not be taken. 
Subjects should refrain from becoming pregnant until one month following the last dose 
of IP (Week 12 or Week 40) 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. 
Subjects should abstain from sexual activity and refrain from the use of douching and 
vaginal and anal lubricants/medication for a period of 24 hours prior to collection of 
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7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
As a requirement for inclusion in the HPV-203 study, Investigators will only be chosen if 
they are experienced in the management of anal cancer, and are experienced in 
performing HRA.  
HPV-203 Investigators are instructed to perform additional, ad hoc HRA exams and 
biopsies if they suspect potential disease progression. Subjects that undergo an 
unscheduled biopsy will be classified as a non-responder in the efficacy analyses. These 
additional measures should minimize the risk of progression of anal or anal/peri-anal 
HSIL and the risk of harboring an undiagnosed occult early invasive anal or anal/peri-
anal cancer. The frequency of close monitoring by experienced Investigators should 
minimize the risk of cancer progression during the study and the additional measures 
are beyond what is expected in standard of care. 
7.2 
ADVERSE EVENTS (AES) 
An 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 AEs 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 eCRF, including the event's seriousness, severity, action taken, 
and relationship to IP. Adverse Events should be followed until resolution or stable and 
the outcome will be documented on the appropriate eCRF. All AEs should be recorded 
in standard medical terminology rather than the subject's own words. 
Adverse Events 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 increased 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); 
• 
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. 
Adverse Events 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; 

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• 
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 ICF is signed is not an AE. It is considered to be pre-existing and 
will be documented on the medical history eCRF; 
• 
Uncomplicated pregnancy; 
• 
An induced elective abortion to terminate a pregnancy without medical reason. 
7.3 
SERIOUS ADVERSE EVENTS 
A 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 (ER) or at home, 2) blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or 3) the development of drug dependency or drug 
abuse.  
Classification of Serious Adverse Events: 
• 
Death is an outcome of an AE, and not an SAE in and of 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. 

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• 
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 7.15. 
7.4 
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 AE is at least a reasonable possibility; i.e., there is evidence to 
suggest a causal relationship between the product and the AEs. An AE or ADR is 
considered unexpected if it is not listed in the applicable product information 
(Investigator's Brochure, protocol, or user manual) or is not listed at the specificity or 
severity which is consistent with the risk information provided. 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 serious 
expected AEs, the identification of a significant hazard to the patient population, or a 
major safety finding from a study conducted in animals.   
7.5 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of SAE that requires expedited reporting on 
the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 
hours. Sponsor will assess each device related SAE to determine if anticipated based on 
prior identification within the investigational plan. 

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7.6 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the eCRF at the maximum severity 
reported. 
The Investigator will grade laboratory AEs and clinical AEs or SAEs with respect to the 
following levels of severity as per CTCAE v 4.03 for applicable patient populations: 
• 
Mild (Grade 1) 
• 
Moderate (Grade 2) 
• 
Severe (Grade 3) 
• 
Potentially Life Threatening (Grade 4) 
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. 
7.7 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS 
A causally related AE is one judged to have a reasonable causal relationship to the 
administration to either or both IP and/or the CELLECTRA™ 5PSP device. The 
Investigator will assess causal relationship of the AE separately to each of the 
investigational drugs and also the investigational device. The reasonable causal 
relationship means that there are facts (evidence) or arguments to suggest a causal 
relationship. An AE may also be assessed as not related to either or both IP and/or 
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 AEs and judging 
the relationship between the administration of the IP and EP 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 Study Subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the IP and/or the device 
indicating "yes" or "no" accordingly. Causality should be assessed by the Investigator as 
related to drug or related to device or related to both drug and device (i.e. indiscernible) 
by the following criteria: 
• 
Yes- there is a reasonable possibility that administration of the Study Treatment 
(drug or device or both drug and device) contributed to the event; 
• 
No- there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
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• 
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. 
7.8 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK) independent of the underlying medical 
condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation or deemed clinically significant by the Investigator must be recorded as 
an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., ECG, x-rays, and vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or 
SAE) as described in Sections 7.2 and 7.3. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory result 
(e.g., decreased hemoglobin). 
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 
Severity is assessed as detailed in Section 7.6. 
Grade is an essential element of these criteria. Each CTCAE grading term in the current 
version is a unique representation of a specific event used for medical documentation 
and scientific analysis and is a single Medical Dictionary for Regulatory Activities 
(MedDRA) Lowest Level Term (LLT). 
Investigators are asked to take the CTCAE grading criteria into account when assessing 
if a laboratory abnormality qualifies as a laboratory AE. Their clinical judgment ultimately 
determines not only the severity of the event but also whether the abnormality in 
question is "clinically significant (CS)" or "NCS." CTCAE v. 4.03 grading criteria can be 
used as a reference when making this determination. It is the responsibility of the 
Investigators to ensure all AEs are accurately reported and graded. 
7.9 
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 
probably or possibly related to the study treatment, he/she should promptly document 
and report the event to the Sponsor. 

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7.10 PROCEDURES FOR DOCUMENTING PREGNANCY DURING THE TRIAL 
Should a subject become pregnant after enrolling in the study, she will not be given any 
further treatments with the IP. A Pregnancy Form will be completed by the Investigator 
and submitted to the Sponsor within 24 hours after learning of the pregnancy. Site 
personnel will submit the Pregnancy Form to the Sponsor or its designee by fax or email, 
as described in Section 7.15. 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 IP. 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 Sponsor. 
Male subjects will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant until the end of follow-up 
period. A Pregnancy Form will be completed by the Investigator and submitted to the 
Sponsor within 24 hours after learning of the pregnancy. Attempts will be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
subject exposed to IP. The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Pregnancy 
Form with additional information on the course and outcome of the pregnancy. An 
Investigator who is contacted by the male subject or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
7.11 METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time 
when informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. The subject's response to questions about his/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 
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All AEs will be reported on the appropriate eCRF. 
Any SAE occurring during the course of the study must be reported to the Sponsor 
within 24 hours of awareness. 
7.12 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 AEs classified by system organ class (SOC), preferred term, 
severity, and relationship to study treatment; 
• 
Changes in safety laboratory parameters (e.g., hematology and serum 
chemistry); 
• 
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. 
7.12.1 ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 5PSP 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 eCRFs. 
Sites will inform the Sponsor via method described in Section 7.15 within 24 hours to 
discuss whether further dosing for the particular subject should continue. 
7.13 ADVERSE EVENT REPORTING 
To assure the safety of the participants, information about all AEs (see Section 7.2), 
whether volunteered by the subject, discovered by the 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. 
7.14 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited AEs will be collected throughout the study and recorded in 
the Electronic Data Capture (EDC) system. The Study Report will analyze and 
summarize all AEs throughout the study. Emphasis will be placed on the following: 
1. Certain AEs of interest will be solicited during the 7 days following each 
administration of Study Treatment and summarized separately 

V G X -3 1 0 0  
H P V -2 0 3  
I n o vi o P h ar m a c e uti c al s, I n c. 
Cli ni c al Pr ot o c ol  
Pr ot o c ol V er si o n D at e:  1 5 M a y 2 0 1 9  
C O N FI D E N TI A L  
Pr ot o c ol V er si o n: 2. 0  
P a g e 7 1  of 8 5  
2.
U n s oli cit e d A E s will b e c oll e ct e d a n d s u m m ari z e d f or t h e e ntir e st u d y p eri o d
7. 1 5   TRI A L R E P O R TI N G P E RI O D O F S E RI O U S A D V E R S E E V E N T S  A N D A E SI S  
T h e r e p orti n g p eri o d f or S A E s ( wit h o ut r e g ar d t o c a u s alit y or r el ati o n s hi p)  a n d A E SI s  i s 
c o m pri s e d of t h e p eri o d f oll o wi n g t h e si g ni n g of t h e I C F t hr o u g h W e e k 8 8. E a c h A E will 
b e a s s e s s e d t o d et er mi n e w h et h er it m e et s s eri o u s n e s s crit eri a. If t h e  A E i s c o n si d er e d 
s eri o u s, t h e I n v e st i g at or will c o m pl et e t h e S A E/ A E SI R e p ort f or m a n d r e p ort t h e e v e nt t o 
t h e S p o n s or wit hi n 2 4 h o ur s of b e c o mi n g a w ar e of t h e e v e nt. T h e I n v e sti g at or m a y al s o 
dir e ctl y r e p ort t hi s e v e nt t o t h e I R B/E C a c c or di n g t o it s st a n d ar d o p er ati n g pr o c e d ur e s. 
E x p e ct e d n e s s of S A E s will b e d et er mi n e d b y t h e S p o n s or u si n g r ef er e n c e s af et y 
i nf or m ati o n s p e cifi e d i n t h e I n v e sti g at or's Br o c h ur e a n d pr ot o c ol.  
A n e v e nt m a y q u alit y f or e x p e dit e d r e p orti n g t o r e g ul at or y a ut h oriti e s if it i s a n S A E, 
u n e x p e ct e d p er r ef er e n c e s af et y i nf or m ati o n a n d c o n si d er e d r el at e d f oll o wi n g t h e 
g ui d eli n e s i n S e cti o n  7. 5  (U A D E) i n li n e wit h r el e v a nt l e gi sl ati o n. All i n v e sti g at or s will 
r e c ei v e a s af et y l ett er n otif yi n g t h e m of r el e v a nt S U S A R r e p ort s. T h e I n v e sti g at or s h o ul d 
n otif y t h e I R B/ E C a s s o o n a s i s pr a cti c al, of s eri o u s e v e nt s i n writi n g w h er e t hi s i s 
r e q uir e d b y l o c al r e g ul at or y a ut h oriti e s, a n d i n a c c or d a n c e wit h t h e l o c al i n stit uti o n al 
p oli c y.  
At a n y ti m e aft er c o m pl eti o n of t h e S A E r e p orti n g p eri o d, if a n i n v e sti g at or b e c o m e s 
a w ar e of a n S A E t h at i s s u s p e ct e d b y t h e I n v e sti g at or t o b e r el at e d t o t h e st u d y dr u g, t h e 
e v e nt will b e r e p ort e d t o t h e S p o n s or or it s d e si g n e e. If t h e I n v e sti g at or b e c o m e s a w ar e 
of a n S A E i n a st u d y s u bj e ct aft er t h e l a st s c h e d ul e d f oll o w -u p vi sit, a n d c o n si d er s t h e 
e v e nt r el at e d  t o pri or St u d y Tr e at m e nt, t h e I n v e sti g at or will r e p ort it t o t h e S p o n s or or t h e 
a p pr o pri at e d e si g n e e.  
S P O N S O R C O N T A C T I N F O R M A TI O N  
M E DI C A L M O NI T O R: 
, M. D., P h. D. 
E M AI L : 
 
S A E R E P O R TI N G I N F O R M A TI O N  
E M AI L : s af et y.i n o vi o @ a p c erl s. c o m  
S A F E T Y F A X: 
 
S A F E T Y P H O N E: 
 
T h e pr ef err e d m et h o d f or pr o vi di n g S A E f or m s or S A E s u p p orti n g d o c u m e nt s t o t h e 
S p o n s or or d e si g n e e i s a n att a c h m e nt t o a n e -m ail m e s s a g e, t o t h e e m ail a d dr e s s a s 
i n di c at e d a b o v e. A n y S A E s u p p orti n g d o c u m e nt s pr o vi d e d b y f a c si mil e ( F a x) ar e t o 
i n cl u d e a c o v er s h e et t h at i d e ntifi e s t h e r e p ort er n a m e a n d c o nt a ct i nf or m ati o n of t h e 
st u d y sit e.  
All s u p p orti n g d o c u m e nt s f or S A E r e p ort s, i n cl u di n g m e di c al r e c or d s a n d di a g n o sti c t e st 
r e s ult s, will i n cl u d e r ef er e n c e t o t h e st u d y s u bj e ct n u m b er. T h e st u d y sit e will r e d a ct all 
P P D
P P D
P P D
P P D

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other patient identifying information present on SAE supporting documents prior to 
sending the report to the Sponsor.  
In addition to providing the SAE report to the Sponsor or designee within 24 hours of 
becoming aware of the event, the AE that is serious must be recorded in the AEs eCRF. 
The entry into the eCRF is required to be done as soon as possible. 
The Investigator will supply the Sponsor and the IRB/EC 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. 
When recording the SAE form, correct medical terminology/concepts are to be used and 
the use of abbreviations and colloquialisms are to be avoided. 
Serious Adverse Events 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. 
7.16 NOTIFICATIONS 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 7.4 and 7.16). 
7.17 REPORTING OF CELLECTRA™5PSP DEVICE RELATED COMPLAINTS OR 
DEFICIENCIES 
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 within 24 hours of becoming aware of the event per Sections 7.2 and 7.3. 
Any problems experienced including potential malfunctions of the device, error 
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the treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation. The error reporting or complaint form provided must be completed and 
emailed to the Sponsor at clinicalcomplaint@inovio.com. 
Additional instructions on complaint reporting to be provided separately. 
7.18 TRIAL DISCONTINUATION 
Inovio Pharmaceuticals Inc. reserves the right to discontinue the trial 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. Additionally, the trial may be 
discontinued at any time by an IRB, INOVIO, the FDA or other government agencies as 
part of their duties to ensure that research subjects are protected.  
Should the trial be terminated and/or the site closed for any reason, all investigational 
drugs & devices must be returned to INOVIO or its representative. The PI should ensure 
their site file documents are complete prior to archiving, and provide copies of any 
requested documents to INOVIO for its Trial Master File (TMF). 
 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by INOVIO or its representative. 
This is a single-arm, multi-center, open-label clinical trial of VGX-3100 in subjects with a 
diagnosis of AIN2, AIN3, PAIN2, or PAIN3 associated with HPV types 16 and/or 18. The 
study's primary endpoint is binary: regression of AIN/PAIN HSIL and viral clearance of 
HPV-16/18 based on tissue collected at Week 36. The primary hypothesis is that the 
treatment will result in regression of HSIL and clearance. Secondary efficacy analyses 
pertain to regression, clearance of HPV-16/18 infection, complete regression, 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, clearance among non-anal 
anatomic locations, and association of miRNA profile, anoscopy, cytology, and virology 
with efficacy. Other exploratory analyses pertain to tissue immunological measures and 
PRO. 
8.3 
STATISTICAL HYPOTHESES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15.  There are no other formal hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations are: 

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• 
The modified intention to treat (mITT) population includes all subjects who 
receive at least one dose of Study Treatment. 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 Treatment and have no protocol violations. 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 locking of the study database. 
• 
The safety analysis set includes all subjects who receive at least one dose of 
Study Treatment. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 
PRIMARY ANALYSES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.05 and the corresponding lower bound of the one-sided 
95% CI exceeds 0.15. 
For the analysis, the efficacy time frame is defined by any time starting from 14 days 
prior to the -specified visit week. 
8.5.2 
SECONDARY ANALYSES 
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
the same as for the primary endpoint. 
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
in surface area and the mean percent change in number of lesions and associated 95% 
t-distribution based confidence intervals. 
Post-baseline ELISA titers will be summarized with geometric mean and associated 95% 
CIs. Post-baseline increases in ELISPOT and Flow responses will be summarized with 
tobit-based means and 95% CIs. Valid samples for statistical analysis purposes will be 
those collected within 14 days of the specified visits. Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.5.3 
SAFETY ANALYSES 
All AEs will be summarized among the safety population by frequency. These 
frequencies will be presented overall and separately by dose, and will depict overall, by 
SOC 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. 

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The main summary of AE data will be based on events occurring within 28 days 
following 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 following any dose and 
regardless of when they occurred. 
8.5.4 
DISPOSITION 
Disposition will be summarized 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. 
8.5.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables for the mITT population. 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system for the mITT population. 
Prior medications are those that were used and stopped before the start of the trial (prior 
to Day 0). Partial stop dates of prior medications will be assumed to be the latest 
possible date consistent with the partial date. Data for all prior medications will be 
summarized with percentages for the mITT population. 
8.5.6 
INTERIM ANALYSES 
No formal interim analyses will be performed for this study. For reasons of futility (early 
evidence of poor efficacy of VGX-3100) or safety issues, the DSMB could recommend 
stopping enrollment at any time. The type I error will not be adjusted for possible early 
stopping due to futility. 
8.5.7 
MULTIPLICITY 
Not applicable, there is one hypothesis that will be tested. 
8.5.8 
MISSING VALUES 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. 
No other missing data will be imputed or replaced. 
8.5.9 
EXPLORATORY ANALYSES 
The exploratory efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
the same as for the primary endpoint. 

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Other analyses will examine the relationship between the primary efficacy endpoint and 
a) miRNA results, b) HRA results, c) cytology 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 as regressor variables. 
The change in tissue immune response magnitude will be summarized with means and 
associated t-distribution based 95% CIs. 
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. 
8.6 
SAMPLE SIZE/POWER 
A sample of 24 subjects provides ~80% power to declare superiority over historical 
control, assuming the true proportion of subjects who achieve the primary endpoint is 
40% for the treatment arm versus 15% for the historical control, and that 90% are 
evaluable at Week 36 from 1st dose. 
8.7 
RANDOMIZATION AND BLINDING 
This is an open-label trial, and therefore, site personnel, individual subjects and INOVIO 
or its representative trial personnel will be aware of the treatment allocations for this trial. 
Randomization does not apply. 
9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
GCP, and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., ICF, 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/EC include the following: 
• 
Submit progress reports to the IRB/EC as required, and request re-review and 
approval of the trial at least once a year during the conduct of the trial. 
• 
Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects. 
• 
Notify the IRB/EC immediately if the Sponsor notifies the Investigator about any 
reportable safety events. 
• 
Obtain approval from the IRB/EC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements, as required. 
• 
Submit reports on, and reviews of, the trial and its progress to the IRB/EC at 
intervals stipulated in their guidelines and in accordance with pertinent 
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• 
Maintain a file of trial-related information (refer to trial files) that include all 
correspondence with the IRB/EC. 
• 
Notify the IRB/EC when the trial is completed (i.e. after the last visit of the final 
trial subject). 
• 
After trial completion (within three (3) months is recommended) provide the 
IRB/EC with a final report on the trial. 
9.3 
IBC APPROVAL AND REPORTING 
Investigator will ensure responsibilities relevant to Institutional Biosafety Committee 
(IBC) approval and reporting if applicable per local regulations. 
9.4 
OFFICE OF BIOTECHNOLOGY ACTIVITIES 
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., 
National Institutes of Health [NIH] Office of Biotechnology Activities [OBA]) governing 
research that involves recombinant or synthetic nucleic acid. 
9.5 
PROTECTION OF HUMAN SUBJECTS 
9.5.1 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to enrollment into the 
trial, 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 
(Section 6.1). 
9.5.2 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This trial 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 trial 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 
should be provided to Sponsor. 
9.5.3 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.5.4 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURE REGULATIONS (21CRF 
PART 11) 
When applicable, this trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.5.5 
COMPLIANCE WITH PROTOCOL 
Subjects will be provided with Investigator emergency contact information and advised to 
report all AEs. While every effort should be made to avoid protocol deviation (PD), 

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should a deviation be discovered, Sponsor must be informed immediately. Any PD 
impacting subject safety must be reported to the Medical Monitor immediately. 
9.5.6 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without prior review and documented approval/favorable opinion from the Sponsor and 
IRB/EC of a protocol amendment, except where necessary to eliminate immediate 
hazards to trial subjects. While every effort should be made to avoid PD, should a 
deviation be discovered, Sponsor must be informed immediately. Any PD impacting 
Subject safety must be reported to the Medical Monitor immediately. 
10.0 DATA COLLECTION, MONITORING, AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the trial 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 trial Sponsor, the governing health 
authorities or the FDA, if they inspect the trial 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 trial, 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 (HIPAA)]. 
Information about trial subjects will be kept confidential and managed in accordance with 
the requirements of the HIPAA of 1996. 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 trial 
• 
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 
In the event that a subject revokes authorization to collect or use PHI, the Sponsor 
retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect vital status, at a minimum, (i.e., 
that the subject is alive) at the end of their scheduled trial period. 
11.0 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, 
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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. The 
Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspections by providing direct access to source data/documents related to 
this trial. 
11.1 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
Case Report Form will be provided for each subject. Subjects must not be identified by 
name on any CRFs. Subjects will be identified with an SID. 
It is the Investigator's responsibility to retain trial essential documents for at least two (2) 
years after the last approval of a marketing application in their country and until there are 
no pending or contemplated marketing applications in their country or at least two (2) 
years have elapsed since the formal discontinuation of clinical development of the IP. 
This retention period may be superseded by country requirements. The Sponsor will 
inform the Investigator/institution as to when these documents are no longer needed to 
be retained. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY AND QUALITY MONITORING 
An independent DSMB will provide safety oversight. The DSMB will be scheduled to 
meet quarterly. 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 there appears to be a regression with VGX-
3100.However, no formal interim analysis will be performed. 
12.2 PATHOLOGY ADJUDICATION COMMITTEE 
All anal 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 four pathologists in separate locations. Each specimen will be read by two 
pathologists independently in a blinded fashion. The logistics and details of the PAC are 
detailed in the PAC Charter. 
12.3 CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced Clinical 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 trial. 
• 
The Clinical Monitor will address and document the following trial conduct 
activities and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution 
trip report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately 
report all SAE and provide subsequent follow-up report of the final 
outcome to the IRB. 
o Throughout the trial, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, 
original, and accurate (ALCOA). 
o Assure that the trial facilities continue to be acceptable. 
o Compare the trial eCRFs with source documents to assure that the data 
are accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and 
reconciliation of records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded 
properly for testing per laboratory manual requirements. 
 
13.0 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 at 
least 60 days prior to submission for publication. The Sponsor will have 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) will 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 US Patent and 
Trademark Office and/or foreign patent office(s). 
 
 
 

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14.0 LIST OF ABBREVIATIONS 
Ab 
Antibody 
ADR 
Adverse Drug Reaction 
AEs 
Adverse events 
AESI 
Adverse Event of Special Interest 
AIN 
Anal Intraepithelial Neoplasia 
AIS 
Adenocarcinoma-in-situ 
ALT 
Alanine Aminotransferase 
BMI 
Body Mass Index 
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CIN 
Cervical Intraepithelial Neoplasia 
CIN1 
Grade 1 Cervical Intraepithelial Neoplasia 
CIOMS-I 
Council for International Organizations of Medical Sciences 
Cr 
Creatinine 
CRF 
Case Report Form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CPK 
Creatine Phosphokinase 
DARE 
Digital Anal Rectal Examination 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELIspot 
Enzyme-linked Immunospot Assay 
EP 
Electroporation with CELLECTRA™5PSP  
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
gbm 
gay and bisexual men 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRA 
High-resolution Anoscopy 
HR-HPV 
High-risk HPV Type 
HSIL 
High Grade Squamous Intraepithelial Lesion 
HIV 
Human Immunodeficiency Virus 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
International Ethics Committee 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
Investigational New Drug 
INOVIO 
Inovio Pharmaceuticals, Inc. 

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IP 
Investigational Product 
IRB 
Institutional Review Board 
IRB/IEC 
Institutional Review Board or Independent Ethics Committee 
ISO 
International Organization for Standardization 
LAST 
Lower Anogenital Squamous Terminology 
LSIL 
Low Grade Squamous Intraepithelial Lesion 
miRNA 
MicroRNA 
mITT 
Modified Intent to Treat 
MSM 
men who have sex with men 
NCS 
Not Clinically Significant 
OBA 
Office of Biotechnology Activities 
OP 
Ororpharyngeal  
PAIN 
Peri-anal Intraepithelial Neoplasia 
PAM 
Protocol Administrative Memo or Letter 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PIN 
Penile Intraepithelial Neoplasia 
PP 
Per Protocol 
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PE 
Physical Exam 
PRO 
Patient-reported Outcome 
SAEs 
Serious Adverse Events 
SF-36v2™ 
36-Item Short Form Health Survey 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPANC 
Study of the Prevention of Anal Cancer 
SSC 
Saline Sodium Citrate 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated (Serious) Adverse Device Effect 
US 
United States 
VAIN 
Vaginal Intraepithelial Neoplasia 
VIN 
Vulvar Intraepithelial Neoplasia 
WFI 
Water for Injection 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 

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15.0  REFERENCES 
1. 
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. 
2. 
Humans IWGotEoCRt. Biological agents. Volume 100 B. A review of human carcinogens. 
IARC Monogr Eval Carcinog Risks Hum 2012,100:1-441. 
3. 
McQuillan G, Kruszon-Moran D, Markowitz LE, Unger ER, Paulose-Ram R. Prevalence 
of HPV in Adults Aged 18-69: United States, 2011-2014. NCHS Data Brief 2017:1-8. 
4. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United 
States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
5. 
Viens LJ, Henley SJ, Watson M, Markowitz LE, Thomas CC, Thompson TD, et al. Human 
Papillomavirus-Associated Cancers - United States, 2008-2012. MMWR Morb Mortal 
Wkly Rep 2016,65:661-666. 
6. 
National Cancer Institute. Fact Sheet: HPV and Cancer. In; 2015. 
7. 
Bruni L, Barrionuevo-Rosas L, Alberto G, Serrano B, Mena M, Gomez D, et al. Human 
Papillomavirus and Related Diseases Report in USA. In: ICO Information Centre on HPV 
and Cancer (HPV Information Centre); 2017. 
8. 
National Cancer Institute SEER Program. Cancer Stat Facts: Anal Cancer. In; 2017. 
9. 
Canadian Cancer Society. Anal Cancer Statistics. In; 2017. 
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. 
Sahasrabuddhe VV, Castle PE, Follansbee S, Borgonovo S, Tokugawa D, Schwartz LM, 
et al. Human papillomavirus genotype attribution and estimation of preventable fraction of 
anal intraepithelial neoplasia cases among HIV-infected men who have sex with men. J 
Infect Dis 2013,207:392-401. 
12. 
Alemany L, Saunier M, Alvarado-Cabrero I, Quiros B, Salmeron J, Shin HR, et al. Human 
papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J 
Cancer 2015,136:98-107. 
13. 
Tong WW, Jin F, McHugh LC, Maher T, Sinclair B, Grulich AE, et al. Progression to and 
spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-
infected and uninfected men. AIDS 2013,27:2233-2243. 
14. 
Machalek DA, Grulich AE, Hillman RJ, Jin F, Templeton DJ, Tabrizi SN, et al. The Study 
of the Prevention of Anal Cancer (SPANC): design and methods of a three-year 
prospective cohort study. BMC Public Health 2013,13:946. 
15. 
Grulich A, Jin F, Poynten IM, Templeton D, Law C, Cornall A, et al. Predictors of 12-month 
persistent high-grade squamous intraepithelial lesions (hsil) in gay and bisexual men 
(gbm): data from the SPANC study. . In: 31st International Papillomavirus Conference 
(HPV2017). Cape Town, South Africa; 2017. 
16. 
Hillman R. Oral comments during a panel discussion. In: 16th World Congress of the 
International Federation of Cervical Pathology and Colposcopy (IFCPC). Orlando, Florida; 
2017. 
17. 
Tong WW, Shepherd K, Garland S, Meagher A, Templeton DJ, Fairley CK, et al. Human 
papillomavirus 16-specific T-cell responses and spontaneous regression of anal high-
grade squamous intraepithelial lesions. J Infect Dis 2015,211:405-415. 
18. 
Dona MG, Vescio MF, Latini A, Giglio A, Moretto D, Frasca M, et al. Anal human 
papillomavirus in HIV-uninfected men who have sex with men: incidence and clearance 

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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version Date:  15May2019 
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rates, duration of infection, and risk factors. Clin Microbiol Infect 2016,22:1004 e1001-
1004 e1007. 
19. 
Shvetsov YB, Hernandez BY, McDuffie K, Wilkens LR, Zhu X, Ning L, et al. Duration and 
clearance of anal human papillomavirus (HPV) infection among women: the Hawaii HPV 
cohort study. Clin Infect Dis 2009,48:536-546. 
20. 
Nyitray AG, Carvalho da Silva RJ, Baggio ML, Smith D, Abrahamsen M, Papenfuss M, et 
al. Six-month incidence, persistence, and factors associated with persistence of anal 
human papillomavirus in men: the HPV in men study. J Infect Dis 2011,204:1711-1722. 
21. 
Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine 
delivery and potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
22. 
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. 
23. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation 
increases in vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
24. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of 
intramuscular and intradermal delivery by CELLECTRA((R)) adaptive constant current 
electroporation device in healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
25. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
26. 
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. 
27. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics 1993,4:353-365. 
 
 
 

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Protocol Version Date:  15May2019 
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Protocol Version: 2.0 
 
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16.0 APPENDICES

 
 
 
 
 
 
 
 
 
 
 
 
HPV-203 
 
A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 
related Anal or Anal/Peri-anal, High grade squamous intraepithelial lesion (HSIL), 
(AIN2, AIN3, PAIN2, PAIN3) in individuals that are seronegative for Human 
Immunodeficiency Virus (HIV)-1/2 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #:  13683 
 
Protocol Version:  3.0 
Protocol Version Date:  22January2020 
 
 
 
 
 

V G X- 3 1 0 0  
H P V -2 0 3  
I n o vi o P h ar m a c e uti c al s, I n c. 
Cli ni c al Pr ot o c ol  
Pr ot o c ol V er si o n D at e:  2 2 J a n 2 0 2 0  
C O N FI D E N TI A L  
Pr ot o c ol V er si o n: 3 . 0 
P a g e 2  of 8 8  
S U M M A R Y O F C H A N G E S 
T h e f oll o wi n g ar e a li st of pr ot o c ol c h a n g e s fr o m V er si o n 2. 0 d at e d 1 4 M a y 2 0 1 9 t o V er si o n 3. 0 
d at e d 2 2 J a n u ar y 2 0 2 0. All ot h er c h a n g e s ar e a d mi ni str ati v e a n d d o n ot si g nifi c a ntl y aff e ct t h e 
s af et y of s u bj e ct s, tri al s c o p e, or s ci e ntifi c q u alit y of t h e pr ot o c ol. 
1.
Eff e cti v e 1 7 J ul y 2 0 1 9, t h e m e di c al M o nit or f or H P V- 2 0 3 i s Dr. 
. T hi s
h a s b e e n pr e vi o u sl y a d dr e s s e d i n P A M # 6 ( 1 8 J ul y 2 0 1 9) a n d i s n o w i n c or p or at e d i nt o
t hi s a m e n d m e nt. Dr.  
 c o nt a ct i nf or m ati o n i s a s f oll o w s:
, M. D., P h. D. 
E m ail: 
 
2.
Cl arif yi n g l a n g u a g e r e g ar di n g t h e d o w nl o a d of E P d at a fr o m t h e C E L L E C T R A ™ 5 P S P
D e vi c e h a s b e e n a d d e d. T h e l a n g u a g e i n Pr ot o c ol V er si o n 2. 0 i n str u ct s sit e s t o
d o w nl o a d E P d at a fr o m t h e C E L L E C T R A ™ 5 P S P d e vi c e wit hi n 2 4 t o 4 8 h o ur s of
st u d y tr e at m e nt. T hi s ti m efr a m e i s n o l o n g er r e q uir e d a n d t h er ef or e, t h e n e w l a n g u a g e
f or Pr ot o c ol V er si o n 3. 0 i s a s f oll o w s: F oll o wi n g e ac h tr e at m e nt wit h V G X- 3 1 0 0, d at a s h o ul d
b e d o w nl o a d e d fr o m t h e E P d e vi c e, a n d t h e d at a fil e t h at i s cr e at e d s h o ul d b e s e nt t o I n o vi o
P h ar m a c e utic al s I nc. or d e si g n e e. I n str u cti o n s o n h o w t o d o w nl o a d t h e d at a a n d c o nt a ct
i nf or m ati o n will b e pr o vi d e d i n t h e Us er M a n u al a n d d uri n g tr ai ni n g. T his h a s b e e n cl arifi e d i n
P A M # 6 ( 1 8 J ul y 2 0 1 9) a n d i s n o w i n c or p or at e d i nt o t hi s a m e n d m e nt.
3.
S e cti o n 3. 8 of t h e pr ot o c ol h a s b e e n u p d at e d t o r efl e ct t h e r e vi s e d st o p pi n g r ul e s f or all
st u di e s wit hi n t h e V G X- 3 1 0 0 pr o gr a m. T hi s c h a n g e a c c o u nt s f or t h e v erifi c ati o n
pr o c e s s r e q uir e d f oll o wi n g t h e e ntr y of a n a d v er s e e v e nt i nt o t h e d at a b a s e.
4.
R e s p o n d er a n d n o n-r e s p o n d er d efi niti o n s f or t h e s e c o n d ar y a n d e x pl or at or y e n d p oi nt s
h a v e b e e n pr o vi d e d i n t h e Cli ni c al Pr ot o c ol S y n o p si s .
5.
T h e Pri m ar y E n d p oi nt h a s b e e n u p d at e d t o r e m o v e “ q u alif yi n g l e si o n s.” A s a r e s ult,
F o ot n ot e 8 h a s b e e n r e vi s e d t o d efi n e i ntr a- a n al a n d/ or p eri- a n al l e si o n ti s s u e f or
Pri m ar y E n d p oi nt a n d st at e s:  A n i ntr a- a n al a n d/ or p eri- a n al l e si o n e v al u at e d b y t h e
P at h ol o g y A dj u di c ati o n C o m mitt e e ( P A C).  Pl e a s e r ef er t o r e vi si o n # 1 6 w hi c h st at e s t h at
t h e pri m ar y e n d p oi nt will b e a n al y z e d b a s e d a)  all l e si o n s a n d b)  o n q u alif yi n g l e si o n s
a n d n e w l e si o n s.
6.
T h e d efi niti o n f or q u alif yi n g l e si o n s h a s b e e n m o v e d fr o m F o ot n ot e 8 t o F o ot n ot e 1 2 a n d
st at e s: A n i ntr a- a n al a n d/ or p eri- a n al l e si o n w hi c h i s c o nfir m e d t o b e H P V- 1 6 a n d/ or
H P V - 1 8 p o siti v e a n d h a v e hi st ol o gi c all y c o nfir m e d a n al or a n al/ p eri- a n al H SI L e v al u at e d
b y t h e P at h ol o g y A dj u di c ati o n C o m mitt e e ( P A C).
7.
S e c o n d ar y o bj e cti v e # 9 h a s b e e n a d d e d t o e v al u at e t h e effi c a c y of t hr e e d o s e s of V G X-
3 1 0 0 wit h r e s p e ct t o hi st o p at h ol o gi c r e gr e s si o n of a n al or a n al/ p eri- a n al H SI L or vir ol o gi c
cl e ar a n c e of H P V- 1 6 a n d/ or H P V- 1 8, a s H P V- 1 6/ 1 8 a s s o ci at e d H SI L i s c o n si d er e d a
si g nifi c a ntl y hi g h er ri s k f or a n al c a n c er.
8.
T h e a s s o ci at e d s e c o n d ar y e n d p oi nt s 8 a a n d 8 b fr o m Pr ot o c ol V er si o n 2. 0 of t h e h a v e
b e e n m o v e d a n d ar e n o w a s s o ci at e d e x pl or at or y e n d p oi nt s 9 a a n d 9 b i n Pr ot o c ol
V er si o n 3. 0.
P P D
P P D
P P D
P P D

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Page 3 of 88 
 
9. Associated secondary endpoint #4 has been revised to remove Week 64 and 88. 
Week 64 and 88 have been added to the corresponding associated exploratory 
endpoint #4.  
 
10. Exploratory objective #4 has been added to describe the long term efficacy of VGX-
3100, as measured by virologic clearance of HPV-16 and/or HPV-18 by intra-anal 
swab testing. This will correspond to secondary objective #4. 
 
11. Exploratory objective #10 has been added to determine the long term efficacy of more 
than three doses of VGX-3100 with respect to the treatment of HPV-16 and/or HPV-18 
to correspond with Secondary objective #9. 
 
12. Section 5.4 has been revised to add an updated 5PSP Array Label as well an updated 
Outer Box Packaging Label. 
 
13. Section 5.5 previously stated: The CELLECTRA™ 5PSP device and its components 
must be stored between the temperature ranges 55.4°F-91.4°F and relative humidity 
ranges of 30-70%. The requirements have been revised removing the relative humidity 
range of 30-70% portion of the statement. The protocol will now state: The 
CELLECTRA™ 5PSP device and its components must be stored between the 
temperature ranges 55.4°F-91.4°F and kept dry. 
 
14. Section 6.12 Assessment of Injection Site Reactions has been updated to clarify the 
timeframe around daily activity for grading injection site reactions in Table 11. The 
Sponsor defines timeframe for ‘daily activity’ is an impact lasting 24 hours or more.  
 
15. The following changes have been made to the Schedule of Events (Table 8): 
 
 
Blood Immunologic testing will no longer take place at Week 64 given that the 
Week 88 immunologic testing is considered sufficient. Blood immunologic 
testing at Week 64 as has been removed. 
 
A footnote has been added with the following language to ensure that virology 
and pathology are obtained on all visible lesions at Week 64: In additional to 
HSIL lesion(s) found at Screening, all visible lesions should have biopsy 
obtained at Week 64 and sent to the central pathology lab for review by PAC. 
 
16. Language has been added to Section 8.5.1 (Primary Analysis) to indicate that the 
primary endpoint will be analyzed in two ways: a) based on all lesions and b) based on 
qualifying and new lesions.  
 
17. Language has been added to Section 8.5.2 (Secondary Analyses) to indicate that all of 
the efficacy binary endpoints will be analyzed in two ways: a) based on all lesions and 
b) based on qualifying and new lesions. This section has also been updated to remove 
language relating to post-baseline ELISA titers and post-baseline increases in 
ELISPOT as this has been moved to Section 8.5.9 (Exploratory Analyses).  
 
18. Language has been added to Section 8.5.9 (Exploratory Analyses) to indicate that all 
of the efficacy binary endpoints will be analyzed in two ways: a) based on all lesions 
and b) based on qualifying and new lesions. Language has also been added to 

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Page 4 of 88 
indicate that binary endpoints of Week 64 and Week 88 will be analyzed in two ways: 
a) overall and b) according to three or four doses received. This section has also been 
updated to move from Secondary Analysis: post-baseline ELISA titers will be 
summarized with geometric means and associated t-distribution based 95%Cls; post 
baseline increases in ELISPOT will be summarized with median and 95% CIs.  
 
19. Table 1 (Minimally Required Procedure at each Biopsy Visit) has been updated to 
indicate that new lesions or lesions that did not qualify at baseline should be biopsied 
at evaluation.  In addition, Language has been added throughout to clarify that under 
Protocol Version 3.0, all visible lesions should be biopsied at the Week 64 Visit to 
ensure that a comprehensive assessment is done.  
 
 

V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
M e di c al M o nit or A p pr o v al P a g e 
Dr u g: 
S p o n s or: 
M e di c al M o nit or: 
V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
6 6 0 W. G er m a nt o w n Pi k e, S uit e 1 1 0 
Pl y m o ut h M e eti n g, P A 1 9 4 6 2 
, M. D., P h. D. 
 
l n o vi o P h ar m a c e uti c al s, I n c. 
l n o vi o P h ar m a c e uti c al s 
D at e 
C O N FI D E N TI A L 
H P V- 2 0 3 
Cli ni c al Pr ot o c ol 
T h e i nf or m ati o n i n t hi s d o c u m e nt i s c o n si d er e d pri vil e g e d a n d c o nfi d e nti al b y l n o vi o 
P h ar m a c e uti c al s I n c. (I N O VI O) a n d m a y n ot b e di s cl o s e d t o ot h er s e x c e pt t o t h e e xt e nt 
n e c e s s ar y t o o bt ai n I n stit uti o n al R e vi e w B o ar d/ Et hi c s c o m mitt e e a p pr o v al a n d i nf or m e d 
c o n s e nt, or a s r e q uir e d b y l o c al r e g ul at or y a ut h oriti e s. P er s o n s t o w h o m t hi s i nf or m ati o n 
i s di s cl o s e d m u st b e i nf or m e d t h at t hi s i nf or m ati o n i s pri vil e g e d a n d c o nfi d e nti al a n d t h at 
it s h o ul d n ot b e f urt h er di s cl o s e d wit h o ut 
t h e writt e n 
p er mi s si o n of I N O VI O. A n y 
s u p pl e m e nt al i nf or m ati o n a d d e d t o t hi s d o c u m e nt i s al s o c o nfi d e nti al a n d pr o pri et ar y 
i nf or m ati o n of I N O VI O a n d m u st b e k e pt i n c o nfi d e n c e i n t h e s a m e m a n n er a s t h e c o nt e nt s 
of t hi s d o c u m e nt. 
Pr ot o c ol V er si o n D at e: 2 2 J a n 2 0 2 0 
C O N FI D E N TI A L 
P a g e 5 of 8 8 
Pr ot o c ol V er si o n: 3. 0 
P P D
P P D
P P D
P P D

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Protocol Version Date:  22Jan2020 
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Page 6 of 88 
 
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 (IRB/IEC) 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 International Conference on Harmonization (ICH)/Good Clinical Practice (GCP) and 
International Organization for Standardization (ISO) guidelines, local legal and regulatory 
requirements, and all stipulations of the protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
<Insert Principal Investigator Printed Name> 
 
Date (dd/Mmm/yyyy) 
 
 
 
 
 
 
 
Site Number: _____________________________________________ 
 
 
Site Name: _______________________________________________ 
 
 

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Page 7 of 88 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT ...................................................... 6 
CLINICAL PROTOCOL SYNOPSIS ............................................................................ 11 
TRIAL SCHEDULE OF EVENTS ................................................................................ 26 
1.0 
INTRODUCTION ........................................................................................... 29 
1.1 
Background and Scientific Rationale ....................................................................29 
1.1.1 
VGX-3100 ........................................................................................................................ 30 
1.1.2 
Electroporation .............................................................................................................. 31 
1.1.3 
Dose Rationale............................................................................................................... 32 
1.2 
Potential Benefits ....................................................................................................32 
1.3 
Potential Risks ........................................................................................................32 
2.0 
PURPOSE AND HYPOTHESIS ....................................................................... 33 
2.1 
Purpose ...................................................................................................................33 
2.2 
Hypothesis ...............................................................................................................33 
3.0 
TRIAL DESIGN AND ENDPOINTS .................................................................. 33 
3.1 
Primary Objective(s) ...............................................................................................34 
3.2 
Primary Endpoint(s) ................................................................................................34 
3.3 
Secondary Objective(s) ..........................................................................................34 
3.4 
Associated Secondary Endpoint(s) .......................................................................35 
3.5 
Exploratory Objective(s) .........................................................................................35 
3.6 
Associated Exploratory Endpoint(s) ......................................................................36 
3.7 
Efficacy Assessment ..............................................................................................37 
3.8 
Safety Assessment .................................................................................................37 
3.9 
Immunogenicity Assessment .................................................................................38 
4.0 
TRIAL POPULATION .................................................................................... 39 
4.1 
Inclusion Criteria .....................................................................................................39 
4.2 
Exclusion Criteria ....................................................................................................40 
4.3 
Discontinuation/Withdrawal of Trial Subjects .......................................................43 
4.3.1 
Criteria for Discontinuation from the Study ............................................................... 43 
4.3.2 
Criteria for Withdrawal from Study .............................................................................. 43 
4.3.3 
Sponsor Notification of Discontinuation/Withdrawal ................................................ 43 
4.3.4 
Reasons for Discontinuation/Withdrawal ................................................................... 44 
5.0 
TRIAL TREATMENT ..................................................................................... 44 
5.1 
Investigational Biologic Product ............................................................................44 
5.2 
Cellectra™ 5PSP Device Description: ...................................................................45 
5.3 
Treatment Regimen .................................................................................................46 
5.4 
Packaging and Handling .........................................................................................46 
5.5 
Handling and Storage of IP and Device .................................................................48 

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5.6 
Preparation and Dispensing ...................................................................................48 
5.7 
Use of Cellectra™5PSP Device ..............................................................................49 
5.8 
Drug and Device Accountability ............................................................................49 
5.8.1 
Investigational Product Accountability ....................................................................... 49 
5.8.2 
Cellectra™ 5PSP Device Accountability ..................................................................... 49 
5.9 
Return and Destruction of Investigational Product and Cellectra™ 5PSP Device
 ..................................................................................................................................50 
5.9.1 
Return of Investigational Product................................................................................ 50 
5.9.2 
Return of Cellectra™ 5PSP Device .............................................................................. 50 
6.0 
TRIAL PROCEDURES AND SCHEDULE .......................................................... 50 
6.1 
Informed Consent ...................................................................................................51 
6.2 
Before Treatment Procedures ................................................................................51 
6.2.1 
Screening Evaluations .................................................................................................. 52 
6.3 
During Treatment Procedures by Visit ..................................................................53 
6.3.1 
Day 0 ............................................................................................................................... 53 
6.3.2 
8-14 Days Post Dose 1 Phone Call .............................................................................. 53 
6.3.3 
Week 4 (± 4 Days) .......................................................................................................... 54 
6.3.4 
8-14 Days Post Dose 2 Phone Call .............................................................................. 54 
6.3.5 
Week 12 (± 4 Days) ........................................................................................................ 55 
6.3.6 
Week 15 (± 1 Week) ....................................................................................................... 55 
6.3.7 
Week 28 (± 1 Week) ....................................................................................................... 56 
6.3.8 
Week 36 (± 1 Week) ....................................................................................................... 56 
6.3.9 
Week 40 (± 1 Week) ....................................................................................................... 57 
6.3.10 8-14 Days Post Dose 4 Phone Call (for subjects who received a 4th dose) ............. 57 
6.3.11 Week 64 (± 2 Weeks) ..................................................................................................... 57 
6.3.12 Week 88 (± 2 Weeks) ..................................................................................................... 58 
6.4 
Trial Procedures ......................................................................................................59 
6.5 
Assignment of Subject Identification Numbers ....................................................59 
6.6 
Demographics .........................................................................................................59 
6.7 
Safety Evaluations ..................................................................................................59 
6.7.1 
Physical Exam ............................................................................................................... 59 
6.7.2 
Vital Signs ...................................................................................................................... 59 
6.7.3 
Height and Weight ......................................................................................................... 59 
6.7.4 
Medical History .............................................................................................................. 60 
6.7.5 
Socio-Behavioral Assessments ................................................................................... 60 
6.7.6 
Laboratory Evaluations ................................................................................................ 60 
6.7.7 
Pregnancy Testing ........................................................................................................ 60 
6.7.8 
ECG ................................................................................................................................. 60 
6.7.9 
Participant Diary Card (PDC) ........................................................................................ 61 
6.8 
Injection and Electroporation (EP) .........................................................................61 
6.9 
Management of Anxiety and Pain due to Electroporation (EP) Procedures .......61 
6.10 Assessment of Laboratory Abnormalities .............................................................62 
6.11 Assessment of Clinical Trial Adverse Events (AEs) .............................................62 

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6.12 Assessment of Injection Site Reactions ................................................................62 
6.13 Assessment of Patient Reported Outcomes .........................................................63 
6.14 Peripheral Blood Immunogenicity Assessments ..................................................63 
6.15 Profiling of MiRNA ..................................................................................................64 
6.16 Tissue Immunogenicity Assessment .....................................................................64 
6.17 Anal and/or Peri-anal HPV Testing.........................................................................64 
6.18 HPV Testing from other Anatomical Site (Non-anal) ............................................64 
6.19 Anal Photographs and Biopsies ............................................................................65 
6.20 Unscheduled Biopsies ............................................................................................65 
6.21 Concomitant Medications/Treatments ...................................................................65 
6.22 Restrictions .............................................................................................................66 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ........................... 66 
7.1 
Safety Parameters ...................................................................................................66 
7.2 
Adverse Events (AEs) .............................................................................................66 
7.3 
Serious Adverse Events .........................................................................................67 
7.4 
Unexpected Adverse Drug Reactions and Expedited Reporting .........................68 
7.5 
Unanticipated (Serious) Adverse Device Effect ....................................................69 
7.6 
Assessing Severity (Intensity) ...............................................................................69 
7.7 
Causal Relationship of Clinical Material to Adverse Events ................................69 
7.8 
Abnormal Laboratory Value ...................................................................................70 
7.9 
Post-Trial Reporting Requirements .......................................................................71 
7.10 Procedures for Documenting Pregnancy During the Trial ...................................71 
7.11 Methods and Timing of Collection of Safety Data ................................................72 
7.12 Safety and Toxicity Management ...........................................................................72 
7.12.1 Adverse Events of Special Interest ............................................................................. 72 
7.13 Adverse Event Reporting .......................................................................................73 
7.14 Trial Reporting Period of Adverse Events .............................................................73 
7.15 Trial Reporting Period of Serious Adverse Events and AESIs ............................73 
7.16 Notifications of Serious Adverse Events ...............................................................75 
7.17 Reporting of CELLECTRA™5PSP Device Related Complaints or Deficiencies .75 
7.18 Trial Discontinuation ..............................................................................................75 
8.0 
STATISTICAL CONSIDERATIONS .................................................................. 76 
8.1 
Statistical and Analytical Plan ................................................................................76 
8.2 
General Considerations ..........................................................................................76 
8.3 
Statistical Hypotheses ............................................................................................76 
8.4 
Analytical Populations ............................................................................................76 
8.5 
Description of Statistical Methods .........................................................................76 
8.5.1 
Primary Analyses .......................................................................................................... 76 
8.5.2 
Secondary Analyses ..................................................................................................... 77 
8.5.3 
Safety Analyses ............................................................................................................. 77 
8.5.4 
Disposition ..................................................................................................................... 77 

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8.5.5 
Demographic and Other Baseline Characteristics .................................................... 77 
8.5.6 
Interim Analyses ............................................................................................................ 78 
8.5.7 
Multiplicity ...................................................................................................................... 78 
8.5.8 
Missing Values............................................................................................................... 78 
8.5.9 
Exploratory Analyses .................................................................................................... 78 
8.6 
Sample Size/Power .................................................................................................79 
8.7 
Randomization and Blinding ..................................................................................79 
9.0 
ETHICS ...................................................................................................... 79 
9.1 
Investigator and Sponsor Responsibilities ...........................................................79 
9.2 
Institutional Review Board or Ethics Committee ..................................................79 
9.3 
IBC Approval and Reporting ..................................................................................80 
9.4 
Office of Biotechnology Activities .........................................................................80 
9.5 
Protection of Human Subjects ...............................................................................80 
9.5.1 
Compliance with Informed Consent Regulations ...................................................... 80 
9.5.2 
Compliance with IRB/EC Requirements ..................................................................... 80 
9.5.3 
Compliance with Good Clinical Practice .................................................................... 80 
9.5.4 
Compliance with Electronic Records/Signature Regulations (21CRF Part 11) ...... 80 
9.5.5 
Compliance with Protocol ............................................................................................ 80 
9.5.6 
Changes to the Protocol ............................................................................................... 80 
10.0 
DATA COLLECTION, MONITORING, AND REPORTING .................................... 81 
10.1 Confidentiality and Privacy ....................................................................................81 
11.0 
SOURCE DOCUMENTS ................................................................................ 81 
11.1 Records Retention ..................................................................................................82 
12.0 
SAFETY AND QUALITY MONITORING ............................................................ 82 
12.1 Safety and Quality Monitoring ................................................................................82 
12.2 Pathology Adjudication Committee .......................................................................82 
12.3 Clinical Monitoring ..................................................................................................82 
13.0 
PUBLICATION POLICY ................................................................................. 83 
14.0 
LIST OF ABBREVIATIONS ............................................................................ 83 
15.0 
REFERENCES ............................................................................................. 86 
16.0 
APPENDICES .............................................................................................. 88 
 
 
 
 
 

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CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: A Phase 2, Open Label, Study of VGX-3100 Delivered Intramuscularly (IM) 
Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 related Anal 
or Anal/Peri-anal High-Grade Squamous Intraepithelial Lesions, HSIL (AIN2, AIN3, PAIN2, 
PAIN3) in individuals that are seronegative for Human Immunodeficiency Virus (HIV)-1/2 
Protocol Number: HPV-203 
 
Trial Phase: 2a 
 
Estimated Number of Trial Centers and Countries/Regions: Approximately 3 study 
centers located in North America 
 
Formulation: VGX-3100 
 
Trial Design: Multi-center, single-arm, open-label phase 2 study 
  
Criteria for Evaluation: To provide a treatment to regress anal or anal/peri-anal HSIL and 
clear the related HPV-16 and/or HPV-18 (HPV16/18) in individuals that are seronegative for 
HIV-1/2. 
 
Research Hypothesis: VGX-3100 followed by electroporation (EP) administered to adults 
with histologically confirmed anal or anal/peri-anal HSIL1, (AIN22, AIN33, PAIN24, PAIN35) 
associated with HPV-16 and/or HPV-18 will result in a higher proportion with 
histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence of anal 
or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than historical controls.  
Dose of VGX-3100: 6 mg (1mL) 
Administration: Intramuscular injection followed by EP 
VGX-3100 Dosing Schedule: Day 0, Week 4 and Week 12 with one additional dose given 
to partial responders at Week 40 
Study Duration: 88 Weeks 
Primary Objective: Determine the efficacy of 3 doses of VGX-3100 with respect to 
combined histopathologic regression of anal or anal/peri-anal HSIL and virologic clearance 
of HPV-16 and/or HPV-18. 
Primary Endpoint: Proportion of subjects with no histologic evidence of anal or anal/peri-
anal HSIL6 on histology (i.e., collected via biopsy or excisional treatment)7and no evidence 
of HPV-16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue 8. 
1 High-grade Squamous Intraepithelial Lesion 
2 Grade 2 Anal Intraepithelial Neoplasia 
3 Grade 3 Anal Intraepithelial Neoplasia             
4 Grade 2 Peri-anal Intraepithelial Neoplasia 
5 Grade 3 Peri-anal Intraepithelial Neoplasia 
6  No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
7  A treatment responder is defined as a subject with no histologic evidence of anal or anal/peri-anal HSIL and no evidence of 
HPV-16 or HPV-18 in anal lesion tissue and who did not receive any non-study treatment of curative intent of intra-anal 
and/or peri-anal lesions. A treatment non-responder is defined as a subject with histologic evidence of anal or anal/peri-anal 
HSIL, adenocarcinoma-in-situ (AIS), anal or anal/peri-anal carcinoma or a subject with evidence of HPV-16/18 in anal lesion 
tissue or a subject who received non-study treatment of curative intent of intra-anal and/or peri-anal lesions. 

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8 An intra-anal and/or peri-anal lesion evaluated by the Pathology Adjudication Committee (PAC). 
 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
1a. Local and systemic events for 7 days 
following each dose as noted in the 
Participant Diary Card (PDC). 
 
1b. All adverse events including SAEs, 
UADEs, and other unexpected AEs 
for the duration of the study (through 
the Week 88 visit) 
2. Determine the efficacy of three doses 
of VGX-3100, as measured by 
histologic regression of anal or 
anal/peri-anal HSIL  
2. Proportion of subjects with no 
evidence of anal or anal/peri-anal 
HSIL on histology (e.g. biopsies or 
excisional treatment) at Week 36  
3. Determine the efficacy of three doses 
of VGX-3100 as measured by virologic 
clearance of HPV-16 and/or HPV-18 by 
testing from lesion tissue  
3. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-189 
from intra-anal and/or peri-anal tissue  
by type specific HPV testing at Week 
36 
4. Determine the efficacy of three doses 
of VGX-3100 as measured by virologic 
clearance of HPV-16 and/or HPV-18 by 
intra-anal swab testing  
4. Proportion of subjects with no 
evidence of HPV-16 and/or HPV-18 
from intra-anal swab by specific HPV 
testing at Week 36 
5. Determine the efficacy of three doses 
of VGX-3100 as measured by complete 
histopathologic regression of anal or 
anal/peri-anal HSIL to normal tissue  
5. Proportion of subjects with no 
evidence10 of anal or anal/peri-anal 
Low grade squamous intraepithelial 
lesion (LSIL) or HSIL (i.e. no 
evidence of AIN2, AIN3, PAIN2, 
PAIN3) on histology (i.e. biopsies or 
excisional treatment) at Week 36  
6. Determine the efficacy of three doses 
of VGX-3100 as measured by 
histopathologic non-progression of 
anal or anal/peri-anal HSIL  
6. Proportion of subjects with no 
progression11 of anal or anal/peri-
anal HSIL to carcinoma from 
baseline to histology (i.e. biopsies or 
excisional treatment) at Week 36 
7. Describe the efficacy of VGX-3100 for 
partial responders, as measured by 
reduction in the number of intra-anal 
and/or peri-anal qualifying lesion(s), as 
applicable and the reduction in size of 
peri-anal lesion(s) if present, and for 
whom the disease has not progressed 
according to Investigator judgment in 
subjects who did not have anal or 
anal/peri-anal HSIL lesion resolution at 
Week 36 
7. Percent reduction in the number of 
qualifying12 intra-anal and/or peri-
anal lesion(s), and the reduction in 
size of peri-anal lesion(s) as 
determined by the Investigator at 
Weeks 36, 64, and 88 compared to 
baseline13. 
8. Determine the cellular immune 
response following dose 3 and 
compared to baseline 
8. Flow Cytometry response magnitude 
at baseline and Week 15  

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9. Determine the efficacy of three 
doses of VGX-3100 with respect to 
histopathologic regression of anal or 
anal/peri-anal HSIL or virologic 
clearance of HPV-16 and/or HPV-18  
9. Proportion of subjects with no 
histologic evidence of anal or 
anal/peri-anal HSIL by histology 
(i.e., collected via biopsy or 
excisional treatment) or no evidence 
of HPV-16/18 at Week 36 from intra-
anal and/or peri-anal lesion tissue  
9 Clearance of HPV-16 or HPV-18 is defined as being undetectable by PCR assay. 
10 No evidence of anal or anal/peri-anal HSIL is defined as normal tissue or anal or anal/peri-anal LSIL. 
11 Progression is defined as advancement to carcinoma by histology according to the Pathology Adjudication Committee. 
12 An intra-anal and/or peri-anal lesion which is confirmed to be HPV-16 and/or HPV-18 positive and have histologically 
confirmed anal or anal/peri-anal HSIL evaluated by the Pathology Adjudication Committee (PAC). 
13 Baseline photographic imaging is defined as photographs obtained pre-biopsy at Screening, or post biopsy at Screening (for      
subjects with historical biopsy tissue). 
 
 
 
 

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Exploratory Objectives 
Associated Exploratory Endpoints 
1. Describe the long term efficacy  of VGX-
3100 with respect to combined 
histopathologic regression of anal or 
anal/peri-anal HSIL and virologic 
clearance of HPV-16 and/or HPV-18  
1.  Proportion of subjects with no histologic 
evidence of anal or anal/peri-anal HSIL 
on histology (i.e. collected via biopsy or 
excisional treatment) and no evidence of 
HPV-16/18 at Week 64 by testing from 
intra-anal and/or peri-anal lesion tissue  
2. Describe the long term efficacy of VGX-
3100, as measured by histologic 
regression of anal or anal/peri-anal HSIL  
2.   Proportion of subjects with no evidence 
of anal or anal/peri-anal HSIL on histology 
(i.e. biopsies or excisional treatment) at 
Week 64  
3. Describe the long term efficacy of VGX-
3100, as measured by virologic 
clearance of HPV-16 and/or HPV-18 by 
testing from lesion tissue  
3.   Proportion of subjects with no HPV-16/18 
at Week 64 by testing from intra-anal 
and/or peri-anal lesion tissue  
4. Describe the long term efficacy of VGX-
3100, as measured by virologic 
clearance of HPV-16 and/or HPV-18 by 
intra-anal swab testing 
4.   Proportion of subjects with no evidence 
of HPV-16 and/orHPV-18 from intra-anal 
swab by specific HPV testing at Week 64 
and Week 88  
5. Evaluate tissue immune responses to 
VGX-3100 in intra-anal and/or peri-anal 
samples 
5.   Assessment of proinflammatory and 
immunosuppressive elements in tissue, 
where feasibile14 
6. Describe the clearance of HPV-16 and/or 
HPV-18 infection from non-anal anatomic 
locations 
6.  Proportion of subjects who have cleared 
HPV-16 and/or HPV-18 on specimens 
from non-anal anatomic locations as 
applicable based upon gender (i.e. 
oropharynx, cervical, vaginal, and penile 
at Week 36) 
7. Describe the association of microRNA 
(miRNA) profile, previous anoscopy, 
cytology and HPV testing results with 
Week 36 histologic regression 
7.   HRA, cytology, and HPV test results and 
miRNA profile (baseline and at the Weeks 
15 and 36) in conjunction with histologic 
regression of anal or anal/peri-anal HSIL 
at Week 36 
8. Describe patient reported outcomes 
(PRO) for subjects treated with VGX-3100 
8.   Patient reported outcome (PRO) 
endpoints prior to first dose (Day 0), on 
the day of and following each dose, and 
at Weeks 36, 64, and 88. There will be an 

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additional PRO assessment at Week 40 if 
a subject receives a 4th dose 
9. Determine the humoral and cellular 
immune response following dose 3 and 
additional time points compared to 
baseline 
9a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline and Weeks 15, 36, and 88  
9b. Interferon-γ ELISpot response spot 
forming units (SFU) at baseline and 
Weeks 15, 36, and 88  
10. Determine the long term efficacy of VGX-
3100 with respect to histopathologic 
regression of anal or anal/peri-anal HSIL 
or virologic clearance of HPV-16 and/or 
HPV-18  
10.   Proportion of subjects with no 
histologic evidence of anal or 
anal/peri-anal HSIL on histology (i.e., 
collected via biopsy or excisional 
treatment) or no evidence of HPV-16 
and/or HPV-18 at Week 64 from intra-
anal and/or peri-anal lesion  
14 Additional assessments may include visualization of PD-L1, Granulysin, Perforin, CD137, CD103 and possible other relevant 
markers identified in the literature as sample allows. 
 

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Study Design: 
 
HPV-203 is a Phase 2, 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 in adult 
men and women who are HIV negative with histologically confirmed anal or anal/peri-anal 
HSIL associated with HPV-16 and/or HPV-18. 
 
Approximately 24 subjects will receive at least 3 doses of VGX-3100. Each dose of VGX-
3100 will be administered in a 1 mL volume IM followed immediately by EP. As shown in 
Figure 1, study subjects will receive at least 3 doses of VGX-3100 depending upon their 
disposition with regard to histologic and lesion area changes during the trial. The first dose 
will be administered on Day 0, the second at Week 4, and the third at Week 12. Partial 
response to VGX-3100 may still be of medical importance by being able to limit the extent of 
surgery necessary. For partial responders at Week 36, a fourth dose may be administered at 
Week 40.  
 
All subjects are scheduled to be followed to Week 88. 
 
Figure 1: HPV-203 Study Visit Schedule 
 
 
 
 
Biopsy(ies) 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 anal or 
anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the biopsy sample(s). All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥ 4mm) will be biopsied at Screening. Subjects 
must also have intra-anal and/or peri-anal lesion(s) tissue test positive for HPV genotype 16 
and/or 18 to be eligible for participation in the study. 
 
 
 
 

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To assess quality of life and related impacts on subjects, patient-reported outcome (PRO) 
instruments will be administered and will include the Short Form Health Survey version 2 (SF-
36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional PRO questions 
assessing quality of life after surgery or biopsy. 
 
Visualization of the lesion and digital anal rectal examination (DARE) alone are insufficient 
evidence to confirm disease regression. Disease regression will be primarily based on 
histopathologic assessment at Week 36 and additionally assessed at Week 64. Subjects will 
be monitored during the course of the study by DARE and HRA. Intra-anal lesion(s) will be 
assessed at Screening, Day 0, and at Weeks 4, 15, 28, 36, 64 and 88 using HRA. All 
qualifying peri-anal lesion(s) will be assessed using the ruler provided. The ruler should be 
placed in the field of vision and should be documented with photography at Screening, Day 0, 
and Weeks 4, 15, 28, 36, 64, and 88. 
 
The decision process following the results of the Week 36 biopsy are described below in  
Figure 2 and are as follows: At Week 36, the subject will undergo repeat intra-anal and/or 
peri-anal punch biopsies of all HSIL lesions confirmed by the PAC at Screening of adequate 
size (≥ 4mm). (See Table 1 Minimally Required Biopsy Procedures). If after evaluation of the 
biopsy tissue(s) by the PAC there is no evidence of HSIL (defined by Subgroups A or B), the 
subject will continue to Week 64 for HRA and undergo biopsies of the same areas (HSIL 
lesions) as the baseline biopsies. Any other visible lesions should also be biopsied at the 
Week 64 visit. If HSIL remains based on the Week 64 biopsy results, the subject will receive 
standard of care and remain on the study for safety and follow up only. 
 
Figure 2: Decision process at Week 40 
 
 
 
 
 
 

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Protocol Version: 3.0 
 
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Table 1: Minimally Required Procedure at each Biopsy Visit 
Pre-biopsy High Resolution Anoscopy 
Finding 
Minimally required procedure 
 
No lesion 
Punch biopsy and photography; biopsy should 
be collected from within the approximate 
original boundaries of the study entry HSIL as 
proximal as possible to the original biopsy site 
which was previously determined to be HSIL by 
the PAC. New lesions or lesions that did not 
qualify at baseline should be biopsied at 
evaluation. 
 
Single lesion (which was also present at 
baseline) 
Punch biopsy and photography; biopsy should 
be collected within the boundaries of the 
original lesion and from the area most 
suspicious for advanced disease within the 
lesion by clinical exam. New lesions or lesions 
that did not qualify at baseline should be 
biopsied at evaluation. 
 
Multiple lesions 
Punch biopsies and photography; biopsy should 
be collected from the same lesions diagnosed 
as HSIL from study entry and from the area 
most suspicious for advanced disease within 
the lesion by clinical exam. New lesions or 
lesions that did not qualify at baseline should be 
biopsied at evaluation. 
 
If HSIL is diagnosed in any Week 36 biopsy, but there is a reduction in the number of intra-
anal and/or peri-anal lesion(s), reduction in peri-anal lesion(s) size or no change in peri-anal 
lesion(s) size from baseline (defined by Subgroup C), the Investigator has the option to 
administer a 4th dose of VGX-3100 at Week 40, and the subject will continue on the study to 
have HRA and biopsy at Week 64 of all lesions (qualifying and any other visible), i.e. the 
second efficacy checkpoint. Alternatively, the Investigator may instead choose to treat the 
subject with standard of care treatment (i.e. electrocautery, ablation, surgical excision), and 
the subject will continue on the study without further biopsy unless it is part of standard of 
care. 
 
In the event of worsening anal or anal/peri-anal HSIL at any time during the trial (defined as 
any increase in lesion(s) area from baseline or worsening of anal or anal/peri-anal HSIL to 
cancer), the subject may receive standard of care treatment (i.e. electrocautery, ablation, 
surgical excision) per the Investigator's judgment but will continue on the study through Week 
88 with HRA, but without further biopsy unless it is part of the standard of care. 
 
If there is histologic progression to carcinoma, subjects will receive surgical treatment, and be 
discontinued from study treatment but will continue through Week 88 with HRA, but without 
further biopsy unless it is part of the standard of care. The event will be reported as an SAE 
per Section 7.3. If wide excision is required, the sample(s) obtained will be sent to the PAC 
for evaluation. 
 
 
 

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Efficacy Assessment: 
 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesion(s) of adequate 
size (≥ 4mm). Visible lesion(s) observed during HRA should be large enough to biopsy, but 
the biopsy (typically 4mm) should not remove the entire lesion in order to allow for continued 
lesion measurement while on the study. 
 
Given that HPV infection persistence is a critical factor in the clinical progression of HPV-
associated anal or anal/peri-anal HSIL and also based upon the findings of the secondary 
objective of the HPV-003 CIN2/3 proof of concept study, the responder definition for the HPV-
203 primary endpoint determination requires both histological regression of anal or anal/peri-
anal HSIL and clearance of HPV-16 and/or HPV-18 [1]. 
 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic assessment 
of intra-anal tissue, utilizing HRA with biopsies. All intra-anal and/or peri-anal lesion(s) of 
adequate size (≥4mm) will be biopsied at Screening. Once the PAC confirms HSIL at 
Screening, the Week 36 and 64 biopsies will be obtained from all HSIL site(s) confirmed by 
the PAC at Screening, unless the Investigator suspects disease progression. In addition to 
HSIL lesion(s) found at Screening, all visible lesions should have biopsy obtained at Week 64 
and samples to be sent to the central pathology lab for PAC review. Tissue samples will be 
analyzed for evidence of histopathologic regression. Clearance of HPV-16 and/or HPV-18 will 
be determined using the type specific HPV PCR test on intra-anal and/or peri-anal tissue 
performed at Screening and Weeks 36 and 64 when applicable. 
 
Intra-anal and/or peri-anal swabs will be collected at Screening, Day 0, and at Weeks 4, 15, 
28, 36, 64 and 88 as a less invasive measure for exploratory purposes to determine the 
presence of HPV-16 and/or -18 as well as other high risk HPV types using HPV testing. 
Similarly, vaginal, cervical (female subjects), penile (male subjects), and oropharyngeal (OP) 
rinse samples will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess 
systemic virologic response to treatment. 
 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction in 
intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size from 
baseline (Subgroup C), the Investigator will have the option to administer a 4th dose of VGX-
3100 at Week 40 and the subject will continue on the study with HRA and biopsy at Week 64. 
Alternatively, the Investigator may choose to treat the subject with standard of care treatment 
(i.e. electrocautery, ablation, surgical excision), and the subject will continue on the study 
without further biopsy. If HSIL remains based on the Week 64 biopsy results, the subject will 
receive standard of care and remain on the study for safety and follow up only. 
 
Immunogenicity Assessment: Humoral and cell mediated immune responses to VGX-3100 
may be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, and 88. Intra-anal and/or peri-anal tissue samples may also 
be analyzed for evidence of proinflammatory and immunosuppressive elements at Week 36 
as compared to baseline (Screening), where feasible. 
 
Virologic Assessment: Intra-anal and/or peri-anal swabs will be obtained to characterize 
HPV infection at Screening, Day 0, and Weeks 4, 15, 28, 36, 64 and 88. Likewise, PCR-
based assessment of histological samples will occur at Screening and Weeks 36 and 64. 
 

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Protocol Version Date:  22Jan2020 
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Page 20 of 88 
For testing of non-anal sites, vaginal, cervical (female subjects), penile (male subjects), and 
oropharyngeal (OP) samples (all subjects) will be obtained to characterize HPV infection at 
Day 0, and at Weeks 4,15, 28, 36, 64 and 88. 
 
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 Card (PCD). 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the 
duration of the study. 
 
All subjects will be followed to Week 88. 
 
Data Safety & Monitoring Board (DSMB): An independent 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. Refer to Section 3.8 for stopping rule criteria. 
 
Definition of Responder and Non-Responder: 
 
Responder and non-responder definitions (Table 2 through Table 7) take into account both 
histopathologic regression of anal or anal/peri-anal HSIL and virologic (HPV-16/18) clearance 
as measured by intra-anal and/or peri-anal tissue, since HPV persistence is an important 
factor in the clinical progression of HSIL. Any case of histologically confirmed progression 
from HPV-16/18 positive anal or anal/peri-anal HSIL to carcinoma according to the PAC is 
considered a non-responder. 
 
 
 
Table 2: Definition of Responder and Non-Responder for Composite Endpoint of 
Regression and Clearance 
Responder 
Non-Responder 
 
No histologic evidence of anal or anal/peri-anal HSIL  
 
AND 
 
Negative PCR for HPV-16 or HPV-18 in anal lesion 
tissue  
 
 
AND 
 
No non-study treatment of curative intent of intra-anal 
and/or peri-anal lesions 
 
 
 
Histologic evidence of anal or anal/peri-anal  HSIL, 
anal Adenocarcinoma-in-situ (AIS), anal or anal/peri-
anal carcinoma  
 
OR 
 
PCR positive for HPV-16 or HPV-18 in anal lesion 
tissue  
 
 
OR 
 
Any non-study treatment of curative intent of intra-anal 
and/or peri-anal lesions 
 
 
 
 
 
 
 

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Table 3: Definition of Responder and Non-responder for HSIL Regression Endpoint  
Responder 
Non-Responder  
No histologic evidence of anal or anal/peri-anal HSIL  
AND 
No non-study treatment of curative intent of intra-anal 
and/or peri-anal  
HSIL 
Histologic evidence of anal or anal/peri-anal HSIL or 
carcinoma at evaluation  
OR 
Any non-study treatment of curative intent of intra-anal 
and/or peri-anal HSIL  
 
 
Table 4: Definition of Responder and Non-responder for Viral Clearance Endpoint  
Responder 
Non-Responder  
No evidence of HPV-16 or HPV-18 in tissue/swab at 
evaluation  
AND 
No non-study treatment of curative intent of intra-anal 
and/or peri-anal  
HSIL 
Evidence of HPV-16 or HPV-18 in tissue/swab at 
evaluation  
OR 
Any non-study treatment of curative intent of intra-anal 
and/or peri-anal HSIL 
 
 
Table 5: Definition of Responder and Non-responder for Complete HSIL Regression 
Endpoint 
Responder 
Non-Responder  
No histologic evidence of anal or anal/peri-anal HSIL 
or LSIL  
AND 
No non-study treatment of curative intent of intra-anal 
and/or peri-anal  
HSIL 
Histologic evidence of anal or anal/peri-anal LSIL, 
HSIL or anal or anal/peri-anal carcinoma at evaluation  
OR 
Any non-study treatment of curative intent of intra-anal 
and/or peri-anal HSIL 
 
 
 
 
 
 
 
 

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Table 6: Definition of Responder and Non-responder for Disease Non-Progression 
Endpoint 
Responder 
Non-Responder  
No histologic evidence of a worsening anal or 
anal/peri-anal condition to anal or anal/peri-anal 
cancer relative to baseline 
 
AND 
No non-study treatment of curative intent of intra-anal 
and/or peri-anal  
HSIL 
Histologic evidence of worsening of anal or anal/peri-
anal condition to anal or anal/peri-anal cancer relative 
to baseline 
 
OR 
Any non-study treatment of curative intent of intra-anal 
and/or peri-anal HSIL 
 
 
Table 7:  Definition of Responder and Non Responder for Endpoint of Regression or 
Clearance 
Responder 
Non-Responder  
No histologic evidence of anal or anal/peri-anal HSIL 
on histology 
 
OR 
 
No evidence of HPV-16 and/or HPV-18 intra-anal 
and/or peri-anal lesion tissue 
AND 
No non-study treatment of curative intent of intra-anal 
and/or peri-anal HSIL  
Histologic evidence of anal or anal/peri-anal HSIL on 
histology 
 
AND 
 
Evidence of HPV-16/18 intra-anal and/or peri-anal 
lesion tissue 
 
OR 
 
Any non-study treatment of curative intent of intra-anal 
and/or peri-anal HSIL 
 
 
 
 
 
 
 
 
 

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Study Population: 
Inclusion: 
1. Must understand, agree and be able to comply with the requirements of the protocol 
and be able to provide voluntary consent to participate and sign an Informed Consent 
Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2a within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16 and/or HPV-18 infection at Screening by 
PCR from HSIL specimen; 
5. Anal tissue (blocks only) provided to the Study Pathology Adjudication Committee 
(PAC) for diagnosis must be collected within 10 weeks of first dose of VGX-3100; 
6. At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
a. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) should 
not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology collection 
procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
a. Post-menopausal as defined by spontaneous amenorrhea for more than 12 
months or spontaneous amenorrhea for 6-12 months with FSH level 
>40mlU/mL; 
b. Surgically sterile due to absence of ovaries or due to bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
c. Subject agreement to avoid pregnancy for one month after last dose (Week 12 
or Week 40); 
d. Women of Child Bearing Potential (WOCBP) are willing to use a contraceptive 
method with a failure rate of less than 1% per year when used consistently and 
correctly from Screening until one month following the last dose of 
investigational product (Week 12 or Week 40). The following are acceptable 
methods: 
i. Hormonal contraception: either combined progestin-alone including 
oral contraceptive, 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. Men who would father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, for 
the duration of study participation and one month after completion of VGX-3100 
administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 
a An HIV rapid test may be used given the following conditions are met: 1. The test is an antigen/antibody 
immunoassay, 2. The test is only done using blood, 3. The test must be performed in the office and done by qualified 
study staff members   

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Exclusion: 
1. Untreated micro invasive cancera; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAINb; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing medical 
care and/or treatment for VINb; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not undergoing 
medical care and/or treatment for CINb; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing medical 
care and/or treatment for PINb; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument; 
7. Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; 
8. Inability to have complete and satisfactory high resolution anoscopic exams (HRAs) 
as defined by full visualization of the anus, entire anal canal from the 
squamocolumnar junction at the border of the distal rectum, anal transformation zone, 
distal canal, anal verge, perianus;  
9. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
Screening; 
10. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
11. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 45 days prior to 
Day 0 or less than Grade 1 but deemed clinically significant by the Investigatorc; 
12. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed Autoimmune disease; 
b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) or oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 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. Prior chemotherapy within 1 year; 
f. History of solid organ or bone marrow transplantation; 
13. History of previous therapeutic HPV vaccination (however, licensed prophylactic HPV 
vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
14. Receipt of any non-study related non-live vaccine within 2 weeks before or after any 
VGX-3100 dose; 
15. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks 
before or after any VGX-3100 dose; 
16. Significant acute or chronic medical illness that could be negatively impacted by the 
electroporation treatment as deemed by the Investigator; 
17. 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 
the study results (e.g. chronic renal failure, angina, myocardial ischemia or 
infarctation, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 
 
a This criterion includes subjects who have microscopic or gross evidence of invasive cancer, or the suspicion of cancer 
in any histopathologic specimen by any pathologist at screening. 
b When observation is the standard of care this will not exclude a subject from the study. 
c If the lab is redrawn and the result from the redrawn sample no longer meets this exclusion criteria, then the subject is 
not excluded on the basis of this criterion 
 

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18. Treatment for non-anogenital malignancy within 2 years of Screening, with the   
exception of superficial skin cancers that only require local excision; 
19. 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; 
20. History of seizures unless seizure free for 5 years with the use of one or fewer 
antiepileptic agents; 
21. 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; 
22. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm 
at Screening or Day 0; 
23. Prior major surgery within 4 weeks of Day 0; 
24. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing informed consent form (participating in an observational 
study is permitted); 
25. 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 on the ipsilateral side (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); 
26. Any illness or condition that in the opinion of the Investigator may affect the safety of 
the subject or evaluation of any study product; 
27. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 personnel; 
d. Study-related staff or family members of study-related staff 
 

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TRIAL SCHEDULE OF EVENTS 
 
Table 8: Schedule of Events 
 
 
1 Subject eligibility will be reconfirmed at every visit. 
 
Study Action 
Screen  (-10 wk. to -1d) 
Day 0 
8-14 days post dose 1 Phone Call 
Week 4 (± 4 days) 
8-14 days post dose 2 Phone Call 
Week 12 (± 4 days) 
Week 15 (± 1 Week) 
Week 28 (± 1 Week)  
Week 36 (± 1 Week) 
Week 40 (± 1 Week) 
8-14 days post dose 4 Phone Call 
Week 64 (± 2 Weeks) 
Week 88 (± 2 Weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medications (prior/concomitant) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Socio-behavioral assessment 
X 
 
 
 
 
 
 
 
X 
 
 
Xn 
X 
Inclusion/Exclusion criteria1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam (PE)/assessment a 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
Xb 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Screening safety (12 lead ECG, 
laboratories) c  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d   
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
HIV Ab by ELISA 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Blood immunologic samples 
Xe 
Xe 
 
 
 
 
Xf 
 
Xe 
 
 
 
Xe 
Oropharyngeal (OP) rinse 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Vaginal, cervical, and penile swab 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Intra-anal and/or peri-anal swab 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Digital Anal Rectal Examination 
DARE g 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
High Resolution Anoscopy (HRA) h 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Lesion photography i 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
Biopsy j  
X 
 
 
 
 
 
 
 
X 
 
 
Xq 
 
Inject VGX-3100 +EPk   
 
X 
 
X 
 
X 
 
 
 
Xk 
 
 
 
Post 
treatment 
reaction 
assessment 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Distribute Participant Diary Card 
(PDC) 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
Review PDC l 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Patient Reported Outcomes 
(PROs) (SF-36v2™) (EQ-5D-5L)m 
 
Xo 
X 
X 
X 
X 
X 
 
X 
X 
Xp 
X 
X 

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a Full Physical exam (PE) mandatory at Screening and study discharge (Week 88), 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 body mass 
index (BMI) (Bodyweight in kilograms divided by height in meters squared). Weight will be 
collected at all dosing visits. 
c Screening 12-lead Electrocardiogram (ECG), complete blood count (CBC), serum electrolytes, 
blood urea nitrogen (BUN), creatinine (Cr), glucose, alanine aminotransferase (ALT), and 
Creatine Phosphokinase (CPK) performed within 45 days prior to first dose administration. 
d Negative spot urine pregnancy test is required for female subjects at Screening, prior to each 
study treatment, high-resolution anoscopy (HRA), and biopsy/surgical excision; the pregnancy 
test at Week 40 would only be needed for subjects who receive an additional dose. 
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 15. 
g Digital Anal Rectal Examinations (DARE) are to be performed once cytology has been 
collected and prior to HRA. 
h An additional visit may be scheduled to perform HRA if worsening of disease is suspected. 
Biopsies should not be performed at any visit other than at entry (Screening) and Weeks 36 
and 64 for Subgroup C unless the Investigator suspects invasive cancer. All biopsy samples 
and/or excision samples must be sent to the Pathology Adjudication Committee (PAC) for 
review. 
i Photography of qualifying lesion(s) must be performed prior to and after biopsy, and at all HRA 
examinations. If a pre-biopsy digital photograph is not available for a historical biopsy sample 
at Screening, a post biopsy photo will be sufficient. Photographs of intra-anal lesion(s) will be 
for documentation purposes only. All qualifying peri-anal lesion(s) will be assessed using the 
ruler provided. The ruler should be placed in the field of vision and should be documented with 
photography at Screening, Day 0, and Weeks 4, 15, 28, 36, 64, and 88. 
j Tissue specimen (paraffin blocks) from all excised tissue lesion(s) that led to eligibility at study 
entry must be reviewed by the PAC and residual tissue from entry and Weeks 36 and 64 
specimen(s) (paraffin blocks) must be sent to the central laboratory for immune analysis and 
Human Papillomavirus (HPV) testing.  
k Potential dosing at Week 40 is applicable for partial responders only.  
l A phone call will be used to review the Participant Diary Card (PDC) with subject within 8-14 
days following doses 1 and 2. The subject will be expected to bring the PDC to the next visits 
for review. Subjects who receive an additional 4th dose will also have a phone call 8-14 days 
post dose 4 where the PDC will be reviewed. The subject should bring the PDC to the next 
visit.  
m Patient-reported outcome (PRO) measures (SF-36v2™ andEQ-5D-5L, plus two additional 
"global" questions will be assessed as described in Section 6.13. 
n This socio-behavioral assessment will only apply to those subjects in Subgroup C who receive 
a 4th dose of investigational product. 
o PROs at this time point must be administered prior to first dose of study drug.  

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p PROs at this time point will only be for subjects who received a 4th dose of study drug. 
q   Under Protocol Amendment 3.0, in additional to HSIL lesion(s) found at Screening, all visible 
lesions should have biopsy obtained at Week 64 and sent to the central pathology lab for review 
by PAC. 
 

VGX-3100 
 
HPV-203 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  22Jan2020 
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Protocol Version: 3.0 
 
Page 29 of 88 
1.0 
INTRODUCTION 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized 
primarily in the ano-genital area and aero-digestive tract, in both men and women. 
Human Papillomavirus 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). In the United States (US), approximately 14 million new genital HPV infections 
occur annually, and approximately half of these infections are with a high-risk HPV type 
(HR-HPV) and thus can cause cancer [2]. In U.S. adults through age 59 years, about 
25% of men and 20% of women have genital HR-HPV infection [3]. Human 
Papillomavirus causes more cancers than any other virus. In U.S. archival tissues of 
cancers diagnosed from 1993 to 2005, HPV Deoxyribonucleic Acid (DNA) was detected 
in 68.8% of vulvar, 90.6% of cervical, 91.1% of anal, 75.0% of vaginal, 70.1% of 
oropharyngeal (OP), 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) [4]. An average of over 
30,000 cases per year of HPV-attributable cancer were diagnosed during the period 
2008 through 2012 in the U.S. [5]. Human Papillomavirus-16 and HPV-18 are the most 
significant among high-risk types since they are responsible for most HPV-caused 
cancers [4].  
With regard to anal cancer, about 95% of cases are caused by HPV, and most of those 
cases are caused by HPV-16 [6, 7]; with some by HPV-18 and perhaps other HPV 
genotypes [2]. An estimated 8,300 new cases of anal cancer in the US are diagnosed 
each year (for year 2017), with an estimated 1,280 deaths annually due to this cancer 
[8]. In Canada, the latest available data is for year 2013, during which 580 new cases of 
anal cancer were diagnosed and 144 persons died due to anal cancer [9]. 
The precursor lesion to HPV-associated anal cancer historically was known as anal 
high-grade dysplasia or intraepithelial neoplasia. In 2012, the Lower Anogenital 
Squamous Terminology (LAST) Standardization Project for HPV-associated lesions 
applied the term HSIL to encompass high grade dysplasia [10]. Among HPV-associated 
anal HSIL cases in the US, about 55% to 80% are associated with HPV-16/18, and 
worldwide about 80% of cases are associated with HPV-16/18 [7, 11, 12]. 
Left untreated, anal HSIL may progress to cancer. Spontaneous regression of these 
lesions may occur, but the available data indicate that such regression is in the minority 
of cases. For example, published results of a small observational study of anal HSIL in 
men who have sex with men (MSM) in Australia found spontaneous regression occurred 
in 29% of those HIV-negative after more than one year of follow-up time, with an even 
lower regression rate in those who were HIV-positive. That study also found that the 
majority (71%) of patients who regressed only did so to anal low-grade SIL (Low grade 
squamous intraepithelial lesion [LSIL]), with the remainder to normal tissue [13]. In an 
ongoing larger observational study of gay and bisexual men – the Study of the 
Prevention of Anal Cancer (SPANC) [14] -- also comprised of patients HIV-negative and 
HIV-positive (though with medically well-controlled CD4 cell counts), preliminary 
published data show that 55% of patients with anal HSIL, regardless of HIV status, had 
their HSIL persist to at least 12 months and HPV-16 was significantly associated with 
persistence as compared to other HPV genotypes (Relative Risk of 1.5) [15].  
 

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Spontaneous regression data from that study are not yet published, but preliminary data 
show spontaneous regression of only about 20% by one year of follow-up. Further, many 
of those patients who regressed later recurred to HSIL, suggesting that HSIL in some 
cases may be merely regressing to a level below the detection limit but is still present 
[16]. Other published data from a sub-study of that larger study indicate that HPV-16 E6-
specific T-cell responses may be associated with recent anal HSIL regression (Pexact = 
0.065) [17]. That finding provides further plausibility, in addition to other data 
summarized later in this protocol, that VGX-3100 plus electroporation treatment could 
cause anal HSIL regression. 
Anal HPV infection spontaneous clearance in non-immunocompromised adults can 
occur, but such data are generally unavailable for persons who have anal HSIL. 
Nevertheless, high-risk HPV (HR-HPV) clearance by one year ranges from 56% to 78%, 
varying by gender and sexual preference etc., as found in large, prospective studies [18-
20] with some wider variation in clearance rates for HPV-16 and HPV-18 specifically in 
those studies. 
Collectively, the aforementioned anal HSIL regression and HPV clearance data 
comprise in part the historical control data that the results of the present trial will be 
compared to. 
1.1.1 
VGX-3100 
VGX-3100 contains plasmids that target 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 (IP) designed as a non-surgical 
treatment of HPV-16/18-related anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, and 
PAIN3) via an immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was Water for Injection (WFI) with 1% w/w poly-L-
glutamate (WFI/LGS) that required frozen storage. This frozen formulation has been 
administered to more than 250 subjects in Phase 1 and 2 clinical trials. A buffered 
formulation of VGX-3100 was developed using a saline sodium citrate (SSC) solution, 
which is stored non-frozen (5°C). This non-frozen formulation of VGX-3100 was 
administered to 117 subjects in a Phase 1 clinical trial, HPV-101 in which subjects were 
randomized 1:1 to receive the non-frozen or frozen formulation of VGX-3100. In study 
HPV-101, healthy adults received three 6 mg IM doses of VGX-3100 in the frozen or 
non-frozen formulations followed by EP with the CELLECTRA™ 5Pdevice. The non-
frozen formulation was found to be non-inferior to the frozen formulation based upon a 2-
fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the plasmids 
per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ enzyme-linked immunospot (ELIspot) assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, 
placebo-controlled Phase 2b study of VGX-3100 (frozen formulation) followed by EP in 
the treatment of high grade cervical dysplasia, cervical HSIL associated with HPV-16/18 
[1]. The Phase 2b study, HPV-003, enrolled 169 subjects with high grade cervical 
dysplasia from seven countries and one US Territory (Australia, Canada, Estonia, 
Republic of Georgia, India, South Africa, US and Puerto Rico). Subjects were 
randomized in a 3:1 ratio to treatment with VGX-3100 or placebo, respectively. All 

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subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to 
repeat cervical biopsy or Loop Electrical Excision Procedure (LEEP) of the cervix at 
Week 36 to assess efficacy defined as regression of high grade Cervical Intraepithelial 
Neoplasia (CIN) by histopathology. The primary endpoint was histopathologic regression 
of cervical lesions (CIN2 or CIN3) to Grade 1 Cervical Intraepithelial Neoplasia (CIN1) or 
less at the Week 36 visit. A secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less. The 
proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol (PP) and modified Intent 
to Treat (mITT) analyses. Robust T-cell activity was detected in VGX-3100 recipients 
compared to placebo recipients. VGX-3100 was generally safe and well tolerated when 
administered intramuscularly with electroporation. 
1.1.2 
ELECTROPORATION 
CELLECTRA® 2000 & CELLECTRA™ 5PSP are both electroporation (EP) devices 
developed by INOVIO. Electroporation with CELLECTRA™5PSP is a physical method of 
tissue transfection whereby the generation of short, controlled electrical pulses creates a 
localized electrical field at the injection site which increases cell membrane permeability 
and improves the transfection of DNA and subsequent immunogenicity [21, 22]. EP is 
believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced immunogenicity by 10 to 100 fold [23, 24]. 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 [21]. The CELLECTRA™ device developed by INOVIO is used for 
investigational purposes to administer plasmid-based DNA, in both prophylactic and 
therapeutic settings. Following successful proof-of-concept studies in animals, INOVIO 
has optimized both pulse pattern and voltage to increase transfection efficiency, and has 
demonstrated that the device helps to elicit favorable immunogenicity in several species 
(e.g., mice, pigs, and rhesus macaques) [22, 23]. 
A next generation device, CELLECTRA™ 5PSP, was created to address ergonomic 
functionality and automate the delivery of VGX-3100 and EP. The technology differences 
between the CELLECTRA® 2000 and CELLECTRA™ 5PSP design do not affect the 
intended mechanism of EP on the activity of VGX-3100 and will not present any new 
risks. The device design change does not affect the indications for use, operating 
principle, energy type, or sterilization specifications. The CELLECTRA™ 5PSP has been 
approved for investigational use in the U.S. with VGX-3100 and is being used in a Phase 
3 clinical study HPV-301, titled "A Prospective, Randomized, Double-blind, Placebo-
Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly (IM) followed by 
Electroporation with CELLECTRA™ 5PSP for the Treatment of HPV-16/18 related HSIL 
of the Cervix". Together, VGX-3100 and the CELLECTRA™ device represent an 
integrated product designed as a non-surgical treatment for HPV-16/18-related cervical 
HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18.  
Inovio Pharmaceuticals Inc. device experience demonstrates that delivery of its 
proprietary electroporation pulses into muscle immediately following injection of DNA 
plasmids (including VGX-3100) is well-tolerated in humans and no significant safety 
issues have been identified [1, 22, 24]. For further information concerning the 
CELLECTRA™ 5PSP device please refer to the User Manual and the Investigator's 
Brochure. 

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1.1.3 
DOSE RATIONALE 
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 the 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. 
This dose-trend was consistent with prior expectation, a feature of the finding that 
suggests it is a true effect rather than random variation. Adverse events (AEs) from 
previous human studies with VGX-3100 and closely related DNA plasmid products have 
been limited to injection site pain from the injection and electroporation procedure, which 
were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in HPV-003, 
Phase 2b study. The results obtained in the phase HPV-003 suggest that the 6 mg dose 
was efficacious with an acceptable safety profile, therefore the 6 mg dose will also be 
evaluated in this Phase 2 trial [1]. 
1.2 
POTENTIAL BENEFITS 
Currently accepted surgical treatments are associated with a high recurrence rate, 
>50%. The current surgical approaches also have risks inherent with any surgical 
procedure including anesthesia, post-operative bleeding, infection, or damage to 
surrounding structures such as the anus. This study has been designed to provide non-
surgical treatment with an aim of regression of the anal or anal/peri-anal HSIL and thus 
avoiding the need for surgical excision, infrared coagulation, electrocautery and laser 
therapy. In the absence of complete resolution of intra-anal and/or peri-anal lesions, 
there would still be potential benefit from a partial response, which would reduce or 
minimize the need for excisional or ablative treatment modalities. 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. Consequently, there is the potential to reduce the risk 
of recurrence of anal or anal/peri-anal HSIL. 
1.3 
POTENTIAL RISKS 
Risks associated with VGX-3100 for the treatment of anal or anal/peri-anal HSIL are 
injection site reactions related to the IM injection and/or electroporation. Based on the 
phase 1 and 2 clinical experience with VGX-3100 with healthy volunteers and in women 
with cervical HSIL, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at 
most. 
A potential risk is the delay of surgical intervention of the high grade anal dysplasia and 
possible missed diagnosis of an occult early invasive cancer for the VGX-3100 non-
responders, who do not spontaneously regress. Although professional guidelines 
typically advocate excisional therapy for adults with HSIL, scientific data indicates that 
the rate of progression from pre-invasive to invasive cervical disease is slow, typically 
thought to take several years [10]. The risk of a missed diagnosis of an occult early 
invasive cancer exists for all current treatment modalities including surgical and ablative 
therapies. To mitigate these potential risks the study design includes numerous 
safeguards to detect disease progression or the presence of an undiagnosed occult 

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early invasive cancer. These include, careful selection of immunocompetent patients, 
thorough screening and baseline evaluation, frequent High-resolution anoscopy (HRA) 
and high-risk HPV testing throughout the trial. Investigators will be comprised of 
experienced physicians, who will have the discretion to obtain biopsies at any point if 
disease progression is suspected. 
An independent Data and Safety Monitoring Board (DSMB) will also advise the Sponsor 
if it appears that the frequency of regression is unacceptably low. These measures 
should minimize the risk of progression of the HSIL and the risk of harboring an 
undiagnosed occult early invasive cancer.  
In the HPV-003 study of women with cervical HSIL, the percentage of subjects with 
micro-invasive cancer found in larger surgical excision samples in subjects who had no 
evidence of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is 
consistent with and even lower than the 6.7% that has been reported under standard of 
care settings [18]. 
For further information concerning the risks associated with VGX-3100 and the 
CELLECTRA™5PSP device please refer to the Investigator's Brochure. 
2.0 
PURPOSE AND HYPOTHESIS 
2.1 
PURPOSE 
To provide a treatment to potentially regress and clear HPV-16/18 related anal or 
anal/peri-anal HSIL in individuals that are seronegative for HIV-1/2. 
2.2 
HYPOTHESIS 
VGX-3100 followed by electroporation (EP) administered to adults with histologically 
confirmed anal or anal/peri-anal high-grade squamous intraepithelial lesions, HSIL, 
(AIN2, AIN3, PAIN2, PAIN3) associated with HPV-16/18 will result in a higher proportion 
with histopathologic regression of intra-anal and/or peri-anal HSIL lesions to no evidence 
of anal or anal/peri-anal HSIL and virologic clearance of HPV-16 and/or 18 than 
historical controls. 
3.0 
TRIAL DESIGN AND ENDPOINTS 
HPV-203 is a Phase 2, 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 
in adult men and women who are HIV negative with histologically confirmed anal or 
anal/peri-anal HSIL associated with HPV-16 and/or 18. Approximately 24 subjects will 
receive at least 3 doses of VGX-3100. Each dose of VGX-3100 will be administered in a 
1 mL volume IM followed immediately by EP. As shown in Figure 1, study subjects will 
receive at least 3 doses of VGX-3100 depending upon their disposition with regard to 
histologic and lesion area changes during the trial. The first dose will be administered on 
Day 0, the second at Week 4, and the third at Week 12. Partial response to VGX-3100 
may still be of medical importance by being able to limit the extent of surgery necessary. 
For partial responders at Week 36, a fourth dose may be administered at Week 40. All 
subjects are scheduled to be followed to Week 88.  
To be eligible for the study, subjects must consent to participate and agree to the 
collection of anal lesion tissue samples for anal cytology and genotyping, a Digital Anal 
Rectal Examination (DARE), blood samples for immunologic) assessments, HRA and 

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HRA guided biopsies. All intra-anal and/or peri-anal lesion(s) of adequate size (≥ 4mm) 
will be biopsied at Screening. 
Biopsy slides 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 anal or anal/peri-anal HSIL (AIN2, AIN3, PAIN2, PAIN3) based on the 
biopsy sample(s). Once the PAC confirms HSIL at Screening, the Week 36 and 
64biopsies will be obtained from all HSIL site(s) confirmed by the PAC at Screening, 
unless the Investigator suspects disease progression. In addition to HSIL lesions 
confirmed at Screening, all visible lesions should also have biopsy obtained at Week 64 
and sent to central pathology lab for review by PAC. Subjects must also have intra-anal 
and/or peri-anal lesion tissue 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 administered and will include the Short Form Health Survey 
version 2 (SF-36v2™), the EQ-5D-5L (EuroQol Research Foundation), and additional 
PRO questions assessing quality of life after surgery or biopsy. 
3.1 
PRIMARY OBJECTIVE(S) 
Determine the efficacy of 3 doses of VGX-3100 with respect to combined histopathologic 
regression of anal or anal/peri-anal HSIL and virologic clearance of HPV-16/18 
3.2 
PRIMARY ENDPOINT(S) 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal HSIL on 
histology (i.e., collected via biopsy or excisional treatment) and no evidence of HPV-
16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue 
3.3 
SECONDARY OBJECTIVE(S) 
 
Evaluate the safety and tolerability of VGX-3100 delivered IM followed by EP 
 
Determine the efficacy of three doses of VGX-3100 as measured by histologic 
regression of anal or anal/peri-anal HSIL  
 
Determine the efficacy of three doses of VGX-3100 as measured by virologic 
clearance of HPV-16 and/or HPV-18 by testing from lesion tissue  
 
Determine the efficacy of three doses VGX-3100 as measured by virologic 
clearance of HPV-16 and/or HPV-18 by intra-anal swab testing  
 
Determine the efficacy of three doses of VGX-3100 as measured by complete 
histopathologic regression of anal or anal/peri-anal HSIL to normal tissue  
 
Determine the efficacy of three doses of VGX-3100 as measured by 
histopathologic non-progression of anal or anal/peri-anal HSIL  
 
Describe the efficacy of VGX-3100 for partial responders, as measured by 
reduction in the number of intra-anal and/or peri-anal lesion(s), as applicable and 
the reduction in the size of peri-anal qualifying lesion(s), if present, and for whom 
the disease has not progressed according to Investigator judgment in subjects 
who did not have anal or anal/peri-anal HSIL lesion resolution at Week 36 
 
Determine the cellular immune response following administration of VGX-3100 at 
post dose 3, and after additional dosing compared to baseline 

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 
Determine the efficacy of three doses of VGX-3100 with respect to 
histopathological regression of anal or anal/peri-anal HSIL or virologic clearance 
of HPV-16 and/or HPV-18  
 
3.4 
ASSOCIATED SECONDARY ENDPOINT(S) 
 
Local and systemic events for 7 days following each dose as noted in the 
Participant Diary Card (PDC) 
 
All AEs including Serious Adverse Events (SAES), unanticipated (serious) 
adverse device effect (UADE), and other unexpected AEs for the duration of the 
study (through the Week 88 visit) 
 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (e.g. biopsies or excisional treatment) at  Week 36  
 
Proportion of subjects with no evidence of HPV-16 and/or HPV-18 from intra-
anal and/or peri-anal tissue by type specific HPV testing at Week 36 
 
Proportion of subjects with no evidence of HPV-16 and/or HPV-18 from intra-
anal swab by specific HPV testing at the Weeks 36 
 
Proportion of subjects with no evidence of anal or anal/peri-anal LSIL or HSIL 
(i.e. no evidence of AIN2, AIN3, PAIN2, and PAIN3) on histology (i.e. biopsies or 
excisional treatment) at Week 36 
 
Proportion of subjects with no progression of anal or anal/peri-anal HSIL to 
carcinoma from baseline on histology (i.e. biopsies or excisional treatment) 
atWeek 36 
 
Percent reduction in the number of qualifying intra-anal and/or peri-anal 
lesion(s) and the size of peri-anal lesion(s) if present, as determined by the 
Investigator at Weeks 36, 64, and 88 compared to baseline. 
 
Flow Cytometry response magnitudes at baseline and Week 15  
 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal 
HSIL on histology (i.e., collected via biopsy or excisional treatment) or no 
evidence of HPV-16/18 at Week 36 from intra-anal and/or peri-anal lesion tissue  
 
3.5 
EXPLORATORY OBJECTIVE(S) 
 
Describe the long term efficacy of VGX-3100 with respect to combined 
histopathologic regression of anal or anal/peri-anal HSIL and virologic 
clearance of HPV-16 and/or HPV-18  
 
Describe the long term efficacy  of VGX-3100, as measured by histologic 
regression of anal or anal/peri-anal HSIL  
 
Describe the long term efficacy of VGX-3100, as measured by virologic 
clearance of HPV-16 and/or HPV-18 by testing from lesion tissue 
 
Describe the long term efficacy of VGX-3100, as measured by virologic 
clearance of HPV-16 and/or HPV-18 by intra-anal swab testing 

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 
Evaluate tissue immune responses to VGX-3100 in intra-anal and/or peri-anal 
samples 
 
Describe the clearance of HPV-16 and/or HPV-18 infection from non-anal 
anatomic locations 
 
 
Describe the association of microRNA (miRNA) profile, previous anoscopy, 
cytology and HPV testing results with Week 36 histologic regression 
 
Describe the patient reported outcomes (PRO) for subjects treated with VGX-
3100 
 
Determine the humoral and cellular immune response following administration of 
VGX-3100 at post dose 3, and after additional dosing compared to baseline 
 
Determine the long term efficacy of VGX-3100 with respect to histopathologic 
regression of anal or anal/peri-anal HSIL or virologic clearance of HPV-16 and/or 
HPV-18 
 
3.6 
ASSOCIATED EXPLORATORY ENDPOINT(S) 
 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal 
HSIL on histology (i.e. collected via biopsy or excisional treatment) and no 
evidence of HPV-16 and/or HPV-18 at Week 64 by testing from intra-anal and/or 
peri-anal lesion tissue  
 
Proportion of subjects with no evidence of anal or anal/peri-anal HSIL on 
histology (i.e. biopsies or excisional treatment) at Week 64  
 
Proportion of subjects with no HPV-16 and/or HPV-18 at Week 64 by testing 
from intra-anal and/or peri-anal lesion tissue  
 
Proportion of subjects with no evidence of HPV-16 and/or HPV-18 from intra-
anal swab by specific HPV testing at Week 64 and Week 88Assessment of 
proinflammatory and immunosuppressive elements in tissue, where feasible.  
 
Proportion of subjects who have cleared HPV-16 and/or HPV-18 on specimens 
from non-anal anatomic locations as applicable based upon gender (i.e. 
oropharynx, cervical, vaginal, and penile at Week 36 ) 
 
HRA, cytology, and HPV test results and miRNA profile (baseline and at Weeks 
15, 28, and 36) in conjunction with histologic regression of anal or anal/peri-anal 
HSIL at Week 36 
 
Patient reported outcome endpoints prior to first dose (Day 0), on the day of and 
following each dose, and at Weeks 36, 64, and 88. There will be an additional 
PRO assessment at Week 40 if a subject receives a 4th dose. 
 
Levels of serum anti-HPV-16 and anti-HPV-18 antibody (Ab) concentrations at 
baseline and  Weeks 15, 36, 64, 88 visits 
 
Interferon- γ ELISpot response magnitudes at baseline, and Weeks 15, 36, 64, 
and 88 
 
Proportion of subjects with no histologic evidence of anal or anal/peri-anal 
HSIL on histology (i.e., collected via biopsy or excisional treatment) or no 

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evidence of HPV-16 and/or HPV-18 at Week 64 from intra-anal and/or peri-anal 
lesion tissue  
 
3.7 
EFFICACY ASSESSMENT 
Screening biopsies will be collected from all intra-anal and/or peri-anal lesions of 
adequate size (≥ 4mm). Visible lesions observed during HRA should be large enough to 
biopsy, but the biopsy (typically 4mm) should not remove the entire lesion in order to 
allow for continued lesion measurement while on the study.  
Given that HPV infection persistence is a critical factor in the clinical progression of 
HPV-associated anal or anal/peri-anal HSIL and also based upon the findings of the 
secondary objective of the HPV-003 CIN2/3 proof of concept study, the responder 
definition for the HPV-203 primary endpoint determination requires both histological 
regression of anal or anal/peri-anal HSIL and clearance of HPV-16 and HPV-18 [1]. 
Regression of anal or anal/peri-anal HSIL will be determined by histopathologic 
assessment of intra-anal and/or peri-anal tissue obtained from biopsies. All intra-anal 
and/or peri-anal lesion(s) of adequate size (≥ 4mm) will be biopsied at Screening. Once 
the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be obtained from 
all HSIL site(s) confirmed by the PAC at Screening, unless the Investigator suspects 
disease progression. In additional to HSIL lesion(s) found at Screening, all visible lesions 
will have biopsy obtained at Week 64 and sent to the central pathology lab for review by 
PAC. Tissue will be analyzed for evidence of histopathologic regression. Clearance of 
HPV-16/18 will be determined using the by type specific HPV polymerase chain reaction 
(PCR) test on intra-anal and/or peri-anal tissue performed at Screening and Weeks 36 
and 64 when applicable. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0 (prior to dosing) 
and Weeks 4, 15, 28, 36, 64 and 88 as a less invasive measure for exploratory purposes 
to determine the presence of HPV-16 and/or -18 as well as other high risk HPV types 
using HPV testing. Similarly, vaginal, cervical (female subjects), penile (male subjects) 
and OP rinse samples (all subjects) will be obtained at Day 0 (prior to dosing), and at 
Weeks 4, 15, 28, 36, 64, and 88 to assess systemic virologic response to treatment. 
If after evaluation of the biopsy tissue at Week 36, HSIL remains, but there is a reduction 
in intra-anal and/or peri-anal lesion(s) number and no increase in peri-anal lesion(s) size 
from baseline (Subgroup C, Figure 2), the Investigator will have the option to administer 
a 4th dose of VGX-3100 at Week 40 and the subject will continue on the study with HRA 
and biopsy at Week 64, i.e. the second efficacy checkpoint. Alternatively, the 
Investigator may choose to treat the subject with standard of care treatment (i.e. 
electrocautery, ablation, surgical excision), and the subject will continue on the study 
without further biopsy unless it is part of the standard of care. If HSIL remains based on 
the Week 64 biopsy results, the subject will receive standard of care and remain on the 
study for safety and follow up only. All tissue samples obtained from biopsies or 
removed per standard of care will be sent to the PAC for review. 
3.8 
SAFETY ASSESSMENT 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each VGX-3100 dose as noted in the 
PDC. 

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2) All AEs including SAEs, UADEs, and for the duration of the study. 
All subjects will be followed for 88 weeks. 
Data Safety & Monitoring Board (DSMB): An independent 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:Stopping Rules 
(Criteria for Pausing of Study) 
 
If at any time during a study one-third (1/3) or more of the subjects experience an 
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 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, 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 
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, Principal 
Investigator 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, 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. 
  
Guidelines for assessing clinical abnormalities are in Section 7.0 in general and in Table 
11 provided in Section 6.1.2. 
 
Guidelines for assessing relatedness are detailed in Section 7.7. 
 
3.9 
IMMUNOGENICITY ASSESSMENT 
Cellular mediated immune responses in response to VGX-3100 treatment  will be 
evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior to 
dosing) and at Week 15. Intra-anal and/or peri-anal tissue samples may also be 
analyzed for evidence of proinflammatory and immunosuppressive elements at Week 36 
as compared to baseline (Screening), where feasible. 

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4.0 
TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
1. Must understand, agree and be able to comply with the requirements of the 
protocol and be able to provide voluntary consent to participate and sign an 
Informed Consent Form (ICF) prior to study-related activities; 
2. Age 18 years and above; 
3. Negative screening test for HIV-1/2a within 30 days of Dose 1; 
4. Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by PCR from 
HSIL specimen; 
5. Anal tissue (blocks only) provided to the Study PAC for diagnosis must be 
collected within 10 weeks of first dose of VGX-3100; 
6. At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is 
histologically-confirmed as HSIL by the PAC at Screening; 
i. The lesion needs to be large enough to biopsy, but the biopsy (≥4mm) 
should not remove the entire lesion in order to allow for continued lesion 
measurement while on the study; 
7. Investigator judges the subject to be an appropriate candidate for histology 
collection procedures (i.e. excision or biopsy); 
8. Female subjects, must meet one of the following criteria with respect to their 
reproductive capacity: 
i. Post-menopausal as defined by spontaneous amenorrhea for more than 
12 months or spontaneous amenorrhea for 6-12 months with follicle-
stimulating hormone (FSH) level >40mlU/mL; 
ii. Surgically sterile due to absence of ovaries or due to a bilateral tubal 
ligation/occlusion performed more than 3 months prior to Screening; 
iii. Subject agreement to avoid pregnancy one month after last dose of IP 
(Week 12 or Week 40); 
iv. Women of Childbearing 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 one month following 
the last dose of IP (Week 12 or Week 40). The following are acceptable 
methods: 
1. 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); 
2. Abstinence from penile-vaginal intercourse when this is the 
subject's preferred and usual lifestyle; 
3. Intrauterine device or intrauterine system; 

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a An HIV rapid test may be used given the following conditions are met: 1. The test is an antigen/antibody 
immunoassay, 2. The test is only done using blood, 3. The test must be performed in the office and done by 
qualified study staff members   
4. 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. Men who could father a child must agree to use at least one form of birth control 
during or continued abstinence from heterosexual intercourse prior to the study, 
for the duration of study participation and one month after completion of VGX-
3100 administration; 
10. Normal Screening electrocardiogram (ECG) or Screening ECG with no clinically 
significant findings as judged by the Investigator 
 
 
 
 
4.2 
EXCLUSION CRITERIA 
1. Untreated micro invasive or invasive cancera; 
2. Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and are not undergoing 
medical care and/or treatment for VAINb; 
3. Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and are not undergoing 
medical care and/or treatment for VINb; 
4. Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and are not 
undergoing medical care and/or treatment for CINb; 
5. Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and are not undergoing 
medical care and/or treatment for PINb; 
6. Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy 
instrument; 
7.   Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at 
Screening;8.Inability to have complete and satisfactory high resolution anoscopic 
exams (HRAs) as defined by full visualization of the anus, entire anal canal from 
the squamocolumnar junction at the border of the distal rectum, anal 
transformation zone, distal canal, anal verge, perianus; 
8. Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of 
Screening; 
9. Pregnant, breast feeding or considering becoming pregnant within one month 
following the last dose of VGX-3100; 
10. Presence of any abnormal clinical laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v4.03 within 45 days prior 
to Day 0 or less than Grade 1 but deemed clinically significant by the 
Investigatorc; 
11. Immunosuppression as a result of underlying illness or treatment including: 
a. Any prior history of other clinically significant immunosuppressive or 
clinically diagnosed Autoimmune disease; 

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b. Any primary immunodeficiency; 
c. Long-term use (≥7 days) of oral or parenteral glucocorticoids at a dose of 
≥20 mg/day of prednisone equivalent (use of inhaled, otic, nasal, topical, 
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 Tumor Necrosis Factor 
(TNF)-α inhibitors (e.g. infliximab, adalmumab or etanercept); 
e. Prior chemotherapy within 1 year; 
f. 
History of solid organ or bone marrow transplantation; 
12. History of previous therapeutic HPV vaccination (however, licensed prophylactic 
HPV vaccines are allowed, e.g. Gardasil®9, Gardasil®, Cervarix®); 
13. Receipt of any non-study related non-live vaccine within 2 weeks before or after 
any VGX-3100 dose; 
14. Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 
weeks before or after any VGX-3100 dose; 
15. Significant acute or chronic medical illness that could be negatively impacted by 
the electroporation treated as deemed by the Investigator; 
16. 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 (e.g. chronic renal failure, angina, myocardial ischemia or 
infarction, class 3 or higher congestive heart failure, cardiomyopathy, or clinically 
significant arrhythmias); 
17. Treatment for non-anogenital malignancy within 2 years of Screening, with the 
exception of superficial skin cancers that only require local excision; 
18. Bleeding or clotting disorder or use of blood thinners (e.g. anticoagulants or 
antiplatelet drugs) that would contraindicate IM injections within 2 weeks of a 
study dose;  
19. History of seizures unless seizure free to 5 years with the use of one or fewer 
antiepileptic agents; 
20. 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; 
21. Resting heart rate <50 beats per minute (bpm) (unless attributable to athletic 
conditioning) or >100 bpm at Screening or Day 0; 
22. Prior major surgery within 4 weeks of Day 0; 
23. Participated in an interventional study with an investigational compound or device 
within 4 weeks of signing the ICF (participation in an observational study is 
permitted); 
24. Less than two acceptable sites available for IM injection considering the deltoid 
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a. Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
treatment site; 
b. Cardioverter-defibrilator or pacemaker on the ipsilateral side (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); 
25. 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; 
26. Vulnerable Populations: 
a. Drug (i.e. prescription or illicit) 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 (involuntary incarcerated) 
for treatment of either a psychiatric or physical (i.e. infectious disease) 
illness; 
c. Active military service personnel; 
d. Study-related staff or family members of study-related staff 
a This criterion includes subjects who have microscopic or gross evidence of invasive cancer, or the suspicion of 
cancer in any histopathologic specimen by any pathologist at screening. 
b  When observation is the standard of care this will not exclude a subject from the study. 
                            c If the lab is redrawn and the result from the redrawn sample no longer meets this exclusion  criteria, then the 
subject is not excluded on the basis of this criterion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.3 
DISCONTINUATION/WITHDRAWAL OF TRIAL SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION FROM THE STUDY 
Subjects who manifest a Grade 4 toxicity attributable to the study treatment will be 
discontinued from further treatment with VGX-3100. Subjects will not receive further 
doses of VGX-3100 followed by 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 VGX-3100/EP, the medical 
monitor and PI will discuss whether further treatment should be continued for that 
subject. 
4.3.2 
CRITERIA FOR WITHDRAWAL FROM STUDY 
Subjects who become ineligible to continue on the study based on no longer meeting the 
inclusion criteria should be discontinued from study treatment and managed per routine 
standard of care but should continue on the study without further biopsy.  
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 anal or anal/peri-anal HSIL, 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 the subject 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 they 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 8). 
At a minimum, the Investigator should make every effort to have the subject complete all 
assessments designated for the discharge visit (Week 88). A subject will be considered 
to have completed the study when he/she completes all scheduled study treatments and 
follow-up visits. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/WITHDRAWAL 
The Investigator or trial coordinator must notify the Sponsor immediately when a subject 
has been discontinued/withdrawn due to an AE. If a subject discontinues from the trial or 
is withdrawn from the trial prior to trial completion, all applicable activities scheduled for 
the final trial visit should be performed at the time of discontinuation. 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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4.3.4 
REASONS 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 of a subject, (including manner of death if known) 
 
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 subject. 
Investigator must consult the Medical Monitor before withdrawing a subject from 
participation in the study. 
 
Protocol Deviation: 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. 
 
Other: The subject was terminated for a reason other than those listed above, 
such as the termination of the study by the Sponsor. 
If more than 10% of subjects who receive study treatment and discontinue prior to Week 
36, primary endpoint procedures, then supplementation of study subjects will be 
considered. 
 
5.0 
TRIAL TREATMENT 
5.1 
INVESTIGATIONAL BIOLOGIC PRODUCT  
The IP to be used in this trial is described in Table 9. The IP will be presented in a clear 
glass cartridge and injected intramuscularly. 

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Table 9: Investigational Biologic Product 
5.2 
CELLECTRA™ 5PSP DEVICE DESCRIPTION: 
VGX-3100 will be delivered using the CELLECTRA™5PSP device. The device consists 
of five (5) main components (see Figure 3). 
Figure 3: CELLECTRA™ 5PSP Base Station with Handset 
 
 
Base Station 
The base station communicates instructions, alerts, and error messages to the user through a 
touch screen graphical user interface (GUI). It also accepts data inputs from the user, e.g., 
patient identification code, height, and weight; it communicates with the handset; provides 
energy access for the system through connection with standard wall electrical power supply 
sources (100-220V, ~0.5Amp, 50-60Hz); and serves as a docking and recharging station for the 
handset.   
Handset 
The handset facilitates delivery of the needles for injection and electroporation into the muscle 
tissue and executes the treatment sequence (drug injection, impedance check, and 
electroporation pulses). It has a display screen and speakers for user feedback and an 
embedded processor for running the system software that controls and measures all of the 
elements of the handset. The handset is powered by a custom, rechargeable battery pack that 
has its own safety circuit and is compliant to International Ethics Committee (IEC) 62133 and UL 
2054. The handset is designed with three independent fail-safes to minimize the risk of electrical 
shock, short, or fire. 

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Array 
The array is a single-use, sterile, disposable component constructed of commonly-used medical 
plastics and metals, with 5 fixed, stainless-steel electrodes (needles) and 1 IM injection needle. 
The needles are covered by a plastic shroud that retracts as the needles are inserted into the 
patient, then returns to the starting position as the needles are removed and locks out to prevent 
accidental needle sticks. The opposite end of the array accepts the drug cartridge, which is 
inserted cap-end-first until the bottom of the cartridge is flush with the opening of the array 
(indicated by an audible 'click'). When properly inserted, the septum is punctured and the 
cartridge cannot be removed. The 5PSP Array features no software. 
The base station and handset with the 5PSP Array are illustrated in  Figure 3). 
Figure 3. 
5.3 
TREATMENT REGIMEN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the 
HPV-003 study, therefore all eligible subjects who consent to participate in the HPV-203 
study will receive the same three 6 mg doses of VGX-3100 administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment will 
be administered on Day 0, the second at Week 4, and the third at Week 12.  A fourth 
dose may be administered at Week 40. 
The first study treatment will be given as soon as possible following confirmation of anal 
or anal/peri-anal HSIL diagnosis and HPV-16/18 status but no more than 10 weeks 
following collection of the subject's biopsy specimen used for diagnosis by the PAC 
during Screening, concurrent with the positive testing for HPV-16/18. 
5.4 
PACKAGING AND HANDLING 
Each cartridge will be labeled with a single-panel label and then individually packaged 
within a pouch that will contain an additional, single-panel label with tear-off. The VGX-
3100 label will include, at minimum, the following information in Table 10. 
Table 10: Example of Packaging and Label Information 
Cartridges 
(primary container) 
Pouches 
(secondary packaging) 
 
 
 
 
LABEL 
 
VGX-3100 
Insert cap end 
Sponsor name 
IM administration 
Investigational Use Only 
LABEL BODY 
Study ID 
VGX-3100 
Single-use cartridge containing 1 mL 
IM administration via CELLECTRA™ 5PSP 
Store at 2-8°C, expiration date 
Caution Statement 
Sponsor name and address 
LABEL TEAR OFF 
Study ID 
VGX-3100 
Patient ID: _________ 
Date: (DD-MMM-YYYY): __________ 
 
Must be used by (time): _________ 

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See Figure 4 below for example of CELLECTRA™ 5PSP device component labels. 
 
Figure 4: Examples of Device Labels (Base, Handset, Array, Outer Box) 
 
Base Station Label 
Handset Label 
 
5PSP Array Label 
 
 

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Outer Box Packaging Label 
 
 
 
5.5 
HANDLING AND STORAGE OF IP AND DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure 
location according to the instructions in the User Manual. The CELLECTRA™ 5PSP 
device and its components must be stored between the temperature ranges 55.4°F-
91.4°F and kept dry. The Sponsor should be notified of any deviations from this 
recommended storage condition. For the specific temperature guidelines for storing, 
please refer to the CELLECTRA™ 5PSP User Manual. 
Unless otherwise specified, IP will be shipped in a refrigerated condition with a 
temperature monitoring device. If the temperature monitoring device records 
temperatures outside the pre-specified range for any product, the Sponsor, or its 
designee should be contacted immediately.  
5.6 
PREPARATION AND DISPENSING 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 
°C (36-46 °F) storage, in a secure area, according to local regulations. Refrigerator 
temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. The Sponsor should be notified of any deviations from 
this recommended storage condition. Inovio Pharmaceuticals Inc. will be responsible for 
assuring the quality of the IP is adequate for the duration of the trial. Preparation and 
Dispensing 
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. 
When a subject is eligible, remove the pouch from the refrigerator and allow to reach 
room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. 
The pouch must not be discarded until: 
1. Administration is completed and 
2. All pertinent information from the pouch label has been documented in source. 

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The product must be used within 4 hours of removal from the refrigerator. If VGX-3100 is 
not used within this timeframe it must be discarded after reconciliation. 
5.7 
USE OF CELLECTRA™5PSP DEVICE 
The instructions for use of the CELLECTRA™ 5PSP are located in the CELLECTRA™ 
5PSP User Manual. Users of the CELLECTRA™ 5PSP device must successfully 
complete training before using the device. Training will include review of the entire 
device user manual as well as hands-on training. After training on the proper use of the 
CELLECTRA™ 5PSP device, the intended users at each site will be required to 
demonstrate their competency in its use to INOVIO personnel or its designee. An 
instructional video has been prepared for review by site personnel on an as needed 
basis. Refer to the User Manual for further instruction. 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 
DRUG AND DEVICE ACCOUNTABILITY 
5.8.1 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of IP 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; 
 
Date and initials of person responsible for each IP 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 
5.8.2 
CELLECTRA™ 5PSP DEVICE ACCOUNTABILITY 
The site is responsible for maintaining the device. The device must have full traceability 
from receipt of the products through the subject use, and the return of the device. The 
site must document acknowledgement of receipt and then notify INOVIO upon receipt of 
the device. This includes the content shipped and condition of the items upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, 
i.e. CELLECTRA™ 5PSP Base Station & Handset serial number, 5PSP Array lot 
number and the study drug lot number. The used Array attachment must be disposed of 
in accordance with institutional policy regarding disposal of sharp needles/instruments. 

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5.9 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT AND CELLECTRA™ 5PSP 
DEVICE  
5.9.1 
RETURN OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at the site 
per the institutions policy or returned to INOVIO or its designee, if the site cannot destroy 
the unused IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps 
container at site. Do not attempt to remove the cartridge from the array once it has been 
used.  
It is the Investigator's responsibility to arrange for the 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 INOVIO personnel, StudyMonitor, or by the authorized site 
representative if the Study Monitor is not present 
The unused IP can only be destroyed after being inspected and reconciled by the 
responsible INOVIO personal or designated Study Monitor. 
If IP is returned to INOVIO, or its designee, it must be accompanied by the appropriate 
documentation. Returned supplies should be in the original containers. Empty containers 
should not be returned to INOVIO.  
5.9.2 
RETURN OF CELLECTRA™ 5PSP DEVICE  
Upon completion or termination of the study, all investigational devices and unused 
components (Base, Station and Handset,) must be returned to INOVIO. Please contact 
an Inovio representative for specific instructions on the return of the device and 
components. Any unused or expired 5PSP Arrays should be destroyed on site per the 
site’s institutional policy. If a site’s policy does not allow for the destruction of the Arrays 
on site, please contact an Inovio representative for further instruction.  
All device components returned to INOVIO must be accompanied by the appropriate 
return documentation. Returned supplies should be in the original containers. The return 
of all device components identified above should be arranged by the responsible Study 
Monitor. 
If any component is to be destroyed on site, it is the Investigator's responsibility to 
ensure that arrangements have been made for the disposal. 
 
Written authorization must be granted by INOVIO, or its designee of the disposal, 
 
Ensure that proper procedures for disposal have been established and followed 
according to applicable local regulations, guidelines and institutional procedures, 
 
Appropriate records of the disposal have been documented. 
6.0 
TRIAL PROCEDURES AND SCHEDULE 
This section lists the procedures and parameters for each planned study evaluation. The 
timing of each assessment is listed in the Schedule of Events. 

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A subject will be required to provide informed consent for the 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. Immediate safety concerns will be 
dealt with as deemed necessary by the Investigator. Adherence to the study design 
requirements, as outlined in the Schedule of Events are essential and required for study 
conduct. Subject eligibility should be reconfirmed at every study visit. 
6.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any trial related procedures being 
performed. The informed consent documentation must be in accordance with applicable 
regulations and GCP. Qualified trial personnel will meet with prospective trial subjects, 
explain the trial, and provide them with an ICF that describes the Screening tests, 
eligibility criteria for entering the trial, trial treatments and follow-up procedures, in a 
language understandable to the subject. Explanation of the trial includes, but is not 
limited to, trial objectives, potential benefits and risks, discomforts/inconveniences, and 
the subject's rights and responsibilities. The subject or subject's legally acceptable 
representative is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject or subject's legally acceptable 
representative. The qualified trial 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. 
6.2 
BEFORE TREATMENT PROCEDURES 
Subjects who consent to participate must have paraffin-embedded tissue block(s) from a 
previous biopsy (ies) and/or newly collected intra-anal and/or peri-anal biopsy tissue 
samples (formalin fixed tissue) sent to the central pathology lab for review by the PAC. 
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 the PAC with HSIL 
consensus diagnosis), until the date of first study treatment (i.e. Day 0).  
For those individuals diagnosed with anal or anal/peri-anal 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, biopsy samples should be collected 
from all intra-anal and/or peri-anal lesions of adequate size during Screening  following 
the consent of the subject. The 10 week Screening window begins upon collection of the 
biopsy sample(s) that will be evaluated by the PAC.  
At Screening, subjects must have a diagnosis of histologic anal or anal/peri-anal HSIL 
confirmed by the PAC and intra-anal and/or peri-anal specimen test positive for HPV-
16/18 by PCR to be eligible for participation in the study (provided the subject also 
meets other eligibility criteria). Subjects whose intra-anal and/or peri-anal specimens 
also test positive for other HPV genotypes are not excluded as long as they have a 
positive result for HPV-16/18.  
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. 
 

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6.2.1 
SCREENING EVALUATIONS 
The following evaluations/actions, unless noted, will be performed within 10 weeks and 
up to Day 0 – except for the HIV test which must be performed within 30 days prior to 
Day 0 and 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. Some of these evaluations/actions will be performed 
again later in the trial (see later text and the Schedule of Events (Table 8) for more 
detail). 
 
Signed ICF 
 
Medical history/demographics, including history of prior anal or anal/peri-anal 
HSIL 
 
Socio-Behavioral Assessment; including smoking history, exposure to second-
hand smoke, alcohol intake history, recreational drug use and contraceptive use 
 
Prior concomitant medications review 
 
Determination of eligibility per inclusion/exclusion criteria 
 
Complete Physical Examination 
 
Vital signs (including oral temperature, respiratory rate, blood pressure and heart 
rate), height, weight and body mass index (BMI) measurements 
 
12-lead ECG (within 45 days prior to Day 0) 
 
Baseline laboratory evaluations (including complete blood count [CBC], serum 
electrolytes, blood urea nitrogen [BUN], creatinine (Cr), glucose, alanine 
aminotransferase [ALT], and creatine phosphokinase [CPK]) (to be performed 
within 45 days prior to Day 0) 
 
Urine pregnancy test 
 
Serology (HIV Ab) within 30 days prior to Day 0 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
Digital Anal Rectal Examination (DARE) 
 
Lesion photography (intra-anal and/or peri-anal) 
 
High Resolution Anoscopy (HRA) with Biopsy (tissue must be reviewed by the 
PAC). 
o If a historical biopsy is used with a corresponding HRA evaluation, then 
the HRA does not need to be repeated for Screening to determine 
eligibility as long as it is within the allowable window of 10 weeks.  
 
Whole blood (at least 68 mL) and serum (at least 8 mL) for baseline immunology 
including miRNA profile must be collected before dosing on Day 0 
o It is acceptable to collect the blood as follows: 
 
Screening: obtain 34 ml of whole blood and 4 ml of serum 

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 
Day 0: obtain 34 ml of whole blood and 4 ml of serum prior to 
dosing 
6.3 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will receive study treatment. Visit dates 
and windows must be calculated from Day 0. 
6.3.1 
DAY 0 
The following study evaluations will be performed at Day 0 (unless noted) prior to 
the first study treatment: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA profile (if whole blood 
and serum were not collected at Screening, then 68 ml of whole blood and 8 ml 
of serum should be drawn at this time point prior to dosing) 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swabs 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcome (SF-36v2™ and EQ-5D-5L) (may be performed at Day 
-1 or on Day 0, again provided it is done prior to the first study treatment) 
 
Study treatment administration 
The following evaluations will be performed on Day 0 after study treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute Participant Diary Card (PDC) 
**Please remember to download EP data from the CELLECTRA™5PSP device 
following each study treatment.** 
6.3.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during the phone call: 

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 
Review Day 0 of PDC (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.3 
WEEK 4 (± 4 DAYS) 
The following study evaluations will be performed at Week 4 prior to study 
treatment: 
 
Reconfirm subject eligibility 
 
Concomitant mediation review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (the subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Collect and review PDC for dose 1 
 
Study treatment administration 
The following study evaluations will be performed at Week 4 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L)  
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
following each study treatment.** 
 
6.3.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during the phone call: 
 
Review of PDC for dose 2 (after reviewing the PDC 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) 

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 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
6.3.5 
WEEK 12 (± 4 DAYS) 
The following study evaluations will be performed at Week 12 prior to study 
treatment: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
 
Collect and review PDC for dose 2 
 
Study treatment administration 
The following study evaluations will be performed at Week 12 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L)  
**Please remember to download EP data from the CELLECTRA™5PSP device 
following each study treatment.** 
6.3.6 
WEEK 15 (± 1 WEEK) 
The following study evaluations will be performed at Week 15: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Whole blood and serum for immunology including miRNA 
o 51 ml of whole blood and 4 ml serum should be drawn at this time point 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  

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 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
6.3.7 
WEEK 28 (± 1 WEEK) 
The following study evaluations will be performed at Week 28: 
 
Reconfirm subject eligibility 
 
Concomitant medical review 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
6.3.8 
WEEK 36 (± 1 WEEK) 
The following study evaluations will be performed at Week 36: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment 
 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Serology (HIV Ab) 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical and penile swabs 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA 

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 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (paraffin blocks) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 
 
6.3.9 
WEEK 40 (± 1 WEEK) 
The following study evaluations will be performed at Week 40: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test  
 
Study treatment administration 
 
Based on biopsy results collected at Week 36 and Investigator judgment, a 4th 
dose may be given at this visit 
**Please remember to download EP data from the CELLECTRA™ 5PSP device 
following each study treatment. .** 
The following study evaluations will be performed at the Week 40 post treatment: 
 
Post treatment AEs and injection site reaction assessment at least 30 minutes 
after study treatment 
 
Distribute PDC 
 
Patient reported outcomes:- the two "global" questions and SF-36v2™ and EQ-
5D-5L 
6.3.10 8-14 DAYS POST DOSE 4 PHONE CALL (FOR SUBJECTS WHO RECEIVED A 4TH DOSE) 
The following information will be evaluated during the phone call: 
 
Review PDC for dose 4 (after reviewing the PDC 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) 
 
Remind subject to self-complete the PRO questionnaires (SF-36v2™ and EQ-
5D-5L) 
 
6.3.11 WEEK 64 (± 2 WEEKS) 
The following study evaluations will be performed at Week 64: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment (only for subjects who received a 4th dose at Week 
40) 

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 
Targeted Physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
Oropharyngeal rinse 
 
Vaginal, cervical and penile swab 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Biopsy (paraffin blocks)  
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L)  
6.3.12 WEEK 88 (± 2 WEEKS) 
The following study evaluations will be performed at Week 88: 
 
Reconfirm subject eligibility 
 
Concomitant medication review 
 
Socio-behavioral assessment 
 
Full Physical assessment 
 
Urine pregnancy test 
 
Vital signs 
 
Whole blood and serum for immunology including miRNA profile 
 
Oropharyngeal rinse 
 
Vaginal, cervical, and penile swabs 
 
Intra-anal and/or peri-anal swab (subject should be requested to abstain from 
any sexual activity and refrain from the use of douching or vaginal and anal 
lubricants/medication for a period of 24 hours prior to sample collection) 
 
DARE 
 
HRA  
 
Lesion photography (intra-anal and/or peri-anal) 
 
Patient reported outcomes (SF-36v2™ and EQ-5D-5L) 

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6.4 
TRIAL PROCEDURES 
6.5 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number 
(SID), which identifies the subject for all trial-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., ANUS01001). Once 
assigned, SIDs cannot be reused for any reason. Information regarding the SID and 
screen date will be documented on a screening and enrollment log/system and in the 
eCRF. 
6.6 
DEMOGRAPHICS 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
 
Age 
 
Gender 
 
Race/ethnicity 
 
Dominant hand/arm 
6.7 
SAFETY EVALUATIONS 
6.7.1 
PHYSICAL EXAM 
A full Physical exam (PE) will be conducted during Screening and study discharge 
(Week 88). 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, and a DARE. 
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. 
6.7.2 
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 prior to measurement 
 
Respiration rate 
 
Heart rate 
 
Oral temperature measured with an automated thermometer 
6.7.3 
HEIGHT AND WEIGHT 
Weight and height will be collected at all dosing visits in order to calculate the BMI. 
 
 

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6.7.4 
MEDICAL HISTORY 
Medical history, including history of prior anal or anal/peri-anal dysplasia and 
gynecologic history will be obtained at Screening. For females, previous history of 
treatment for VIN, CIN and/or VAIN will be collected. All relevant past and present 
conditions, as well as prior surgical procedures at least 6 months prior to enrollment will 
be recorded for the main body systems.  
6.7.5 
SOCIO-BEHAVIORAL ASSESSMENTS 
Socio-Behavioral Assessment, including self-reporting of the following: smoking history, 
history of exposure to second-hand smoke, alcohol intake history, recreational drug use 
history, history of contraceptive use and type of contraceptive if known, reproductive 
history, sexual preference and sexual practices history, and pregnancy history will be 
obtained at Screening.  
At Weeks 36, 64 (only for subjects who receive a 4th dose), and 88, a socio-behavioral 
assessment will be performed to document any changes from Screening and/or other 
time periods. 
6.7.6 
LABORATORY EVALUATIONS 
At Screening, blood samples will be taken to be tested for serum chemistry and 
hematology. 
Complete Blood Count: 
 
White blood cell (WBC) count with differential 
 
Red blood cell (RBC) count 
 
Hemoglobin, Hematocrit 
 
Platelet count 
Serum Chemistry: 
 
Glucose 
 
Blood urea nitrogen 
 
Creatinine 
 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 
Creatine Phosphokinase 
6.7.7 
PREGNANCY TESTING 
For women of reproductive potential, a negative spot urine pregnancy test is required at 
Screening, and prior to each study treatment, HRA, DARE and surgical excision or 
biopsy. 
6.7.8 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for at least 10 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 

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interpretations of ECG should not be used). Abnormal ECGs should be interpreted as 
"clinically significant (CS)" or "not clinically significant (NCS)" by the Investigator. 
6.7.9 
PARTICIPANT DIARY CARD (PDC) 
Subjects will be provided and trained on a PDC and will be asked to record the following 
the evening of study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PDC will be reviewed with the subject by the study staff at the 8-14 days 
post dose phone calls and at the next in-person visits. 
The study staff will review the PDC 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. 
Any PDC entry determined to meet the criteria for a Grade 1 or higher AEs should be 
documented as an AE unless deemed part of the subject's ongoing medical history. If 
the PDC entry does not meet the criteria of a Grade 1 or higher AE as per the CTCAE 
guidelines, clinical judgment can be used to determine whether the entry should be 
recorded as an AE and documented accordingly in the site's source. For cases where 
the PDC entry and final AE reporting (i.e. grading) do not agree, the reasoning should be 
recorded in the source documents. 
6.8 
INJECTION AND ELECTROPORATION (EP) 
Subjects will receive at least three doses of VGX-3100 (6 mg DNA/dose) in a volume of 
1 mL by IM injection in the deltoid or lateral quadriceps muscles (preferably deltoid) 
followed immediately by EP with the CELLECTRA™ 5PSP.  A fourth dose is optional for 
those assessed to be partial responders at the Week 36 efficacy assessment. 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. EP may not be performed in the 
same arm adjacent to an implantable medical device (e.g., cardiac pacemaker, 
defibrillator or retained leads following device removal). The timing of the initial dose will 
be designated Day 0 with the subsequent doses scheduled for administration at Weeks 
4, 12, and at Week 40 (for Subgroup C, Figure 2 only). Please refer to the Investigator's 
Brochure for further information. 
6.9 
MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
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, and Weeks 4 and/or Week 12. 

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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 should be added to the concomitant medications. 
6.10 ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well 
as urine pregnancy testing at Screening and will be performed for inclusion into the 
study as listed in the Schedule of Events (Table 8). 
6.11 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
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 PDC which will be reviewed with study 
personnel 8 – 14 days after doses 1 and 2, Week 15, and 8-14 days after dose 4 (if 
applicable).  
An assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any AEs, 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 AEs will be captured from the time of the informed consent to study 
discharge. These events will be recorded on the subject's Case Report Form (CRF). 
6.12 ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the Investigator will be 
instructed to use the following grading scale in Table 11. 
 
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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6.13 ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, PRO instruments will be 
administered. The following PRO questionnaires will be used: 
 
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) [25]. 
SF-36v2™ will be administered at the following time points:  
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (post dose 2) 
 
8-14 days post dose 2 
 
Weeks 12 (post dose 3), 15, 36, 40 
 
8-14 days post dose 4* (only for those who received a 4th dose) 
 
Weeks 64, 88 
 
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) [26, 27] and will be administered as described below: 
 
Day 0 (before the first study treatment) 
 
8-14 days post dose 1 
 
Week 4 (post dose 2) 
 
8-14 days post dose 2 
 
Weeks 12 (post dose 3), 15, 36, 40 
 
8-14 days post dose 4* (only for those who received a 4th dose) 
 
Weeks 64, 88 
 
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.    
 
Additional Global PRO Questions- regarding quality of life after surgery or biopsy. 
These two questions will be administered at Week 40 only. 
6.14 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, 36, and 88. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual. 
A standardized binding enzyme-linked immunosorbent assay (ELISA) may be performed 
to measure the anti–HPV-16/18 Ab response induced by VGX-3100. 
Peripheral Blood Mononuclear Cells 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 will occur via the application Flow 
Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic 
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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. 
6.15 PROFILING OF MIRNA 
Profiling of miRNA may occur via the use of either sera or plasma obtained at Screening, 
Day 0 and Weeks 15 and 36.  Assessment of Day 0 samples alone will explore 
predictive algorithms for response to treatment with VGX-3100 prior to dosing. 
Assessment of Week 15 samples may 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. 
6.16 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue in the paraffin block after histologic diagnoses have been 
rendered, then the relevant paraffin blocks may be collected for the assessment of 
proinflammatory and immunosuppressive elements. . Assessment of markers may 
include, but are not limited to, CD8+ and FoxP3+ infiltrating cells as well as Granulysin, 
Perforin, CD137, CD103 and PD-L1 in intra-anal and/or peri-anal tissue as sample 
allows. Markers listed here may change as new relevant information becomes available. 
6.17 ANAL AND/OR PERI-ANAL HPV TESTING 
All intra-anal and/or peri-anal lesions of adequate size (≥4 mm) will be biopsied at 
Screening. Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will 
be obtained from all HSIL sites(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. In addition to HSIL lesion(s) found at 
Screening, all visible lesions should have biopsy obtained at Week 64 and sent to the 
central pathology lab for review by PAC. Intra-anal and/or peri-anal swabs will undergo 
HPV testing using a PCR based assay, SPF10. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching to eliminate potential interference with the results of HPV testing. 
Intra-anal and/or peri-anal swabs will be obtained at Screening, Day 0, and at Weeks 4, 
15, 28, 36, 64, and 88 in ThinPrep™ collection media. The HPV Cobas test will be 
performed on the ThinPrep™ specimens at Screening, and Weeks 36 and 64 when 
applicable. Anal cytology will be performed on intra-anal samples. At each of these 
visits, a recent history will be collected via self-report.   
6.18 HPV TESTING FROM OTHER ANATOMICAL SITE (NON-ANAL) 
Vaginal, cervical (female subjects), penile (male subjects), and OP rinse samples (all 
subjects) will be obtained at Day 0, and Weeks 4, 15, 28, 36, 64, and 88 to assess 
virologic clearance at non-anal sites using a PCR based HPV assay. All samples will be 
read in a central laboratory. 
The subject will be requested to abstain from sexual activity and refrain from the use of 
douching or vaginal and anal lubricants/medication for a period of 24 hours prior to 
collection of samples to eliminate potential interference with the results of HPV testing. 

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6.19 ANAL PHOTOGRAPHS AND BIOPSIES 
Eligible subjects are enrolled in the study based on the diagnosis of anal or anal/peri-
anal HSIL confirmed by the PAC at Screening. Subjects will undergo HRA at Screening, 
Day 0, and at Weeks 4, 15, 28, 36, 64, and 88 to identify all intra-anal lesion(s). All intra-
anal and/or peri-anal lesion(s) of adequate size (≥4 mm) will be biopsied at Screening. 
Once the PAC confirms HSIL at Screening, the Week 36 and 64 biopsies will be 
obtained from all HSIL site(s) confirmed by the PAC at Screening, unless the 
Investigator suspects disease progression. Investigators should follow Table 1: 
Minimally Required Procedure at each Biopsy Visit for the Weeks 36 and 64 biopsies. 
Under the Protocol 3.0 Amendment, in additional to HSIL lesion(s) found at Screening, 
all visible lesions should have biopsy obtained at Week 64 and sent to the central 
pathology lab for review by PAC. Photography of all qualifying intra-anal and/or peri-anal 
lesion(s) must be performed prior to and after biopsy, and at all HRA examinations. If a 
pre-biopsy digital photograph is not available for a historical biopsy sample at Screening, 
a post biopsy photo will be sufficient. Photographs of intra-anal lesion(s) will be for 
documentation purposes only. All qualifying peri-anal lesion(s) will be assessed using 
the ruler provided. The ruler should be placed in the field of vision and should be 
documented with photography at Screening, Day 0, and Weeks 4, 15, 28, 36, 64, and 
88. 
If the intra-anal and/or peri-anal tissue sample(s) result suggests progression to cancer, 
the Investigator may schedule an ad hoc visit to perform HRA and possible biopsy if 
clinically indicated. 
6.20 UNSCHEDULED BIOPSIES 
Unscheduled biopsies may be performed on new lesions or suspected progression of 
original lesions per the Investigator’s medical judgment during the study. The subject will 
be managed according to standard of care and the Investigator’s judgment based on the 
results of the histological diagnosis from the unscheduled biopsy. All biopsy 
samples/excised tissue (including standard of care) will be sent to the central pathology 
lab for review by the PAC.  
6.21 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the 
Screening biopsy date of eligible subjects must be recorded on the eCRF. Actual or 
estimated start and stop dates must be provided. Medical procedures performed within 8 
weeks prior to the 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 eCRFs. 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 eCRF. 
The following medications and treatments are prohibited: 
 
Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent; use of inhaled, otic, nasal, topical, and ophthalmic 
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 
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, live vaccine; 
 
Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that 
affects blood clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study 
treatment, biopsy or excisional procedure. 
The decision to administer a prohibited medication/treatment is done with the safety of 
the study participant as the primary consideration. When possible, the Sponsor should 
be notified before the prohibited medication/treatment is administered. All medications 
should be recorded in the appropriate sections of the subject's eCRF. 
6.22 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, including illicit 
drugs, taken to the Investigator and/or other study personnel. To remain in the study, 
illicit drugs should not be taken. 
Subjects should refrain from becoming pregnant until one month following the last dose 
of IP (Week 12 or Week 40) 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. 
Subjects should abstain from sexual activity and refrain from the use of douching and 
vaginal and anal lubricants/medication for a period of 24 hours prior to collection of 
ThinPrep™ samples. 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
As a requirement for inclusion in the HPV-203 study, Investigators will only be chosen if 
they are experienced in the management of anal cancer, and are experienced in 
performing HRA.  
HPV-203 Investigators are instructed to perform additional, ad hoc HRA exams and 
biopsies if they suspect potential disease progression. Subjects that undergo an 
unscheduled biopsy will be classified as a non-responder in the efficacy analyses. These 
additional measures should minimize the risk of progression of anal or anal/peri-anal 
HSIL and the risk of harboring an undiagnosed occult early invasive anal or anal/peri-
anal cancer. The frequency of close monitoring by experienced Investigators should 
minimize the risk of cancer progression during the study and the additional measures 
are beyond what is expected in standard of care. 
7.2 
ADVERSE EVENTS (AES) 
An 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 
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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 AEs 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 eCRF, including the event's seriousness, severity, action taken, 
and relationship to IP. Adverse Events should be followed until resolution or stable and 
the outcome will be documented on the appropriate eCRF. All AEs should be recorded 
in standard medical terminology rather than the subject's own words. 
Adverse Events 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 increased 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); 
 
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. 
Adverse Events 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 ICF is signed is not an AE. It is considered to be pre-existing and 
will be documented on the medical history eCRF; 
 
Uncomplicated pregnancy; 
 
An induced elective abortion to terminate a pregnancy without medical reason. 
7.3 
SERIOUS ADVERSE EVENTS 
A 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 
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 
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 (ER) or at home, 2) blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or 3) the development of drug dependency or drug 
abuse.  
Classification of Serious Adverse Events: 
 
Death is an outcome of an AE, and not an SAE in and of 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 7.15. 
7.4 
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 AE is at least a reasonable possibility; i.e., there is evidence to 
suggest a causal relationship between the product and the AEs. An AE or ADR is 
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(Investigator's Brochure, protocol, or user manual) or is not listed at the specificity or 
severity which is consistent with the risk information provided. 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 serious 
expected AEs, the identification of a significant hazard to the patient population, or a 
major safety finding from a study conducted in animals.   
7.5 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT 
Unanticipated adverse device effect means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
Per the definition above, a UADE is a type of SAE that requires expedited reporting on 
the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 
hours. Sponsor will assess each device related SAE to determine if anticipated based on 
prior identification within the investigational plan. 
7.6 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the eCRF at the maximum severity 
reported. 
The Investigator will grade laboratory AEs and clinical AEs or SAEs with respect to the 
following levels of severity as per CTCAE v 4.03 for applicable patient populations: 
 
Mild (Grade 1) 
 
Moderate (Grade 2) 
 
Severe (Grade 3) 
 
Potentially Life Threatening (Grade 4) 
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. 
7.7 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS 
A causally related AE is one judged to have a reasonable causal relationship to the 
administration to either or both IP and/or the CELLECTRA™ 5PSP device. The 

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Investigator will assess causal relationship of the AE separately to each of the 
investigational drugs and also the investigational device. The reasonable causal 
relationship means that there are facts (evidence) or arguments to suggest a causal 
relationship. An AE may also be assessed as not related to either or both IP and/or 
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 AEs and judging 
the relationship between the administration of the IP and EP 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 Study Subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an AE is considered to be related to the IP and/or the device 
indicating "yes" or "no" accordingly. Causality should be assessed by the Investigator as 
related to drug or related to device or related to both drug and device (i.e. indiscernible) 
by the following criteria: 
 
Yes- there is a reasonable possibility that administration of the Study Treatment 
(drug or device or both drug and device) contributed to the event; 
 
No- there is no reasonable possibility that administration of the Study Treatment 
contributed to the event and there are more likely causes. 
The following guidance should also be taken into consideration: 
 
Temporal relationship of event to administration of IP and/or EP; 
 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
 
Known association of the event with the IP, EP or with similar treatments; 
 
Known association of the event with the disease under study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications 
known to increase the occurrence of the event. 
7.8 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK) independent of the underlying medical 
condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation or deemed clinically significant by the Investigator must be recorded as 
an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., ECG, x-rays, and vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or 
SAE) as described in Sections 7.2 and 7.3. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (e.g., anemia) not the laboratory result 
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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 
Severity is assessed as detailed in Section 7.6. 
Grade is an essential element of these criteria. Each CTCAE grading term in the current 
version is a unique representation of a specific event used for medical documentation 
and scientific analysis and is a single Medical Dictionary for Regulatory Activities 
(MedDRA) Lowest Level Term (LLT). 
Investigators are asked to take the CTCAE grading criteria into account when assessing 
if a laboratory abnormality qualifies as a laboratory AE. Their clinical judgment ultimately 
determines not only the severity of the event but also whether the abnormality in 
question is "clinically significant (CS)" or "NCS." CTCAE v. 4.03 grading criteria can be 
used as a reference when making this determination. It is the responsibility of the 
Investigators to ensure all AEs are accurately reported and graded. 
7.9 
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 
probably or possibly related to the study treatment, he/she should promptly document 
and report the event to the Sponsor. 
7.10 PROCEDURES FOR DOCUMENTING PREGNANCY DURING THE TRIAL 
Should a subject become pregnant after enrolling in the study, she will not be given any 
further treatments with the IP. A Pregnancy Form will be completed by the Investigator 
and submitted to the Sponsor within 24 hours after learning of the pregnancy. Site 
personnel will submit the Pregnancy Form to the Sponsor or its designee by fax or email, 
as described in Section 7.15. 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 IP. 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 

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of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome will be reported directly to the Sponsor. 
Male subjects will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant until the end of follow-up 
period. A Pregnancy Form will be completed by the Investigator and submitted to the 
Sponsor within 24 hours after learning of the pregnancy. Attempts will be made to collect 
and report details of the course and outcome of any pregnancy in the partner of a male 
subject exposed to IP. The pregnant partner will need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Pregnancy 
Form with additional information on the course and outcome of the pregnancy. An 
Investigator who is contacted by the male subject or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
7.11 METHODS AND TIMING OF COLLECTION OF SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time 
when informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. The subject's response to questions about his/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 eCRF. 
Any SAE occurring during the course of the study must be reported to the Sponsor 
within 24 hours of awareness. 
7.12 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 AEs classified by system organ class (SOC), preferred term, 
severity, and relationship to study treatment; 
 
Changes in safety laboratory parameters (e.g., hematology and serum 
chemistry); 
 
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. 
7.12.1 ADVERSE EVENTS OF SPECIAL INTEREST 

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Adverse events of special interest (AESI) are the adverse events deemed related to 
VGX-3100 delivered with CELLECTRA™ 5PSP 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 eCRFs. 
Sites will inform the Sponsor via method described in Section 7.15 within 24 hours to 
discuss whether further dosing for the particular subject should continue. 
7.13 ADVERSE EVENT REPORTING 
To assure the safety of the participants, information about all AEs (see Section 7.2), 
whether volunteered by the subject, discovered by the 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. 
7.14 TRIAL REPORTING PERIOD OF ADVERSE EVENTS 
All solicited and unsolicited AEs will be collected throughout the study and recorded in 
the Electronic Data Capture (EDC) system. The Study Report will analyze and 
summarize all AEs throughout the study. Emphasis will be placed on the following: 
1. Certain AEs of interest will be solicited during the 7 days following each 
administration of Study Treatment and summarized separately 
2. Unsolicited AEs will be collected and summarized for the entire study period 
7.15 TRIAL REPORTING PERIOD OF SERIOUS ADVERSE EVENTS AND AESIS 
The reporting period for SAEs (without regard to causality or relationship) and AESIs is 
comprised of the period following the signing of the ICF through Week 88. Each AE will 
be assessed to determine whether it meets seriousness criteria. If the AE is considered 
serious, the Investigator will complete the SAE/AESI Report form 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 IRB/EC 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 7.5 (UADE) in line with relevant legislation. All investigators will 
receive a safety letter notifying them of relevant SUSAR reports. The Investigator should 
notify the IRB/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.  

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At a n y ti m e aft er c o m pl eti o n of t h e S A E r e p orti n g p eri o d, if a n i n v e sti g at or b e c o m e s 
a w ar e of a n S A E t h at i s s u s p e ct e d b y t h e I n v e sti g at or t o b e r el at e d t o t h e st u d y dr u g, t h e 
e v e nt will b e r e p ort e d t o t h e S p o n s or or it s d e si g n e e. If t h e I n v e sti g at or b e c o m e s a w ar e 
of a n S A E i n a st u d y s u bj e ct aft er t h e l a st s c h e d ul e d f oll o w- u p vi sit, a n d c o n si d er s t h e 
e v e nt r el at e d t o pri or St u d y Tr e at m e nt, t h e I n v e sti g at or will r e p ort it t o t h e S p o n s or or t h e 
a p pr o pri at e d e si g n e e. 
S P O N S O R C O N T A C T I N F O R M A TI O N 
M E DI C A L M O NI T O R: 
, M. D., P h. D. 
E M AI L: 
 
S A E R E P O R TI N G I N F O R M A TI O N 
E M AI L: s af et y.i n o vi o @ a p c erl s. c o m  
S A F E T Y F A X: 
 
S A F E T Y P H O N E: 
 
T h e pr ef err e d m et h o d f or pr o vi di n g S A E f or m s or S A E s u p p orti n g d o c u m e nt s t o t h e 
S p o n s or or d e si g n e e i s a n att a c h m e nt t o a n e- m ail m e s s a g e, t o t h e e m ail a d dr e s s a s 
i n di c at e d a b o v e. A n y S A E s u p p orti n g d o c u m e nt s pr o vi d e d b y f a c si mil e ( F a x) ar e t o 
i n cl u d e a c o v er s h e et t h at i d e ntifi e s t h e r e p ort er n a m e a n d c o nt a ct i nf or m ati o n of t h e 
st u d y sit e. 
All s u p p orti n g d o c u m e nt s f or S A E r e p ort s, i n cl u di n g m e di c al r e c or d s a n d di a g n o sti c t e st 
r e s ult s, will i n cl u d e r ef er e n c e t o t h e st u d y s u bj e ct n u m b er. T h e st u d y sit e will r e d a ct all 
ot h er p ati e nt i d e ntif yi n g i nf or m ati o n pr e s e nt o n S A E s u p p orti n g d o c u m e nt s pri or t o 
s e n di n g t h e r e p ort t o t h e S p o n s or.  
I n a d diti o n t o pr o vi di n g t h e S A E r e p ort t o t h e S p o n s or or d e si g n e e wit hi n 2 4 h o ur s of 
b e c o mi n g a w ar e of t h e e v e nt, t h e A E t h at i s s eri o u s m u st b e r e c or d e d i n t h e A E s e C R F. 
T h e e ntr y i nt o t h e e C R F i s r e q uir e d t o b e d o n e a s s o o n a s p o s si bl e. 
T h e I n v e sti g at or will s u p pl y t h e S p o n s or a n d t h e I R B/ E C wit h m or e i nf or m ati o n a s it 
b e c o m e s a v ail a bl e a n d a n y a d diti o n al r e q u e st e d i nf or m ati o n. T h e ori gi n al S A E f or m 
m u st b e k e pt at t h e st u d y sit e. T h e S p o n s or or it s r e pr e s e nt ati v e will b e r e s p o n si bl e f or 
d et er mi ni n g a n d i n t ur n, r e p orti n g S A E s t o r e g ul at or y a ut h oriti e s a c c or di n g t o t h e 
a p pli c a bl e r e g ul at or y r e q uir e m e nt s. 
W h e n r e c or di n g t h e S A E f or m, c orr e ct m e di c al t er mi n ol o g y/ c o n c e pt s ar e t o b e u s e d a n d 
t he u s e of a b br e vi ati o n s a n d c oll o q ui ali s m s ar e t o b e a v oi d e d. 
S eri o u s A d v er s e E v e nt s m u st b e f oll o w e d b y t h e I n v e sti g at or u ntil r e s ol uti o n, e v e n if t hi s 
e xt e n d s b e y o n d t h e st u d y-r e p orti n g p eri o d. R e s ol uti o n of a n S A E i s d efi n e d a s t h e r et ur n 
t o b a s eli n e st at u s or st a bili z ati o n of t h e c o n diti o n wit h t h e e x p e ct ati o n t h at it will r e m ai n 
c hr o ni c. 
P P D
P P D
P P D
P P D

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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. 
7.16 NOTIFICATIONS 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 7.4 and 7.16). 
7.17 REPORTING OF CELLECTRA™5PSP DEVICE RELATED COMPLAINTS OR 
DEFICIENCIES 
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 within 24 hours of becoming aware of the event per Sections 7.2 and 7.3. 
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. The error reporting or complaint form provided must be completed and 
emailed to the Sponsor at clinicalcomplaint@inovio.com. 
Additional instructions on complaint reporting to be provided separately. 
7.18 TRIAL DISCONTINUATION 
Inovio Pharmaceuticals Inc. reserves the right to discontinue the trial 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. Additionally, the trial may be 
discontinued at any time by an IRB, INOVIO, the FDA or other government agencies as 
part of their duties to ensure that research subjects are protected.  
Should the trial be terminated and/or the site closed for any reason, all investigational 
drugs & devices must be returned to INOVIO or its representative. The PI should ensure 
their site file documents are complete prior to archiving, and provide copies of any 
requested documents to INOVIO for its Trial Master File (TMF). 
 

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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by INOVIO or its representative. 
This is a single-arm, multi-center, open-label clinical trial of VGX-3100 in subjects with a 
diagnosis of AIN2, AIN3, PAIN2, or PAIN3 associated with HPV types 16 and/or 18. The 
study's primary endpoint is binary: regression of AIN/PAIN HSIL and viral clearance of 
HPV-16/18 based on tissue collected at Week 36. The primary hypothesis is that the 
treatment will result in regression of HSIL and clearance. Secondary efficacy analyses 
pertain to regression, clearance of HPV-16/18 infection, complete regression, 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, clearance among non-anal anatomic locations, and 
association of miRNA profile, anoscopy, cytology, and virology with efficacy. Other 
exploratory analyses pertain to humoral and cellular immunological measures, tissue 
immunological measures, and PRO. 
8.3 
STATISTICAL HYPOTHESES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15.  There are no other formal hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations are: 
 
The modified intention to treat (mITT) population includes all subjects who 
receive at least one dose of Study Treatment. 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 Treatment and have no protocol violations. 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 locking of the study database. 
 
The safety analysis set includes all subjects who receive at least one dose of 
Study Treatment. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 
PRIMARY ANALYSES 
The true treatment effect on the primary endpoint is p, where p denotes the true 
population probability of the primary endpoint. The primary hypothesis of superiority is: 
H0: p≤ 0.15 vs. H1: p > 0.15. 

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A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact method of Clopper-Pearson. Superiority will be concluded 
if the one-sided p-value is <0.05 and the corresponding lower bound of the one-sided 
95% CI exceeds 0.15. 
For the analysis, the efficacy time frame is defined by any time starting from 14 days 
prior to the specified visit week. 
The endpoint will be analyzed in two ways: a) based on all lesions and b) based on 
qualifying and new lesions. 
8.5.2 
SECONDARY ANALYSES 
The secondary efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
defined in the same manner as for the primary endpoint.  All of the efficacy binary 
endpoints will be analyzed in two ways: a) based on all lesions and b) based on 
qualifying and new lesions. 
The anatomic extent endpoint will be analyzed by calculating the mean percent change 
in surface area and the mean percent change in number of lesions and associated 95% 
t-distribution based confidence intervals. 
Post-baseline increases in Flow responses will be summarized with medians and 95% 
CIs. Valid samples for statistical analysis purposes will be those collected within 14 days 
of the specified visits. Baseline is defined as the last measurement prior to the first 
treatment administration. 
8.5.3 
SAFETY ANALYSES 
All AEs will be summarized among the safety population by frequency. These 
frequencies will be presented overall and separately by dose, and will depict overall, by 
SOC 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 AE data will be based on events occurring within 28 days 
following 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 following any dose and 
regardless of when they occurred. 
8.5.4 
DISPOSITION 
Disposition will be summarized 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. 
8.5.5 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 

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Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables for the mITT population. 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system for the mITT population. 
Prior medications are those that were used and stopped before the start of the trial (prior 
to Day 0). Partial stop dates of prior medications will be assumed to be the latest 
possible date consistent with the partial date. Data for all prior medications will be 
summarized with percentages for the mITT population. 
8.5.6 
INTERIM ANALYSES 
No formal interim analyses will be performed for this study. For reasons of futility (early 
evidence of poor efficacy of VGX-3100) or safety issues, the DSMB could recommend 
stopping enrollment at any time. The type I error will not be adjusted for possible early 
stopping due to futility. 
8.5.7 
MULTIPLICITY 
Not applicable; there is one hypothesis that will be tested. 
8.5.8 
MISSING VALUES 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. 
No other missing data will be imputed or replaced. 
8.5.9 
EXPLORATORY ANALYSES 
The exploratory efficacy binary endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy time frame is 
defined in the same manner as for the primary endpoint.  All of the efficacy binary 
endpoints will be analyzed in two ways: a) based on all lesions and b) based on 
qualifying and new lesions.  Also, the Week 64/88 binary endpoints will be analyzed a) 
overall and b) according to three or four doses received. 
Other analyses will examine the relationship between the primary efficacy endpoint and 
a) miRNA results, b) HRA results, c) cytology 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 as regressor variables. 
Post-baseline ELISA titers will be summarized with geometric means and associated t-
distribution based 95% CIs. Post-baseline increases in ELISPOT will be summarized 
with medians and 95% CIs. 
The change in tissue immune response magnitude will be summarized with means and 
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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. 
8.6 
SAMPLE SIZE/POWER 
A sample of 24 subjects provides ~80% power to declare superiority over historical 
control, assuming the true proportion of subjects who achieve the primary endpoint is 
40% for the treatment arm versus 15% for the historical control, and that 90% are 
evaluable at Week 36 from 1st dose. 
8.7 
RANDOMIZATION AND BLINDING 
This is an open-label trial, and therefore, site personnel, individual subjects and INOVIO 
or its representative trial personnel will be aware of the treatment allocations for this trial. 
Randomization does not apply. 
9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
GCP, and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., ICF, 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/EC include the following: 
 
Submit progress reports to the IRB/EC as required, and request re-review and 
approval of the trial at least once a year during the conduct of the trial. 
 
Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects. 
 
Notify the IRB/EC immediately if the Sponsor notifies the Investigator about any 
reportable safety events. 
 
Obtain approval from the IRB/EC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements, as required. 
 
Submit reports on, and reviews of, the trial and its progress to the IRB/EC at 
intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
 
Maintain a file of trial-related information (refer to trial files) that include all 
correspondence with the IRB/EC. 
 
Notify the IRB/EC when the trial is completed (i.e. after the last visit of the final 
trial subject). 
 
After trial completion (within three (3) months is recommended) provide the 
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9.3 
IBC APPROVAL AND REPORTING 
Investigator will ensure responsibilities relevant to Institutional Biosafety Committee 
(IBC) approval and reporting if applicable per local regulations. 
9.4 
OFFICE OF BIOTECHNOLOGY ACTIVITIES 
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., 
National Institutes of Health [NIH] Office of Biotechnology Activities [OBA]) governing 
research that involves recombinant or synthetic nucleic acid. 
9.5 
PROTECTION OF HUMAN SUBJECTS 
9.5.1 
COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to enrollment into the 
trial, 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 
(Section 6.1). 
9.5.2 
COMPLIANCE WITH IRB/EC REQUIREMENTS 
This trial 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 trial 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 
should be provided to Sponsor. 
9.5.3 
COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.5.4 
COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURE REGULATIONS (21CRF 
PART 11) 
When applicable, this trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.5.5 
COMPLIANCE WITH PROTOCOL 
Subjects will be provided with Investigator emergency contact information and advised to 
report all AEs. While every effort should be made to avoid protocol deviation (PD), 
should a deviation be discovered, Sponsor must be informed immediately. Any PD 
impacting subject safety must be reported to the Medical Monitor immediately. 
9.5.6 
CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol 
without prior review and documented approval/favorable opinion from the Sponsor and 
IRB/EC of a protocol amendment, except where necessary to eliminate immediate 
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deviation be discovered, Sponsor must be informed immediately. Any PD impacting 
Subject safety must be reported to the Medical Monitor immediately. 
10.0 DATA COLLECTION, MONITORING, AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this trial may be published or sent to the appropriate health 
authorities in any country in which the trial 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 trial Sponsor, the governing health 
authorities or the FDA, if they inspect the trial 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 trial, 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 (HIPAA)]. 
Information about trial subjects will be kept confidential and managed in accordance with 
the requirements of the HIPAA of 1996. 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 trial 
 
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 
In the event that a subject revokes authorization to collect or use PHI, the Sponsor 
retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect vital status, at a minimum, (i.e., 
that the subject is alive) at the end of their scheduled trial period. 
11.0 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. The 
Investigator/institution will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspections by providing direct access to source data/documents related to 
this trial. 

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11.1 RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the 
Investigator/institution should make available for direct access all requested trial related 
records. 
Case Report Form will be provided for each subject. Subjects must not be identified by 
name on any CRFs. Subjects will be identified with an SID. 
It is the Investigator's responsibility to retain trial essential documents for at least two (2) 
years after the last approval of a marketing application in their country and until there are 
no pending or contemplated marketing applications in their country or at least two (2) 
years have elapsed since the formal discontinuation of clinical development of the IP. 
This retention period may be superseded by country requirements. The Sponsor will 
inform the Investigator/institution as to when these documents are no longer needed to 
be retained. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY AND QUALITY MONITORING 
An independent DSMB will provide safety oversight. The DSMB will be scheduled to 
meet quarterly. 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 there appears to be a regression with VGX-
3100.However, no formal interim analysis will be performed. 
12.2 PATHOLOGY ADJUDICATION COMMITTEE 
All anal 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 four pathologists in separate locations. Each specimen will be read by two 
pathologists independently in a blinded fashion. The logistics and details of the PAC are 
detailed in the PAC Charter. 
12.3 CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced Clinical 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 trial. 
 
The Clinical Monitor will address and document the following trial conduct 
activities and obligations: 

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o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution 
trip report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately 
report all SAE and provide subsequent follow-up report of the final 
outcome to the IRB. 
o Throughout the trial, inspect all source documents to ensure they are 
complete, logical, consistent, attributable, legible, contemporaneous, 
original, and accurate (ALCOA). 
o Assure that the trial facilities continue to be acceptable. 
o Compare the trial eCRFs with source documents to assure that the data 
are accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and 
reconciliation of records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded 
properly for testing per laboratory manual requirements. 
 
13.0 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 at 
least 60 days prior to submission for publication. The Sponsor will have 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) will 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 US Patent and 
Trademark Office and/or foreign patent office(s). 
 
 
 
14.0 LIST OF ABBREVIATIONS 
Ab 
Antibody 
ADR 
Adverse Drug Reaction 
AEs 
Adverse events 
AESI 
Adverse Event of Special Interest 
AIN 
Anal Intraepithelial Neoplasia 
AIS 
Adenocarcinoma-in-situ 
ALT 
Alanine Aminotransferase 

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BMI 
Body Mass Index 
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CIN 
Cervical Intraepithelial Neoplasia 
CIN1 
Grade 1 Cervical Intraepithelial Neoplasia 
CIOMS-I 
Council for International Organizations of Medical Sciences 
Cr 
Creatinine 
CRF 
Case Report Form 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CPK 
Creatine Phosphokinase 
DARE 
Digital Anal Rectal Examination 
DNA 
Deoxyribonucleic Acid 
EC 
Ethics Committee 
ELISA 
Enzyme-linked Immunosorbent Assay 
ELIspot 
Enzyme-linked Immunospot Assay 
EP 
Electroporation with CELLECTRA™5PSP  
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ER 
Emergency Room 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
gbm 
gay and bisexual men 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRA 
High-resolution Anoscopy 
HR-HPV 
High-risk HPV Type 
HSIL 
High Grade Squamous Intraepithelial Lesion 
HIV 
Human Immunodeficiency Virus 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
International Ethics Committee 
IHC 
Immunohistochemistry 
IM 
Intramuscular 
IND 
Investigational New Drug 
INOVIO 
Inovio Pharmaceuticals, Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRB/IEC 
Institutional Review Board or Independent Ethics Committee 
ISO 
International Organization for Standardization 
LAST 
Lower Anogenital Squamous Terminology 
LSIL 
Low Grade Squamous Intraepithelial Lesion 
miRNA 
MicroRNA 
mITT 
Modified Intent to Treat 
MSM 
men who have sex with men 

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NCS 
Not Clinically Significant 
OBA 
Office of Biotechnology Activities 
OP 
Ororpharyngeal  
PAIN 
Peri-anal Intraepithelial Neoplasia 
PAM 
Protocol Administrative Memo or Letter 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PIN 
Penile Intraepithelial Neoplasia 
PP 
Per Protocol 
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC 
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PE 
Physical Exam 
PRO 
Patient-reported Outcome 
SAEs 
Serious Adverse Events 
SF-36v2™ 
36-Item Short Form Health Survey 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPANC 
Study of the Prevention of Anal Cancer 
SSC 
Saline Sodium Citrate 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TNF 
Tumor Necrosis Factor 
UADE 
Unanticipated (Serious) Adverse Device Effect 
US 
United States 
VAIN 
Vaginal Intraepithelial Neoplasia 
VIN 
Vulvar Intraepithelial Neoplasia 
WFI 
Water for Injection 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
 
 
 
 

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Protocol Version Date:  22Jan2020 
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Protocol Version: 3.0 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:  22Jan2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
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16.0 APPENDICES