An Open-label Multi-center Study of INO-3107 With Electroporation (EP) in Subjects With HPV-6- and/or HPV-11-associated Recurrent Respiratory Papillomatosis (RRP)
Phase: PHASE1
Conditions: Respiratory Papillomatosis
Sponsor: Inovio Pharmaceuticals

 
 
Official Title:
 
An Open-label Multi-center Study of INO-3107 With Electroporation (EP) in 
Subjects With HPV-6- and/or HPV-11-associated Recurrent Respiratory Papillomatosis (RRP)
NCT ID:
 
NCT04398433
Document Date:
 
Study Protocol
 
Version
 
4.0:
 
23 July 2021
 
 
 
Summary of Changes from V1.0 to V2.0 : 20 February 2020
 
 
 
Summary of Changes from V2.0 to V3.0: 12 April 2021

CONFIDENTIAL 
 
Page 1 of 61 
RRP-001 
An open-label multi-center study of INO-3107 with electroporation (EP) in 
subjects with HPV-6- and/or HPV-11-associated recurrent respiratory 
papillomatosis (RRP) 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND#: 19508 
Protocol Version: 4.0 
Protocol Version Date: 23 July 2021 
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RRP-001 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date: 23Jul2021 
CONFIDENTIAL 
Protocol Version: 4.0 
Page 2 of 61 
Medical Monitor Approval Page 
Drug: 
INO-3107 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
Medical Monitor: 
 MD 
Inovio Pharmaceuticals, Inc. 
Approval Signature: 
 MD 
Inovio Pharmaceuticals, Inc. 
Date (ddMmmyyyy) 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
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INO-3107 
RRP-001 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date: 23Jul2021 
CONFIDENTIAL 
Protocol Version: 4.0 
Page 3 of 61 
Principal Investigator Acknowledgement 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
Principal Investigator Signature: 
Principal Investigator Printed Name 
Principal Investigator Signature 
Date (ddMmmyyyy) 
Clinical Trial Site Number: 
Clinical Trial Site Name: 
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RRP-001 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 23Jul2021 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 4 of 61 
 
 
SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 3.0 dated 12 April 2021 to Version 4.0 
dated 23 July 2021.  Changes not listed in this summary are administrative and do not affect the 
safety of subjects, trial scope, or scientific quality of the protocol. 
1. This protocol amendment adds an additional 10 subjects to the study to explore the use of the 
Side Port Needle.  The Side Port Needle is described in Section 1.2 of the protocol and has 
been referenced in Sections 5.1.3, 5.3.2, 5.5, and 6.5 .   
2. Section 6.4.4 has been updated to add serum bilirubin to the list of serum chemistry analytes 
at Day 0, Weeks 3, 6, and 9.  This was inadvertently not included. 
3. Formatting and grammar have been edited throughout. 
 
 
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INO-3107 
  
RRP-001 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 23Jul2021 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 5 of 61 
 
Table of Contents 
Summary of Changes ................................................................................................................ 4 
Clinical Protocol Synopsis .........................................................................................................10 
Schedule of Events ...................................................................................................................16 
1.0 
Introduction .................................................................................................................17 
1.1 Background and Scientific Rationale: RRP ......................................................................17 
1.2 Background Information: DNA and Electroporation with CELLECTRA® 2000 ..................18 
1.3 Rationale .........................................................................................................................19 
1.4 Potential Benefits and Risks ............................................................................................19 
2.0 
Objectives and Purpose ..............................................................................................21 
2.1 Hypothesis .......................................................................................................................21 
3.0 
Clinical Trial Design and Endpoints ............................................................................21 
3.1 Primary Objective ............................................................................................................22 
3.2 Primary Endpoint .............................................................................................................22 
3.3 Secondary Objective(s) ...................................................................................................22 
3.4 Secondary Endpoint(s) ....................................................................................................23 
23 
23 
3.7 Efficacy Assessment .......................................................................................................23 
3.8 Safety Assessment ..........................................................................................................24 
3.9 Immunogenicity Assessment ...........................................................................................24 
24 
4.0 
Clinical Trial Population ..............................................................................................24 
4.1 Inclusion Criteria ..............................................................................................................24 
4.2 Exclusion Criteria .............................................................................................................25 
4.3 Discontinuation/Withdrawal of Clinical Trial Subjects .......................................................26 
4.3.1 Criteria for Discontinuation of Investigational Product ...............................................26 
4.3.2 Criteria for Discontinuation from the study .................................................................26 
5.0 
Clinical Trial Treatment ...............................................................................................27 
5.1 Investigational Product (IP) and Study Device .................................................................27 
5.1.1 
INO-3107 .............................................................................................................27 
5.1.2      CELLECTRA® 2000 .............................................................................................27 
5.1.3 
Side Port Needle ..................................................................................................27 
5.2  Treatment Regimen ........................................................................................................28 
5.3 Packaging and Labeling ..................................................................................................28 
5.3.1 INO-3107 ..................................................................................................................28 
5.3.2 CELLECTRA® 2000 and Side Port Needle ................................................................28 
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Clinical Protocol 
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5.4 Handling and Storage ......................................................................................................28 
5.4.1 INO-3107 ..................................................................................................................28 
5.4.2 CELLECTRA® 2000 ..................................................................................................29 
5.5 Preparation and Dispensing.............................................................................................29 
5.6 Use of Study Device ........................................................................................................29 
5.7 Investigational Drug and Study Device Accountability .....................................................29 
5.7.1 INO-3107 ..................................................................................................................29 
5.7.2 CELLECTRA® 2000 Accountability ............................................................................29 
5.8 Return and Destruction of Investigational Drug and Study Device ...................................30 
5.8.1 INO-3107 ..................................................................................................................30 
5.8.2 CELLECTRA® 2000 ..................................................................................................30 
6.0 
Clinical Trial Procedures and Schedule ......................................................................31 
6.1 Procedure by Visit ...........................................................................................................31 
6.1.1 Clinical Trial Screening Evaluations ..........................................................................31 
6.1.1.1 Medical History .......................................................................................................32 
6.1.1.2 Demographics ......................................................................................................32 
6.1.1.3 Smoking History ...................................................................................................32 
6.1.2 
Clinical Trial Evaluations and Procedures ............................................................32 
6.1.2.1 Day 0 ...................................................................................................................32 
6.1.2.2 Week 3 ................................................................................................................33 
6.1.2.3 Week 6 ................................................................................................................33 
6.1.2.4 Week 9 ................................................................................................................33 
6.1.2.5 Week 11 ..............................................................................................................34 
6.1.2.6 Week 26 ..............................................................................................................34 
6.1.2.7 Week 52/End of Study visit ..................................................................................34 
6.2 
Informed Consent .......................................................................................................35 
6.3 
Assignment of Subject Identification Numbers ............................................................35 
6.4 
Safety Evaluations ......................................................................................................35 
6.4.1 
Physical Exam and Targeted Physical Assessments ...........................................35 
6.4.2 
Vital Signs ............................................................................................................35 
6.4.3 
Height and Weight ...............................................................................................35 
6.4.4 
Laboratory Evaluations ........................................................................................35 
6.4.5 
Laryngoscopy and Staging Assessment ..............................................................36 
6.5 
Injection and Electroporation (EP) ...............................................................................37 
6.5.1 
Downloading of EP Data from CELLECTRA® 2000 Device ..................................37 
6.6 
Management of Anxiety and Pain Due to Electroporation (EP) Procedures ................37 
6.7 
Assessment of Laboratory Abnormalities ....................................................................37 
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Clinical Protocol 
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6.8 
Assessment of Clinical Trial Adverse Events (AEs).....................................................37 
6.9 
Assessment of Injection Site Reactions ......................................................................37 
6.10 
Peripheral Blood Immunogenicity Assessments ..........................................................38 
6.11 
HPV-6/11 testing .........................................................................................................38 
6.12 
Tissue Immunogenicity Assessment ...........................................................................38 
6.13 
Concomitant Medications/Treatments .........................................................................39 
6.14 
Restrictions .................................................................................................................39 
7 
Evaluation of Safety and Management of Toxicity ......................................................40 
7.1 
Safety Parameters ......................................................................................................40 
7.2 
Adverse Events (AEs) .................................................................................................40 
7.3 
Adverse Drug Reaction (ADR) ....................................................................................40 
7.4 
Serious Adverse Events (SAEs) ..................................................................................40 
7.5 
Unexpected Adverse Drug Reaction ...........................................................................41 
7.6 
Unanticipated (Serious) Adverse Device Effect (UADE) ..............................................41 
7.7 
Device Deficiency .......................................................................................................42 
7.8 
Safety and Toxicity Management ................................................................................42 
7.8.1 
Dose Limiting Toxicity (DLT) ................................................................................42 
7.8.2 
Abnormal Laboratory Value .................................................................................42 
7.8.3 
Clinical Trial Stopping Rules ................................................................................43 
7.9 
Safety Data Reporting Period, Method of Collection and Submission .........................43 
7.10 
Adverse Event Reporting ............................................................................................44 
7.10.1 
Submitting the Initial Serious Adverse Event (SAE) Report Form .........................44 
7.10.2 
Recording the Event ............................................................................................44 
7.10.3 
Assessing Severity (Intensity) ..............................................................................44 
7.10.4 
Causal Relationship of Clinical Material to Adverse Events (AEs) ........................44 
7.11 
Reporting Pregnancy During the Clinical Trial .............................................................45 
7.12 
Reporting Device-Related Complaints or Deficiencies ................................................46 
7.13 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Ethics 
Committees (ECs) of Safety Information .....................................................................46 
7.13.1 
Sponsor Responsibilities ......................................................................................46 
7.13.2 
Principal Investigator (PI) Responsibilities ...........................................................46 
7.14 
Post-Trial Reporting Requirements .............................................................................47 
7.15 
Clinical Trial Discontinuation .......................................................................................47 
8 
Statistical Considerations ...........................................................................................48 
8.1 
Statistical and Analytical Plan .....................................................................................48 
8.2 
General Considerations ..............................................................................................48 
8.3 
Statistical Hypotheses .................................................................................................48 
8.4 
Analytical Populations .................................................................................................48 
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8.5 
Description of Statistical Methods ...............................................................................48 
8.5.1 
Primary Analyses .................................................................................................48 
8.5.2 
Secondary Analyses ............................................................................................49 
8.5.2.1    Efficacy ...............................................................................................................49 
8.5.2.2    Immunogenicity ...................................................................................................49 
8.5.3 
Disposition ...........................................................................................................50 
8.5.4 
Demographic and Other Baseline Characteristics ................................................50 
8.5.4.1    Demographics .....................................................................................................50 
8.5.4.2    Prior medication ..................................................................................................50 
8.5.5 
Interim Analyses ..................................................................................................50 
8.5.6 
Multiplicity ............................................................................................................50 
8.5.7 
Missing Values .....................................................................................................50 
 
51 
8.5.8.1    Efficacy ...............................................................................................................51 
8.5.8.2    Immunogenicity ...................................................................................................51 
8.5.8.3    Concomitant Medication ......................................................................................51 
8.5.8.4    Vital Signs ...........................................................................................................51 
8.6  
Sample Size/Power .....................................................................................................51 
8.7   Randomization and Blinding ..........................................................................................51 
9 
Ethics .........................................................................................................................52 
9.1 
Investigator and Sponsor Responsibilities ...................................................................52 
9.2 
Institutional Review Board (IRB) .................................................................................52 
9.3 
Protection of Human Subjects .....................................................................................52 
9.3.1 
Compliance with Informed Consent Regulations ..................................................52 
9.3.2 
Compliance with IRB Requirements .....................................................................52 
9.3.3 
Compliance with Good Clinical Practice ...............................................................53 
9.3.4 
Compliance with Electronic Records/Signatures Regulations ..............................53 
9.3.5 
Compliance with Protocol.....................................................................................53 
9.3.6 
Changes to the Protocol ......................................................................................53 
9.3.7 
Vulnerable Subjects .............................................................................................53 
10 
Data Collection, Monitoring and Reporting ..................................................................53 
10.1 
Confidentiality and Privacy ..........................................................................................53 
11 
Source Documents .....................................................................................................53 
11.1 
Records Retention ......................................................................................................54 
12 
Safety and Quality Monitoring .....................................................................................54 
12.1 Safety Review................................................................................................................54 
12.2 Clinical Monitoring .........................................................................................................55 
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Clinical Protocol 
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Protocol Version: 4.0 
 
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13 
Financing and Insurance ............................................................................................55 
14 
Publication Policy .......................................................................................................55 
15 
List of Abbreviations ...................................................................................................57 
16 
References .................................................................................................................59 
 
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RRP-001 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 23Jul2021 
CONFIDENTIAL 
Protocol Version: 4.0 
 
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CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: An open-label multi-center study of INO-3107 with electroporation (EP) in subjects 
with HPV-6- and/or HPV-11-associated recurrent respiratory papillomatosis (RRP) 
Protocol Number: RRP-001 
Clinical Trial Phase: 1/2 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 12 sites in the 
US 
Clinical Trial Design: This is a Phase 1/2 open-label, multicenter trial to evaluate the safety, 
tolerability, immunogenicity, and efficacy of INO-3107 in subjects with HPV-6 and/or HPV-11- 
associated RRP. 
INO-3107 will be administered IM followed by EP in subjects at Day 0, Weeks 3, 6, and 9.  
Approximately 20 subjects will receive INO-3107 via standard needle, followed by approximately 
10 subjects who will receive INO-3107 via the Side Port Needle. 
            
 
This study will enroll approximately 30 adults (≥18 years old) who have been diagnosed with 
either Juvenile-Onset RRP (J-O RRP) as defined by age at first diagnosis <12 years or with Adult-
Onset RRP (A-O RRP) as defined by age at first diagnosis ≥12 years. 
This study will have a safety-run in: 
Up to six subjects will be enrolled with a one week waiting period between each enrolled subject.  
Each subject will be assessed up to Week 6. Once the first three subjects of up to these six have 
completed Week 6 assessments, in the absence of dose-limiting toxicity (DLT), subject enrollment 
may begin in full after review of safety data and discussion between the Sponsor’s Medical 
Monitor and the Investigator(s) at the subjects’ site. However, if prior to the first three to six 
subjects completing Week 6, a single subject from the first six experiences a DLT then enrollment 
will be limited to six subjects until all six subjects have reached Week 6 and are assessed for 
DLT. 
If a second subject within the first 6 experiences a DLT within the first 6 weeks, enrollment will 
stop, and the Sponsor’s Medical Monitor and Investigator(s) at the subjects’ site(s) will discuss 
the case, and a decision will be made whether to cease further enrollment.  If a change to the 
protocol is required, enrollment will only be re-initiated after amendment of the protocol and 
approval of the amended protocol by the respective study IRBs. 
Enrollment will continue until approximately 30 subjects are enrolled.   
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RRP-001 
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Clinical Protocol 
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Protocol Version: 4.0 
 
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Safety and tolerability will continue to be assessed throughout the study after initial tolerability has 
been established in the first six subjects.  If more than two subjects experience a DLT at any time 
during the study, after the initial six subjects are enrolled, the Sponsor will pause enrollment until 
further discussion with the site Investigator determines that the study may reopen to enrollment. 
Tolerability will be determined by the reported incidence of dose-limiting toxicity (DLT), which is 
defined as: 
- 
Treatment-related NCI Common Terminology Criteria for Adverse Events (CTCAE, 
version 5.0) Grade ≥3 non-hematological toxicity that does not respond to supportive 
therapy and lasts for longer than 48 hours, or; 
- 
Treatment-related NCI CTCAE v5.0 Grade ≥3 hematological toxicity that does not respond 
to supportive therapy and lasts for longer than 48 hours. 
Additionally, enrollment and additional dosing will be paused until Sponsor discussion with the site 
Investigator determines that enrollment and dosing may continue if the following CTCAE v5.0 
events are reported at any time in the study:  
• 
One Grade 4 or 5 related SAE;  
• 
Two Grade 3 related SAEs  
Subjects will undergo routine surgical procedure for removal of papilloma(s) during the screening 
period within 14 days prior to Day 0 dosing (papilloma removal and Day 0 dose may be performed 
same day if other eligibility criteria have been fulfilled).  Biopsy tissue will be collected and sent to 
 for evaluation of secondary 
 endpoints.  Archival tissue (slides 
or blocks) obtained within one year of the screening window may be used, or a biopsy conducted 
during routine surgery.   
Status of disease during the trial will be monitored by the Investigator during laryngoscopy, 
including documentation with Staging Assessment scores.  If at any time during the trial, surgical 
removal (including laser) of papilloma is clinically indicated per PI judgement, the subject may 
undergo procedure for papilloma removal, but this must be captured on the electronic case report 
form.   
Documentation of the Staging Assessment score prior to surgery is required, and explanation for 
requirement of surgical removal of papilloma must be documented.  Surgical interventions during 
the trial must be documented to include information about the appearance and location of tissue 
being removed and instruments used. Video/photographic documentation of laryngoscopy is 
required. 
This trial will not utilize a Data Safety Monitoring Board.  This is a single-arm, open-label trial. The 
Sponsor will have access to unblinded safety and tolerability data during the trial. At a minimum, 
the Sponsor’s Medical Monitor will review reported adverse events quarterly. 
Criteria for Evaluation:  
 
Research Hypothesis: INO-3107, 
 
 
delivered intramuscularly (IM) followed by electroporation (EP) with 
CELLECTRA® 2000 will be generally safe and well-tolerated in subjects with recurrent 
respiratory papillomatosis secondary to HPV-6 and/or HPV-11. 
 
Primary Objective: To evaluate the safety and tolerability of INO-3107 in subjects with HPV-6 
and/or HPV-11- associated RRP.  
 
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Clinical Protocol 
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Primary Endpoint: Safety and tolerability as assessed by reported adverse events (AE) and 
serious adverse events (SAE). 
 
Secondary Objective(s): 
1. To evaluate the efficacy of INO-3107, as determined by the frequency of RRP surgical 
interventions in the year following the first dose of investigational product, compared to 
the frequency in the year prior to Day 0. 
2. To evaluate the efficacy of INO-3107 as assessed by changes in the RRP Staging 
Assessment over time. 
3. To evaluate the cellular immune response to INO-3107 when given IM, followed by EP.  
4. To evaluate the immunogenicity of INO-3107 as assessed by pro-inflammatory and 
immunosuppressive elements in resected tumor tissue at study entry and, if available, 
at subsequent tissue resections. 
5. To evaluate any potential association of microRNA (miRNA) profile with decreased 
frequency of RRP surgical intervention. 
 
Secondary Endpoint(s): 
1. Number of RRP surgical interventions in the one year following Day 0, compared to the 
one year prior to Day 0. 
2. Changes in Staging Assessment as measured by the RRP Staging Assessment score 
over time. 
3. Antigen-specific cellular immune responses assessed by: 
• 
IFN-γ secreting cells in peripheral blood mononuclear cells (PBMCs) by ELISpot  
• 
T cell phenotype and lytic potential in PBMCs by flow cytometry 
4. Assessment of pro-inflammatory and immunosuppressive elements in resected tumor 
tissue, if available. 
5. miRNA profile as related to the reduction in frequency of RRP surgical intervention, if 
possible. 
  
Exploratory Objective(s):  
1. To describe the virologic clearance of HPV-6/11 in resected tissue, if available. 
2. To evaluate the humoral immunogenicity to INO-3107 when given IM, followed by EP.  
3. To evaluate the immunogenicity of INO-3107 as assessed by pro-inflammatory and 
immunosuppressive elements in peripheral blood. 
4. To evaluate circulating free HPV DNA (cfHPV DNA) 6/11 as a correlate of disease burden 
and clinical outcomes in RRP patients treated with INO-3107. 
5. To evaluate the response to INO-3107 by needle type. 
 
Exploratory Endpoint(s):  
1. Clearance of HPV-6 and/or 11 in resected tissue compared to baseline. 
2. Antigen-specific humoral immune responses assessed by ELISA. 
3. Assessment of pro-inflammatory and immunosuppressive elements in peripheral blood. 
4. Quantity of cfHPV DNA 6/11 pre- and post-INO-3107 as a correlate of disease burden 
and clinical outcomes in RRP patients treated with INO-3107. 
5. 
 
Safety Assessment: Subjects will be followed for safety from the time of signing informed consent 
through Week 52, or the subject’s last visit.  All adverse events including SAEs, UADEs, DLTs 
and other AEs will be recorded. Clinically significant changes in laboratory parameters and vital 
signs from baseline assessments will be assessed. 
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Efficacy Assessment: A detailed medical history will be obtained for each subject which will 
include documentation of HPV-6 and/or HPV-11 RRP, a list of RRP surgeries and therapies 
occurring within 3 years prior to screening, and any periods of remission.  Subjects must have 
had at least two surgical RRP interventions (including laser) in the year prior to and including 
Day 0, to be eligible for the trial.  Subjects must require RRP intervention at the time of entry 
into this study and will undergo routine surgical removal of their papilloma(s) during screening, 
within 14 days prior to Day 0 dosing, to maximize standardization of baseline staging across 
subjects. 
 
The efficacy assessment will be based upon the number of RRP surgical interventions in the 
52 weeks post Day 0 compared to the number of RRP surgical interventions in the year prior 
to Day 0 dosing.  RRP surgical interventions include laser therapies.  The trial will also evaluate 
changes in RRP Staging Assessment over time.  
Immunogenicity Assessment: The trial will explore 
 cell mediated immune responses 
in blood samples taken at baseline (i.e. Screening and Day 0 prior to dosing) and Weeks 6, 9, 11, 
26, and 52. Tissue samples will be collected at baseline and if clinically indicated during the study. 
 
Clinical Trial Population: Subjects with HPV-6- and/or HPV-11-associated RRP, who require at 
least two surgical interventions per year for the past year (minimum), for removal of associated 
papilloma(s). Approximately 30 adult subjects (aged 18 and older) diagnosed with Juvenile-Onset 
RRP (age at diagnosis <12 years) or Adult-Onset RRP (age at diagnosis ≥12 years) will be 
enrolled. 
Inclusion Criteria; Subjects Must: 
1. Provide written IRB-approved informed consent in accordance with institutional guidelines; 
2. Be ≥18 years of age on the day of signing the informed consent, and able and willing to 
comply with all trial procedures; 
3. Have histologically documented HPV-6- and/or HPV-11-positive respiratory papilloma or 
documentation of low-risk positive HPV using a Sponsor approved HPV-6/11 type-specific 
assay; 
4. Have a requirement for frequent RRP intervention in order to remove or resect respiratory 
papilloma, as defined as at least two RRP surgical (including laser) interventions in the year 
prior to and including Day 0; 
5. Must be appropriate candidate for upcoming surgical intervention per investigator judgement 
and RRP Staging Assessment score (see Section 6.4.5);  
6. Have adequate bone marrow, hepatic, and renal function as defined by: ANC (Absolute 
Neutrophil Count) ≥1000 cells/mm3, platelets ≥50,000/mm3, hemoglobin ≥9 g/dL; 
concentrations of total serum bilirubin within 1.5 x upper limit of normal (ULN), AST and ALT 
within 1.5 x ULN, serum creatinine ≤ 1.5 x ULN;  
7. Agree that during the trial, male participants will not father a child, and female participants 
cannot be or become pregnant if they are of child-bearing potential. Subjects must meet one 
of the below requirements: 
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a. Be of non-childbearing potential (≥12 months of non-therapy-induced amenorrhea, 
confirmed by follicle stimulating hormone [FSH], if not on hormone replacement);  
b. Be surgically sterile (vasectomy in males or absence of ovaries and/or uterus in females);  
c. Agree to use one highly effective or combined contraceptive methods that result in a failure 
rate of <1% per year during the treatment period and at least through week 12 after last 
dose. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.  
d. Agree to abstinence from penile-vaginal intercourse, when this is the subject’s preferred 
and usual lifestyle. 
Exclusion Criteria; Subjects Must Not: 
1. Receive therapy directed towards RRP disease (other than surgery or ablation) including 
but not limited to anti-virals (including cidofovir), radiation, chemotherapy, anti-angiogenic 
therapy (including bevacizumab), prophylactic HPV vaccination (including Gardasil) as 
therapeutic intervention, or therapy with an experimental agent within 3 months prior to 
Day 0; 
2. Have ongoing or recent (within one year) evidence of autoimmune disease that required 
treatment with systemic immunosuppressive treatments, with the exception of: vitiligo, 
childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that requires 
only hormone replacement, or psoriasis that does not require systemic treatment; 
3. Have a diagnosis of immunodeficiency or treatment with systemic immunosuppressive 
therapy within 28 days prior to the first dose of trial treatment, including systemic 
corticosteroids; 
4. Have a high risk of bleeding or require the use of anti-coagulants for management of a 
known bleeding diathesis; 
5. Receive any live virus vaccine within 4 weeks prior to first dose of trial treatment or any 
non-live vaccine within two weeks prior to the first dose of trial treatment; 
6. Have a history of clinically significant, medically unstable disease which, in the judgment 
of the Investigator, would jeopardize the safety of the subject, interfere with trial 
assessments or endpoint evaluation, or otherwise impact the validity of the trial results.  
This may include chronic renal failure; myocardial ischemia or infarction; New York Heart 
Association (NYHA) class III/ IV cardiac disease); any cardiac pre-excitation syndromes 
(such as Wolff-Parkinson-White; cardiomyopathy, or clinically significant arrhythmias); 
current malignancy with the exception of treated basal or squamous cell skin cancers, 
prostate cancer, or carcinoma of the cervix in situ; HIV, which may impact the ability to 
mount an immune response to the study therapy; or drug or alcohol dependence; 
7. Have fewer than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles. The following are unacceptable sites: 
a. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment 
site; 
b. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) 
that is located ipsilateral to the deltoid injection site (unless deemed acceptable by 
a cardiologist); 
c. Metal implants or implantable medical device within the intended treatment site; 
8. Be imprisoned, or compulsory detainment (involuntary incarceration) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
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9. Be pregnant or currently breastfeeding; 
10. As determined by the Investigator, have any medical or psychological or non-medical 
condition that might interfere with the subject’s ability to participate or affect the safety of 
the subject. 
Clinical Trial Treatment:  
Subjects will receive a 1 mL injection of INO-3107 IM followed by EP.  Doses will be administered 
at Day 0, Weeks 3, 6, and 9. 
 
 
Device: CELLECTRA® 2000. 
 
 
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SCHEDULE OF EVENTS 
Schedule of Events 
 
Screening 
Day 0 
Week 3 (±4 days) 
Week 6 (±4 days) 
Week 9 (±4 days) 
Week 11 (±1 week) 
Week 26 (±2 week) 
Week 52 /End of study (±2 
weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history, smoking history 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Concomitant medications, AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exama 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
Height, weight, BMI 
 
X 
X 
X 
X 
 
 
 
Safety labsb 
X 
X 
X 
X 
X 
 
 
 
Pregnancy test, if applicablec 
X 
X 
X 
X 
X 
 
 
 
INO-3107  
 
X 
X 
X 
X 
 
 
 
Immunology samples 
X 
X 
 
X 
X 
X 
X 
X 
Laryngoscopy and Staging 
assessmente 
Xf 
 
 
X 
 
X 
X 
X 
Tissue sampleg 
X 
 
 
 
 
 
 
X 
 
 
a. 
Full physical examination (PE) mandatory at screening and study discharge (Week 52/End of Study visit or 
relapse), otherwise targeted physical assessment as determined by the Investigator or per subject complaints. 
b. 
Collected within 72 hours prior to dosing such that results are available and assessed against DLT criteria 
prior to dosing. 
c. 
For women of childbearing potential, a negative serum pregnancy test is required at screening and a negative 
spot urine pregnancy test is required prior to each study treatment. 
 
 
e. 
Staging assessment to be performed during each laryngoscopy and prior to any RRP intervention using the 
RRP Staging Assessment tool.  Video/photographic documentation of laryngoscopy is required.    
f. 
Staging to be performed prior to Routine RRP intervention at Screening, followed by dosing within 14 days.  
g. 
Biopsy tissue should be sent for HPV typing and immunological evaluation at Screening, Week 52, and at any 
tissue resection, if applicable. Archival tissue collected within 1 year of Day 0 may be sent at screening.  Biopsy 
required with laryngoscopy at Week 52. 
 
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1.0 
INTRODUCTION 
1.1 BACKGROUND AND SCIENTIFIC RATIONALE: RRP 
Human papilloma virus (HPV)-associated malignancies are an emerging global epidemic 
[1]. The role of HPV-6 and -11 in the etiology of recurrent respiratory papillomatosis (RRP), 
the most common benign tumor(s) of the laryngeal epithelium, is well-established [2, 3]. 
RRP is rare, with an incidences estimated at 1.8 per 100,000 adults in the United States 
[4], and age of diagnosis ranging from young children to older adults. Although most lesions 
are benign, some undergo malignant transformation, and patients with RRP have a higher 
risk of developing laryngeal carcinomas [5].  
 
HPV-6 and -11 RRP-associated lesions can occur in the oropharynx, larynx, and upper 
respiratory tract and the clinical course of RRP varies amongst affected individuals. 
Selection of treatment, including active monitoring without treatment, surgery, adjuvant 
therapy, or a combination, depends on clinical history and expected clinical course.  
Repeated surgical removal of papillomas for symptomatic management remains the 
mainstay of treatment and results in significant morbidity considering the number of 
surgical procedures required, impact on voice, effects of repetitive anesthesia, 
psychological impact, etc [6]. Rarely, malignant transformation may occur, which is usually 
associated with a dismal prognosis. A few such patients with malignant disease may be 
candidates for salvage therapies, including potentially definitive surgery [7, 8]. Selected 
patients in this setting may benefit from radiation although the morbidity of this approach 
is substantial [8]. Recently, a Phase 2 study of pembrolizumab in patients with RRP 
demonstrated a response rate of 43%, and this observation supports a rationale for 
immunotherapeutic management of RRP [9]. 
 
Current treatment of HPV-6- and HPV-11-related RRP could potentially be improved or 
replaced with the addition of HPV-specific immunotherapy. Available preventive HPV 
vaccines can generate neutralizing antibodies against the HPV major capsid protein L1, 
but they have not demonstrated therapeutic effects on HPV infection or existing lesions, 
and are unlikely to engender a cytolytic T-cell response [10]. HPV-specific immunotherapy 
targeting E6 and E7 proteins, on the other hand, may have therapeutic potential to 
eliminate preexisting lesions and infections by generating immunity against the HPV virus 
itself and HPV infected cells. HPV E6 and E7 oncoproteins represent ideal targets for this 
type of therapeutic intervention because of their constitutive expression in HPV associated 
tumors and their crucial role in the induction and maintenance of HPV associated diseases 
[10]. 
 
Preclinical studies of INO-3106, a synthetic DNA plasmid encoding versions of the E6 and 
E7 proteins of HPV-6, have demonstrated strong and specific immune response in animal 
models [10]. HPV-16/18-specific therapy (VGX-3100) designed and evaluated based on the 
same synthetic consensus platform, has demonstrated cellular immune responses that 
correlated with clinical benefit in the form of dysplastic lesion regression and elimination 
of HPV-16/18 infection in  a Phase 2 study, and now support late-phase ongoing clinical 
trials targeting HPV-16 and HPV-18 associated diseases [11].   
 
A pilot clinical study was conducted in three subjects with HPV-6-associated 
papillomatosis (HPV-006), treated with INO-3106, and was deemed tolerable.  
Importantly, INO-3106 was able to demonstrate immunogenicity against HPV-6 E6 and 
E7 proteins, and evidence of clinical benefit, in two of the three patients treated.  Two 
patients with RRP who previously required every six-month debridement of their RRP 
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lesions, extended their intersurgical times in a meaningful way; one patient sustaining a 
surgery-free interval for over 900 days, and another for over 500 days, following therapy 
with INO-3106 on-study [12].  Following on this study, Inovio is conducting a study of INO-
3107, comprised of a single plasmid that encodes for both HPV-6 and HPV-11 E6 an E7 
proteins, plus a single plasmid that encodes for IL-12.  Inovio is conducting this study in 
adults with RRP who are at risk of requiring additional and continuous surgery to manage 
their disease.  It is hypothesized that INO-3107 will be safe, tolerable, immunogenic and 
efficacious in the treatment of patients with HPV-6 and/or HPV-11-associated RRP. 
1.2 BACKGROUND INFORMATION: DNA AND ELECTROPORATION WITH CELLECTRA® 
2000 
Synthetic DNA (sDNA) represents a novel approach for immunotherapy, and offers 
several potential advantages over current immunotherapies [13]. First, potent T-cell 
immune responses can be generated to virtually any antigenic sequence. Second, sDNA-
based therapies do not include any biological pathogen and therefore cannot revert to a 
virulent form as opposed to viral- or bacterial-based vaccines, which may mutate back to 
a virulent form or spread to unintended individuals. Toxicology studies have found no 
evidence of genome integration from sDNA vaccines [14, 15]. Third, repeated dosing of 
sDNA therapies is not hindered by neutralization from neutralizing antibodies that target 
for example viral vector sequences, resulting in decreased or no immunogenicity from 
these viral-based vaccines. Thus, sDNA therapy allows repeated dosing (or boosting) to 
potentially increase or maintain immunogenicity over long periods of time. Finally, sDNA 
therapies are relatively easy to manufacture in large quantities and are generally 
temperature-stable for long periods of time. Prior work by Inovio on DNA vaccines for 
HPV-specific therapy has demonstrated promising preliminary results that support late-
phase clinical trials targeting HPV 16 and 18 associated diseases and cancers [11]. 
 
This study will utilize Inovio’s INO-3107 drug product. 
 
 
  INO-
3107 is given IM, followed by EP. 
 
Preclinical studies have shown that the immunogenicity of DNA therapies can be 
substantially increased by the use of cytokine adjuvants [16-20]. Importantly, the concomitant 
injection of a plasmid encoding for the human IL-12 cytokine has been shown to enhance 
sDNA therapy-mediated immunogenicity in humans when delivered using the 
CELLECTRA® 2000 EP device [21, 22]. We have established in multiple clinical studies 
targeting both IM and intradermal (ID) delivery that sDNA delivered with the CELLECTRA® 
2000 device is a reproducible method of generating immunity in humans for various 
potential clinical indications ranging from the treatment of cancer to the induction of 
pathogen prophylaxis [1, 11, 21-27].   
 
Electroporation has repeatedly shown to be an efficient way to introduce DNA into cells 
[28, 29]. The mechanism of EP is to create a transient electric field that induces temporary 
and reversible pores in the cell membrane, allowing DNA plasmids to enter the cells. This 
technology has been used for more than three decades by molecular biologists for cell 
transfection but in the treatment of human diseases, EP remains experimental in the clinic. 
Clinical applications of EP have been tested in treatment of cancer and for gene therapy 
[30-32]. The CELLECTRA® 2000 EP device to be used in this study has been used in several 
clinical trials, demonstrating a tolerable safety prolife and improved efficacy of DNA 
transfection (see Section 1.4).  
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This clinical trial will be conducted in compliance with the clinical study protocol, Good 
Clinical Practice, and applicable regulatory requirements. 
1.3 RATIONALE 
Inovio’s sDNA therapy VGX-3100 has demonstrated tolerability, immunogenicity and 
efficacy in a randomized Phase 2b study in HPV-16/18 pre-malignant disease of the 
cervix, and a pilot study of INO-3106 with INO-9012 in three patients with HPV-6-related 
aerodigestive disease which demonstrated tolerability, immunogenicity and preliminary 
efficacy, specifically in two patients with RRP.  RRP, although rare, continues to be 
diagnosed in adults and adolescents, and in children.  Therapeutic treatment consists of 
frequently recurring surgery, and there are few other therapies currently in development.  
Historical or ongoing clinical studies include evaluating anti-virals (cidofovir), angiogenesis 
inhibitors (bevacizumab), and checkpoint inhibitors (pembrolizumab, others), and those 
have shown some promising results [2].  However, no product has been labeled for RRP.  
INO-3107 has the potential to generate robust T cell responses against HPV-6 and HPV-
11 E6 and E7, resulting in eradication of RRP lesions and ideally, eradication of HPV-6 or 
HPV-11, in patients treated with INO-3107.  This study will assess the safety and 
tolerability, immunogenicity, and efficacy of INO-3107 in adults with RRP. 
 
This study will utilize the dose and schedule previously used in the Inovio HPV-006 study 
of INO-3106 and INO-9012, in which 6 mg of INO-3106 was given IM followed by EP every 
three weeks for four doses.  In this study, 6.25 mg of INO-3107 will be given every three 
weeks for four doses.  Subjects will be required to have demonstrated a prior history of 
requiring surgical intervention to manage their RRP, and follow-up will assess safety, 
tolerability, immunogenicity and the frequency of RRP surgical interventions post Day 0 
compared to pre-dose.  Patients will be followed for approximately 12 months after the 
first dose. 
1.4 POTENTIAL BENEFITS AND RISKS 
INO-3107 has the potential to treat patients with HPV-6 and/or HPV-11-associated RRP, 
reducing the number of surgical interventions required to control the disease, and 
potentially to eradicate the virus in treated patients, potentially resulting in a disease cure.  
This not only would reduce exposure to future inevitable surgical intervention but would 
also remove the signs and symptoms associated with RRP and the potential for malignant 
transformation and development of HPV-6- or HPV-11-associated cancer. 
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The risks associated with DNA therapy have been well described and are coupled with 
the risks of EP with the CELLECTRA® 2000 device.  Over 6000 injections have been 
delivered and over 2000 subjects have received injections with the Inovio platform utilizing 
the CELLECTRA® 2000 device to date.  In general, the risks associated with DNA therapy 
and the CELLECTRA® 2000 device are limited to localized injection reactions, including 
injection site pain, erythema, edema or bruising; fever, fatigue, headache, myalgia, and 
arthralgia have also been reported.  Pain associated with the CELLECTRA® device has 
been well-characterized and is largely transient [33]. 
 
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2.0 
OBJECTIVES AND PURPOSE 
This is a Phase 1/2 open-label, multicenter trial to evaluate the safety, tolerability, 
immunogenicity, and efficacy of INO-3107 in subjects with RRP. 
2.1 HYPOTHESIS 
INO-3107,
 
 
delivered intramuscularly (IM) followed by electroporation (EP) with CELLECTRA® 2000 
will be generally safe and well-tolerated in subjects with recurrent respiratory 
papillomatosis secondary to HPV-6 and/or HPV-11. 
3.0 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is a Phase 1/2 open-label, multicenter trial to evaluate the safety, tolerability, 
immunogenicity, and efficacy of INO-3107 in subjects with RRP.  INO-3107 will be 
administered IM followed by EP in subjects at Day 0, Weeks 3, 6, and 9.  Approximately 
20 subjects will receive INO-3107 via standard needle, followed by approximately 10 
subjects who will receive INO-3107 via the Side Port Needle. 
This trial will enroll approximately 30 adults (≥18 years old) who have been diagnosed 
with either Juvenile-Onset RRP (J-O RRP) as defined by age at first diagnosis <12 years 
or Adult-Onset RRP (A-O RRP) as defined by age at first diagnosis ≥12 years. 
This study will have a safety-run in: 
Up to six, subjects will be enrolled with a one week waiting period between each enrolled 
subject.  Each subject will be assessed up to Week 6. Once the first three subjects of up 
to these six have completed Week 6 assessments, in the absence of dose-limiting 
toxicity (DLT), subject enrollment may begin in full after review of safety date and 
discussion between the Sponsor’s Medical Monitor and the Investigator’s at the subjects’ 
site. However, if prior to the first three to six subjects completing Week 6, a single subject 
from the first six experiences a DLT then enrollment will be limited to six subjects until 
all six subjects have reached Week 6 and are assessed for DLT. 
If a second subject within the first 6 experiences a DLT within the first 6 weeks, 
enrollment will stop, and the Sponsor’s Medical Monitor and Investigator(s) at the 
subjects’ site(s) will discuss the case, and a decision will be made whether to cease 
further enrollment. If a change to the protocol is required, enrollment will only be re-
initiated after amendment of the protocol and approval of the amended protocol by the 
respective study IRBs. 
Enrollment will continue until approximately 30 subjects are enrolled.   
Safety and tolerability will continue to be assessed throughout the study after tolerability 
has been established in the first six subjects.  If more than two subjects experience a 
DLT at any time during the study, after the initial six subjects are enrolled, the Sponsor 
will pause enrollment until further discussion with the site Investigator determines that 
the study may reopen to enrollment. 
Tolerability will be determined by the reported incidence of dose-limiting toxicity (DLT), 
which is defined as: 
o Treatment-related NCI Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0) Grade ≥3 non-hematological toxicity that does not respond 
to supportive therapy and lasts for longer than 48 hours, or; 
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o Treatment-related NCI CTCAE v5.0 Grade ≥3 hematological toxicity that does 
not respond to supportive therapy and lasts for longer than 48 hours. 
Additionally, enrollment and additional dosing will be paused until Sponsor discussion 
with the site Investigator determines that enrollment and dosing may continue, if the 
following CTCAE v5.0 events occur at any time in the study:  
• 
One Grade 4 or 5 related SAE;  
• 
Two Grade 3 related SAEs 
Subjects will undergo routine surgical procedure for removal of papilloma(s) during the 
screening period within 14 days prior to Day 0 dosing (papilloma removal and Day 0 
dose may be performed same day if other eligibility criteria have been fulfilled). Biopsy 
tissue will be collected and sent to 
 for evaluation of secondary 
 
 endpoints.  Archival tissue (slides or blocks) obtained within one year of the 
screening window may be used, or a biopsy conducted during routine surgery. 
Status of disease during the trial will be monitored by the Investigator during 
laryngoscopy including documentation with Staging Assessment scores.  If at any time 
during the trial, surgical removal (including laser) of papilloma is clinically indicated per 
PI judgement, the subject may undergo procedure for papilloma removal but this must 
be captured on the electronic case report form.  Documentation of the Staging 
Assessment score prior to surgery is required, and explanation for requirement of 
surgical removal of papilloma must be documented. 
Surgical interventions during the trial must be documented to include at a minimum, 
information about the appearance and location of tissue being removed and instruments 
used. Video/photographic documentation of laryngoscopy is required. 
This trial will not utilize a Data Safety Monitoring Board.  This is a single-arm, open-label 
trial. The Sponsor will have access to unblinded safety and tolerability data during the 
trial. At a minimum, the Sponsor’s Medical Monitor will review reported adverse events 
quarterly. 
3.1 PRIMARY OBJECTIVE 
To evaluate the safety and tolerability of INO-3107 in subjects with HPV-6 and/or HPV-
11- associated RRP. 
3.2 PRIMARY ENDPOINT 
Safety and tolerability as assessed by reported adverse events (AE) and serious adverse 
events (SAE). 
3.3 SECONDARY OBJECTIVE(S) 
1. To evaluate the efficacy of INO-3107, as determined by the frequency of RRP 
surgical interventions in the year following the first dose of investigational product, 
compared to the frequency in the year prior to Day 0. 
2. To evaluate the efficacy of INO-3107 as assessed by changes in the RRP Staging 
Assessment over time. 
3. To evaluate the cellular immune response to INO-3107 when given IM, followed 
by EP.  
4. To evaluate the immunogenicity of INO-3107 as assessed by pro-inflammatory 
and immunosuppressive elements in resected tumor tissue at study entry and, if 
available, at subsequent tissue resections. 
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5. To evaluate any potential association of microRNA (miRNA) profile with decreased 
frequency of RRP surgical intervention. 
3.4 SECONDARY ENDPOINT(S) 
1. Number of RRP surgical interventions in the one year following Day 0, compared 
to the one year prior to Day 0. 
2. Changes in Staging Assessment as measured by the RRP Staging Assessment 
score over time. 
3. Antigen-specific cellular immune responses assessed by: 
• 
IFN-γ secreting cells in peripheral blood mononuclear cells (PBMCs) by 
ELISpot  
• 
T cell phenotype and lytic potential in PBMCs by flow cytometry 
4. Assessment of pro-inflammatory and immunosuppressive elements in resected 
tumor tissue, if available. 
5. miRNA profile as related to the reduction in frequency of RRP surgical intervention, 
if possible. 
  
1. To describe the virologic clearance of HPV-6 and/or 11 in resected tissue, if 
available. 
2. To evaluate the humoral immune response to INO-3107 when given IM, followed 
by EP.  
3. To evaluate the immunogenicity of INO-3107 as assessed by pro-inflammatory 
and immunosuppressive elements in peripheral blood. 
4. To evaluate circulating free HPV DNA (cfHPV DNA) 6/11 as a correlate of disease 
burden and clinical outcomes in RRP patients treated with INO-3107. 
5. To evaluate the response to INO-3107 by needle type. 
  
1. Clearance of HPV-6/11 in resected tissue compared to baseline. 
2. Antigen-specific humoral immune responses assessed by ELISA. 
3. Assessment of pro-inflammatory and immunosuppressive elements in peripheral 
blood. 
4. Quantity of cfHPV DNA 6/11 pre- and post-INO-3107 as a correlate of disease 
burden and clinical outcomes in RRP patients treated with INO-3107. 
5. Clinical, and antigen-specific cellular and 
 
 
 
 
 
3.7 EFFICACY ASSESSMENT  
A detailed medical history will be obtained for each subject which will include 
documentation of HPV-6 and/or HPV-11 RRP, a list of RRP surgeries and therapies 
occurring within 3 years prior to screening, and any periods of remission.  Subjects 
must have had at least two surgical RRP interventions (including laser) in the year 
prior to and including Day 0, to be eligible for the study.  Subjects must require RRP 
intervention at the time of entry into this study and will undergo surgical removal of 
their papilloma(s) during screening, within 14 days prior to Day 0 dosing, to maximize 
standardization of baseline staging across subjects.   
The efficacy assessment will be based upon the number of RRP surgical interventions 
in the 52 weeks post Day 0 compared to the number of RRP surgical interventions in 
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the year prior to Day 0 dosing.  RRP surgical interventions include laser therapies.  
The trial will also evaluate changes in RRP Staging Assessment over time as a 
secondary endpoint. 
3.8 SAFETY ASSESSMENT 
Subjects will be followed for safety from the time of signing informed consent through 
Week 52, or the subject’s last visit.  All adverse events including SAEs, UADEs, and DLTs. 
Clinically significant changes in laboratory parameters and vital signs from baseline 
assessments will be assessed.  
3.9 IMMUNOGENICITY ASSESSMENT 
The study will explore 
 cell mediated immune responses in blood samples 
taken at baseline (i.e. Screening and Day 0 prior to dosing) and Weeks 6, 9, 11, 26, and 
52. Tissue samples will be collected at baseline and if clinically indicated during the study. 
 
 
 
 
 
4.0 
CLINICAL TRIAL POPULATION 
4.1 INCLUSION CRITERIA 
1. 
Provide written IRB-approved informed consent in accordance with institutional 
guidelines; 
2. 
Be ≥18 years of age on the day of signing the informed consent, and able and willing 
to comply with all trial procedures; 
3. 
Have histologically documented HPV-6- or HPV-11-positive respiratory papilloma or 
documentation of low-risk positive HPV using a Sponsor approved HPV-6/11 type-
specific assay; 
4. 
Have a requirement for frequent RRP intervention in order to remove or resect 
respiratory papilloma, as defined as at least two RRP surgical (including laser) 
interventions in the year prior to and including Day 0; 
5. 
Must be appropriate candidate for upcoming surgical intervention per investigator 
judgement and RRP Staging Assessment score (see Section 6.4.5);  
6.  Have adequate bone marrow, hepatic, and renal function as defined by: ANC 
(Absolute Neutrophil Count) ≥1000 cells/mm3, platelets ≥50,000/mm3, hemoglobin ≥9 
g/dL; concentrations of total serum bilirubin within 1.5 x upper limit of normal (ULN), 
AST and ALT within 1.5 x ULN, serum creatinine ≤ 1.5 x ULN; 
7. 
Agree that during the trial, male participants will not father a child, and female 
participants cannot be or become pregnant if they are of child-bearing potential. 
Subjects must meet one of the below requirements: 
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a.  Be of non-childbearing potential (≥12 months of non-therapy-induced 
amenorrhea, confirmed by follicle stimulating hormone [FSH], if not on hormone 
replacement;  
b.  Be surgically sterile (vasectomy in males or absence of ovaries and/or uterus in 
females);  
c.  Agree to use one highly effective or combined contraceptive methods that result 
in a failure rate of <1% per year during the treatment period and at least through 
week 12 after last dose. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.  
d.  Agree to abstinence from penile-vaginal intercourse, when this is the subject’s 
preferred and usual lifestyle. 
4.2 EXCLUSION CRITERIA 
Subjects Must Not: 
1. Receive therapy directed towards RRP disease (other than surgery or ablation) 
including but not limited to anti-virals (including cidofovir), radiation, chemotherapy, 
anti-angiogenic therapy (including bevacizumab), prophylactic HPV vaccination 
(including Gardasil) as therapeutic intervention, or therapy with an experimental agent 
within 3 months prior to Day 0; 
2. Have ongoing or recent (within one year) evidence of autoimmune disease that 
required treatment with systemic immunosuppressive treatments, with the exception 
of: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual 
hypothyroidism that requires only hormone replacement, or psoriasis that does not 
require systemic treatment; 
3. Have a diagnosis of immunodeficiency or treatment with systemic immunosuppressive 
therapy within 28 days prior to the first dose of trial treatment, including systemic 
corticosteroids; 
4. Have a high risk of bleeding or require the use of anti-coagulants for management of 
a known bleeding diathesis;  
5. Receive any live virus vaccine within 4 weeks prior to first dose of trial treatment or 
any non-live vaccine within two weeks prior to the first dose of trial treatment; 
6. Have a history of clinically significant, medically unstable disease which, in the 
judgment of the Investigator, would jeopardize the safety of the subject, interfere with 
trial assessments or endpoint evaluation, or otherwise impact the validity of the trial 
results.  This may include chronic renal failure; myocardial ischemia or infarction; New 
York Heart Association (NYHA) class III/ IV cardiac disease); any cardiac pre-
excitation syndromes (such as Wolff-Parkinson-White; cardiomyopathy, or clinically 
significant arrhythmias); current malignancy with the exception of treated basal or 
squamous cell skin cancers, prostate cancer, or carcinoma of the cervix in situ; HIV, 
which may impact the ability to mount an immune response to the study therapy; or 
drug or alcohol dependence; 
7. Have fewer than two acceptable sites available for IM injection considering the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
a. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment 
site; 
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b. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) 
that is located ipsilateral to the deltoid injection site (unless deemed acceptable by 
a cardiologist); 
c. Metal implants or implantable medical device within the intended treatment site; 
8. Be imprisoned, or compulsory detainment (involuntary incarceration) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
9. Be pregnant or current breastfeeding; 
10. As determined by the Investigator, have any medical or psychological or non-medical 
condition that might interfere with the subject’s ability to participate or affect the safety 
of the subject. 
4.3 DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
A subject will be considered to have completed the trial when the subject has completed 
all study visits through Week 52.  Subjects may withdraw consent at any time for any 
reason or be dropped from the trial at the discretion of the Investigator should any 
untoward effect occur.  In addition, the Investigator or the Sponsor has the right to 
discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor within 24 hours when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). 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.   
4.3.1 CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
A subject should not receive any further investigational product (IP) if any of the 
following occur: 
• 
Subject withdrawal of consent or subject is lost to follow up 
• 
An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing of any trial medication 
• 
Pregnancy 
• 
Subject non-compliance that, in the opinion of the Investigator or Sponsor, warrants 
discontinuation 
• 
Initiation of new contraindicated therapy 
In the absence of any of the above criterion, if limited clinical benefit is suspected at any 
time, IP may be discontinued after consultation between the Investigator and the Medical 
Monitor.   
4.3.2 CRITERIA FOR DISCONTINUATION FROM THE STUDY 
All subjects should be encouraged to complete all study treatments and follow up visits.  
If a subject is discontinued from treatment, the subject should be encouraged to stay in 
the study and complete all follow-up visits and procedures and have all scheduled immune 
assessment blood samples collected as indicated in the Schedule of Events (Table 1). At 
a minimum, the Investigator should request to have the subject complete the End of Study 
visit assessments as indicated in the schedule of events at the subject’s final visit.      
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5.0 
CLINICAL TRIAL TREATMENT 
5.1 INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
5.1.1 
INO-3107 
Investigational product (IP) is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-3107 is the IP to be used in this study. 
 
 
 
 
  
 
 
 
 
   
5.1.2      CELLECTRA® 2000 
The CELLECTRA® 2000 is a portable, battery-powered medical device designed to 
generate a minimally controlled, electric field which temporarily and reversibly increases 
cellular membrane permeability without damaging the tissue. During the period of 
increased permeability an indicated injected plasmid DNA formulation can be introduced 
into the cells. 
The CELLECTRA® 2000 device is indicated to enhance the uptake and expression of DNA 
plasmid-based biologics in order to enhance efficacy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
5.1.3 SIDE PORT NEEDLE 
As noted above, this study will utilize the Side Port Needle in approximately 10 of 30 
subjects
 
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5.2  TREATMENT REGIMEN 
Subjects will be administered one 6.25 mg injection of INO-3107 IM followed by EP at Day 
0, Week 3, Week 6, and Week 9.  
5.3 PACKAGING AND LABELING 
5.3.1 INO-3107 
Each vial of IP will be labeled with a single panel label consistent with the example product 
label provided in the Investigator’s Brochure (IB).  All subjects will receive active INO-
3107.   
5.3.2 CELLECTRA® 2000 AND SIDE PORT NEEDLE 
Please see shipping box for shipping documents and contents, and unpacking 
instructions. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. The CELLECTRA® 2000 
Pulse Generator and IM Applicator have unique serial numbers. Each IM Array has a Lot 
Number and Expiration Date. Examples of device labels are provided in the Investigator’s 
Brochure (IB). 
The CELLECTRA® 2000 device and its components will be shipped directly from the 
manufacturer to the study site. 
Side Port Needles will be provided to the study site and are packaged with the 
CELLECTRA® 2000 IM Array in a sterile enclosure. 
5.4 HANDLING AND STORAGE 
5.4.1 INO-3107 
 
 
 
 
 
 
 
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5.4.2 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
5.5 PREPARATION AND DISPENSING 
  
INO-3107 will be provided to the investigational pharmacy in vial form directly from the 
manufacturing facility or designee.  It is the responsibility of the Investigator to ensure that 
INO-3107 is only dispensed to study subjects.  
 
 
   
 
 
 
 
 
  
5.6 USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device is provided in the User Manual. 
Each clinical site will receive training for use of the CELLECTRA® 2000 device prior to first 
dose.  
 
 
 
 
5.7 INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
5.7.1 INO-3107 
It is the responsibility of the Investigator to ensure that a current record of IP accountability 
is maintained at the study site. The IP must have full traceability from the receipt of the 
product through participant use, disposal or return of the products. Records or logs must 
comply with applicable regulations and guidelines. The accountability information is 
provided in the Pharmacy Manual. 
5.7.2 CELLECTRA® 2000 ACCOUNTABILITY 
Each clinical site is responsible for maintaining investigational device accountability. The 
device must have full traceability from the receipt of the products through participant use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject treatment, there must be a record of each product used for that subject, 
i.e. Pulse generator and IM applicator serial numbers, and IM Array lot number. The IM 
Applicator is intended to be used multiple times on the same subject and then disposed 
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after final use in accordance with accepted medical practice and any applicable local, 
state, and federal laws and regulations. Once the IM Applicator is assigned to a subject, 
it may NOT be used on another subject. The used sterile disposable Array must be 
discarded after use in accordance with institutional policy for disposal of sharp 
needles/instruments. 
Site personnel will be requested to download EP data and provide to Inovio after each 
treatment. 
5.8 RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
5.8.1 INO-3107 
Upon completion or termination of the study, all unused and/or partially used IP must be 
destroyed at site per institution policy or returned to Inovio Pharmaceuticals, Inc. or its 
designee, if site cannot destroy IP. If IP is to be destroyed on site, it is the Investigator's 
responsibility to ensure that arrangements have been made for the disposal, written 
authorization has been granted by Inovio Pharmaceuticals, Inc., or its designee, 
procedures for proper disposal have been established according to applicable regulation 
and guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. Reconciliation of any unused IP must be performed and provided to 
the responsible Inovio Pharmaceuticals, Inc. or designated Study Monitor for review prior 
to on-site destruction. 
The used IP vials will be discarded per site’s used IP disposal procedure. It is the 
Investigator’s responsibility to arrange for disposal of all empty vials, 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.  
If requested by the Sponsor, the return of unused IP should be arranged by the responsible 
Inovio Representative or by the authorized site representative if an Inovio representative 
is not present. All IP returned to Inovio Pharmaceuticals, Inc., or its designee, must be 
accompanied by the appropriate documentation. Returned supplies should be in the 
original containers. Empty containers should not be returned to Inovio Pharmaceuticals, 
Inc. 
5.8.2 CELLECTRA® 2000  
Upon completion or termination of dosing, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All product returned to Inovio Pharmaceuticals Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the Inovio Representative. 
Used IM Arrays should be discarded in the sharp’s container immediately after use. The 
used IM Applicators can either be destroyed at the site, shipped to a destruction vendor, 
or returned to Inovio per instructions provided. If the used IM Applicators are destroyed on 
site, it is the Investigator’s responsibility to ensure that: 
• 
Arrangements have been made for disposal; 
• 
Written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
designee; 
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• 
Procedures for proper disposal have been established according to applicable 
regulation and guidelines and institutional procedures, and;  
• 
Appropriate records of the disposal have been documented. 
6.0 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Trial Schedule of Events in the Clinical Protocol Synopsis summarizes the trial 
procedures to be performed at each visit. Individual trial procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A participant will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
6.1 PROCEDURE BY VISIT 
Refer to sections 6.1.1 and 6.1.2 for study procedures and the times at which they are to 
be carried out. 
6.1.1 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and their ability to comply with protocol requirements by completing all screening 
assessments. Subjects’ post-menopausal status must meet requirements as specified in 
the inclusion criteria. The following screening evaluations will be performed within 60 days 
prior to dosing on Day 0. All screening assessment values must be reviewed prior to the 
first Study IP administration.  
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 60-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• Signed and dated informed consent (Section 6.2); 
• Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• Obtain and document complete medical history, surgical history (including all past 
procedures), present conditions and concomitant illnesses (Section 6.1.1.1); document all 
present and/or new or ongoing adverse events prior to administration of IP; 
• Collect demographics (Section 6.1.1.2); 
• Smoking history (Section 6.1.1.3); 
• Full physical examinations (Section 6.4.1); 
• Record current concomitant medications/treatments (Section 6.13); 
• Record vital signs heart rate (HR), respiratory rate (RR), blood pressure (BP) and body 
temperature (Section 6.4.2); 
• Record body weight, height and determine BMI (Section 6.4.3); 
• Collect blood for screening laboratory evaluations (Section 6.4.4); 
• Collect blood for serum pregnancy test, if applicable (Section 6.4.4); 
• Collect whole blood 
 for immunology assessment (Section 6.10); 
• Perform laryngoscopy and Staging assessment (Section 6.4.5) prior to surgical removal 
of papilloma(s). 
• Surgical removal of papilloma(s) 
• Biopsy tissue (archival slides or blocks) obtained within one year of screening, or during 
surgical removal of papilloma(s) will be collected.   
 
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Subjects will undergo routine procedure for removal of papilloma(s) during the screening 
period, however dosing on Day 0 must be performed within 14 days following the 
procedure. If other eligibility criteria have been confirmed, Day 0 dosing may be performed 
the same day immediately following the papilloma removal. The following assessments 
should be noted at the time of the procedure: 
• Record vital signs heart rate (HR), respiratory rate (RR), blood pressure (BP) and body 
temperature (Section 6.4.2); 
• Record current concomitant medications/treatments (Section 6.13); 
• Collect any new adverse events. 
6.1.1.1 MEDICAL HISTORY 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, past conditions, initial 
diagnosis date, HPV type (if available), and all prior surgical procedures and therapies 
directed toward RRP disease including adjuvant therapies, especially those occurring 
within the 3 years prior to Screening, as well as any periods of disease remission. Illnesses 
first occurring or detected after the signing of the informed consent, or during the study 
and/or worsening of an existing illness in severity, frequency or nature after signing of the 
informed consent are to be documented as AEs on the CRF. All prior treatments should 
be recorded in the CRF as prior medications. Concomitant treatments, defined as 
continuing or new treatments taken at or after the signing of the informed consent, should 
be recorded in the CRF as concomitant medications.  
6.1.1.2  DEMOGRAPHICS 
Demographic information will be collected via self-report (unless note otherwise), 
including but not limited to age, biological sex and race and ethnicity. 
6.1.1.3 SMOKING HISTORY 
Smoking history will be collected at Screening via self-report.  
6.1.2 
CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject’s Day 0 dose will be scheduled within 14 
days after the next planned surgical intervention. If timing allows, the Day 0 dose may be 
given on the same day immediately following the next planned surgical intervention. Visit 
dates and windows must be calculated from Day 0, unless otherwise noted. All subjects 
will be followed until the Week 52 visit. All subjects will be followed per assessments 
outlined below. 
6.1.2.1 Day 0 
The following evaluations will be performed on Day 0 prior to IP administration: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
• 
Targeted physical examination (Section 6.4.1); 
• 
Record vital signs (Section 6.4.2); 
• 
Record body weight, height and determine BMI (Section 6.4.3); 
• 
Collect urine for urine pregnancy test, if applicable (Section 6.4.4); 
• 
Collect whole blood 
 for immunology assessment (Section 6.10); 
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• 
Collect safety labs within 72 hours prior to dosing such that results are 
available and assessed against DLT criteria prior to dosing (Section 6.4.4); 
The following evaluations will be performed on Day 0 after IP administration: 
• 
Collect any new adverse events; 
• 
Download EP Data (Section 6.5.1). 
6.1.2.2 Week 3 
The following evaluations will be performed at this visit prior to IP 
administration: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
• 
Targeted physical examination (Section 6.4.1); 
• 
Record vital signs (Section 6.4.2); 
• 
Record body weight, height and determine BMI (Section 6.4.3); 
• 
Safety labs collected within 72 hours prior to dosing such that results are 
available and assessed against DLT criteria prior to dosing (Section 6.4.4); 
• 
Collect urine for urine pregnancy test, if applicable (Section 6.4.4). 
The following evaluations will be performed after IP administration: 
• 
Collect any new adverse events; 
Download EP Data (Section 6.5.1). 
6.1.2.3 
Week 6 
The following evaluations will be performed prior to IP administration: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
• 
Targeted physical examination (Section 6.4.1); 
• 
Record vital signs (Section 6.4.2); 
• 
Record body weight, height and determine BMI (Section 6.4.3) 
• 
Safety labs collected within 72 hours prior to dosing such that results are 
available and assessed against DLT criteria prior to dosing (Section 6.4.4). 
• 
Collect urine for urine pregnancy test, if applicable (Section 6.4.4); 
• 
Collect whole blood 
 for immunology assessment (Section 6.10). 
• 
Laryngoscopy and Staging assessment (Section 6.4.5). 
o If it is the Investigator’s practice to routinely biopsy during laryngoscopy, 
this should be performed at this visit. 
The following evaluations will be performed after IP administration: 
• 
Collect any new adverse events; 
• 
Download EP Data (Section 6.5.1). 
6.1.2.4 
Week 9 
The following evaluations will be performed prior to IP administration: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
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• 
Targeted physical examination (Section 6.4.1); 
• 
Record vital signs (Section 6.4.2); 
• 
Record body weight, height and determine BMI (Section 6.4.3) 
• 
Safety labs collected within 72 hours prior to dosing such that results are 
available and assessed against DLT criteria prior to dosing (Section 6.4.4); 
• 
Collect urine for urine pregnancy test, if applicable (Section 6.4.4); 
• 
Collect whole blood 
 for immunology assessment (Section 6.10). 
The following evaluations will be performed after IP administration: 
• 
Collect any new adverse events; 
• 
Download EP Data (Section 6.5.1). 
6.1.2.5 
Week 11 
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
• 
Collect whole blood 
 for immunology assessment (Section 6.10); 
• 
Laryngoscopy and Staging assessment (Section 6.4.5). 
o If it is the Investigator’s practice to routinely biopsy during laryngoscopy, 
this should be performed at this visit. 
6.1.2.6 
Week 26  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
• 
Targeted physical examination (Section 6.4.1); 
• 
Record vital signs (Section 6.4.2); 
• 
Collect whole blood 
 for immunology assessment (Section 6.10); 
• 
Laryngoscopy and Staging assessment (Section 6.4.5); 
o If it is the Investigator’s practice to routinely biopsy during laryngoscopy, this 
should be performed at these visits. 
6.1.2.7 
Week 52/End of Study visit 
The following evaluations will be performed: 
• 
Collect all present and/or new or ongoing adverse events; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.13); 
• 
Full physical examinations (Section 6.4.1); 
• 
Record vital signs (Section 6.4.2). 
• 
Collect whole blood 
 for immunology assessment (Section 6.10). 
• 
Laryngoscopy and Staging assessment (Section 6.4.5). 
• 
Biopsy 
o Tissue will be sent to the study laboratory for 
 immuno-
assessment 
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6.2 
INFORMED CONSENT  
All participants 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 participants, 
explain the trial, and provide them with an informed consent form (ICF) that describes the 
screening tests, eligibility criteria for entering the trial, trial IP and follow-up procedures, in 
a language understandable to the participant. Explanation of the trial includes, but is not 
limited to, trial objectives, potential benefits and risks, discomforts/inconveniences, and 
the participant’s rights and responsibilities. The participant or participant’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 participant or participant’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 
participant’s source records and must be accessible for verification at any time. Signing of 
the ICF begins the screening period. 
6.3 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each participant who consents will be assigned a unique subject identification number 
(SID), which identifies the participant for all trial-related procedures. SIDs are a 
combination of a four-digit site code and a four-digit participant number starting with 0001. 
Once assigned, SIDs cannot be reused for any reason. Information regarding the SID and 
screen date will be documented in the eCRF. 
6.4 
SAFETY EVALUATIONS 
6.4.1 PHYSICAL EXAM AND TARGETED PHYSICAL ASSESSMENTS 
A full physical examination will be conducted during Screening and at study discharge 
(Week 52 or any other study discontinuation visit). A targeted physical assessment will be 
performed at other visits indicated per schedule of events as determined by the 
Investigator or directed per participant complaints. 
6.4.2 VITAL SIGNS 
Vital signs including oral temperature, respiration rate, blood pressure and heart rate will 
be measured at Screening and all other in-person study visits.  
6.4.3 HEIGHT AND WEIGHT 
Weight (kg) and height (cm) will be collected at Screening and at each dosing visit in order 
to calculate BMI. 
6.4.4 LABORATORY EVALUATIONS 
At Screening and select times during the study, blood samples will be collected for safety 
assessments. Safety labs will be collected within 72 hours prior to dose such that results 
are available and assessed against DLT criteria prior to dosing. 
Approximately 450 mL of blood will be drawn from each participant over the course of the 
study for safety and immunology assessments. A description of the immunology 
assessments can be found in Section 6.10.  
 
 
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Hematology (Complete blood count (CBC) with automated differential): 
White blood cell (WBC) count, Red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening, and prior to dosing at Day 0, Weeks 3, 6, 
and 9. 
• 
Approximately 2.5 mL of whole blood to be drawn per visit 
Serum chemistry: 
Electrolytes (Sodium [Na], Potassium [K], Chloride [Cl], Bicarbonate [HCO3], Calcium [Ca], 
Phosphate [PO4]), glucose, BUN (blood urea nitrogen), serum bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and Creatinine (Cr) will be 
measured at Screening, and prior to dosing at Day 0, Weeks 3, 6, and 9. 
• 
Approximately 4 mL of whole blood to be drawn per visit 
Pregnancy Testing:  
For women of childbearing potential (WOCBP), a serum pregnancy test will be obtained 
at Screening and a urine pregnancy test will be performed prior to each dose. A negative 
result for urine β-HCG (test must have a sensitivity of at least 25 mIU/mL) must be 
available prior to each administration of IP. If the β-HCG test is positive, indicating that the 
participant is pregnant prior to completing the specified dose regimen, then no further IP 
will be administered. Every attempt should be made to follow pregnant participants for the 
remainder of the study and to determine the outcome of the pregnancy. 
• 
Approximately 0.5 mL of whole blood to be drawn for serum pregnancy test at 
Screening 
6.4.5 LARYNGOSCOPY AND STAGING ASSESSMENT 
Laryngoscopy will be performed at Screening (prior to routine removal of papilloma(s)), 
and at Weeks 6, 11, 26, and 52. If it is the Investigator’s practice to routinely biopsy during 
laryngoscopy, this should be performed at these visits. Biopsy will be performed at Week 
52.   
The status of disease will be assessed during each laryngoscopy and an RRP Staging 
Assessment score will be determined using a modified Derkay staging tool [34].  Specific 
instructions and guidelines will be provided under separate cover. 
Subjects will undergo surgery for removal of papilloma(s) during the screening period 
within 14 days prior to Day 0 dosing (papilloma removal and Day 0 dose may be performed 
same day if other eligibility criteria have been fulfilled). 
Status of disease during the trial will be monitored by the Investigator during laryngoscopy 
including documentation with Staging Assessment scores.  If at any time during the trial, 
surgical removal (including laser) of papilloma is clinically indicated per PI judgement, the 
subject may undergo procedure for papilloma removal but this must be captured on the 
electronic case report form.  Documentation of the Staging Assessment score prior to 
surgery is required, and explanation for requirement of surgical removal of papilloma must 
be documented. 
Surgical interventions during the trial must be documented to include at a minimum, 
information about the appearance and location of tissue being removed and instruments 
used. Video/ photographic documentation of laryngoscopy is required. Further instructions 
will be provided under separate cover. 
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6.5 
INJECTION AND ELECTROPORATION (EP)  
Subjects will receive a four-dose series of INO-3107 by IM injection in the deltoid (or 
anterolateral quadriceps muscle as an alternate option, if deltoid muscle is not possible or 
appropriate) followed immediately by EP with CELLECTRA® 2000 at Day 0, Week 3, 6, 
and 9. 
Approximately 20 subjects will be administered INO-3107 by standard needle, followed by 
approximately 10 subjects who will be administered INO-3107 by Side Port Needle.  
Study treatment should not be given within 2 cm of a tattoo, keloid or hypertrophic scar. If 
there is implanted metal, implanted device, within the same limb then use of the deltoid 
muscle on the same side of the body is excluded. 
6.5.1 DOWNLOADING OF EP DATA FROM CELLECTRA® 2000 DEVICE 
Following each Study IM Administration, data will be downloaded from the 
CELLECTRA® 2000 device and the data file that is created should be provided to the 
Sponsor. Instructions on how to download the data and Sponsor contact information are 
provided separately. Training will also be provided. 
6.6 
MANAGEMENT OF ANXIETY AND PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
Participants may be offered topical anesthetic (e.g., EMLA or equivalent) to prevent 
significant discomfort from the injection/EP procedure. If a topical anesthetic is used, an 
approximate 1.5 cm diameter amount will be applied with occlusion to the administration 
site ~30 minutes prior to injection/EP.  
In case of pain, participants may be treated with a non-narcotic analgesic 
(e.g.,acetaminophen) after injection/EP.  
Participants who are allergic to or have contraindications to EMLA, acetaminophen, or a 
mild sedative may be offered a suitable alternative. 
Medication taken for pain management will be documented as concomitant medications. 
6.7 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry and hematology at the visits listed in the Schedule 
of Events as listed in Section 6.4.4.  
Laboratory AEs will be evaluated based on the Common Terminology Criteria for Adverse 
Events (CTCAE version 5.0). Laboratory values that are not clinically significant (NCS) in 
the Investigator’s opinion will not be reported as adverse events. 
6.8 
ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
An adverse event assessment will be conducted at each visit which subjects will be 
queried regarding the occurrence of any adverse events, concomitant medications, new 
onset illness or disease, as well as contraceptive compliance.  Subjects will be reminded 
to contact study personnel and immediately report any event that happens for the duration 
of the study. Adverse events will be captured from the time of the informed consent to 
study discharge. These events will be recorded on the subject’s CRF. 
6.9 
ASSESSMENT OF INJECTION SITE REACTIONS  
The injection site will be assessed by study personnel prior to and at least 30 minutes after 
each study treatment and at the subsequent study visit following dosing. 
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When evaluating injection site reactions throughout the study, it is important to be as 
specific as possible by selecting the most appropriate term and use the grading scale as 
listed in CTCAE v5.0. Injection site reactions and administration site pain will be evaluated 
starting 30 minutes following injection/EP and reported as adverse events on the CRF. 
6.10 PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood 
 samples will be obtained at baseline (screening and Day 0 prior 
to dosing) and at Weeks 6, 9, 11, 26 and 52.  Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual. 
PBMCs will be isolated from whole blood samples. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
6.11 HPV-6/11 TESTING 
Historic HPV-6/11 genotyping results may be used to determine a subject’s eligibility for 
the trial. If historic results are not available, archival tissue collected during previous 
papilloma removal procedures or biopsy tissue obtained during screening may be used to 
determine eligibility.   
Archival tissue (within 1 year of the screening visit) or biopsy tissue collected at screening, 
, will undergo HPV-6/11 testing at a central laboratory. 
 
 
   
 
Details of sample collection and shipment information will be provided in the Laboratory 
Manual. 
6.12 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue in the paraffin block after HPV genotyping from the tissue 
collected at screening, Week 52, and as clinically indicated during the course of the study, 
the block or unstained slides prepared from the block will be collected for the assessment 
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of pro-inflammatory and immunosuppressive elements and their association with 
treatment success.  
 
 Additional markers may be assessed, and the markers 
listed here may change as new relevant information becomes available.  
  
 
 
 
6.13 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2,  Exclusion Criteria) must be recorded 
on the case report forms (CRFs). 
Actual or estimated start and stop dates must be provided. 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. If the 
permissibility of a specific medication/treatment is in question, please contact the Sponsor.  
6.14 RESTRICTIONS 
Prohibited Concomitant Medications and Treatments 
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 (nasal or bronchial), otic and ophthalmic 
corticosteroids are allowed; 
• 
Disease 
modifying 
doses 
of 
anti-rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, cyclosporine, methotrexate), and biologic disease modifying drugs 
such as TNF-α inhibitors (e.g. infliximab, adalimumab or etanercept) at screening and 
throughout the study; 
• 
Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study, live vaccine 
(prophylactic HPV vaccination, including Gardasil) as attempted therapeutic 
intervention while on-study is not permitted); 
• 
Use of bevacizumab and cidofovir should be stopped at least 3 months prior to Day 0 
visit; 
• 
Post-surgical course of anti-inflammatory medication and steroids should be avoided. 
Other Restrictions 
Subjects should not use alcohol or drugs that would interfere with study requirements 
during the course of the study and should report ALL medications/drugs taken to the 
investigator and/or other study personnel. 
Subjects should refrain from becoming pregnant for the duration of the trial by using 
appropriate contraceptive measures as (See Inclusion Criteria, Section 4.1).  Lapses in 
contraceptive use should be reported to investigator and/or other study personnel. 
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7 EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
The safety of INO-3107 will be measured and graded in accordance with the CTCAE v5.0. 
7.2 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug) 
• Any pre-existing condition, with the exception of the condition under investigation in this 
study, that increases in severity, or changes in nature during or as a consequence of 
the clinical trial drug administration phase 
• Complications of pregnancy (refer to section 7.11: Reporting Pregnancy During the 
Clinical Trial) 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen 
• Recurrences of RRP (disease under study) 
• 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 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
7.4 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death  
• Is life-threatening 
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o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless 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 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject's body function/structure, physical 
activities and/or quality of life). 
• Results in congenital anomaly or birth defect and/or 
• An important medical event  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Clarification of Serious Adverse Events (SAEs) 
• Death in itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event 
• Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE 
7.5 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
7.6 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is 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.   
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with section 
7.9: Safety Data Reporting Period, Method of Collection and Submission. 
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7.7 
DEVICE DEFICIENCY 
Please refer to Section 7.12 for more information. 
7.8 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to: 
• Incidence of all adverse events classified by system organ class (SOC), preferred term, 
severity and causal relationship to clinical trial IP administration 
• Changes in laboratory parameters 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site 
• Dose Limiting Toxicities (DLT) 
7.8.1 Dose Limiting Toxicity (DLT)  
For the purpose of this clinical trial, the following are DLTs and are to be reported to the 
Sponsor in accordance with section 7.9: Safety Data Reporting Period, Method of 
Collection and Submission. 
• 
≥Grade 3 non-hematological toxicity (graded per CTCAE v.  5.0) that does not respond 
to supportive therapy and lasts for longer than 48 hours   
• 
≥Grade 3 hematological toxicity (graded per CTCAE v. 5.0) that does not respond to 
supportive therapy and lasts for longer than 48 hours 
Refer to Section 3.0 for information about management of DLTs. 
7.8.2 Abnormal Laboratory Value 
Laboratory results will be evaluated based on the normal ranges and toxicity scale within 
CTCAE v. 5.0. The PI will annotate each abnormal lab value as clinically significant (CS) 
or not clinically significant (NCS). 
Laboratory values that are NCS in the PI’s opinion should not be reported as an adverse 
event. 
Any abnormal laboratory value 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 clinical trial treatment 
• 
Has accompanying or inducing symptoms or signs 
• 
Is judged by the PI as clinically significant (CS) 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9: Safety Data Reporting Period, Method of Collection and 
Submission. 
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7.8.3 Clinical Trial Stopping Rules 
Enrollment and additional dosing will be paused until Sponsor discussion with the site 
Investigator determines that enrollment and dosing may continue, if the following CTCAE 
v5.0 events occur at any time in the study:  
•
One Grade 4 or 5 related SAE;
•
Two Grade 3 related SAEs
7.9 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION
All AEs will be collected from the time when informed consent is obtained to Week 52 or 
at participant’s last visit due to early discontinuation. This information will be captured in 
the Electronic Data Capture (EDC) system. 
If the PI determines that the AE meets serious criteria, then the AE will be recorded as an 
SAE. 
SAEs and DLTs will be reported to the Sponsor from the time the subject signs the 
informed consent until Week 52 or at participant’s last visit due to early discontinuation. 
All SAEs (regardless of causal relationship) and DLTs, will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event.
 
 
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the EDC. 
For the events that are considered a DLT, the PI will contact the Sponsor within 24 hours 
of becoming aware of the event to discuss whether dosing should continue. 
SAE Contact Information 
Safety Email: 
 
Safety Fax: 
 
Safety Phone: 
 
Medical Monitor Direct contact Information 
Medical Monitor: 
 M.D. 
Email: 
 
Cell Phone: 
 
All SAEs, and DLTs must be followed by the PI until resolution or return to baseline status, 
or stabilization of the event (i.e., the expectation that it will remain chronic), even if it 
extends beyond the clinical trial reporting period. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
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• 
Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information (PII) 
• 
Provide the assigned clinical trial subject number (SID) on the records 
7.10 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
7.10.1 Submitting the Initial Serious Adverse Event (SAE) Report Form 
The PI should include as much safety information as possible when submitting the initial 
report, but the report must include the following at a minimum:  
• 
The Adverse Event 
• 
The subject’s assigned identification (SID) number 
• 
Investigational product(s) (IP) and/or device 
• 
Investigator Causal Relationship to the IP(s) and/or device 
• 
Serious criteria 
• 
Reporter name and contact information 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
7.10.2 Recording the Event 
Principal Investigators (PIs) should use correct medical terminology/concepts when 
recording adverse events on the EDC and Safety Report Form. The use of colloquialisms 
and abbreviations should be avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previously signs and/or symptoms will be 
nullified and replaced with a single medical diagnosis. 
7.10.3 Assessing Severity (Intensity) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The PI will assess and grade clinical AEs or SAEs (based on discussions with clinical trial 
subjects) in accordance with National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), v5.0. 
7.10.4 Causal Relationship of Clinical Material to Adverse Events (AEs) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the PI is knowledgeable about the 
subject (e.g., medical history, concomitant medications), administers the IP, and monitors 
the subject’s response to the IP, the PI is responsible for reporting AEs and judging the 
relationship between the administration of the IP and EP and a subsequent AE. The PI is 
aware of the subject’s clinical state and may have observed the event, and thus may be 
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sensitive to distinctions between events due to the underlying disease process versus 
events that may be product-related.  
Principal Investigators (PIs) should use their knowledge of the clinical trial subject, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether an AE is considered to be related to the IP and/or the study 
device and the causal relationship reported as "Yes" or "No" accordingly. Causality should 
be assessed by the PI as related to drug, related to device, or related to both drug and 
device (i.e., related to both or indiscernible) by the following criteria: 
• 
Yes - there is a reasonable possibility that administration of the clinical trial treatment 
(drug or device or both drug and device) contributed to the event 
• 
No - there is no reasonable possibility that administration of the clinical trial 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 trial 
• 
Presence of risk factors in the clinical trial subject or use of concomitant medications 
known to increase the occurrence of the event 
The rationale for the PI’s causal assessment is to be recorded on the SAE Report Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
7.11 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects who are pregnant or expect to become pregnant during the course of the clinical 
trial will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through the study completion (last visit) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after enrolling in the clinical trial, she 
will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the PI and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The PI will report this event to their IRB/REB/EC in accordance with their policies and 
procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional treatments, must not be performed. The PI should use clinical 
judgment regarding subsequent clinical trial-related blood collection based on the 
presence or absence of anemia in each subject.  
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Male subjects will be instructed through the ICF to immediately inform the PI if their partner 
becomes pregnant until study completion (last visit). A Pregnancy Form will be completed 
by the PI and submitted to the Sponsor within 24 hours after becoming aware of the 
pregnancy. The pregnant partner will be asked to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. If the 
authorization has been signed, the PI will collect and report details of the course and 
outcome of the pregnancy in the partner of a male subject exposed to IP. The PI will 
update the Pregnancy Form with additional information on the course and outcome of the 
pregnancy and submit the form to the Sponsor.  
If a PI is contacted by the male subject or his pregnant partner, the PI 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. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
7.12 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to 
the Sponsor at 
 
Device deficiencies include malfunctions, use errors 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. 
Any problems experienced during the treatment procedure including potential 
malfunctions of the device, error messages displayed on the device screen following 
treatment, or errors that occur during the treatment procedure must immediately be 
reported to the Sponsor or its designee for evaluation. 
7.13 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS
(IRBS)/ETHICS COMMITTEES (ECS) OF SAFETY INFORMATION 
7.13.1 Sponsor Responsibilities 
•
Determine whether the safety information meets the requirements for expedited
reporting to the applicable regulatory authorities
•
Prepare and submit the safety report to the applicable regulatory authorities
•
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear
Investigator Letter) that will include a statement if there is or is not any significant new
safety information that might influence the risk-benefit assessment of the IP and/or
study device, sufficient to consider changes in product administration or overall
conduct of the clinical investigation
7.13.2 Principal Investigator (PI) Responsibilities 
•
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the
governing policy and/or procedures
•
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, etc.) that occur
at their clinical trial site in accordance with their local institutional policy
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7.14 POST-TRIAL REPORTING REQUIREMENTS 
Principal Investigators (PIs) are not obligated to actively seek AEs or SAEs beyond the 
clinical trial reporting period. However, if the PI becomes aware of an AE or SAE that 
occurs after the Completion or Termination Visit and the event is deemed by the PI to be 
probably or possibly related to the clinical trial treatment, the PI should promptly document 
and report the event to the Sponsor. 
7.15 CLINICAL TRIAL DISCONTINUATION  
The Sponsor reserves the right to discontinue the clinical trial at this site or at multiple 
sites for safety or administrative reasons at any time. In particular, a clinical trial site that 
does not recruit at a reasonable rate may be discontinued. Additionally, the clinical trial 
may be discontinued at any time by an IRB/REB/EC, the Sponsor, or a regulatory authority 
as part of their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any reason, an 
Inovio Representative will provide instructions regarding which device components should 
be returned to Inovio Pharmaceuticals, Inc., destroyed onsite and/or shipped to a 
destruction vendor. The PI should ensure that their site file documents are complete prior 
to archiving and provide copies of any requested documents to the Sponsor for its Trial 
Master File (TMF). 
 
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8 STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The 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 Pharmaceuticals or its 
representative. 
This is a single-arm, multi-center clinical trial in subjects with HPV-6- and/or HPV-11-
associated recurrent respiratory papillomatosis (RRP).  The primary objective is to 
evaluate safety.  The primary endpoint is safety and tolerability as assessed by 
reported adverse events (AE) and serious adverse events (SAE).  Secondary efficacy 
analyses include evaluation of frequency of RRP surgical interventions in the year 
following the first dose of investigational product, compared to the frequency in the 
year prior to Day 0 dosing, and changes in RRP Staging Assessment over time. Other 
secondary analyses concern cellular immunological measures, and tissue 
immunological measures.  
 
 
 
 
8.3 
STATISTICAL HYPOTHESES 
No formal statistical hypothesis will be tested in this study. 
8.4 
ANALYTICAL POPULATIONS 
The analysis populations will be the following. 
The intention to treat (ITT) population includes all subjects who are eligible.   
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of INO-3107.   
The per-protocol (PP) population comprises subjects who receive all doses of INO-3107 
and have no protocol violations. Subjects excluded from the PP population will be 
identified and documented prior to locking of the trial database. 
The safety analysis set includes all subjects who receive at least one dose of INO-3107. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 Primary Analyses 
The primary analyses for this trial are safety analyses of Treatment Emergent Adverse 
Events (TEAE) and clinically significant changes in safety laboratory parameters from 
baseline. 
TEAEs are defined for this trial as any AEs that occur following Day 0 following 
administration of study drug (IM + EP), until 30 days following the last dose.  All TEAEs 
will be summarized among the Safety Population by frequency.  These frequencies will be 
presented overall, by system organ class and by preferred term, the percentage of 
subjects affected. Additional frequencies will be presented with respect to maximum 
severity and to strongest relationship to study treatment.  Multiple occurrences of the same 
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AE will be counted only once following a worst-case approach with respect to severity and 
relationship to study treatment. All serious TEAEs will also be summarized as above. 
The main summary of safety data will be based on TEAEs. For this summary, the 
frequency of preferred term events will be calculated along with 95% confidence intervals, 
using the exact method of Clopper-Pearson.  Separate summaries will be based on events 
occurring within 7 days of any dose and regardless of when they occurred.  AEs and SAEs 
that are not TEAEs or serious TEAEs will be presented in listings. 
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. 
AE duration will be calculated as (Stop Date – Start Date) + 1. 
Laboratory response variables will be descriptively summarized per time point and as 
changes from baseline including 95% confidence intervals. Shifts from baseline according 
to the CTCAE will also be presented. Laboratory values considered clinically significant 
will be presented in listings. 
All of the safety analyses will be conducted on the subjects in the safety analysis set. 
Analyses will be summarized and presented by number of prior surgical interventions (≤2, 
3-5, and ≥6) and overall. 
8.5.2 Secondary Analyses 
8.5.2.1    EFFICACY 
The frequency of RRP surgical interventions in the year following the first dose of 
investigational product, compared to the frequency in the year prior to Day 0 dosing, will 
be summarized descriptively using mean fold-change and a 95% t-distribution-based CI. 
Changes in RRP Staging Assessment scores from baseline pre-dose to each post-dose 
evaluation will be analyzed.  Median changes and associated 95% confidence intervals 
will be computed. 
  
 
 
Intersurgical intervals will also be summarized. 
Analyses will be summarized and presented by number of prior surgical interventions (≤2, 
3-5, and ≥6) and overall.  Efficacy analysis using the mITT population will be conducted. 
The PP population will also be used for a supportive analysis. 
8.5.2.2    IMMUNOGENICITY 
Increases from baseline in interferon-γ ELISpot and flow response magnitudes will be 
summarized.  The median increases and associated 95% confidence intervals will be 
calculated. 
Changes from baseline in tumor tissue response magnitudes will be summarized.  
 
 
 
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Valid samples for statistical analysis purposes will be those collected within 7 days of the 
specified visit. Baseline is defined as the last measurement prior to the first treatment 
administration. 
The mITT population will be used for immunogenicity analyses. 
Analysies will be summarized and presented by number of prior surgical interventions (≤2, 
3-5, and ≥6) and overall. 
8.5.3 Disposition 
Disposition will be summarized and will include the number and percentage eligible, 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.    
Analysis will be summarized and presented by number of prior surgical interventions (≤2, 
3-5, and ≥6) and overall. 
 
8.5.4 Demographic and Other Baseline Characteristics 
8.5.4.1    DEMOGRAPHICS 
Demographic and baseline characteristic 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 ITT population.  
Analysis will be summarized and presented by number of prior surgical interventions (≤2, 
3-5, and ≥6) and overall. 
8.5.4.2    PRIOR MEDICATION 
Prior medications are those that were used 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; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages for the mITT population.    
Analyses will be summarized and presented by number of prior surgical interventions (≤2, 
3-5, and ≥6) and overall.  
8.5.5 Interim Analyses  
No formal interim analyses will be performed for this study. 
8.5.6 Multiplicity 
Not applicable. 
8.5.7 Missing Values 
All analyses will be based upon observed data. 
 
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8.6  
SAMPLE SIZE/POWER 
No formal power analysis is applicable to this study, as descriptive statistics will be used 
to summarize the data. 
 
For 30 INO-3107 administered subjects, the trial provides 95% confidence that the true 
incidence of SAEs is <12% if no SAEs are observed. 
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 for this trial.  
Randomization does not apply. 
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9 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, 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD (IRB) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., informed consent form, advertising) has been obtained from the 
Institutional Review Board (IRB) and a copy of this approval has been received by the 
Sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
• 
Submit progress reports to the IRB 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 immediately if the Sponsor notifies the Investigator about any reportable 
safety events. 
• 
Obtain approval from the IRB for protocol amendments and for revisions to the consent 
form or participant recruitment advertisements, as required. 
• 
Submit reports on, and reviews of, the trial and its progress to the IRB 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 includes all 
correspondence with the IRB. 
• 
Notify the IRB when the trial is completed (i.e., after the last trial visit of the final trial 
participant). 
• 
After trial completion (within three [3] months is recommended) provide the IRB with a 
final report on the trial. 
9.3 
PROTECTION OF HUMAN SUBJECTS 
9.3.1 Compliance with Informed Consent Regulations 
Written informed consent is to be obtained from each participant prior to enrollment into 
the trial, and/or from the participant’s legally authorized representative. The process for 
obtaining informed consent must also be documented in the participant’s medical record. 
(Also refer to section 6.2.) 
9.3.2 Compliance with IRB Requirements 
This trial is to be conducted in accordance with applicable Institutional Review Board (IRB) 
regulations. The Investigator must obtain approval from a properly constituted IRB prior to 
initiating the trial and re-approval or review at least annually. Sponsor is to be notified 
immediately if the responsible IRB has been disqualified or if proceedings leading to 
disqualification have begun. Copies of all IRB correspondence with the Investigator should 
be provided to Sponsor. 
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9.3.3 Compliance with Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.3.4 Compliance with Electronic Records/Signatures Regulations 
When applicable, this trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.3.5 Compliance with Protocol 
Participants are not required to follow special instructions specific to the IP used in this 
trial. Participants will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should a deviation be discovered, Sponsor must be informed immediately. Any protocol 
deviation impacting participant safety must be reported to the Medical Monitor 
immediately. 
9.3.6 Changes to the Protocol 
The Investigator should not implement any deviation from or changes to the protocol 
without approval by Sponsor and prior review and documented approval/favorable opinion 
from the IRB of a protocol amendment, except where necessary to eliminate immediate 
hazards to trial participants, or when the changes involve only logistical or administrative 
aspects of the trial (e.g., change in monitors, change of telephone numbers). While every 
effort should be made to avoid protocol deviations, should a deviation be discovered, 
Sponsor must be informed immediately. Any protocol deviation impacting participant 
safety must be reported to the Medical Monitor immediately. 
9.3.7 Vulnerable Subjects 
This study prohibits the enrollment of subjects who are imprisoned, or compulsory 
detainment (involuntary incarceration) for treatment of either a psychiatric or physical (i.e. 
infectious disease) illness, as well as of children. 
10 DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subject’s medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection.  
11 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 clinical trial. Source data are contained in original source documents. 
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Examples of original source 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 of electronic medical records (EMR) certified after verification as being accurate 
and complete 
• 
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, at the medical records 
facility and within information technology (IT) systems that are involved in the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
11.1 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical 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 local requirements. The Sponsor will 
inform the Investigator/institution when these documents are no longer needed to be 
retained. 
12 SAFETY AND QUALITY MONITORING12.1 SAFETY REVIEW 
A safety run-in period will be implemented such that the study will evaluate safety in up to 
6 adult subjects prior to opening to full enrollment.  This is described in more detail in 
Section 3.   
This trial will not utilize a Data Safety Monitoring Board.  This is a single-arm, open-label 
trial. The Sponsor’s Medical Monitor will have access to unblinded safety and tolerability 
data during the trial. At a minimum, the Sponsor’s Medical Monitor will review reported 
adverse events quarterly. 
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12.2 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. Records for all clinical trial subjects in this clinical 
trial will be monitored. The following clinical trial site monitoring tasks will be performed 
at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to review all 
relevant forms and documentation, and ensure that the clinical trial site staff are qualified 
and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following clinical trial conduct 
activities and obligations: 
o Assure that the clinical trial is being conducted in accordance with the protocol, 
applicable regulatory authority regulations and IRB/REB/EC policies 
o Discuss clinical trial conduct issues and incidents of noncompliance with the 
Investigator and/or clinical trial personnel and document them on the Monitoring 
Visit Report. Report any significant unresolved problems immediately to the 
Sponsor 
o Remind the Investigator as necessary of the obligation to immediately report all 
SAEs and DLTs and provide subsequent follow-up report(s) of the final outcome to 
the IRB/REB/EC 
o Throughout the clinical trial, inspect all source documents to ensure that they are 
Attributable, legible, contemporaneous, original, accurate and complete 
(ALCOA-C) 
o Assure that the clinical trial facilities continue to be acceptable 
o Compare the clinical 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 study device accountability and reconciliation 
of records are complete and accurate 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements 
13 FINANCING AND INSURANCE 
Inovio Pharmaceuticals, Inc. is the Sponsor and is funding this study. Clinical trial 
insurance has been obtained in accordance with the laws of the countries where the study 
will be conducted. The investigative site is being compensated for the conduct of this study 
and will follow the terms described in the clinical trial agreement. This agreement was 
executed separately from this clinical trial protocol. The Investigators will be required to 
provide full financial disclosure information in accordance with 21CFR Part 54. 
14 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
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15 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOA 
Attributable, Legible, Contemporaneous, Original, and Accurate 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
 
 
Cl 
Chloride 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DLT 
Dose Limiting Toxicity  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Records 
EP 
Electroporation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPC 
Glycoprotein 
HPV 
Human Papillomavirus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
IM 
Intramuscular 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
mRNA 
Messenger RNA 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
pDNA 
Plasmid DNA 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PT 
Preferred Term 
RBC 
Red blood cell 
RR 
Respiratory Rate 
RRP 
Recurrent Respiratory Papillomatosis 
SAE 
Serious Adverse Event 
sDNA 
Synthetic DNA 
SID 
Subject Identification Number 
SMMP 
Safety and Medical Monitoring Plan 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
TEAE 
Treatment Emergent Adverse Event 
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TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 
 
 
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Infectious Diseases 2013. 
 
 
 
23. Tebas P, Roberts CC, Muthumani K, Reuschel EL, Kudchodkar SB, Zaidi FI, et al. Safety 
and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report. N Engl 
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25. 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 
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B, Perforin in HIV Infected Individuals. Mol Ther 2015; 23(3):591-601. 
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29. Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
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33. Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of 
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papillomatosis. Laryngoscope 1998; 108(6):935-937. 
 
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Signature Page for VV-TMF-00028 v4.0
Signature Page for VV-TMF-00028 v4.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 26-Jul-2021 20:11:03 GMT+0000
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SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 1.0 dated 09 January 2020 to Version 
2.0 dated 20 February 2020.  Changes not listed in this summary are administrative and do not 
affect the safety of subjects, trial scope, or scientific quality of the protocol. 
 
1. The dosing schedule has been reduced from eight doses to four doses over the course of the 
study.  Subjects will be dosed at Day 0, Week 3, 6, and 9, but will not receive booster doses 
at Week 26, 52, 78 and 104.   
2. Visits at weeks 39, 61, 95 and 106 for immunology blood collection and assessment of AEs 
have been removed.  Blood for immunology and AE assessments will be performed at Week 
26, 52, 78 and 104.  Additionally, the final study visit will occur at Week 104.   
3. The enrollment of adolescent subjects into this protocol has been removed at this time.  Only 
subjects aged 18 years and above at the time of consent will be enrolled. 
4. The protocol has been amended to provide staggered enrollment for up to the first six subjects 
in the study.  Up to the first six subjects will be enrolled into either Cohort A or Cohort B with 
a one-week waiting period between each enrolled subject.  This change is intended to provide 
additional time for observation of acute and/or potentially chronic toxicities. 
5. The eligibility criteria has been updated to exclude subjects with a high risk of bleeding, 
including subjects requiring anti-coagulation medication or who have a known bleeding 
diathesis. 
6. Stopping rules for non-DLTs have been added to the protocol such that enrollment and 
additional dosing will be paused if one CTCAE v5.0 Grade 4 or 5 related SAE or two Grade 3 
related SAEs occur at any time in the study. 
7. Inclusion criterion regarding organ function has been edited to restrict enrollment to subjects 
who have a serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to 
within 1.5 x upper limit of normal (ULN). 
8. Section 6.1.1 was updated to collect smoking history information at Screening.  This update 
was made to the Schedule of Events and is reflected in Section 6.1.1.3.   
9. Sections 8.5.5 and 8.5.9 were updated to remove the analysis of subjects with abnormal 
medical history findings and abnormal physical examination findings.  Medical history and 
physical exam findings will be included in data listings.  
 
 
RRP-001 Protocol | VV-TMF-00028 | 2.0
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INO-3107 
  
RRP-001 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 12Apr2021 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 4 of 60 
 
 
SUMMARY OF CHANGES 
The following are a list of protocol changes from Version 2.0 dated 20 February 2020 to Version 
3.0 dated 12 April 2021.  Changes not listed in this summary are administrative and do not affect 
the safety of subjects, trial scope, or scientific quality of the protocol. 
1. The clinical trial design of RRP-001 has been amended to focus on safety and tolerability of 
INO-3107 in a small population of subjects with HPV-6 and/or HPV-11 associated RRP.  The 
primary efficacy endpoint has been modified and moved to a secondary endpoint, and the 
primary objective and endpoint will now be based on reported adverse events and serious 
adverse events. This change is intended to gain essential safety data, while allowing an early 
read on immunogenicity and efficacy to support a Phase 3 program.  The sample size has 
been reduced to approximately 20 subjects and the study duration has been reduced to 52 
weeks (Weeks 78 and 104 have been removed).  The data gathered with these changes are 
deemed sufficient to justify Phase 3 planning.  These design changes have been implemented 
throughout the protocol.    
2. The Sponsor does not believe there is a difference in the safety profile of INO-3107 in adult 
subjects with Juvenile-Onset RRP (JO-RRP) compared to adult subjects with Adult-Onset 
RRP (AO-RRP), therefore the cap on the number of JO-RRP or AO-RRP subjects has been 
removed.   
3. Text in the safety run-in section of the protocol synopsis and Section 3.0 has been updated 
to indicate that a review of safety data and a discussion between the Medical Monitor and the 
Investigator(s) with subjects in the safety run-in will take place prior to opening enrollment in 
full, in the absence of dose limiting toxicities (DLTs). 
4. Biopsy language has been added to the protocol synopsis and Section 3.0 of the protocol, to 
allow the collection of archival tissue obtained within 1 year of screening to be used for the 
applicable secondary 
 endpoints.  This is also outlined in Section 6.1.1 and 
Section 6.11 of the protocol.   
5. The protocol synopsis and Section 3.0 of the protocol was clarified to specify that surgery for 
papilloma removal is allowed per PI judgment but must be recorded as such in the electronic 
case report form.  Systemic or intralesional therapy is restricted per Section 4.3.1 and 6.14 of 
the protocol. 
6. The efficacy objective and endpoint has been modified from doubling of inter-surgical time 
post-Day 0, to the frequency of RRP surgical interventions in the one-year post-Day 0 
compared to the same time period prior to Day 0.     
7. 
 
 
 
8. 
 
  
9. Inclusion Criterion #3 has been updated to indicate that a low-risk positive HPV result that 
uses a Sponsor approved HPV-6/11 type-specific assay, is acceptable documentation of 
HPV-6/11 positivity for inclusion in the study. 
10. Inclusion Criterion #4, requirement for eligible patients to have a minimum of 2 RRP 
interventions per year for the three consecutive years prior to Day 0 has been reduced to 2 
RRP-001 Protocol | VV-TMF-00028 | 3.0
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INO-3107 
  
RRP-001 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 12Apr2021 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 5 of 60 
 
RRP interventions in the one year prior to and including Day 0.  This modification is meant to 
assist sites with enrolling subjects with currently active RRP disease who have had a break 
in their treatment due to various reasons.  Three years of RRP history will continue to be 
obtained on each enrolled subject where available. 
11. Inclusion Criterion #10 has been updated to clarify that subjects must meet one of the 
contraception requirements, but not all.  The examples of contraception have been simplified 
to reduce redundancies and confusion. 
12. Exclusion Criterion #1 has been updated to clarify the exclusion of prophylactic HPV 
vaccination for therapeutic use, and to reduce the wash-out period from 6 months to 3 months 
for systemic and intralesional RRP treatments, to take the half-life of the systemic therapies 
into consideration.  
13. Exclusion Criterion #5 has been updated to include a restriction around timing of study entry 
when given a non-live vaccine.  This guidance is included in the Protocol Restrictions, Section 
6.14 but was inadvertently missed in the exclusion criteria.  
14. The Schedule of Events have been updated with the following changes: 
a. The Week 104 End of Study visit has been replaced with a Week 52 End of Study 
Visit, and the prior Week 52 and Week 78 visits have been removed. 
 
  
 
c. Laryngoscopy and Staging at Day 0 has been removed from the table since it is 
already performed at Day -14 to Day 0.  Footnote ‘e’ has also been corrected to remove 
laryngoscopy every three months and to indicate that staging should be performed 
prior to any RRP surgical intervention.   
d. Footnote ‘f’ has been added to indicate that staging should be performed prior to the 
routine RRP intervention during Screening, within 14 days of Day 0. 
e. 
 
   
15. Section 4.3.2 of the protocol has been updated to clarify that subjects that are discontinued 
from treatment should remain on study to complete their follow-up visits and procedures. 
16. Sections 6.1.1, 6.1.2, 6.1.2.1, 6.1.2.6, and 6.1.2.7 provide clarifications of procedures 
described elsewhere in the protocol.     
17. Section 6.4.5 has been updated to be in line with the Schedule of Events as described in item 
#15c. above. 
18. Section 6.6 of the protocol has been updated to replace ibuprofen and ketorolac for pain 
management with acetaminophen. 
19. Section 7.2 was updated to indicate that recurrences of the disease under study, RRP, are 
not considered adverse events. 
20. Section 6.14 has been updated to clarify that prophylactic HPV vaccination (including 
Gardasil) as attempted therapeutic intervention is prohibited while on study. 
21. Section 8 of the protocol has been amended to address the revised primary, secondary, 
 
 objectives. 
 
 
RRP-001 Protocol | VV-TMF-00028 | 3.0
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