VGX-3100 Delivered Intramuscularly (IM) Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 Related Anal or Anal/Peri-Anal, High Grade Squamous Intraepithelial Lesion (HSIL) in Individuals Seronegative for Human Immunodeficiency Virus (HIV)-1/2

Study Overview
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Brief Summary
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This is a phase 2, open-label efficacy study of VGX-3100 administered by intramuscular (IM) injection followed by electroporation (EP) in adult men and women who are human immunodeficiency virus (HIV) negative with histologically confirmed anal or anal/peri-anal high-grade squamous intraepithelial lesion (HSIL) associated with human papilloma virus (HPV)-16 and/or HPV-18. Approximately 24 participants will receive at least 3 doses of VGX-3100.

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

Conditions
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Anal Neoplasm

Intervention / Treatment
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* Biological: VGX-3100
* Device: CELLECTRA™ 5PSP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Negative screening test for HIV-1/2 within 30 days of Dose 1; Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by polymerase chain reaction (PCR) from HSIL specimen; Anal tissue specimen/slides for diagnosis must be collected within 10 weeks of first dose of VGX-3100; At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is histologically-confirmed as HSIL at Screening; Appropriate candidate for histology collection procedures (i.e. excision or biopsy) as judged by the Investigator; Female subjects must be post-menopausal, surgically sterile or agree to avoid pregnancy by continued abstinence or use of a contraceptive method with failure rate of less than 1% per year from Screening to one month after last dose of study medication (Week 12 or Week 40) Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse prior to the study, for the duration of study participation and one month after last dose of study medication. Normal Screening electrocardiogram (ECG). Exclusion Criteria: Untreated micro invasive or invasive cancer; Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and not undergoing medical care and/or treatment for VAIN; Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and not undergoing medical care and/or treatment for VIN; Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and not undergoing medical care and/or treatment for CIN; Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and not undergoing medical care and/or treatment for PIN; Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument; Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening; Inability to have complete and satisfactory high resolution anoscopic exams (HRAs) Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of Screening; Pregnant, breast feeding or considering becoming pregnant within one month following the last dose of study medication; Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 within 45 days prior to Day 0 or less than Grade 1 but deemed clinically significant by the Investigator; Immunosuppression as a result of underlying illness or treatment; History of previous therapeutic HPV vaccination; Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-3100 dose; Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of any VGX-3100 dose; Significant acute or chronic medical illness that could be negatively impacted by the electroporation treated as deemed by the Investigator; Current or history of clinically significant, medically unstable disease which, in the judgment of the investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the study results; Prior major surgery within 4 weeks of Day 0; Participation in an interventional study with an investigational compound or device within 4 weeks of signing the ICF; Any illness or condition that in the opinion of the Investigator may affect the safety of the subject or the evaluation of any study endpoint.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VGX-3100<br>Adult participants who were HIV negative with histologically confirmed anal or anal/peri-anal HSIL associated with HPV-16 and/or 18, received four 6 mg doses of VGX-3100 as an IM injection on Day 0, Week 4, Week 12, and Week 40 followed immediately by EP using the CELLECTRA™ 5PSP device. | Biological: VGX-3100<br>* One milliliter (1 mL) VGX-3100 (deoxyribonucleic acid [DNA] plasmids encoding E6 and E7 proteins of HPV types 16 and 18) will be injected IM and delivered by EP using CELLECTRA™ 5PSP on Day 0, Week 4 and Week 12, and potentially Week 40.<br>Device: CELLECTRA™ 5PSP<br>* IM injection of VGX-3100 is followed by EP with the CELLECTRA™ 5PSP device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL and no Evidence of HPV-16/18 at Week 36 |  | Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Local and Systemic Treatment-emergent Adverse Event (TEAE) During 7 Days Following Each Dose | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can include any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the first dose of study drug. | 7 days following each dose: Day 0 (Days 0 to 7), Week 4 (Days 22 to 28), Week 12 (Days 78 to 84), and Week 40 (Days 274 to 280) | 
| Number of Participants With at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can include any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | From first injection up to Week 88 | 
| Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal HSIL at Week 36 |  | Week 36 | 
| Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal and/or Peri-Anal Tissue by Type-Specific HPV Testing at Week 36 |  | Week 36 | 
| Percentage of Participants With no Evidence of HPV-16/18 From Intra-Anal Swab by Specific HPV Testing at Week 36 |  | Week 36 | 
| Percentage of Participants With no Evidence of Anal or Anal/Peri-Anal Low-Grade Squamous Intraepithelial Lesion (LSIL) or HSIL at Week 36 |  | Week 36 | 
| Percentage of Participants With no Progression of Anal or Anal/Peri-Anal HSIL to Carcinoma From Baseline to Week 36 |  | From Baseline to Week 36 | 
| Percent Change From Baseline in the Number of Intra-Anal and/or Peri-Anal Lesions as Determined by the Investigator at Weeks 36, 64, and 88 |  | From Baseline to Weeks 36, 64, and 88 | 
| Mean Change From Baseline in Frequency of HPV-16/17 E6/E7-specific CD8+/CD137+ Peripheral Blood Mononuclear Cells (PBMCs) That Were Perforin Positive at Week 15 | PBMCs were isolated from whole blood samples. The assessment of cellular immune activity occurred via the application Flow Cytometry for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay examined cluster of differentiation (CD)8/CD137 cellular markers and Perforin (proteins involved in lytic degranulation and cytotoxic potential) intracellular marker. The frequency was presented as number of perforin-positive CD8 i.e., CD8+/ CD137+ PBMCs cells per million CD8+/ CD137+ PBMCs cells. | Baseline and Week 15 | 
| Percentage of Participants With no Histologic Evidence of Anal or Anal/Peri-Anal HSIL or no Evidence of HPV-16/18 at Week 36 |  | Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High-grade squamous intraepithelial lesions (HSIL), Human papillomavirus (HPV), HPV-16, HPV-18, Anal intraepithelial neoplasia 2 (AIN2), Anal intraepithelial neoplasia 3 (AIN3), Peri-anal intraepithelial neoplasia 2 (PAIN2), Peri-anal intraepithelial neoplasia 3 (PAIN3)