Evaluation of VGX-3100 and Electroporation Alone or in Combination With Imiquimod for the Treatment of HPV-16 and/or HPV-18 Related Vulvar HSIL (Also Referred as: VIN 2 or VIN 3)

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

Official Title
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A Phase 2, Randomized, Open Label, Efficacy Study of VGX-3100 Delivered Intramuscularly Followed by Electroporation With CELLECTRA™ 2000 Alone or in Combination With Imiquimod, for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous Intraepithelial Lesion (HSIL) of the Vulva

Conditions
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VIN2, Vulvar High Grade Squamous Intraepithelial Lesion (HSIL), Vulvar Dysplasia, Vulvar Intraepithelial Neoplasia (VIN), VIN3, Pre-cancerous Lesions of the Vulva, Human Papillomavirus (HPV)

Intervention / Treatment
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* Biological: VGX-3100
* Drug: Imiquimod 5% Cream
* Device: CELLECTRA™ 2000


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18 and above; Have high grade squamous intraepithelial lesion (HSIL) of the vulva (VIN2 or VIN3) caused by infection with HPV types 16 and/or 18 confirmed at screening visit; Exclusion Criteria: Biopsy-proven differentiated VIN; Any previous treatment for vulvar HSIL within 4 weeks prior to screening; Allergy to imiquimod 5% cream or to an inactive ingredient in imiquimod 5% cream; Pregnant, breastfeeding or considering becoming pregnant within 6 months following the last dose of investigational product; Immunosuppression as a result of underlying illness or treatment; Significant acute or chronic medical illness.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VGX-3100 + EP<br>Participants with histologically confirmed vulvar high-grade squamous intraepithelial lesion (HSIL) associated with human papilloma virus (HPV) 16 and/or 18, received four doses of 6 mg VGX-3100 as an intramuscular (IM) injection on Day 0, Week 4, Week 12, and Week 24 followed by electroporation (EP) using the CELLECTRA™ 2000 device. Participants with vulvar HSIL who had a reduction in lesion size or no increase in lesion size at Week 48, received a fifth dose of VGX-3100 at Week 52. | Biological: VGX-3100<br>* One milliliter (1 mL) VGX-3100 injected IM and delivered by EP using CELLECTRA™ 2000 on Day 0, Week 4, Week 12 and Week 24.<br>Device: CELLECTRA™ 2000<br>* IM injection of VGX-3100 was followed by EP with the CELLECTRA™ 2000 device.<br>|
| Experimental: VGX-3100 + EP + Imiquimod<br>Participants with histologically confirmed vulvar HSIL associated with HPV-16 and/or 18, received four doses of 6 mg VGX-3100 as an IM injection on Day 0, Week 4, Week 12, and Week 24 followed by EP using the CELLECTRA™ 2000 device. Participants with vulvar HSIL who had a reduction in lesion size or no increase in lesion size at Week 48, received a fifth dose of VGX-3100 at Week 52. In addition, participants applied imiquimod 5% cream to the vulvar lesion three times per week for 20 weeks. | Biological: VGX-3100<br>* One milliliter (1 mL) VGX-3100 injected IM and delivered by EP using CELLECTRA™ 2000 on Day 0, Week 4, Week 12 and Week 24.<br>Drug: Imiquimod 5% Cream<br>* Participants applied imiquimod 5% cream to the vulvar lesion three times per week for 20 weeks.<br>Device: CELLECTRA™ 2000<br>* IM injection of VGX-3100 was followed by EP with the CELLECTRA™ 2000 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 Vulvar HSIL and No Evidence of HPV-16 and/or HPV-18 in Vulvar Tissue Samples | A treatment responder for the primary endpoint was defined as a participant with no histologic evidence of vulvar HSIL (normal tissue or vulvar low grade squamous intraepithelial lesions (LSIL) [vulval intraepithelial neoplasia 1 (VIN1)] or condyloma) and no evidence of HPV-16 or HPV-18 (i.e., elimination of the specific genotypes [16, 18, or both]) in vulvar tissue at evaluation and who did not receive any non-study related treatment for vulvar HSIL. All lesions were evaluated for histologic evidence of vulvar HSIL or evidence of HPV-16/18 in vulvar tissue. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With at Least One Local and Systemic Treatment-emergent Adverse Event (TEAE) During 7 Days Following Each Dose | An adverse event (AE) was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body, or worsening of a pre-existing condition, temporally associated with the use of a product whether or not considered related to the use of the product. A TEAE was defined per protocol as any AE with onset after the administration of study medication through the end of the study (i.e., study discharge). | 7 days following each dose: Day 0 (Days 0 to 7), Week 4 (Days 22 to 28), Week 12 (Days 78 to 84), Week 24 (Days 162 to 168), and Week 52 (Days 358 to 364) | 
| Percentage of Participants With Adverse Events (AEs) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body, or worsening of a pre-existing condition, temporally associated with the use of a product whether or not considered related to the use of the product. | From baseline up to Week 100 | 
| Percentage of Participants With No Histologic Evidence of Vulvar HSIL | Participants with no histologic evidence of vulvar HSIL (normal tissue or vulvar LSIL [VIN1] or condyloma) based on histology (i.e. biopsies or excisional treatment) were considered. All lesions were evaluated for histologic evidence of vulvar HSIL. | Week 48 | 
| Percentage of Participants With No Evidence of HPV-16 and/or HPV-18 in Vulvar Tissue Samples | Participants with no evidence of HPV-16 and/or HPV-18 indicated the clearance of the specific HPV genotypes [16, 18, or both]. All lesions were evaluated for evidence of HPV-16/18 in vulvar tissue. | Week 48 | 
| Percentage of Participants With No Histologic Evidence of Vulvar HSIL or No Evidence of HPV-16/18 in Vulvar Tissue | A treatment responder for the endpoint was defined as a participant with no histologic evidence of vulvar HSIL (normal tissue or LSIL [VIN1] or condyloma) based on histology (i.e. biopsies or excisional treatment) or no evidence of HPV-16 or HPV-18 (i.e., elimination of the specific genotypes [16, 18, or both]) in vulvar tissue at evaluation and who did not receive any non-study related treatment for vulvar HSIL. All lesions were evaluated for histologic evidence of vulvar HSIL or evidence of HPV-16/18 in vulvar tissue. | Week 48 | 
| Percentage of Participants With No Evidence of Vulvar HSIL, No Evidence of Vulvar LSIL (VIN1), and No Evidence of Condyloma on Histology | Histologic regression was defined as a participant with no histologic evidence of vulvar HSIL, no evidence of LSIL (VIN1), and no evidence of condyloma. Histologic regression of vulvar HSIL to normal tissue was assessed. | Week 48 | 
| Percentage of Participants With No Progression of Vulvar HSIL to Vulvar Cancer | Non-progression of vulvar HSIL to vulvar cancer was evaluated from baseline to Week 48. Progression was defined as advancement to carcinoma by histology. | From baseline up to Week 48 | 
| Percent Change From Baseline in the Cumulative Surface Area of the Acetowhite Vulvar Lesion(s) | Lesion(s), defined as areas that stain acetowhite were assessed. Analysis of qualifying lesions was defined as the change in total surface area of only lesions with both baseline and Week 48 measurements. Percent change in the cumulative surface area of the acetowhite vulvar lesion(s) was determined by the quantitative analysis of standardized prebiopsy photographic imaging of qualifying lesion(s) at Week 48 compared to baseline. | From baseline to Week 48 | 
| Change From Baseline in Interferon-Gamma (IFN-γ) Response Magnitude | Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples. Assessment of cellular immune activity was performed by IFN-γ enzyme-linked immunosorbent spot-forming (ELISpot) assay. | Baseline; Weeks 15, 27, 48, 74, and 96 | 
| Levels of Serum Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations | A standardized binding enzyme-linked immunosorbent assay (ELISA) was performed to measure the anti-HPV-16/18 antibody response induced by VGX-3100. | Weeks 15, 27, 48, 74, and 96 | 
| Change From Baseline in Flow Cytometry Response Magnitude | Assessment of cellular immune activity was measured using the application of flow cytometry for the purpose of performing a Lytic Granule Loading Assay. The Lytic Granule Loading Assay examines the following external cellular markers: cluster of differentiation 3 (CD3), CD4, CD8 (T-cell identification), CD137, CD38, and CD69 (T-cell activation markers) as well as PD-1 (exhaustion/activation marker). Here, a change from baseline in CD8+/CD137+ PBMCs expressing Perforin+ was reported. | Baseline; Week 27 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV-16, HPV-18