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Patients receive HPV DNA plasmids therapeutic vaccine VGX-3100 IM and then undergo electroporation over 10 seconds for 4 doses in week 0, 4, 12, and 24 in the absence of disease progression or unacceptable toxicity.

Electroporation

HPV DNA Plasmids Therapeutic Vaccine VGX-3100

Laboratory Biomarker Analysis

Chia-Ching (Jackie) Wang

This phase II trial studies the use of human papillomavirus (HPV) deoxyribonucleic acid (DNA) plasmids therapeutic vaccine VGX-3100 (VGX-3100) and electroporation in treating patients with human immunodeficiency virus (HIV)-positive high-grade anal lesions. Vaccines made from DNA may help the body build an effective immune response to kill tumor cells. Electroporation helps pores in your body's cells take in the drug to strengthen your immune system's response. Giving VGX-3100 and electroporation together may work better in treating patients with high-grade anal lesions.

PRIMARY OBJECTIVES:

I. To determine the proportion of participants with HPV-16 and/or HPV-18-positive anal high grade squamous intraepithelial neoplasia (HSIL) that achieve either complete or partial response (which is defined as histopathological regression from HSIL to low grade squamous intraepithelial neoplasia \[LSIL\] or normal) at 48 weeks after the first dose of VGX-3100 (VGX-3100).

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability as assessed by Common Terminology Criteria for Adverse Events version 5 (CTCAE v5.0).

II. To determine the proportion of participants with HPV-16 and/or HPV-18-positive anal HSIL that achieve complete response (which is defined as histopathological regression from HSIL to normal) at 48 weeks after the first dose of VGX-3100.

III. To determine the proportion of participants who clear HPV-16 and/or HPV-18 (defined as changing from presence to absence of HPV-16 or 18 by anal histological specimen) at 48 weeks after the first dose of VGX-3100.

IV. To determine proportion of participants who clear HPV-16 and/or HPV-18 (defined as changing from presence to absence of HPV-16 and/or 18 by anal swab) at 48 weeks after the first dose of VGX-3100.

V. To compare the proportion of participants with HPV-16 and/or HPV-18-positive anal HSIL who achieve either complete or partial response (which is defined as histopathological regression from HSIL to LSIL or normal) versus those who do not at 72 weeks after the first dose of VGX-3100.

TERTIARY OBJECTIVES:

I. To determine the proportion of non-HPV-16 or HPV-18-positive anal HSIL lesions that achieve either complete or partial response (which is defined as histopathological regression from HSIL to LSIL or normal) at 48 weeks after the first dose of VGX-3100.

II. To determine the T cell response to VGX-3100 as measured by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot (ELISpot), flow cytometric assessments, and T cell infiltration into anal mucosal tissue.

III. To determine the antibody response to VGX-3100 as measured by enzyme-linked immunosorbent assay (ELISA) against HPV-16 E7 and HPV-18 E7 target antigens.

IV. To determine the association of the addition of a fourth dose of VGX-3100 with T-cell and antibody responses.

V. To determine the association of VGX-3100 immune response with CD4+ lymphocyte count over time.

VI. To determine the association of VGX-3100 immune response with HIV-1 ribonucleic acid (RNA) over time.

VII. To determine if CD4 + lymphocyte count affects the overall or complete response rate at 48 weeks after the first dose of VGX-3100.

VIII. To assess the effect of tissue PD-L1 (programmed death ligand 1) expression and T-cell infiltration on clinical benefit.

OUTLINE:

Patients receive HPV DNA plasmids therapeutic vaccine VGX-3100 intramuscularly (IM) and then undergo electroporation over 10 seconds for 4 doses in week 0, 4, 12, and 24 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 72 weeks.

VGX-3100 and Electroporation in Treating Patients With HIV-Positive High-Grade Anal Lesions

A Phase 2 Evaluation of VGX-3100, a Synthetic DNA Immunotherapy Targeting Human Papillomavirus 16 and 18 E6 and E7 Proteins, for Anal High-Grade Squamous Intraepithelial Lesions (HSIL) in HIV-Positive Individuals

Defined as histopathological regression of non-HPV-16 or HPV-18-positive HSIL to LSIL or AIN1 or normal. The one-sample test of proportions will be used to compare the proportion of non-HPV-16 or HPV-18-positive anal HSIL that achieve a complete or partial response (which is defined as histopathological regression from HSIL to LSIL or normal) versus the proportion of non-HPV-16 or HPV-18-positive anal HSIL that did not achieve a complete or partial response of at 48 weeks after the first dose of HPV DNA plasmids therapeutic vaccine VGX-3100.

A tobit regression model will be used to test the increase from baseline for all patients completing at least the 24-week dose.

To assess the change in antibody responses, the Wilcoxon signed rank test will be used to test the change from baseline for all patients completing at least the 24-week dose.

Assess the association of the addition of fourth dose of HPV DNA plasmids therapeutic vaccine VGX-3100 with T-cell responses.A tobit regression model will be used to test the increase from baseline for all patients completing at least the 24-week dose who receive a fourth dose of VGX-3100.

Assess the association of the addition of fourth dose of HPV DNA plasmids therapeutic vaccine VGX-3100 with antibody responses. To assess the change in antibody responses, the Wilcoxon signed rank test will be used to test the change from baseline for all patients completing at least the 24-week dose.

A paired t-test will be used to assess the effect of HPV DNA plasmids therapeutic vaccine VGX-3100 on CD4+ lymphocyte count over time by comparing the CD4 counts at each time-point to participant baseline values.

Changes in in human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) over time will be assessed over time. A paired t-test will be used to assess the effect of HPV DNA plasmids therapeutic vaccine VGX-3100 on HIV-1 RNA over time by comparing the viral loads at each time-point to participant baseline values.

Will assess association of CD4+ lymphocyte count in participants with a complete response at 48 weeks after the first dose of HPV DNA plasmids therapeutic vaccine VGX-3100. The two-sample t-test will be used to compare the CD4+ lymphocyte counts between those with an complete response and those without.

Will assess association of CD4+ lymphocyte count in participants with an overall response at 48 weeks after the first dose of HPV DNA plasmids therapeutic vaccine VGX-3100. The two-sample t-test will be used to compare the CD4+ lymphocyte counts between those with an overall response to those without.

Will assess the effect of tissue PD-L1 expression on clinical benefit. Chi-square test or Fisher's exact test, as appropriate, will be used to test the effect of tissue PD-L1 expression on overall response.

Will assess the effect of T-cell infiltration on clinical benefit. Chi-square test or Fisher's exact test, as appropriate, will be used to test the effect of T-cell infiltration on overall response.

Defined as histopathological regression of human papillomavirus (HPV)-16 and/or 18-positive anal high grade squamous intraepithelial neoplasia (HSIL) to low grade squamous intraepithelial neoplasia (LSIL) \[anal intraepithelial neoplasia (AIN)1\] or normal.

Safety and tolerability of treatment as assessed by incidence of adverse events assessed by Common Toxicity Criteria for Adverse Events version 5 (CTCAE v.5). Toxicity data will be presented by type and severity.

Complete response is defined as histopathological regression to normal. The one-sample test of proportions will be used to compare the proportion of participants with HPV-16 and/or HPV-18 positive anal HSIL who were complete responders at 48 weeks after the first dose versus the proportion of participants with HPV-16 and/or HPV-18 positive anal HSIL who were not complete responders at 48 weeks after the first dose of HPV deoxyribonucleic acid (DNA) plasmids therapeutic vaccine VGX-3100.

Viral clearance rate of HPV-16 and/or HPV-18 defined as changing from presence to absence of HPV-16/18 in anal HSIL by anal histological specimen. Proportions and their corresponding confidence intervals will be used to estimate the viral clearance rate of HPV-16 and HPV-18.

Viral clearance rate of HPV-16 and/or HPV-18 defined as changing from presence to absence of HPV-16/18 in anal HSIL by anal swab. Proportions and their corresponding confidence intervals will be used to estimate the viral clearance rate of HPV-16 and HPV-18.

Overall response rate defined as histopathological regression from HSIL to LSIL or normal. The one-sample test of proportions will be used to compare the proportion of participants with HPV-16 or HPV-18 positive anal HSIL who were complete or partial responders at 72 weeks after the first dose versus the proportion of participants with HPV-16 or HPV-18 positive anal HSIL who were not complete or partial responders at 72 weeks after the first dose of HPV DNA plasmids therapeutic vaccine VGX-3100.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
VGX-3100 and Electroporation in Treating Patients With HIV-Positive High-Grade Anal Lesions	NCT03603808	Anal Intraepith... High Grade Squa... HIV Positivity Human Papilloma... Human Papilloma...	Electroporation HPV DNA Plasmid... Laboratory Biom...	18 Years -	AIDS Malignancy Consortium
VGX-3100 and Electroporation in Treating Patients With HIV-Positive High-Grade Anal Lesions	NCT03603808	Anal Intraepith... High Grade Squa... HIV Positivity Human Papilloma... Human Papilloma...	Electroporation HPV DNA Plasmid... Laboratory Biom...	18 Years -	AIDS Malignancy Consortium

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