Summary

This phase II trials studies how well bizalimogene ralaplasmid (VGX-3100) and electroporation work in treating patients with human immunodeficiency virus (HIV)-positive high-grade anal lesions. Vaccines made from deoxyribonucleic acid (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-grad anal lesions.

Objectives

PRIMARY OBJECTIVE:
I. To determine the proportion of participants with human papillomavirus (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.

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.

EXPLORATORY 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 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 HPV16 E7 and HPV18 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 expression and T-cell infiltration on clinical benefit.

OUTLINE:
Patients receive 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 after the first dose of VGX-3100.

Eligibility

1. Biopsy-proven intra-anal or peri-anal HSIL (anal intraepithelial neoplasia [AIN]2 with a positive p16 stain, PAIN2-3, AIN2-3, or PAIN3/AIN3) within 90 days before study enrollment
2. At least one focus of HSIL must be large enough to be monitored for response, i.e., not completely removed after the screening biopsy
3. Must be positive for HPV-16 or -18 on genotyping performed on screening anal swab within 90 days before study enrollment
4. HIV positive; documentation of HIV-1 infection by means of any one of the following: * Documentation of HIV diagnosis in the medical record by a licensed health care provider * Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay; NOTE: A “licensed” assay refers to a U.S. Food and Drug Administration (FDA)-approved assay, which is required for all investigational new drug (IND) studies
5. Must be documented to be on an effective antiretroviral therapy (ART) regimen, generally a 3-drug regimen based on Department of Health and Human Services (DHHS) treatment guidelines by a licensed health care provider; documentation may be a record of an ART prescription in the participant’s medical record, a written prescription in the name of the participant for ART, or pill bottles for ART with a label showing the participant’s name; each component agent of a multi-class combination ART regimen will be counted separately
6. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
7. Within 90 days before enrollment: Leukocytes: >= 3,000/mm^3
8. Within 90 days before enrollment: Absolute neutrophil count: >= 1,500/mm^3
9. Within 90 days before enrollment: Platelets: >= 100,000/mm^3
10. Within 90 days before enrollment: CD4 count >= 350 cells/mm^3
11. Within 90 days before enrollment: HIV plasma HIV-1 RNA below detected limit obtained by Food and Drug Administration (FDA)-approved assays (limit of detection: 75 copies/mL or less)
12. For females, must have cervical cytology and visual examination of the vulva, vagina, and cervix within 12 months prior to enrollment with confirmation of no evidence of carcinoma; for women who underwent hysterectomy with removal of the cervix, cytology from the vagina within 12 months is required
13. For women of child-bearing potential (WOCBP), they must have a negative serum or urine pregnancy test within 72 hours of receiving the first dose of VGX-3100 and be at least 3 months post-partum; the effects of VGX-3100 on the developing human fetus are unknown; it is not known whether VGX-3100 can cross the placenta or cause harm to the fetus when administered to pregnant women or whether it affects reproductive capacity; for this reason, WOCBP and men must agree to use adequate contraception (oral contraceptive pills, intrauterine device, Nexplanon, Depo-Provera, or permanent sterilization, etc., or another acceptable method as determined by the investigator) prior to study entry, for the duration of study participation, and 4 months after completion of VGX-3100 administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; 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 4 months after completion of VGX-3100 administration * A WOCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
14. 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 4 months after completion of VGX-3100 administration
15. Ability to understand and the willingness to sign a written informed consent document