Lopinavir/Ritonavir in PLWH With High-Grade AIN

A Phase I Study of Intra-anally Administered Lopinavir/Ritonavir in People Living With HIV (PLWH) With High-Grade Anal Intraepithelial Neoplasia (AIN 2/3)

This study is being done to assess the safety of lopinavir/ritonavir in patients with PLWH with AIN. 30 participants will be recruited and can expect to be on active study for approximately 3 months and long term follow up for 40 weeks.

This is a Phase I modified 3 + 3 design, in which the maximum tolerated dose (MTD) will be identified. The 3 + 3 dose escalation will consist of 6 dose levels (18 participants; planned escalation described in arms below) in combination with variation in dosing schedules of the drug lopinavir/ritonavir. This design also allows for some possible intermediate doses to be examined if dose-limiting toxicities (DLTs) occur and de-escalation is needed. An expansion cohort of 12 participants will occur at the MTD. Once the MTD is determined, then secondary outcomes will be evaluated. Primary Objective To evaluate the safety and tolerability of intra-anal administration of lopinavir/ritonavir, administered via suppository with 3 different schedules, in PLWH with high-grade anal intraepithelial neoplasia (HGAIN) (AIN 2/3). Secondary Objectives To measure the effect of intra-anal topical lopinavir/ritonavir administration To evaluate clearance of human papillomavirus (HPV) To elucidate the mechanism of action of protease inhibitors

modified 3+3 design with increasing concentrations of study drug and thorough assessment of potential toxicities.

Cohort 1 will receive two 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0 and 2

Cohort 1b will receive three 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0, 2, and 4 if Cohort 2 has one dose-limiting toxicity (DLT).

Cohort 2 will receive two 5-day cycles of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0 and 2, if Cohort 1 dose is safe.

Cohort 2b will receive three 5-day cycle of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0, 2 and 4 if Cohort 3 has one DLT.

Cohort 3 will receive two 5-day cycles of the highest dose of the suppository (Lopinavir/Ritonavir (600mg/150mg)) in Weeks 0 and 2, if the Cohort 2 dose is safe.

Cohort 4 will receive three 5-day cycles of the highest dose of the suppository (Lopinavir/Ritonavir (600mg/150mg)) in Weeks 0, 2, and 4, if the Cohort 3 dose is safe.

Maximum Tolerated Dose (MTD) as determined by the number of participants at each dose level in the escalation cohorts who experienced a dose-limiting toxicity (DLT)

The MTD is the highest explored dose of lopinavir/ritonavir is the dose at which less than 33% of patients experienced a DLT. A DLT is defined as any toxicity at least possibly related to ritonavir/lopinavir with a drug-related Grade greater than or equal to 3.

Number of Participants in the Expansion Cohort Who Experience Regression of AIN2/3 Determined by Pathology

Efficacy of intra-anal topical lopinavir/ritonavir administration determined by pathology, based on the regression of AIN2/3 at study weeks 16, 28, and 40. Regression defined as either AIN1 or no AIN lesion detected by High resolution anoscopy (HRA)/biopsy and anal cytology. Down grade of disease from AIN2/3 to AIN1 or normal.

Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with activated caspase 3 indicate evidence of apoptosis.

Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with LC3β and p62 indicate evidence of autophagy.

Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with Ki-67 indicate evidence of cellular proliferation.

Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with p16 indicate evidence of HPV positivity.

Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue).

Inclusion Criteria: willing to provide informed consent greater than or equal to 18 years of age Diagnosis of biopsy-confirmed HGAIN Human immunodeficiency virus (HIV)-positive with CD4 count greater than 200 cells/mm^3 at screening and virologically suppressed on HIV-1 antiretroviral therapy (ART) within last 12 months willing to comply with all study procedures Exclusion Criteria: Diagnosis of low-grade anal dysplasia (AIN, low-grade squamous intraepithelial lesion (LSIL)) by HRA. CD4 count less than 200 cells/mm^3 at the time of consideration for entry into the study unable to provide informed consent Pregnant or breastfeeding female Currently receiving systemic chemotherapy or radiation therapy for another cancer. Lipid profile abnormalities total cholesterol greater than 240 mg/dL low density lipoproteins (LDL) greater than 160 mg/dL high density lipoproteins (HDL) less than 40 mg/dL triglycerides greater than 500 mg/dL Have received topical therapy for anal dysplasia previously Participants who need to take drugs that are contraindicated with lopinavir/ritonavir