Clinical trial NCT05334004: Lopinavir/Ritonavir in PLWH With High-Grade AIN
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: High-Grade Anal Intraepithelial Neoplasia
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: Wisconsin Partnership Program
First posted: 2022-04-19
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: modified 3+3 design with increasing concentrations of study drug and thorough assessment of potential toxicities.
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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.
* Have received topical therapy for anal dysplasia previously

Primary outcomes:
measure: 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)
timeFrame: up to 5 weeks
measure: Rate of Grade 3 or above Toxicities in any Organ System in the Escalation Cohorts
timeFrame: up to 5 weeks
Secondary outcomes:
measure: Number of Participants in the Expansion Cohort Who Experience Regression of AIN2/3 Determined by Pathology
timeFrame: week 12, week 40
measure: Number of Participants in the Expansion Cohort Determined clear of HPV by PCR test
timeFrame: week 12, week 40
measure: Number of Tissue Samples with evidence of apoptosis measured by presence of Activated Caspase 3
timeFrame: week 12, week 40
measure: Number of Tissue Samples with evidence of autophagy measured by presence of LC3β and p62
timeFrame: week 12, week 40
measure: Number of Tissue Samples with evidence of cellular proliferation measured by presence of Ki-67
timeFrame: week 12, week 40
measure: Number of Tissue Samples with evidence of HPV positivity measured by presence of p16
timeFrame: week 12, week 40
measure: Number of Tissue Samples with p53 expression
timeFrame: week 12, week 40
Other outcomes:
Locations:
city: Madison
country: United States
facility: UW Digestive Health Center Anoscopy Clinic
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Evie Carchman, MD, FACS
role: PRINCIPAL_INVESTIGATOR
References: