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.

Study Overview

• Status: Recruiting
• Conditions: High-Grade Anal Intraepithelial Neoplasia
• Intervention / Treatment: Drug: Lopinavir / Ritonavir

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

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Cancer Connect, MD, FACS; Phone Number: 800-622-8922; Email: clinicaltrials@cancer.wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Recruiting
      • UW Digestive Health Center Anoscopy Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• willing to provide informed consent
• greater than or equal to 18 years of age
• Diagnosis of biopsy-confirmed HGAIN
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Lopinavir/Ritonavir 200mg/50mg (2 cycles); Cohort 1 will receive two 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0 and 2	Drug: Lopinavir / Ritonavir; Human Immunodeficiency Virus (HIV) antiviral, given via suppository
Experimental: Cohort 1b: Lopinavir/Ritonavir 200mg/50mg (3 cycles); 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).	Drug: Lopinavir / Ritonavir; Human Immunodeficiency Virus (HIV) antiviral, given via suppository
Experimental: Cohort 2: Lopinavir/Ritonavir 400mg/100mg (2 cycles); 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.	Drug: Lopinavir / Ritonavir; Human Immunodeficiency Virus (HIV) antiviral, given via suppository
Experimental: Cohort 2b: Lopinavir/Ritonavir 400mg/100mg (3 cycles); 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.	Drug: Lopinavir / Ritonavir; Human Immunodeficiency Virus (HIV) antiviral, given via suppository
Experimental: Cohort 3: Lopinavir/Ritonavir 600mg/150mg (2 cycles); 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.	Drug: Lopinavir / Ritonavir; Human Immunodeficiency Virus (HIV) antiviral, given via suppository
Experimental: Cohort 4: Lopinavir/Ritonavir 600mg/150mg (3 cycles); 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.	Drug: Lopinavir / Ritonavir; Human Immunodeficiency Virus (HIV) antiviral, given via suppository

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	up to 5 weeks
Rate of Grade 3 or above Toxicities in any Organ System in the Escalation Cohorts	Grade 3 or above as delineated in Common Terminology Criteria for Adverse Events v 5.0 (CTCAE)	up to 5 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	week 12, week 40
Number of Participants in the Expansion Cohort Determined clear of HPV by PCR test	HPV clearance determined by quantitative polymerase chain reaction (PCR) test.	week 12, week 40
Number of Tissue Samples with evidence of apoptosis measured by presence of Activated Caspase 3	Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with activated caspase 3 indicate evidence of apoptosis.	week 12, week 40
Number of Tissue Samples with evidence of autophagy measured by presence of LC3β and p62	Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with LC3β and p62 indicate evidence of autophagy.	week 12, week 40
Number of Tissue Samples with evidence of cellular proliferation measured by presence of Ki-67	Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with Ki-67 indicate evidence of cellular proliferation.	week 12, week 40
Number of Tissue Samples with evidence of HPV positivity measured by presence of p16	Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with p16 indicate evidence of HPV positivity.	week 12, week 40
Number of Tissue Samples with p53 expression	Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue).	week 12, week 40

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Wisconsin Partnership Program
• Investigators: Principal Investigator: Evie Carchman, MD, FACS, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 1, 2022
• First Submitted That Met QC Criteria: April 11, 2022
• First Posted (Actual): April 19, 2022

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Neoplasms; Carcinoma in Situ; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Pyrimidinones; Lopinavir
• Other Study ID Numbers: 2023-0052; SMPH/SURGERY/COLON RECT (Other Identifier: UW Madison); 2022-0468 [former] (Other Identifier: UW Madison); UW22123 (Other Identifier: UWCCC ID); Protocol Version 2/24/2026 (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No