Lopinavir/Ritonavir in PLWH With High-Grade AIN
Study Details
Study Description
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 study for up to 40 weeks.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1: Lopinavir/Ritonavir 200mg/50mg 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 2: Lopinavir/Ritonavir 200mg/50mg Cohort 2 will receive three 5-day cycle of the same low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0, 2 and 4 if Cohort 1 dose is safe. |
Drug: Lopinavir / Ritonavir
Human Immunodeficiency Virus (HIV) antiviral, given via suppository
|
| Experimental: Cohort 3: Lopinavir/Ritonavir 400mg/100mg Cohort 3 will receive two 5-day cycles of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) 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 400mg/100mg Cohort 4 will receive three 5-day cycles of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0, 2, and 4, if the Cohort 3 dose is safe. |
Drug: Lopinavir / Ritonavir
Human Immunodeficiency Virus (HIV) antiviral, given via suppository
|
| Experimental: Cohort 5: Lopinavir/Ritonavir 600mg/150mg Cohort 5 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 4 dose is safe. |
Drug: Lopinavir / Ritonavir
Human Immunodeficiency Virus (HIV) antiviral, given via suppository
|
| Experimental: Cohort 6: Lopinavir/Ritonavir 600mg/150mg Cohort 6 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 5 dose is safe. |
Drug: Lopinavir / Ritonavir
Human Immunodeficiency Virus (HIV) antiviral, given via suppository
|
Outcome Measures
Primary Outcome Measures
- 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) [up to 5 weeks]
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.
- Rate of Grade 3 or above Toxicities in any Organ System in the Escalation Cohorts [up to 5 weeks]
Grade 3 or above as delineated in Common Terminology Criteria for Adverse Events v 5.0 (CTCAE)
Secondary Outcome Measures
- Number of Participants in the Expansion Cohort Who Experience Regression of AIN2/3 Determined by Pathology [week 16, week 28, week 40]
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.
- Number of Participants in the Expansion Cohort Determined clear of HPV by PCR test [week 16, week 28, week 40]
HPV clearance determined by quantitative polymerase chain reaction (PCR) test.
- Number of Tissue Samples with evidence of apoptosis measured by presence of Activated Caspase 3 [week 16, week 28, week 40]
Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with activated caspase 3 indicate evidence of apoptosis.
- Number of Tissue Samples with evidence of autophagy measured by presence of LC3β and p62 [week 16, week 28, week 40]
Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with LC3β and p62 indicate evidence of autophagy.
- Number of Tissue Samples with evidence of cellular proliferation measured by presence of Ki-67 [week 16, week 28, week 40]
Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with Ki-67 indicate evidence of cellular proliferation.
- Number of Tissue Samples with evidence of HPV positivity measured by presence of p16 [week 16, week 28, week 40]
Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). Samples with p16 indicate evidence of HPV positivity.
- Number of Tissue Samples with p53 expression [week 16, week 28, week 40]
Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
willing to provide informed consent
-
greater than or equal to 18 years of age
-
Human papillomavirus (HPV) positive
-
Diagnosis of HGAIN
-
Human immunodeficiency virus (HIV) positive with CD4 count greater than 200 cells/mm^3
-
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UW Digestive Health Center Anoscopy Clinic | Madison | Wisconsin | United States | 53705 |
Sponsors and Collaborators
- University of Wisconsin, Madison
- Wisconsin Partnership Program
Investigators
- Principal Investigator: Evie Carchman, MD, FACS, University of Wisconsin, Madison
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2022-0468
- A539707
- Protocol Version 3/11/2022