High-Grade Anal Intraepithelial Neoplasia
Conditions
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
Interventions
Human Immunodeficiency Virus (HIV) antiviral, given via suppository
Sponsors
University of Wisconsin, Madison
Wisconsin Partnership Program
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
modified 3+3 design with increasing concentrations of study drug and thorough assessment of potential toxicities.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in the Expansion Cohort Who Experience Regression of AIN2/3 Determined by Pathology | week 12, 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 12, 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 12, 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 12, 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 12, 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 12, 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 12, week 40 | Mechanism of action of protease inhibitors investigated with biomarker studies (immunohistochemistry and Immunofluorescence of tissue). |
Countries
United States
Contacts
CONTACTCancer Connect, MD, FACS
PRINCIPAL_INVESTIGATOREvie Carchman, MD, FACS
University of Wisconsin, Madison
Outcome results
None listed