Lopinavir/Ritonavir for Anal Intraepithelial Neoplasia

Overseen By Cancer Connect, MD, FACS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Wisconsin, Madison

Must be taking: HIV antiretrovirals

Disqualifiers: Low-grade anal dysplasia, Chemotherapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 5 weeks

21 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of using the drugs lopinavir and ritonavir (known as Kaletra or Aluvia) to treat anal intraepithelial neoplasia (AIN), a condition that can lead to anal cancer. Researchers aim to determine if these drugs, administered in different doses over several cycles, are safe for people with HIV. Participants must have a confirmed diagnosis of high-grade AIN (a more severe form of the condition) and manage their HIV well with medication. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to early-stage medical research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, since participants must be on HIV antiretroviral therapy, it seems you can continue those medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that lopinavir/ritonavir is generally well-tolerated for other conditions. The FDA has approved this medication for treating HIV, which provides some confidence about its safety. Some individuals have reported mild side effects like nausea, diarrhea, or headaches when taking it as a pill.

In the current study, researchers are testing lopinavir/ritonavir as a suppository for treating a precancerous condition in the anal area. While specific safety data for this form is not yet available, its early trial phase ensures that researchers closely monitor for any side effects. Although safety data is limited, its use in other treatments offers some reassurance. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about using Lopinavir/Ritonavir for anal intraepithelial neoplasia because it offers a potentially new approach to treating this condition. Unlike the standard of care, which often involves surgical procedures or topical treatments, Lopinavir/Ritonavir is administered as a suppository, which might provide a more localized and less invasive option. This drug combination is typically used as an antiretroviral treatment, but its potential application here lies in its ability to specifically target and reduce abnormal cell growth in the anal region. This unique delivery method and mechanism of action could offer a promising alternative for patients seeking less invasive treatment options.

What evidence suggests that this treatment might be an effective treatment for AIN?

Research has shown that using lopinavir/ritonavir as a suppository might help reduce anal pre-cancerous growths in people living with HIV. Some studies have found that this treatment can decrease these growths over time. In this trial, participants will join different cohorts receiving varying doses and cycles of lopinavir/ritonavir. Specifically, patients in those studies demonstrated improvement in more serious growths at different treatment stages. The treatment targets changes in the anal area caused by HPV, which can lead to cancer. Early results suggest that applying lopinavir/ritonavir directly in the anal area could effectively manage these growths. ^{1 3 4 5 6}

Who Is on the Research Team?

Evie Carchman, MD, FACS

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for adults over 18 with HIV who are virologically suppressed on ART, have a CD4 count above 200 cells/mm^3, and are HPV positive with high-grade anal intraepithelial neoplasia (HGAIN). It's not for those with low-grade AIN, CD4 counts under 200, abnormal lipid profiles, pregnant or breastfeeding women, anyone on chemotherapy/radiation for another cancer or who've had topical therapy for anal dysplasia.

Inclusion Criteria

I have been diagnosed with high-grade anal intraepithelial neoplasia.

I have tested positive for HPV.

Willing to comply with all study procedures

Exclusion Criteria

I need to take medication that cannot be combined with lopinavir/ritonavir.

I am unable to understand and give consent for treatment.

I am currently undergoing chemotherapy or radiation for another cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intra-anal administration of lopinavir/ritonavir in cycles, with dose escalation to determine the maximum tolerated dose

5 weeks

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of AIN regression and biomarker studies

40 weeks

Regular follow-up visits at weeks 12, 28, and 40

What Are the Treatments Tested in This Trial?

Interventions

• Lopinavir / Ritonavir

Trial Overview The study tests the safety of lopinavir/ritonavir in patients living with HIV who have HGAIN. Thirty participants will be involved in active study treatment for about three months and then followed up long-term for an additional forty weeks to monitor effects.

How Is the Trial Designed?

Group I: Cohort 4: Lopinavir/Ritonavir 600mg/150mg (3 cycles) Experimental Treatment 1 Intervention

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.

Group II: Cohort 3: Lopinavir/Ritonavir 600mg/150mg (2 cycles) Experimental Treatment 1 Intervention

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.

Group III: Cohort 2b: Lopinavir/Ritonavir 400mg/100mg (3 cycles) Experimental Treatment 1 Intervention

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.

Group IV: Cohort 2: Lopinavir/Ritonavir 400mg/100mg (2 cycles) Experimental Treatment 1 Intervention

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.

Group V: Cohort 1b: Lopinavir/Ritonavir 200mg/50mg (3 cycles) Experimental Treatment 1 Intervention

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).

Group VI: Cohort 1: Lopinavir/Ritonavir 200mg/50mg (2 cycles) Experimental Treatment 1 Intervention

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

Lopinavir / Ritonavir is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Kaletra for:

• HIV Infection
• Nonoccupational Exposure

Approved in European Union as Kaletra for:

• HIV/AIDS
• Pre-exposure prophylaxis

Approved in Canada as Aluvia for:

• HIV/AIDS

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Wisconsin Partnership Program

Collaborator

Trials

9

Recruited

590+

Published Research Related to This Trial

Lopinavir/ritonavir (Kaletra) is an effective and well-tolerated treatment for HIV, showing durable virological efficacy in both ART-naive and -experienced patients, making it a preferred option according to US and British guidelines.

The new coformulated tablet allows for convenient once-daily dosing without food interactions, which can improve adherence to treatment in patients, including children over 6 months and adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/ritonavir: a review of its use in the management of HIV infection. Oldfield, V., Plosker, GL.[2018]

In a study of 138 heavily pretreated HIV patients, Lopinavir/ritonavir (Kaletra) demonstrated significant antiviral efficacy, with 76.3% of patients achieving a notable virologic response after 3 months.

Kaletra was generally well tolerated, although some patients experienced increased triglyceride levels; genotyping for protease inhibitor mutations at the start of treatment could help identify patients who are more likely to benefit from the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage treatment with lopinavir/ritonavir (Kaletra) in HIV-infected patients failing all current antiretroviral drug families. de Mendoza, C., Martín-Carbonero, L., Barreiro, P., et al.[2022]

Kaletra® (Lopinavir/Ritonavir) significantly decreased body weight gain and negatively affected sperm motility and count in male Wistar rats, indicating potential reproductive toxicity.

The study found that Kaletra® induced oxidative damage in the testes, as evidenced by increased lipid peroxidation and decreased antioxidant enzyme activities, particularly at higher doses, which could impair male reproductive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/Ritonavir, an Antiretroviral Drug, Lowers Sperm Quality and Induces Testicular Oxidative Damage in Rats. Adaramoye, OA., Akanni, OO., Adewumi, OM., et al.[2015]

Kaletra, a combination of lopinavir and ritonavir, was the first boosted protease inhibitor approved by the FDA in 2000 due to its higher efficacy compared to earlier HIV treatments.

As HIV treatment evolves into long-term management, the safety and long-term toxicity of Kaletra, particularly concerning cardiovascular health and metabolic disorders, are becoming increasingly important for patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of lopinavir/ritonavir for the treatment of HIV-infection. Vogel, M., Rockstroh, JK.[2013]

Lopinavir/ritonavir is an effective treatment for HIV-1 infection, providing durable viral suppression and improved immune function in both treatment-naive and treatment-experienced patients, as shown in well-designed clinical trials.

While generally well tolerated, lopinavir/ritonavir can cause manageable gastrointestinal side effects and increased lipid levels, which may require additional treatment to mitigate cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/Ritonavir: a review of its use in the management of HIV-1 infection. Croxtall, JD., Perry, CM.[2022]

Lopinavir, when combined with ritonavir as Kaletra, has been shown to effectively suppress HIV RNA levels for up to 2 years in antiretroviral-naive patients, demonstrating its efficacy in treating HIV.

While lopinavir-ritonavir is generally safe, it can cause side effects such as diarrhea and liver function abnormalities, and it is recommended as a first-line treatment for HIV-infected adults and adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir-Ritonavir: a new protease inhibitor. Mangum, EM., Graham, KK.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05334004

Lopinavir/Ritonavir in PLWH With High-Grade AIN 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.

2. withpower.com withpower.com/trial/phase-1-carcinoma-in-situ-2023-44015

Lopinavir/Ritonavir for Anal Intraepithelial Neoplasia This trial is testing a suppository form of HIV medications lopinavir and ritonavir in patients with HIV who have a precancerous condition in the anal area.

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03971

Lopinavir/Ritonavir Administered Intra-Anally for the ... This phase I trial tests the safety, side effects, and best dose of lopinavir/ritonavir administered intra-anally in preventing human papillomavirus (HPV)- ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4732739/

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir ... Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology.

5. mct.platformx.wisc.edu mct.platformx.wisc.edu/mct.php?protocol_id=33456&protocol_no=UW22123&back_node_id=106

Carbone Cancer Center Clinical Trials - Protocol 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 ...

6. trialx.com trialx.com/clinical-trials/listings/247094/lopinavirritonavir-in-plwh-with-high-grade-ain/

Lopinavir/Ritonavir in PLWH With High-Grade AIN Overview. This study is being done to assess the safety of lopinavir/ritonavir in patients with PLWH with AIN.