Cervical cancer remains a significant health concern in the US, impacting an estimated 14,000 women annually. Despite advances, existing treatments for cervical precancer or cervical intraepithelial neoplasia (CIN), while effective in some cases, are invasive procedures (e.g., loop electrosurgical excision procedure (LEEP), cryotherapy, thermal ablation) that carry risks of adverse effects, including pain, bleeding, scarring, and potential impacts on future fertility. This underscores the critical need for non-invasive, easily accessible treatment options. This Phase 1a/1b pilot study will evaluate the safety, acceptability, and preliminary activity of a novel, non-invasive intervention: a self-administered vaginal capsule containing the protease inhibitors Lopinavir/Ritonavir (LPV/r). Preclinical evidence demonstrates LPV/r's anti-cancer and anti-HPV activity. Promising results were observed in a prior proof-of-concept trial using a different LPV/r ratio (4:1), and these findings are supported by additional data from clinical studies (unpublished data). Furthermore, in vitro research has identified a potentially more effective 12:1 LPV/r ratio, warranting clinical investigation. This study will investigate this optimized 12:1 formulation of LPV/r. Aim 1 will assess the safety and acceptability of the LPV/r capsule in 15 US women with CIN 2/3 (precancer) at a hospital-based colposcopy clinic in Cincinnati, OH, using a dose duration escalation design (7-, 14, or 21 days) to determine the maximum tolerated duration. Aim 2 will evaluate the preliminary activity of LPV/r against histologic evidence of precancer and HPV in 20 immunocompetent women at the maximum tolerated duration. Aim 3 will compare LPV/r activity against visual and/or histologic evidence of precancer and HPV in 40 immunocompetent and 40 immunocompromised women to that in 10 women receiving usual care. Participants in all arms will undergo cervical cytology, high-risk HPV testing, colposcopy, and biopsy (if indicated) at baseline and at 3-, 6-, and 12-months post-treatment. We hypothesize that the LPV/r capsule will be safe, acceptable, and demonstrate preliminary signals of activity against precancer and HPV in both immunocompetent and immunocompromised women, with potential differences in response between groups, and greater activity compared to usual care. These findings will inform future large-scale trials, including studies of the vaginal microenvironment and detailed immunological assessments, to rigorously evaluate LPV/r's efficacy as a potential new, non-invasive, cost-effective, self-administered treatment for cervical precancer, addressing a critical unmet need and improving cervical cancer outcomes in the U.S.
