Cornelia L Trimble1, Kimberly Levinson2, Leonel Maldonado3, Michael J Donovan4, Katharine T Clark5, Jie Fu5, Maria E Shay5, Mary Elizabeth Sauter5, Stephanie A Sanders6, Peter S Frantz7, Mihaela Plesa8. 1. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 600 North Wolfe St, Phipps 255, Baltimore, MD 21287, United States of America. Electronic address: ctrimbl@jhmi.edu. 2. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 600 North Wolfe St, Phipps 255, Baltimore, MD 21287, United States of America; Greater Baltimore Medical Center, 6701 N. Charles St, Physicians Pavilion West Suite 306, Towson, MD 21204, United States of America. 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States of America. 4. Department of Pathology, Icahn School of Medicine at Mount Sinai, Anbg 15-5, 1468 Madison Avenue, Box 1134, New York, NY 10029, United States of America. 5. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, 600 North Wolfe St, Phipps 255, Baltimore, MD 21287, United States of America. 6. Greater Baltimore Medical Center, 6701 N. Charles St, Physicians Pavilion West Suite 306, Towson, MD 21204, United States of America. 7. Amarex Clinical Research, LLC, Amarex Clinical Research, 20201 Century Blvd, Germantown, MD 20874, United States of America. 8. Department of Pediatrics, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 1100, Baltimore, MD 21287, United States of America.
Abstract
OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.
OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.
Authors: Fuguang Zhao; Olesya Vakhrusheva; Sascha D Markowitsch; Kimberly S Slade; Igor Tsaur; Jindrich Cinatl; Martin Michaelis; Thomas Efferth; Axel Haferkamp; Eva Juengel Journal: Cells Date: 2020-12-09 Impact factor: 6.600
Authors: Laura C Gunder; Simon Blaine-Sauer; Hillary R Johnson; Myeong-Kyun Shin; Andrew S Auyeung; Wei Zhang; Glen E Leverson; Ella T Ward-Shaw; Renee E King; Stephanie M McGregor; Kristina A Matkowskyj; Paul F Lambert; Evie H Carchman Journal: Viruses Date: 2022-07-26 Impact factor: 5.818