Phase I/II clinical safety studies of terameprocol vaginal ointment

Objectives.Terameprocol (M4N, EM-1421) is a novel transcription inhibitor that selectively interferes with HPV viral genes E6/E7 with Sp1-dependent promoters, and induces apoptosis by inactivation of the CDC2/cyclin B complex (maturation promoting factor)and production and phosphorylation of survivin. This trial was designed to define the maximum tolerated dose (MTD), dose-limiting toxicity and determine the pharmacokinetic profiles of intravaginal terameprocol in women with HPV-linked cervical squamous intraepithelial neoplasia.Methods.An open label, dose escalation Phase I/II clinical trial enrolled women with biopsy confirmed CIN 1, 2 or 3. Terameprocol (45 or 90 mg) was physician-administered directly to the cervix uteri in 3 once weekly applications. The pharmacokinetics after administration were examined on Day 1 of dosing. Patients underwent colposcopic examinations, HPV testing, biomarker assessments, cytology and cervical punch biopsy.Results.Recruitment ended March 30, 2006 and 7 patients were enrolled. Median age was 24 years. There were no serious adverse events (SAEs) and possible treatment-related Adverse Events (AEs) reported were mild and self-limiting. There was no detectable absorption of terameprocol from the vaginal ointment application.Conclusions.Terameprocol in 1% and 2% vaginal ointment use in Phase I/II trials with women with HPV-linked cervical intraepithelial neoplasia has an excellent safety profile, no SAEs reported and mild, self-limiting treatment-related AEs. There was no detectable absorption of terameprocol. These data support the continued evaluation of terameprocol in in vitro and animal efficacy models followed by definitive human Phase II clinical trials in CIN.