Novel LHRH-receptor-targeted cytolytic peptide, EP-100: first-in-human phase I study in patients with advanced LHRH-receptor-expressing solid tumors

PURPOSE: To conduct a phase I study determining the safety, pharmacokinetics and preliminary efficacy of EP-100, a novel anticancer drug consisting of natural luteinizing-hormone-releasing hormone (LHRH) ligand linked to a cationic membrane-disrupting peptide. METHODS: Patients with advanced, solid tumors, positive for LHRH receptor by immunohistochemistry (IHC), received EP-100 weekly or twice weekly for 3 of 4 weeks in a 28 day cycle. A modified Fibonacci 3 + 3 dose-escalation schema was used. Initial cohorts received EP-100 once weekly (cohorts 1–7, 0.6–7.8 mg/m(2), n = 21). Later cohorts received doses twice weekly (cohorts 7–11, 7.8–40 mg/m(2), n = 16). RESULTS: LHRH-receptor expression was confirmed by IHC in 52 of 89 consented patients; 37 patients received at least 1 dose. Cohorts receiving doses of 5.2 mg/m(2) and above achieved therapeutic levels from in vitro studies Clearance was rapid (mean half-life 7.1 ± 3.8 to 15.9 ± 3.6 min). The maximum-tolerated dose was not reached at the highest dose evaluated (40 mg/m(2) twice weekly). Grade 2 increase in alanine aminotransferase/serum aspartate aminotransferase in one patient resolved, did not recur upon re-treatment, and was not observed in other patients. The only drug-related adverse event was transient infusion-related dermatologic reactions (10 patients). No complete or partial tumor responses were observed; seven patients had stable disease of 16 weeks. CONCLUSIONS: EP-100 was well tolerated in patients with advanced, LHRH-receptor-expressing solid tumors. The recommended phase 2 dose is 40 mg/m(2) twice weekly for 3 of 4 weeks per cycle. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2424-x) contains supplementary material, which is available to authorized users.