title: Novel LHRH-receptor-targeted cytolytic peptide, EP-100: first-in-human phase I study in patients with advanced LHRH-receptor-expressing solid tumors.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic Cancer Center, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA, curtis.kelly1@mayo.edu.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Curtis
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Barnhart
authors.forename: John K
authors.initials: JK
authors.lastname: Whisnant
authors.forename: Carola
authors.initials: C
authors.lastname: Leuschner
authors.forename: Hector
authors.initials: H
authors.lastname: Alila
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011966:Receptors, LHRH / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011966:Receptors, LHRH