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

Kelly K Curtis, John Sarantopoulos, Donald W. Northfelt, Glen J. Weiss, Kerry M. Barnhart, John K. Whisnant, Carola Leuschner, Hector Alila, Mitesh J. Borad, Ramesh K. Ramanathan

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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/m2, n = 21). Later cohorts received doses twice weekly (cohorts 7-11, 7.8-40 mg/m2, 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/m2 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/m2 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/m2 twice weekly for 3 of 4 weeks per cycle.

Original languageEnglish (US)
Pages (from-to)931-941
Number of pages11
JournalCancer chemotherapy and pharmacology
Volume73
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Advanced/metastatic solid tumors
  • Cytolytic peptide
  • Cytolytic peptide conjugate
  • EP-100
  • LHRH receptor

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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