Phase I clinical trial of exherin (ADH-1) in patients with advanced solid tumors

Nirit Yarom, David Stewart, Rajesh Malik, Julie Wells, Leonard Avruch, Derek J. Jonker

Research output: Contribution to journalArticlepeer-review

Abstract

ADH-1 (Exherin™) is a pentapeptide, which competitively inhibits N-cadherin, resulting in vascular disruptive effect of tumor vasculature in preclinical models. This study was designed to assess the toxicity of ADH-1 and to determine the maximal tolerated dose (MTD). Patients and Methods: Adult patients with advanced measurable solid tumors were stratified according to their tumor N-cadherin status. ADH-1 was administered as a short infusion, every six weeks. Assessment of response was done every 6 weeks. PK parameters included: estimated volume of distribution of the central compartment, the α and β phase half-lives, area under the plasma concentration- time curve (AUC), clearance, and volume of distribution. Target lesions were assessed by dynamic contrast enhancing- magnetic resonance imaging (DCE-MRI). Results: 46 patients were enrolled, 25 (54%) had N-cadherin positive status. The doses administered ranged from 50 mg/m2 to 1000 mg/m2, and the MTD was not reached. The PK analysis of the concentration-time data displayed a biphasic profile. Most of the toxicities were grade 1 and 2 with fatigue, nausea, chest pain and dysgeusia being the most common. Eleven patients had disease control, the single patient who had partial response had N-cadherin positive tumor. Conclusion: ADH-1 is a well tolerated drug with a modest anti tumor effect in tumors which express N-cadherin.

Original languageEnglish
Pages (from-to)81-88
Number of pages8
JournalCurrent Clinical Pharmacology
Volume8
Issue number1
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Adh-1
  • Dynamic contrast enhanced magnetic resonance imaging (dce-mri)
  • E-cadherin
  • N-cadherin
  • Phase i
  • Solid tumors

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