title: Phase I clinical trial of Exherin (ADH-1) in patients with advanced solid tumors.
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).
  
  
  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.
  
  
  CONCLUSIONS
  ADH-1 is a well tolerated drug with a modest anti tumor effect in tumors which express N-cadherin.
authors.affiliation: Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario, Canada. nirit.yarom@gmail.com
authors.forename: Nirit
authors.initials: N
authors.lastname: Yarom
authors.forename: David
authors.initials: D
authors.lastname: Stewart
authors.forename: Rajesh
authors.initials: R
authors.lastname: Malik
authors.forename: Julie
authors.initials: J
authors.lastname: Wells
authors.forename: Leonard
authors.initials: L
authors.lastname: Avruch
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C541294:N-Ac-CHAVC-NH2; D010456:Peptides, Cyclic