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

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.

Keywords: ADH-1, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), E-cadherin, N-cadherin, phase I, solid tumors, STUDY DESIGN AND DOSING, Primary PK parameters, PHARMACOKINETICS, electrocardiogram (ECG), TUMOR VASCULAR TARGETING