Phase i trial of CYT997, a novel cytotoxic and vascular-disrupting agent.

Abstract

Background: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. Method(s): This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. Result(s): Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m-2). Doses up to 202 mg m-2 were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m 2, consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour Ktrans values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of 65 mg m-2. Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for 2 cycles. Conclusion(s): CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours. © 2010 Cancer Research UK All rights reserved.