Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent

Summary Purpose CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. Experimental design We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results A total of 56 doses were administered to 21 patients over 8 dose levels (15–164 mg/m 2 ). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m 2 and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour K trans in some patients. Conclusions CYT997 is orally bioavailable. The 118 mg/m 2 dose level should be used to guide dosing in future studies.