Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/85440
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Type: Journal article
Title: Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent
Author: Burge, M.
Francesconi, A.
Kotasek, D.
Fida, R.
Smith, G.
Wilks, A.
Vasey, P.
Lickliter, J.
Citation: Investigational New Drugs, 2013; 31(1):126-135
Publisher: Springer
Issue Date: 2013
ISSN: 0167-6997
1573-0646
Statement of
Responsibility: 
Matthew Burge, Alessandra B. Francesconi, Dusan Kotasek, Rosa Fida, Gregg Smith, Andrew Wilks, Paul A. Vasey, Jason D. Lickliter
Abstract: 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/m2). 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/m2 and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour Ktrans in some patients. Conclusions. CYT997 is orally bioavailable. The 118 mg/m2 dose level should be used to guide dosing in future studies.
Keywords: Oral CYT997; vascular-disrupting agent; phase I clinical trial; pharmacokinetics; dynamic contrast-enhanced magnetic resonance imaging
Rights: © Springer Science+Business Media, LLC 2012
DOI: 10.1007/s10637-012-9813-y
Published version: http://dx.doi.org/10.1007/s10637-012-9813-y
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Pharmacology publications

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