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

Burge, M., Francesconi, A. B., Kotasek, D., Fida, R., Smith, G., Wilks, A., Vasey, P. A. and Lickliter, J. D. (2013) Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent. Investigational New Drugs, 31 1: 126-135. doi:10.1007/s10637-012-9813-y


Author Burge, M.
Francesconi, A. B.
Kotasek, D.
Fida, R.
Smith, G.
Wilks, A.
Vasey, P. A.
Lickliter, J. D.
Title Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent
Journal name Investigational New Drugs   Check publisher's open access policy
ISSN 0167-6997
1573-0646
Publication date 2013
Sub-type Article (original research)
DOI 10.1007/s10637-012-9813-y
Open Access Status
Volume 31
Issue 1
Start page 126
End page 135
Total pages 10
Place of publication New York NY United States
Publisher Springer
Collection year 2014
Language eng
Subject 3004 Pharmacology
2736 Pharmacology (medical)
2730 Oncology
Abstract 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/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/m 2 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.
Keyword Dynamic contrast-enhanced magnetic resonance imaging
Oral CYT997
Pharmacokinetics
Phase I clinical trial
Vascular-disrupting agent
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Medicine Publications
 
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Created: Sun, 02 Feb 2014, 15:39:10 EST by Matthew Lamb on behalf of School of Medicine