TY - JOUR
T1 - Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent
AU - Burge, Matthew
AU - Francesconi, Alessandra B
AU - Kotasek, Dusan
AU - Fida, Rosa
AU - Smith, Gregg
AU - Wilks, Andrew Frederick
AU - Vasey, Paul
AU - Lickliter, Jason Derrick
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://goo.gl/mhucyj
U2 - 10.1007/s10637-012-9813-y
DO - 10.1007/s10637-012-9813-y
M3 - Article
SN - 0167-6997
VL - 31
SP - 126
EP - 135
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -