Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
Invest New Drugs. 2013 Feb;31(1):126-35. doi: 10.1007/s10637-012-9813-y. Epub 2012 Mar 27.
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.
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).
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.
CYT997 is orally bioavailable. The 118 mg/m(2) dose level should be used to guide dosing in future studies.
CYT997 是一种新型的微管抑制剂和血管破坏剂。本 I 期临床试验研究了口服 CYT997 的安全性、耐受性、药代动力学和血管破坏作用。
我们对晚期实体瘤患者进行了 I 期加速剂量递增研究，每 2-3 周口服一次 CYT997。通过测量血浆血管性血友病因子（vWF）水平和动态对比增强磁共振成像（DCE-MRI）来评估血管破坏作用。
21 名患者共接受了 56 个剂量，分为 8 个剂量水平（15-164mg/m²）。3 级疲劳和 3 级缺氧是剂量限制毒性。在 11 倍剂量范围内，观察到口服生物利用度呈近似线性药代动力学。在 84mg/m² 及以上剂量时，血浆 vWF 水平高于基线，DCE-MRI 扫描显示部分患者肿瘤 K(trans) 降低。
CYT997 可口服生物利用。118mg/m² 的剂量水平应作为未来研究的给药指导。
