Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston 4029, Queensland, Australia.
Br J Cancer. 2010 Aug 24;103(5):597-606. doi: 10.1038/sj.bjc.6605841.
CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity.
This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours.
Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles.
CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.
CYT997 是一种新型的微管抑制剂和血管破坏剂，具有显著的临床前抗肿瘤活性。
这项 I 期剂量递增研究评估了 CYT997 连续静脉输注 24 小时，每 3 周一次，用于治疗晚期实体瘤患者的安全性、耐受性、药代动力学和药效学。
31 名患者接受了 CYT997 治疗，共 12 个剂量水平（7-358mg/m2）。剂量高达 202mg/m2 时耐受性良好。在 269 和 358mg/m2 时观察到剂量限制毒性，包括两名患者的 3 级延长校正 QT 间期和一名患者的 3 级缺氧和 4 级呼吸困难。所有毒性均为可逆的。CYT997 的药代动力学在整个剂量范围内呈线性。动态对比增强磁共振成像扫描显示，11 名可评估患者中有 7 名在 CYT997 剂量≥65mg/m2 时，肿瘤 K(trans)值发生了与血管破坏一致的显著变化。此外，在更高剂量水平下，血浆血管性血友病因子和半胱氨酸蛋白酶切割细胞角蛋白 18 水平升高。在 22 名可评估反应的患者中，18 名患者的疾病稳定持续了>2 个周期。
在与肿瘤血管破坏的药效学证据相关的剂量下，CYT997 具有良好的耐受性。
