5,6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent
5,6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent
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DOI：
10.1158/1078-0432.ccr-05-1939
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发表时间：
2006-03-15
影响因子：
11.5
通讯作者：
Jameson, MB
中科院分区：
文献类型：
--
作者：
McKeage, M;Fong, P;Jameson, MB
这项I期安全性研究旨在确定联合研究中血管阻断剂5，6-二甲基咕吨酮-4-乙酸（DMXAA）的最佳剂量。采用交叉设计，15名难治性肿瘤患者被随机分配接受6个连续剂量的DMXAA（300、600、1，200、1，800、2，400和3，000 mg m（-2）），每个剂量每周一次，静脉输注20分钟。这种药物通常耐受良好。在两个最高剂量下，心率校正的心脏QT间期出现一过性中度延长。DMXAA引起血压一过性剂量依赖性升高。在两个最高剂量下发生了一过性、剂量相关的视觉障碍。在给予DMXAA后，未观察到K-transs和k（ep）的显著变化，但V（次要动态对比增强磁共振成像变量）显著增加。在1，200 mg/m2时，24小时内总DMXAA和游离DMXAA血浆浓度的Cmax和浓度-时间曲线下面积分别为315 +/- 25.8 μ g/mL、29 +/- 6.4 μ g/mL.d、8.0 +/- 1.77 μ g/mL和0.43 +/- 0.07 μ g/mL.d。血管损伤生物标志物5-羟基吲哚乙酸的血浆水平在治疗后4小时内以剂量依赖性方式增加至1，2 00 mg m（-2），此后达到平台期。选择1，200 mg m-2范围内的剂量进行进一步研究（紫杉烷类和铂类的11期联合研究正在进行中），因为该剂量对心率校正的心脏QT间期无显著影响，产生接近最大水平的5-羟基吲哚乙酸，DMXAA血浆浓度在临床前治疗范围内，耐受性良好。
This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone- 4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600,1,200,1,800, 2,400, and 3,000 mg m(-2)), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate -corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in K-trans and k(ep) were observed but V, a secondary dynamic contrast - enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m(-2), the C-max and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 +/- 25.8 mu g/mL, 29 +/- 6.4 mu g/mL.d, 8.0 +/- 1.77 mu g/mL, and 0.43 +/- 0.07 mu g/mL.d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,2 00 mg m(-2), with a plateau thereafter. Doses in the range of 1,200 mg m-2 have been selected for further studies (phase 11 combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate -corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.