Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies
Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies
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DOI：
10.1023/a:1006448516938
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发表时间：
2001-02-01
影响因子：
3.4
通讯作者：
Bender, JF
中科院分区：
文献类型：
--
作者：
Streiff, RR;Bender, JF
这是一项剂量递增的1期试验，旨在确定DENSPM的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。方法：对成人顽固性实体瘤患者，用生理盐水100ml静脉滴注DENSPM治疗30分钟。DENSPM的日剂量分为三等量剂量，大约每8小时给药，连续六天。每28天重复一次疗程。结果：28例患者入组研究。DENSPM的剂量水平分别为25 mg/m(2)/天（3例）、50 mg/m(2)/天（9例）、60 mg/m(2)/天（5例）、75 mg/m(2)/天（6例）、94 mg/m(2)/天（3例）和118 mg/m(2)/天（2例）。当剂量大于或等于94 mg/m(2)/天时，DENSPM的DLT为中枢神经系统毒性，表现为失语、共济失调、头晕、眩晕和言语不清，这也是MTD。安全性：最常见的药物相关不良事件是虚弱（9例）、注射部位反应（6例）和贫血（6例）。一名患者因中枢神经系统毒性退出研究。没有与治疗相关的死亡。没有观察到血液毒性、生化变化或生命体征变化的趋势。疗效：参与研究的28名患者中有19名被评估为反应。未观察到客观反应。5例患者对治疗的最佳反应是病情稳定。结论：由于DLT是中枢神经系统，并且与每天一次的方案相比，该方案的安全剂量相对较低，因此不推荐该方案用于2期。
This was a dose escalation Phase 1 trial designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of DENSPM. Methods: Adult patients with refractory solid tumors were treated with DENSPM administered by intravenous infusion in 100 ml of normal saline over 30 minutes. The daily dose of DENSPM was divided into three equal doses administered approximately every eight hours for six days. Courses were repeated every 28 days. Results: Twenty-eight patients were enrolled in the study. Dose levels of DENSPM explored were 25 mg/m(2)/day (3 patients), 50 mg/m(2)/day (9 patients), 60 mg/m(2)/day (5 patients), 75 mg/m(2)/day (6 patients), 94 mg/m(2)/day (3 patients) and 118 mg/m(2)/day (2 patients). The DLT for DENSPM was central nervous system toxicity characterized by aphasia, ataxia, dizziness, vertigo and slurred speech occurring at dose levels greater than or equal to 94 mg/m(2)/day, which was also the MTD. Safety: The most frequent drug-related adverse events were asthenia (9 patients), injection site reaction (6 patients) and anemia (6 patients). One patient was removed from the study due to CNS toxicity. There were no treatment-related deaths. No trends were observed regarding hematologic toxicities, biochemical changes or changes in vital signs. Efficacy: Nineteen of the 28 patients enrolled in the study were assessed for response. No objective responses were observed. Five patients had stable disease as the best response to therapy. Conclusions: Because the DLT was CNS and because of the relatively low doses that could be safely administered on this schedule as compared with a once-a-day schedule, this regimen was not recommended for Phase 2.