Phase I and pharmacokinetic study of sequences of the rebeccamycin analogue NSC 655649 and cisplatin in patients with advanced solid tumors
Phase I and pharmacokinetic study of sequences of the rebeccamycin analogue NSC 655649 and cisplatin in patients with advanced solid tumors
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DOI：
10.1158/1078-0432.ccr-05-1572
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发表时间：
2005-12-15
影响因子：
11.5
通讯作者：
Rowinsky, EK
中科院分区：
文献类型：
--
作者：
Ricart, AD;Hammond, LA;Rowinsky, EK
目的：评估NSC 655649（一种可抑制拓扑异构酶I和拓扑异构酶II的水溶性雷霉素类似物）与顺铂（CDDP）联合应用于成人实体恶性肿瘤的可行性。两种给药顺序之间的主要毒理学和药理学差异也进行了评估。实验设计：NSC 655649静脉滴注60分钟；CDDP于第1天NSC 655649前后静脉注射。每3周交替用药；每种药物的剂量在不同的新患者队列中逐步增加。NSC 655649或CDDP的顺序剂量递增导致NSC 655649/CDDP的三种剂量排列：440/50,550/50和440/75 mg/m(2)。在确定最大耐受剂量水平后，探索使用粒细胞集落刺激因子允许进一步剂量增加的可行性。结果：20例患者接受NSC 655649/CDDP治疗70个疗程。骨髓抑制是主要的毒性。在NSC 655649/ CDDP剂量水平为550/ 50mg /m(2)且不含粒细胞集落刺激因子的最低限度预处理患者中，严重中性粒细胞减少症（通常与严重血小板减少症相关）的发生率高得令人无法接受。NSC 655649与CDDP的主要药代动力学相互作用不明显。毒性或药代动力学变量没有相关的序列依赖差异。3例患者出现部分反应。结论：NSC 655649和CDDP分别在440 mg/m和50 mg/m(2)的剂量下在最低限度预处理的受试者中具有良好的耐受性。药物之间的药代动力学相互作用和序列依赖的毒理学或药代动力学效应都不明显。观察到的这种组合的耐受性和初步活性表明，对该方案进行以疾病为导向的评估是必要的。
Purpose: To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed.Experimental Design: NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50,550/50, and 440/75 mg/m(2). After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored.Results: Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/ CDDP dose level of 550/50 mg/m(2) without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses.Conclusions: NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m(2), respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.