Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors
Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors
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DOI：
10.1158/1078-0432.ccr-06-1832
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Dancey, Janet
中科院分区：
文献类型：
--
作者：
Edelman, Martin J.;Bauer, Kenneth S., Jr.;Dancey, Janet
用途：基于显示7-羟基星孢菌素（UCN-01）与铂剂之间的协同作用的临床前数据，在晚期实体瘤患者中进行了卡铂与UCN-01作为3小时输注给药的I期试验。本试验的主要目标是评估这种组合的耐受性和UCN-01的药代动力学时，超过3小时给药，并比较的耐受性和药代动力学与先前描述的schedule.Patients和方法：晚期实体瘤，良好的性能状态，正常的器官功能，并没有潜在的治愈性治疗的患者有资格参加试验。卡铂从曲线下面积（AUC）3递增至AUC 5。UCN-01从50 mg/m2递增至90 mg/m2。结果：23例晚期实体瘤患者（20例既往接受过铂类药物治疗）共接受了60个周期的治疗。两种药物均可全剂量给药（第1周期卡铂AUC 5，UCN-01 go mg/m2，后续周期45 mg/m2）。观察到的主要毒性是低血压，可通过使用盐水预水合和后水合来消除。未观察到任何反应;然而，7名患者能够接受两个以上疗程的治疗。值得注意的是，三分之二的难治性、进展性小细胞肺癌患者能够接受六个周期的治疗而没有进展的证据。1例患者出现抗利尿激素分泌不当的副肿瘤综合征消退。3小时输注的药代动力学变量C-max和t（1/2）与先前在72小时内给予UCN-01时观察到的结果基本相同。第1周期的平均t（1/2）为506 +/- 301 h，所有剂量水平的平均C-max> 30 μ mol/L。各剂量水平给药间隔内的平均AUC范围为6，000 - 9，000 μ mol/L h。因此，UCN-01的AUC在3小时输注后低于72小时输注后观察到的AUC。结论：卡铂和UCN-01（作为3小时输注给药）的方案耐受性良好。这种联合治疗的进一步发展，特别是在小细胞肺癌中，是必要的。
Purpose: Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules.Patients and Methods: Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m(2).Results: Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 go mg/m(2) in cycle 1, 45 mg/m(2) in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables C-max and t(1/2) Of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t(1/2) for cycle 1 was 506 +/- 301 h, and the mean C-max for all dose levels was > 30 mu mol/L. The mean AUC over the dosing interval for each dose level ranged from similar to 6,000 to 9,000 mu mol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion.Conclusion: The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted.