第一阶段研究sns - 032(原bms - 387032),强大的细胞周期蛋白依赖性激酶抑制剂2、7和9管理作为一个单一口服剂量和每周输液患者的转移性难治性实体肿瘤。

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希思EI,圣经K,马爹利,阿德尔曼,Lorusso点

第一阶段研究sns - 032(原bms - 387032),强大的细胞周期蛋白依赖性激酶抑制剂2、7和9管理作为一个单一口服剂量和每周输液患者的转移性难治性实体肿瘤。

新药投资。2008年2月,26 (1):59 - 65。Epub 2007年10月16日。

PubMed ID

17938863 (在PubMed

]

文摘

目的:sns - 032,(以前bms - 387032)是一个强大的和选择性抑制剂细胞周期蛋白依赖性激酶(CDK) 2、7和9。这项研究的主要目标是建立的最大耐受剂量(MTD)的最大注射剂量(疯狂),剂量限制毒性(DLT),推荐第二阶段剂量sns - 032在使用以每周1小时输液。次要目标是评估的安全性和耐受性sns - 032和评估其作为口服生物利用度的解决方案。方法:转移性实体瘤或难治性淋巴瘤患者服用4毫克/平方米的起始剂量静脉注射超过1小时周期定义为3周剂量的sns - 032每21天。三个病人群的剂量递增模式。进行药代动力学研究。13和16 mg / m2剂量组,第一剂量的周期2被作为口服解估计人类药物的口服生物利用度。结果:共21患者登记。二十治疗患者共39个周期的治疗。最常见的治疗相关的不良事件发生率大于20%是发生疲劳(25%)和恶心(20%)。 Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean Cmax and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 microg/ml and 0.103 to 0.553 microg h/ml, respectively. The CL and Vss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug. CONCLUSIONS: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.

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药物

sns - 032