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Clin Cancer Res：人体首例第二代非安莎霉素HSP90抑制剂（AT13387）治疗晚期实体瘤的一期临床试验

2014-10-23 MedSci MedSci原创

HSP90抑制剂
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目的：  AT13387作为一个强效热休克蛋白90(HSP90)的分子抑制剂，在治疗晚期肿瘤特别是顽固性肿瘤方面有较大的潜力。本次临床试验目的是测试实体瘤患者对该药物的最大耐受剂量（MTD,maximum tolerated dose)，并且为二期临床的参考用药量（RP2D, recommended phase 2 dose)、用药安全、药代动力学及药效特性提供借鉴。试验设计： 

实验目的：
 
AT13387作为一个强效热休克蛋白90(HSP90)的分子抑制剂，在治疗晚期肿瘤特别是顽固性肿瘤方面有较大的潜力。本次临床试验目的是测试实体瘤患者对该药物的最大耐受剂量（MTD,maximum tolerated dose)，并且为二期临床的参考用药量（RP2D, recommended phase 2 dose)、用药安全、药代动力学及药效特性提供借鉴。
 
试验设计：
 
采用标准的3+3设计法进行剂量递增，并分别根据剂量限制性毒性（DLT,dose-limiting toxicity)和整体毒性来确定MTD和RP2D的剂量。药代动力学参数基于单次和多次剂量而测量得出。同时，观察血浆、外周血单核细胞及活体检视中因AT13387介导而导致的HSP70水平的变化（在临床上，HSP70表达上调可以作为HSP90抑制的生物标记）。
 
试验结果：
 
62名实体瘤患者在2008年5月 至 2013 年8月期间使用两种用药方法进行治疗，一种是每周两次用药，剂量范围10-120 mg/m2 ；另一种为一周一次，剂量范围150-310 mg/m2。两种用药都以28天为一疗程。一名患者在120 mg/m2时有DLT检出，因此在每周两次用药的方案中这一浓度可以考虑作为MTD和RP2D。在一周一次的方案中，未发现严格意义上的DLT， 但发现有一定程度的副作用，比如腹泻、恶心、呕吐、疲劳和输液反应。因此研究人员选用260mg/m2作为RP2D。此外，药效学分析结果显示HSP70的表达在两个用药方案中在所有用药水平都升高。同时，在4名用药患者的活体组织样本中，3人的HSP70活性显示出较高水平。但是，血浆中的HSP70水平表现出较大的差异性，因此很难用血浆的HSP70水平来判断HSP90的受抑制程度。受试人群中，1(2%)人有局部反应，21(34%)人病情稳定，而22人(35%)有恶化迹象。

HSP70 plasma ELISA data were expressed as the greatest-fold induction post-dose for each individual patient.

结论：
 
这是首例AT13387治疗实体瘤的一期临床试验。研究人员在本次试验中检测了晚期实体瘤患者对AT13387的耐受性，并对该药的药代动力学及抗肿瘤活性进行了系统研究。该临床试验为将来AT13387作为单一药物或是联合酪氨酸激酶抑制剂对由HSP异常导致的癌症的治疗提供了必要的理论支撑和实践指导。

本文是MedSci原创编译整理，欢迎转载！转载请注明来源并附原文链接。谢谢！

原始出处:
Geoffrey I. Shapiro,*,Eunice L Kwak,Bruce J Dezube,Murray Yule,John Ayrton,John Lyons.Daruka Mahadevan First-in-Human Phase 1 Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors Clin Cancer Res. 2014 Oct 21.

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    2015-02-09 jklm09

    #抑制剂#

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    2015-03-29 flyingeagle89

    #HSP90抑制剂#

    0

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    2015-08-03 ms5906905816781247

    #HSP90#

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    2014-10-25 446798725_87912766

    #晚期实体瘤#

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