A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma
A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma
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DOI：
10.1007/s10637-010-9493-4
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发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Eisen, Tim
中科院分区：
文献类型：
--
作者：
Pacey, Simon;Gore, Martin;Eisen, Tim
目的进行热休克蛋白90（HSP 90）抑制剂17-AAG（17-烯丙基氨基-17-去甲氧基格尔德霉素）抗黑色素瘤活性筛选的II期研究。主要终点是17-AAG治疗的进展性转移性黑色素瘤患者的疾病稳定率。次要终点是确定：17-AAG的毒性、反应持续时间、中位生存期，并进一步研究17-AAG的药代动力学和药效学。患者和方法转移性黑色素瘤患者（在进入研究6个月时记录为千分之几货币符号的进展性疾病）每周静脉注射17-AAG治疗。使用Simon单样本两阶段极大极小设计。认为6个月时的稳定发病率为千分之一日元25%与17-AAG具有活性相容。结果14例患者（男8例，女6例）入组，11例接受17-AAG（体力状态0或1）。中位年龄为60岁（范围29-81岁）。大多数（93%）接受过既往化疗，并患有M1 c期疾病（71%）。毒性的严重程度很少为2级，通常包括疲劳、头痛和胃肠道紊乱。11例接受17-AAG治疗的患者中有1例病情稳定6个月，所有患者的中位生存期为173天。在完成第一阶段招募和有限的计划药代动力学和药效学分析之前，研究提前关闭。结论尽管提前终止研究意味着未达到研究终点，但仍观察到17-AAG活性的一些证据。稳定的疾病率可以纳入筛选抗黑色素瘤活性的试验，并应考虑进一步研究黑色素瘤中的HSP 90抑制剂。
Purpose A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG. Patients and Methods Patients with metastatic melanoma (progressive disease documented a parts per thousand currency sign6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of a parts per thousand yen25% at 6 months was considered compatible with 17-AAG having activity. Results Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely a parts per thousand yen Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses. Conclusion Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered.