A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies
A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies
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DOI：
10.1186/1471-2407-13-152
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发表时间：
2013-03-25
期刊：
影响因子：
3.8
通讯作者：
Rosen, Lee S.
中科院分区：
文献类型：
--
作者：
Goldman, Jonathan W.;Raju, Robert N.;Rosen, Lee S.
背景：这项I期研究调查了格奈特匹布在实体肿瘤患者中的最大耐受量(MTD)、安全性、药代动力学和抗肿瘤活性。方法：患者被纳入剂量递增的队列，每周静脉滴注1小时，连续3周，然后休息1周，直到疾病进展或不可接受的毒性。终点包括安全性、药动学和药效学参数以及初步临床活性。结果：53例患者的剂量从7 mg/m(2)递增到259 mg/m(2)。最常见的不良反应是1级和2级腹泻、乏力、恶心或呕吐。观察到的剂量限制毒性(DLT)为：3级淀粉酶升高1例(150 mg/m(2))，3级腹泻1例，3级和4级乏力1例(259 mg/m(2))。MTD为216 mg/m(2)，推荐的2期剂量为200 mg/m(2)，静脉滴注，每4周1，8，15天。剂量与暴露之间存在线性关系。治疗后一周以上，血浆HSP70蛋白水平持续升高。疾病控制率(客观有效和病情稳定的16周)为24.4%。结论：每周给药3次，每4周周期3次，耐受性良好。推荐的II期剂量为200 mg/m(2)，并与可接受的耐受性相关。
Background: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies.Methods: Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity.Results: Fifty-three patients were treated at doses escalating from 7 to 259 mg/m(2). The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at >= 16 weeks) was 24.4%.Conclusions: Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m(2), and is associated with an acceptable tolerability profile.