Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies
Phase I pharmacokinetic and pharmacodynarnic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies
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DOI：
10.1200/jco.2005.00.612
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发表时间：
2005-06-20
影响因子：
45.3
通讯作者：
Judson, I
中科院分区：
文献类型：
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作者：
Banerji, U;O'Donnell, A;Judson, I
目的 研究 17-烯丙氨基、17-去甲氧基格尔德霉素 (17-AAG) 的毒性和药代动力学-药效学特征，并推荐 II 期试验的剂量。 患者和方法 这是一项检查 17-AAG 每周一次给药方案的 I 期研究。治疗了30名晚期恶性肿瘤患者。结果达到的最高剂量水平为450 mg/m(2)/周。所遇到的剂量限制性毒性（DLT）为三名患者的 3 级腹泻（一名患者在 320 mg/m(2)/周，两名患者在 450 mg/m(2)/周），一名患者在 450 mg/m(2)/周时出现 3 至 4 级肝毒性 (AST/ALT)。九个 DLT 中有两个处于最高剂量水平。两名转移性黑色素瘤患者病情稳定，分别接受了 15 个月和 41 个月的治疗。 17-AAG 的剂量与曲线下面积的关系在 10 至 450 mg/m(2)/周的剂量范围内呈线性 (r(2) = .71)，最高剂量水平下的血浆峰值浓度为 8,998 μg/L（标准差为 2,881）。在证明治疗前和治疗后 24 小时外周血白细胞的药效学变化后，进行了肿瘤活检，并证明了剂量水平为 320 和 450 mg/m(2)/周时的靶向抑制作用（6 名患者中的 4 名抑制 c-RAF-1，9 名患者中的 8 名消除 CDK4，9 名患者中的 8 名诱导 HSP70）。不可能在治疗后 5 天进行的活检中重复证明这些变化。结论 已经可以证明 17-AAG 表现出可耐受的毒性特征，具有治疗血浆浓度和治疗后 24 小时的目标抑制作用，以及在剂量水平 450 mg/m(2)/周时的一些临床活性迹象。我们推荐该剂量用于 II 期临床试验。
Purpose To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17-demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials.Patients and Methods This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated.Results The highest dose level reached was 450 mg/m(2)/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m(2)/week and two at 450 mg/m(2)/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m(2)/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r(2) = .71) over the dose range 10 to 450 mg/m(2)/week, with peak plasma concentrations of 8,998 mu g/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m(2)/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment.Conclusion It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m(2)/week. We recommend this dose for phase II clinical trials.