Phase I study of everolimus in pediatric patients with refractory solid tumors
Phase I study of everolimus in pediatric patients with refractory solid tumors
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DOI：
10.1200/jco.2007.11.4017
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发表时间：
2007-10-20
影响因子：
45.3
通讯作者：
Furman, Wayne L.
中科院分区：
文献类型：
--
作者：
Fouladi, Maryam;Laningham, Fred;Furman, Wayne L.
目的 确定哺乳动物雷帕霉素靶点 (mTOR) 抑制剂依维莫司在难治性或复发性实体瘤儿童中的最大耐受剂量 (MTD)、剂量限制毒性 (DLT) 以及药代动力学和药效学特性。 患者和方法 依维莫司按每日剂量 2.1、3、5 或 6.5 mg/m(2) 口服给药，每个剂量为 3 至 6 名患者。水平。在第一个疗程期间进行药代动力学和药效学研究。在从接受治疗的患者中分离的外周血单核细胞 (PBMC) 中评估 mTOR 信号通路各个成分的磷酸化状态。 结果 共有 26 名患者入组； 18 个可评估。 DLT 包括腹泻 (n = 1)、粘膜炎 (n = 1) 和 ALT 升高 (n = 1) 6.5 mg/m(2)。在MTD为5 mg/m(2)时，中位依维莫司清除率为15.2 L/h/m(2)，血浆依维莫司浓度-时间曲线下面积(AUC)从0到无穷大为239.6 ng/mL中心点·h。在达到 AUC >= 200 ng/mL center dot h 的患者的 PBMC 中观察到 mTOR 通路信号传导的显着抑制，相当于 3 至 5 mg/m(2) 依维莫司的剂量。没有观察到客观的肿瘤反应。 结论 持续口服依维莫司对于患有复发性或难治性实体瘤的儿童具有良好的耐受性，并且表现出与成人中观察到的相似的药代动力学特性。依维莫司在 MTD 时显着抑制儿童的 mTOR 信号通路。实体瘤儿童的推荐 II 期剂量为 5 mg/m(2)。
Purpose To determine the maximum- tolerated dose (MTD), dose- limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors.Patients and Methods Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m(2) in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral- blood mononuclear cells (PBMCs) isolated from treated patients.Results There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m(2). At the MTD of 5 mg/m(2), the median everolimus clearance was 15.2 L/h/m(2), with a plasma everolimus concentration- time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL center dot h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs >= 200 ng/mL center dot h, equivalent to dosages of 3 to 5 mg/m(2) of everolimus. No objective tumor responses were observed.Conclusion Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m(2).