Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer
Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer
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DOI：
10.1200/jco.2004.08.116
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发表时间：
2004-06-15
影响因子：
45.3
通讯作者：
Armand, JP
中科院分区：
文献类型：
--
作者：
Raymond, E;Alexandre, J;Armand, JP
目的建立哺乳动物靶向雷帕霉素选择性抑制剂CCI-779在晚期癌症患者中的安全性、耐受性和药代动力学参数。患者与方法采用改进的连续再评估方法，进行I期研究，CCI-779每周静脉滴注30分钟。结果24例患者接受CCI-779 7.5~220 mg/m(2)的剂量。没有免疫抑制作用的报道。两名患者在34或45 mg/m(2)剂量范围内出现了剂量限制性的血小板减少。在220 mg/m(2)的剂量限制毒性中，9名患者中有2名出现躁狂抑郁综合征、口腔炎和乏力，防止了剂量的进一步增加。最常见的药物相关毒性是痤疮样、斑丘疹和粘膜炎或口腔炎。所有毒性反应在停止治疗后都是可逆的。浓度-时间曲线下的最大浓度和面积随剂量的增加而近乎成比例地增加。平均稳态分布体积为127~385L。西罗莫司是主要的代谢物(代谢物与母体的比例范围为2.5至3.5)。全血清除率为非线性，范围为19~51 L/小时(34~220m/mg(2))。用固定剂量预测的可变性似乎与基于体表面积归一化治疗的数据相似。1例肾透明细胞癌和1例乳腺癌患者出现部分反应。结论CCI-779在220 mg/m(2)剂量范围内无免疫抑制作用，不良反应可控且可逆，为受试最高剂量。根据我们的结果，每周剂量为25、75和250毫克的CCI-779不是基于最大耐受剂量的经典定义，正在进行乳腺癌和肾癌患者的11期试验。(C)2004年，美国临床肿瘤学会
PurposeTo establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of he mammalian target of rapamycin, in patients with advanced cancer.Patients and MethodsUsing a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (IV) infusion.ResultsTwenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m(2). No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m(2). At 220 Mg/m(2) dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 m/mg(2)). Variability predicted with flat doses appears comparable with data based on body-surface area-normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma.ConclusionCCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m(2), the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase 11 trials in patients with breast and renal cancer. (C) 2004 by American Society of Clinical Oncology