Phase I trial of imexon in patients with advanced malignancy
Phase I trial of imexon in patients with advanced malignancy
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DOI：
10.1200/jco.2006.08.9672
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发表时间：
2007-05-01
影响因子：
45.3
通讯作者：
Dorr, Robert
中科院分区：
文献类型：
--
作者：
Dragovich, Tomislav;Gordon, Michael;Dorr, Robert
目的Imexon 是一种促氧化小分子，在临床前模型中具有抗肿瘤活性。该药物通过活性氧的积累诱导细胞凋亡。本试验的目的是确定晚期癌症患者中伊美克的最大耐受剂量 (MTD)、毒性、药代动力学和药效学。 患者和方法 49 名转移性癌症患者每月每隔一周（第 1 至 5 天和第 15 至 19 天）接受连续 5 天（一个疗程）静脉注射伊美克，每次 30 至 45 分钟。最初使用加速试验设计来增加剂量，然后使用改进的斐波那契方法。通过高效液相色谱法测定血浆伊美克水平和六种不同的硫醇。结果评估了13个剂量水平，从20 mg/m(2)/天到1,000 mg/m(2)/天。 II 期研究推荐的 MTD 为 875 mg/m(2)/d，每 2 周 5 天（n = 9 名患者）。 1,000 mg/m(2)/d 的两种剂量限制性毒性涉及 3 级腹痛和疲劳以及 4 级中性粒细胞减少症，各发生在一名患者身上。其他常见的毒性包括恶心和呕吐（58%）和便秘（63%）；两者都通过预防性药物得到了很好的控制。一名接受过大量治疗的非霍奇金淋巴瘤患者获得了部分缓解。药代动力学研究显示清除率与剂量无关，平均半衰期为 95 分钟。血浆硫醇研究显示，在≥ 750 mg/m(2)/天给药后8小时，胱氨酸水平呈剂量和曲线下面积依赖性下降。结论伊美克的II期推荐剂量为875 mg/m(2)/天，每隔一周服用5天。血浆硫醇的减少确实与伊美克暴露相关。
PurposeImexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers.Patients and MethodsForty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days ( one course) every other week ( days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays.ResultsThere were 13 dose levels evaluated, from 20 mg/m(2)/ d to 1,000 mg/m(2)/ d. The MTD recommended for phase II studies was 875 mg/m(2)/ d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m(2)/ d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose-and area under the curve - dependent decrease in cystine levels 8 hours after dosing at >= 750 mg/m(2)/ d.ConclusionThe phase II recommended dose of imexon is 875 mg/m(2)/ d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.