A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors
A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors
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DOI：
10.1007/s10637-013-0046-5
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发表时间：
2014-06-01
影响因子：
3.4
通讯作者：
LoRusso, P.
中科院分区：
文献类型：
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作者：
Hong, D. S.;Kurzrock, R.;LoRusso, P.
本研究旨在确定E7107在晚期实体瘤患者中的最大耐受剂量、剂量限制性毒性以及药代动力学特征。在这项I期、开放标签、单臂、剂量递增研究中，患者患有转移性或局部晚期实体瘤，并接受E7107静脉输注30分钟，剂量分别为0.6、1.2、1.8、2.4、3.2、4.3和5.7 mg/m²。共有26名患者参与研究。在5.7 mg/m²剂量下，2名患者在E7107给药后的第1 - 3天出现剂量限制性毒性，包括腹泻、呕吐、脱水和心肌梗死。另外在较低剂量下招募了3名患者，这6名患者均耐受4.3 mg/m²的E7107，未出现剂量限制性毒性。因此，E7107的最大耐受剂量为4.3 mg/m²。最常见的药物相关不良事件为恶心、呕吐和腹泻。2名患者分别在第2周期和第7周期出现视力丧失，每名患者接受的剂量分别为3.2 mg/m²和4.3 mg/m²。这导致研究被临床搁置。药代动力学分析显示，E7107分布迅速，消除半衰期适中（6 - 13小时），清除率高。E7107的暴露量与剂量相关。8名患者的最佳肿瘤反应为病情稳定。E7107是一种独特的首创新药分子。两例可能与E7107相关的视力丧失事件导致研究终止。
The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.