St George's Hospital, Blackshaw Rd, London, UK.
Invest New Drugs. 2012 Aug;30(4):1493-500. doi: 10.1007/s10637-011-9682-9. Epub 2011 May 18.
The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors.
Patients aged ≥ 18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m(2)/day × 3 days or 1.0 mg/m(2)/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan.
Twenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m(2)/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting.
Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.
本 I 期研究旨在确定奥拉帕尼（AZD2281）与拓扑替康联合口服治疗晚期实体瘤患者的安全性和耐受性，并确定最大耐受剂量（MTD）。
纳入年龄≥18 岁、组织学或细胞学诊断为晚期实体瘤且无合适有效治疗方法的患者。4 个队列的患者接受拓扑替康（0.5 mg/m²/天×3 天或 1.0 mg/m²/天×3 天）静脉滴注，联合奥拉帕尼 50、100 或 200 mg，bid，共 6 个周期。主要目的是确定奥拉帕尼联合拓扑替康的安全性和耐受性，并确定其 MTD。
共纳入 21 例患者，19 例接受治疗。剂量限制性毒性为中性粒细胞减少和血小板减少。确定 MTD 为拓扑替康 1.0 mg/m²/天×3 天加奥拉帕尼 100 mg，bid。最常见的不良反应（AE）包括疲劳和胃肠道事件。中性粒细胞减少与奥拉帕尼和拓扑替康剂量相关，且具有剂量限制性。
由于血液学不良反应具有剂量限制性且导致 MTD 低于治疗范围，因此未进一步探索奥拉帕尼和拓扑替康联合用药的开发。
