Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study
Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study
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DOI：
10.1016/s1470-2045(13)70037-8
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发表时间：
2013-04-01
期刊：
影响因子：
51.1
通讯作者：
Kantarjian, Hagop
中科院分区：
文献类型：
--
作者：
Cortes, Jorge;Feldman, Eric;Kantarjian, Hagop
背景 Tosedostat 是一种新型口服氨肽酶抑制剂，在先前针对患有复发或难治性急性髓系白血病 (AML) 的老年患者的 1-2 期研究中具有临床活性。我们的目的是比较托塞多的两种给药方案。 方法 在这项随机 2 期研究中，年龄为 60 岁或以上的 AML 患者在第一次完全缓解持续不到 12 个月后复发，或之前未达到完全缓解，被随机分配 (1:1) 接受首次挽救托塞多 120 mg 每天一次，持续 6 个月或 240 mg 每天一次，持续 2 个月，随后接受 120 mg 持续 2 个月。 4个月。随机化是通过交互式网络响应系统采用分块方法，使用外部供应商生成的随机化时间表，没有分层。该研究是开放标签的。主要终点是获得完全缓解或完全缓解但血小板不完全恢复的患者比例。分析包括随机分配到接受至少一剂口服托西司他治疗组的所有患者。该研究已在 ClinicalTrials.gov 注册，编号为 NCT00780598。结果 38 名患者被随机分配接受 120 mg 托西司他治疗，38 名患者接受 240 mg 至 120 mg 托西司他治疗方案。 120 mg 组中的 38 名患者和 240 mg 至 120 mg 组中的 35 名患者接受了托西司他治疗。七名患者（10%）获得完全缓解或完全缓解但血小板不完全恢复：120 mg 组有 2 名患者（5%），240 mg 至 120 mg 组有 5 名患者（14%）。最常见的3级或更严重不良事件是发热性中性粒细胞减少症（120 mg组中有11名[29%]患者，240 mg至120 mg组有10名[29%]患者）、血小板减少症（8名[21%]和8名[23%]患者）、疲劳（7名[18%]和8名[23%]患者）、呼吸困难（5名[13%]和7名患者） [20%] 患者），以及 肺炎（四名 [11%] 和六名 [17%] 患者）。有 5 例致命不良事件被认为与治疗相关：120 mg 组有 3 例，240 mg 至 120 mg 组有 2 例。这些事件包括急性肝炎、呼吸衰竭、肺炎、心房颤动和左心室功能障碍。 解释 托塞司他无论采用哪种剂量方案，对患有复发性或难治性 AML 的老年患者均具有活性。托塞司他的其他研究正在进行或计划进行，包括与低甲基化药物和低剂量阿糖胞苷联合治疗高危骨髓增生异常综合征和 AML 患者。资助 Chroma Therapeutics。
Background Tosedostat is a novel oral aminopeptidase inhibitor with clinical activity in a previous phase 1-2 study in elderly patients with relapsed or refractory acute myeloid leukaemia (AML). We aimed to compare two dosing regimens of tosedostat.Methods In this randomised phase 2 study, patients aged 60 years or older with AML that had relapsed after a first complete remission lasting less than 12 months, or had achieved no previous complete remission, were randomly assigned (1:1) to receive as first salvage tosedostat 120 mg once daily for 6 months or 240 mg once daily for 2 months followed by 120 mg for 4 months. Randomisation was by block method via an interactive web response system using a randomisation schedule generated by an external vendor, with no stratification. The study was open label. The primary endpoint was the proportion of patients who obtained a complete remission or complete remission with incomplete platelet recovery. Analyses included all patients randomly assigned to treatment groups who received at least one oral dose of tosedostat. The study is registered with ClinicalTrials.gov, number NCT00780598.Findings 38 patients were randomly assigned to receive tosedostat 120 mg and 38 to receive the tosedostat 240 mg to 120 mg regimen. 38 patients in the 120 mg group and 35 in the 240 mg to 120 mg group received tosedostat. Seven patients (10%) had complete remission or complete remission with incomplete platelet recovery: two (5%) in the 120 mg group and five (14%) in the 240 mg to 120 mg group. The most common grade 3 or worse adverse events were febrile neutropenia (11 [29%] patients in the 120 mg group and ten [29%] of the 240 mg to 120 mg group), thrombocytopenia (eight [21%] and eight [23%] patients), fatigue (seven [18%] and eight [23%] patients), dyspnoea (five [13%] and seven [20%] patients), and pneumonia (four [11%] and six [17%] patients). There were five fatal adverse events deemed to be treatment-related: three in the 120 mg group and two in the 240 mg to 120 mg group. The events were acute hepatitis, respiratory failure, pneumonia, atrial fibrillation, and left ventricular dysfunction.Interpretation Tosedostat, at either dose schedule, has activity in older patients with relapsed or refractory AML. Additional studies of tosedostat including combination with hypomethylating agents and low-dose cytarabine in patients with high-risk myelodysplastic syndromes and AML are ongoing or planned.Funding Chroma Therapeutics.