Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lancet Oncol. 2013 Apr;14(4):354-62. doi: 10.1016/S1470-2045(13)70037-8. Epub 2013 Feb 28.
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.
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.
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.
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.
Chroma Therapeutics.
Tosedostat 是一种新型口服氨肽酶抑制剂，在先前的一项 1-2 期研究中，在复发或难治性急性髓系白血病（AML）的老年患者中具有临床活性。我们旨在比较两种 Tosedostat 剂量方案。
在这项随机 2 期研究中，年龄在 60 岁或以上、在第一个完全缓解持续时间少于 12 个月后复发的 AML 患者，或以前没有完全缓解的 AML 患者，按 1:1 比例随机分配（1:1）接受首次挽救性 Tosedostat 120mg 每日一次治疗 6 个月或 240mg 每日一次治疗 2 个月，然后 120mg 治疗 4 个月。随机化采用通过交互式网络响应系统进行的块方法，使用外部供应商生成的随机化方案进行，无分层。该研究是开放标签的。主要终点是获得完全缓解或不完全血小板恢复的完全缓解的患者比例。分析包括接受至少一剂 Tosedostat 的随机分配至治疗组的所有患者。该研究在 ClinicalTrials.gov 上注册，编号为 NCT00780598。
38 名患者被随机分配接受 Tosedostat 120mg，38 名患者接受 Tosedostat 240mg 至 120mg 方案。120mg 组的 38 名患者和 240mg 至 120mg 组的 35 名患者接受了 Tosedostat 治疗。7 名患者（10%）获得完全缓解或不完全血小板恢复的完全缓解：120mg 组 2 名（5%），240mg 至 120mg 组 5 名（14%）。最常见的 3 级或更高级别的不良事件是发热性中性粒细胞减少症（120mg 组 11 例[29%]，240mg 至 120mg 组 10 例[29%]）、血小板减少症（8 例[21%]和 8 例[23%]）、疲劳（7 例[18%]和 8 例[23%]）、呼吸困难（5 例[13%]和 7 例[20%]）和肺炎（4 例[11%]和 6 例[17%]）。有五例死亡不良事件被认为与治疗有关：120mg 组 3 例，240mg 至 120mg 组 2 例。这些事件是急性肝炎、呼吸衰竭、肺炎、心房颤动和左心室功能障碍。
Tosedostat，无论剂量方案如何，在复发或难治性 AML 的老年患者中均具有活性。正在或计划进行 Tosedostat 的其他研究包括与低剂量阿糖胞苷联合用于高危骨髓增生异常综合征和 AML 患者。
Chroma Therapeutics。
