Weill Medical College of Cornell University and New York Presbyterian Hospital, 525 East 68th St, New York, NY 10021, USA.
J Clin Oncol. 2011 Mar 10;29(8):979-85. doi: 10.1200/JCO.2010.30.5961. Epub 2011 Jan 31.
This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.
CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred.
The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours.
The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.
本 I 期剂量递增试验旨在确定 CPX-351 的最大耐受剂量、剂量限制性毒性和药代动力学。
48 例复发或难治性急性髓系白血病（AML）或高危骨髓增生异常综合征患者接受 CPX-351 诱导治疗，方案为第 1、3 和 5 天给予 90 分钟输注。起始剂量为 3 单位/m²，在单患者队列中进行剂量加倍，直至观察到药效学效应（与治疗相关的不良事件或骨髓细胞减少或原始细胞计数减少），随后在 3 个患者队列中进行 33%的递增，直至出现剂量限制性毒性（DLT）。
最大耐受剂量为 101 单位/m²。DLT 包括高血压危象、充血性心力衰竭和持续的血细胞减少症。不良事件与阿糖胞苷和柔红霉素治疗一致。在低至 32 单位/m²的剂量下也有反应。43 例 AML 患者中，9 例达到完全缓解（CR），1 例 CR 伴血小板恢复不完全；3 例急性淋巴细胞白血病患者中，1 例达到 CR。在 31 例既往接受阿糖胞苷和柔红霉素治疗的患者中，有 8 例达到 CR。AML 中的 CR 发生在 26 例年龄≥60 岁的患者中 5 例和 17 例年龄小于 60 岁的患者中 5 例。半寿期中位数为 31.1 小时（阿糖胞苷）和 21.9 小时（柔红霉素），末次给药后>7 天仍可检测到药物及其代谢物。在高达 24 小时的所有剂量水平，均维持 5:1 的目标摩尔比。
CPX-351 的推荐剂量为 101 单位/m²。在 AML 新诊断和首次复发患者的 II 期试验中，正在进一步探索疗效和安全性。
