First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
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DOI：
10.1200/jco.2010.30.5961
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发表时间：
2011-03-01
影响因子：
45.3
通讯作者：
Louie, Arthur C.
中科院分区：
文献类型：
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作者：
Feldman, Eric J.;Lancet, Jeffrey E.;Louie, Arthur C.
目的进行I期剂量递增试验以确定CPX-351的最大耐受剂量、剂量限制性毒性和药代动力学。患者和方法48例复发或难治性急性髓性白血病（AML）或高危骨髓增生异常患者在第1、3和5天通过90分钟输注给予CPX-351诱导。剂量从3单位/m2开始，在单个患者队列中进行剂量doubling，直到观察到药效学效应（治疗相关的不良事件或骨髓细胞或原始细胞计数减少），随后在3个患者队列中进行33%的剂量递增，直到发生剂量限制性毒性（DLT）。DLT包括高血压危象、充血性心力衰竭和长期血细胞减少。不良事件与阿糖胞苷和柔红霉素治疗一致。反应发生在剂量低至32单位/m2时。在43例AML患者中，9例完全缓解（CR），1例CR伴血小板不完全恢复;在急性淋巴细胞白血病患者中，1/3例CR。31例既往接受阿糖胞苷和柔红霉素治疗的患者中有8例获得CR。年龄≥ 60岁的26例AML患者中有5例发生CR，年龄小于60岁的17例患者中有5例发生CR。中位半衰期为31.1小时（阿糖胞苷）和21.9小时（柔红霉素），最后一次给药后> 7天可检测到两种药物及其代谢物。目标5：1摩尔比在所有剂量水平下维持长达24 h.ConclusionThe推荐剂量的CPX-351的II期研究是101单位/m2。在新诊断和首次复发的AML患者中进行的II期试验正在进一步探索疗效和安全性。
PurposeThis phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.Patients and MethodsCPX-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.ResultsThe 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.ConclusionThe 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.