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

Abstract

A B S T R A C T 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 Ն 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 Ͼ 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. J Clin

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…This agent is a nanoscale liposome which contains a fixed molar ratio of cytarabine and daunorubicin of 5:1 [130]. Preclinical studies suggested this molar ratio to offer optimal synergy.…”

Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm

“…In patients with relapsed/refractory leukemia, in whom CPX-351 was administered on days 1, 3, and 5 of a treatment cycle, a maximum tolerated dose (MTD) of 101 units/m 2 was identified, but responses were seen with doses as low as 32 units/m 2 . 3 In a subsequent study in fit adults age 60-75 years with newly diagnosed AML who were randomized 2:1 between CPX-351 (100 units/m 2 ) and 7+3, 60-day mortality was lower with CPX-351 (4.7% vs. 14.6%, p=0.053) while response rates were higher (66.7% vs. 51.2%, p=0.07). 4 Pre-planned subset analyses indicated improved survival in patients with secondary leukemias.…”

Novel agents in acute myeloid leukemia

“…The initial experience of CPX-351 in the treatment of 48 patients with relapsed or refractory MDS/AML defined the MTD at 101 U/m 2 when given on days 1, 3, and 5 of an induction cycle, and nine out of the 43 patients with AML achieved a CR. Doselimiting toxicities included hypertensive crisis, congestive heart failure, and prolonged cytopenias [36]. Phase II trials investigating the use of CPX-351 versus standard cytarabine/daunorubicin in elderly patients and CPX-351 versus intensive salvage therapy in relapsed disease in patients under the age of 60 have recently been completed.…”