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

Purpose: This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

Fig 1.

Schematic representation of CPX-351 (cytarabine:daunorubicin) liposome injection. The liposomes are bilamellar with a diameter of 100 nm for the outer vesicle. The membrane is composed of desaturated phosphatidylcholine (DSPC): distearylphosphatidylglycerol (DSPG):cholesterol in a 7:2:1 molar ratio. The active agents, cytarabine and daunorubicin, are encapsulated in the aqueous space of both vesicles at a 5:1 molar ratio. The liposomes are suspended in phosphate-buffered sucrose, pH 7.4. While inside the liposome, daunorubicin is complexed with copper as copper gluconate, giving CPX-351 its characteristic purple color. The strength of CPX-351 is 5 units/mL, where 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin (base).

Fig 2.

(A) Day 1 mean plasma cytarabine, daunorubicin, uracil arabinoside, and daunorubicinol concentrations, time 0 to 48 hours, 101 units/m², 90-minute infusion. (B) Day 5 mean plasma cytarabine, daunorubicin, uracil arabinoside, and daunorubicinol concentrations, time 0 to 168 hours, 101 units/m², 90-minute infusion.