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

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/m2 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/m2. 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/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete ...