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

Purpose: CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1in patients with advanced solid tumors. Experimental Design: Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m 2 (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1and 15 of cycle 1. Results: Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m 2