title: 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: OBJECTIVE
  This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Weill Medical College of Cornell University and New York Presbyterian Hospital, 525 East 68th St, New York, NY 10021, USA. ejf2001@med.cornell.edu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Feldman
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Ritchie
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Ekatherine
authors.initials: E
authors.lastname: Asatiani
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
authors.forename: Christine
authors.initials: C
authors.lastname: Swenson
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Louie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D012008:Recurrence; D016879:Salvage Therapy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D008081:Liposomes; D003561:Cytarabine; D003630:Daunorubicin