title: Efficacy of CPX-351, (cytarabine:daunorubicin) liposome injection, against acute lymphoblastic leukemia (ALL) xenograft models of the Pediatric Preclinical Testing Program.
abstract: BACKGROUND
  CPX-351, a liposomal formulation of cytarabine and daunorubicin co-encapsulated at an optimized synergistic 5:1 molar ratio, has demonstrated improved clinical outcomes over conventional cytarabine/daunorubicin treatment in a randomized phase 2 trial in patients with AML as well as superior efficacy against preclinical leukemia models when compared to the free drugs in combination.
  
  
  METHODS
  Given the promising phase 2 data, limited toxicities observed, and the known clinical activities of cytarabine/daunorubicin, we assessed the efficacy of CPX-351 against a panel of childhood ALL xenograft models. Plasma pharmacokinetics of cytarabine and daunorubicin following CPX-351 treatment were determined by HPLC in order to correlate efficacy with drug exposure.
  
  
  RESULTS
  CPX-351, at a dose of 5 units/kg (corresponding to 5 mg/kg cytarabine and 2.2 mg/kg daunorubicin), was highly efficacious against all xenografts tested, inducing complete responses in four B-lineage xenografts and partial response in one T-lineage xenograft. These therapeutic responses were achieved with CPX-351 doses that provided drug exposures (based on Cmax and AUC) comparable to those observed in patients with AML.
  
  
  CONCLUSIONS
  These results suggest that CPX-351 may be a promising chemotherapeutic to be utilized in the treatment of ALL and support its testing in pediatric patients with leukemia.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Mannie M Y
authors.initials: MM
authors.lastname: Fan
authors.forename: Troy O
authors.initials: TO
authors.lastname: Harasym
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boehm
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Mayer
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010372:Pediatrics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D003561:Cytarabine; D003630:Daunorubicin
keywords: CPX-351; acute leukemia; efficacy; pharmacokinetics; synergy