title: Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium.
abstract: OBJECTIVE
  Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients.
  
  
  METHODS
  Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML).
  
  
  RESULTS
  Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours).
  
  
  CONCLUSIONS
  Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
authors.affiliation: Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands. c.m.zwaan@erasmusmc.nl
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rizzari
authors.forename: Francoise
authors.initials: F
authors.lastname: Mechinaud
authors.forename: Donna L
authors.initials: DL
authors.lastname: Lancaster
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehrnbecher
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: van der Velden
authors.forename: B Berna
authors.initials: BB
authors.lastname: Beverloo
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Michael
authors.initials: M
authors.lastname: Dworzak
authors.forename: Julie
authors.initials: J
authors.lastname: Rosenberg
authors.forename: George
authors.initials: G
authors.lastname: Manos
authors.forename: Shruti
authors.initials: S
authors.lastname: Agrawal
authors.forename: Lewis
authors.initials: L
authors.lastname: Strauss
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Kearns
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D000069439:Dasatinib; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009325:Nausea / Q000139:chemically induced; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D018401:Sample Size; D035703:Therapies, Investigational; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib