title: Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia.
abstract: OBJECTIVE
  To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.
  
  
  METHODS
  Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m(2)) and clofarabine (stratum one: 40 mg/m(2), n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m(2), n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m(2) and 150 mg/m(2) twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.
  
  
  RESULTS
  At sorafenib 200 mg/m(2), two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2). Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3-internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.
  
  
  CONCLUSIONS
  Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. hiroto.inaba@stjude.org
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Elaine
authors.initials: E
authors.lastname: Coustan-Smith
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.forename: Brian D
authors.initials: BD
authors.lastname: Furmanski
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Mascara
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Heym
authors.forename: Robbin
authors.initials: R
authors.lastname: Christensen
authors.forename: Mihaela
authors.initials: M
authors.lastname: Onciu
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Pounds
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001557:Benzenesulfonates / Q000008:administration & dosage*; D002648:Child; D000077866:Clofarabine; D003561:Cytarabine / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage*; D012008:Recurrence; D000077157:Sorafenib
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D003561:Cytarabine; D009536:Niacinamide; D000077866:Clofarabine; D000077157:Sorafenib