title: Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study.
abstract: OBJECTIVE
  TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma.
  
  
  METHODS
  Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle.
  
  
  RESULTS
  Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M(2)/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3-4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M(2) with uniform inhibition at 120 mg/M(2). There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M(2)/dose BID was established.
  
  
  CONCLUSIONS
  Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.
authors.affiliation: Department of Pediatrics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Minturn
authors.forename: Audrey E
authors.initials: AE
authors.lastname: Evans
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Suzanne
authors.initials: S
authors.lastname: Shusterman
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
authors.forename: Debra
authors.initials: D
authors.lastname: Bensen-Kennedy
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Brodeur
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005663:Furans; D006801:Humans; D020714:Maximum Tolerated Dose; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D047428:Protein Kinase Inhibitors; C119379:lestaurtinib; D020813:Receptor, trkB