Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 4, pp 1057–1065

Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study

  • Jane E. Minturn
  • Audrey E. Evans
  • Judith G. Villablanca
  • Gregory A. Yanik
  • Julie R. Park
  • Suzanne Shusterman
  • Susan Groshen
  • Edward T. Hellriegel
  • Debra Bensen-Kennedy
  • Katherine K. Matthay
  • Garrett M. Brodeur
  • John M. Maris
Original Article

DOI: 10.1007/s00280-011-1581-4

Cite this article as:
Minturn, J.E., Evans, A.E., Villablanca, J.G. et al. Cancer Chemother Pharmacol (2011) 68: 1057. doi:10.1007/s00280-011-1581-4

Abstract

Purpose

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/M2/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/M2 with uniform inhibition at 120 mg/M2. 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/M2/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.

Keywords

Neuroblastoma Receptor tyrosine kinase Targeted therapy Lestaurtinib Signal transduction 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jane E. Minturn
    • 1
  • Audrey E. Evans
    • 1
  • Judith G. Villablanca
    • 2
  • Gregory A. Yanik
    • 3
  • Julie R. Park
    • 4
  • Suzanne Shusterman
    • 5
  • Susan Groshen
    • 2
  • Edward T. Hellriegel
    • 6
  • Debra Bensen-Kennedy
    • 6
  • Katherine K. Matthay
    • 7
  • Garrett M. Brodeur
    • 1
    • 9
  • John M. Maris
    • 1
    • 8
  1. 1.Department of Pediatrics and Center for Childhood Cancer Research, Children’s Hospital of PhiladelphiaUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Departments of Pediatrics and Biostatistics, Keck School of MedicineUniversity of Southern California and Childrens Hospital Los AngelesLos AngelesUSA
  3. 3.University of Michigan and C.S. Mott Children’s HospitalAnn ArborUSA
  4. 4.Department of PediatricsSeattle Children’s Hospital and University of WashingtonSeattleUSA
  5. 5.Department of PediatricsChildren’s Hospital Boston and Dana-Farber Cancer InstituteBostonUSA
  6. 6.Departments of Drug Safety and Disposition and Clinical Research, OncologyCephalon, Inc.FrazerUSA
  7. 7.Department of PediatricsUniversity of California San Francisco School of MedicineSan FranciscoUSA
  8. 8.Division of OncologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  9. 9.Division of OncologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA

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