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01.10.2011 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2011

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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.

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Titel: Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study
verfasst von: 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
Publikationsdatum: 01.10.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1581-4

Springer Medizin

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