期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 68, 期 4, 页码 1057-1065出版社
SPRINGER
DOI: 10.1007/s00280-011-1581-4
关键词
Neuroblastoma; Receptor tyrosine kinase; Targeted therapy; Lestaurtinib; Signal transduction
资金
- NIH [P01-CA81403, P01-CA97323, R01-CA-094194]
- Giulio D'Angio Endowed Chair in Neuroblastoma Research (Maris)
- NIH/NCRR UCSF-CTSI [UL1 RR024131]
- Alex's Lemonade Stand Foundation
- Children's Neuroblastoma Cancer Foundation
- Dougherty Family Foundation
- Evan T.J. Dunbar Memorial Foundation
- Neuroblastoma Children's Cancer Society
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/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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据