Phase I trial of lestaurtinib for children with refractory neuroblastoma (NB): A New Approach to Neuroblastoma Therapy (NANT) Consortium study.

Abstract

9532 Background: TrkB acts as an oncogenic kinase in a subset of human NB. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated anti-tumor activity in preclinical models of human NB. Methods: We performed a Phase I trial of Lestaurtinib in patients with recurrent or refractory high-risk neuroblastoma starting at 80% of the adult recommended Phase II dose. Subjects received lestaurtinib twice daily for five days on, two days off continuous dosing. Lestaurtinib dose was escalated using a 3+3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle defined as 28 days. Response data were obtained after the first and then every other cycle. Results: Forty-seven patients were enrolled, and 10 dose levels explored starting at 25 mg/m2/dose BID, with 42 patients evaluable for dose escalation and 47 patients evaluable for response. Asymptomatic and reversible gr 3-4 transaminase elevation was dose limiting in 4 patients. Pancreatitis (gr 2) was observed in 3 patients after prolonged treatment (≥5 cycles) at dose levels ≥5 and considered possibly related to drug. Symptoms resolved with discontinuation or dose reduction. Other toxicities were mild and reversible. Pharmacokinetic analyses indicate that drug is rapidly absorbed in children, however systemic exposure (Cmax and AUC on d1, Ctrough on d5 and d26) did not consistently increase with increasing dose, and inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 hour post-dosing at 85 mg/m2 with uniform inhibition at 120 mg/m2. There were two objective responses and 10 patients had prolonged stable disease at dose levels ≥5, (median: 12 cycles) before disease progression (pending review). A biologically effective and recommended phase II dose of 120 mg/m2/dose BID was established. Conclusions: Lestaurtinib was well tolerated in this heavily pre-treated patient group with refractory NB, and a dose level required to provide enough free drug to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrants further evaluation of this drug or other Trk-directed therapies in NB. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cephalon Cephalon Cephalon