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

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.

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

“…No TRKA inhibitors were explored in clinical trials with the possible exception of lestaurtinib (CEP-701), a staurosporine-derivative multikinase inhibitor that was investigated in clinical settings with reported TRKA overexpression, without evidence of efficacy (7,38). However, recent studies that have identified recurring oncogenic NTRK1 rearrangements in subsets of NSCLC and colorectal carcinoma patients (11,12), as well as other studies suggesting a potential role of activated TRKA in other tumor types, including glioblastoma and Spitz melanoma (14)(15)(16)39), have created much renewed interest in the identification and clinical investigation of effective TRKA inhibitors (13).…”

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…Overexpression of TrkB in pediatric NB is associated with an unfavorable prognosis and resistance to chemotherapy. In a phase I clinical trial, the TRK inhibitor lestaurtinib has been shown to induce stabilization of disease in recurrent/refractory NB [34]. Combining conventional chemotherapy with more specific Trk inhibitors (e.g.…”

TrkA is a binding partner of NPM‐ALK that promotes the survival of ALK+ T‐cell lymphoma

“…Of important consideration to our studies, CEP‐701 also increases CD30L, which could support the survival of NPM‐ALK + T‐cell lymphoma (Atsaves et al ., 2014). Although the CEP‐751‐related compounds have been utilized in clinical trials of patients with cancer (Chan et al ., 2008; Hexner et al ., 2014; Knapper et al ., 2006; Minturn et al ., 2011; Santos et al ., 2010), we decided not to use these compounds in our study because of the concerning issues listed above. Instead, we used the TrkAi, which has been recently shown to induce significant inhibitory effects on TrkA without known effects on other targets (Kokona et al ., 2012).…”