NANT 2001-03: PHASE 1 STUDY OF CEP-701 IN PATIENTS WITH REFRACTORY NEUROBLASTOMA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study is designed to treat children who have refractory or progressive high-risk neuroblastoma after conventional treatment has been given. It is a single agent phase I study using CEP - 701, given orally. CEP - 701 is a kinase inhibitor. Kinases are proteins that work by adding a phosphate group to other proteins to turn them on. Specifically, CEP - 701 inhibits several cell surface receptor-linked kinases, with the highest effectiveness for a family of kinases called Trk kinases. Trk kinases have been shown to play an important role in neuroblastoma biology by functioning in the growth stimulatory and / or survival pathways when they are turned on. CEP - 701 is meant to work by preventing Trk kinases from stimulating neuroblastoma growth and / or survival. Targeteded inhibition of this pathway has proved efficacious in preclinical models of human neuroblastoma. This New Advances in Neuroblastoma Therapy (NANT) phase 1 dose escalation study will establish the maximum tolerated dose, and recommended phase 2 dosing in patients with refractory high-risk neuroblastoma. The drug has high oral bioavailability, but a relatively short plasma half-life and will therefore be given orally twice daily. Due to the lack of hematologic toxicity, but cumulative gastrointestinal toxicity, it will be delivered on a chronic administration schedule of five days on, two days off. Plasma pharmacokinetics will be measured with the first course, which is defined as 28 days. Pharmacodynamic, biological and patient outcome endpoints will also be measured.