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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究旨在治疗常规治疗后患有难治性或进行性高危神经母细胞瘤的儿童。 这是一项使用CEP - 701口服给药的单药I期研究。 CEP - 701是一种激酶抑制剂。 激酶是一种蛋白质，通过向其他蛋白质添加磷酸基团来启动它们。具体来说，CEP - 701抑制几种细胞表面受体连接的激酶，对一种称为Trk激酶的激酶家族的效果最高。 Trk激酶已被证明在神经母细胞瘤生物学中起重要作用，当它们被开启时，通过在生长刺激和/或存活途径中起作用。CEP - 701意在通过防止Trk激酶刺激神经母细胞瘤生长和/或存活而起作用。 靶向抑制该途径已被证明在人神经母细胞瘤的临床前模型中有效。这项神经母细胞瘤治疗新进展（NANT）1期剂量递增研究将确定难治性高危神经母细胞瘤患者的最大耐受剂量和推荐的2期剂量。 该药物具有高口服生物利用度，但血浆半衰期相对较短，因此每天口服两次。 由于没有血液学毒性，但累积胃肠道毒性，它将按照5天给药，2天停药的长期给药方案进行给药。 将在第一个疗程（定义为28天）中测量血浆药代动力学。 还将测量药效学、生物学和患者结局终点。

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.