CLINICAL TRIAL: A PHASE I STUDY OF MK-0752 IN PEDIATRIC PATIENTS WITH RECURREN

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要： 对于患有复发或难治性中枢神经系统(CNS)恶性肿瘤的儿童，MK-0752将连续口服3天，每7天一次，共28天。起始剂量为200毫克/平方米/天，患者之间的剂量将以设定的增量增加或减少(估计最大剂量为400毫克/平方米/天)。在推荐的MTD，我们将治疗至少6名12岁的可评估患者。虽然剂量的增加将基于在第一个疗程中观察到的毒性，但在第一个疗程之后发生的任何3/4级毒性都将被记录在案，并可能需要审查治疗方案。治疗可持续6个疗程。如果患者正在从治疗中获益，并且在疗程6结束时至少有临床和放射学稳定的疾病，患者可以在研究主席和默克公司的代表事先批准的情况下继续治疗额外的13个疗程(总共19个疗程)。 一、假说 MK-0752将对患有难治性原发中枢神经系统肿瘤的儿童和青少年具有抗肿瘤活性。 二、具体目标 主要目标 目的评估复发或难治性中枢神经系统(CNS)恶性肿瘤患儿应用MK-0752的MTD，并推荐使用MK-0752，连续3天，每7天一次，共28天。 次要目标 目的：研究MK-0752的药代动力学。 记录和描述与本附表所用MK-0752相关的毒性。 初步确定MK-0752在一期实验范围内的抗肿瘤活性。 目的：探讨复发或难治性中枢神经系统肿瘤组织中Notch受体和配体的表达及通路激活情况。 评估复发或难治性中枢神经系统肿瘤标本中肿瘤干细胞的比例及其与肿瘤血管的关系。 探讨服用MK-0752的儿童相关磁共振成像的变化。体积磁共振成像结果可以通过类似的PBTC方案组合在一起，以增加检测扫描之间的相关性和与结果的关联的能力。 探讨MK-0752代谢酶基因多态性及其与药代动力学的关系。 目的：探讨缺口裂解形式和缺口通路靶基因与MK-0752药代动力学的关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT: MK-0752 will be administered orally for 3 consecutive days of every 7 days for 28 days to children with recurrent or refractory central nervous system (CNS) malignancies. The starting dose is 200 mg/m2/day and inter-patient dose escalation or reduction will occur in set increments (to an estimated maximum of 400mg/m2/day). At the recommended MTD, we will treat a minimum of 6 evaluable patients who are 12 years of age. Although the dose escalation will be based on toxicities observed during the first course, any grade 3/4 toxicities that occur after the first course will be documented and may warrant a review of the treatment regimen. Therapy may continue for 6 courses. If patients are deriving benefit from the therapy and have at least clinical and radiographic stable disease at the end of course 6, patients may continue therapy for an additional 13 courses (for a total of 19 courses) with the prior approval of the study Chair and representatives from Merck and Co. I. HYPOTHESIS MK-0752 will have anti-tumor activity in children and adolescents with refractory primary CNS tumors. II. SPECIFIC AIMS PRIMARY OBJECTIVES To estimate the MTD and recommend a Phase II dose of MK-0752 administered for 3 consecutive days of every 7 days for 28 days to children with recurrent or refractory central nervous system (CNS) malignancies. SECONDARY OBJECTIVES To characterize the pharmacokinetics of MK-0752 administered on this schedule. To document and describe toxicities associated with MK-0752 administrated on this schedule. To preliminarily define the antitumor activity of MK-0752 within the confines of a Phase I setting. To explore the incidence of NOTCH receptor and ligand expression and pathway activation in recurrent or refractory CNS tumor samples. To estimate the fraction of cancer stem cells and their association with the tumor vasculature in recurrent or refractory CNS tumor samples. To explore changes in correlative magnetic resonance imaging in children receiving MK-0752. Volumetric MR imaging findings may be combined across similar PBTC protocols to increase the power for detecting correlations among scans and associations with outcome. To explore the pharmacogenetic polymorphisms in MK-0752 metabolizing enzymes and relate these polymorphisms to MK-0752 pharmacokinetics. To explore the pharmacodynamic relationships between NOTCH-cleaved forms and NOTCH pathway target genes and MK-0752 pharmacokinetics.