PBTC-005: TEMOZOLOMIDE & O6-BENZYLGUANINE IN CHILDREN WITH BRAIN TUMORS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。替莫唑胺已被证明在高级别胶质瘤患者中产生反应。本研究将使医生能够描述替莫唑胺和O 6-苄基鸟嘌呤（O 6-BG）联合使用时的药代动力学特征，从而能够描述这两种药物联合使用（有或无G-CSF支持）相关的毒性特征。该基金会将提供指导方针，以确定最大耐受剂量的替莫唑胺（Temodar）时，与O 6-BG管理，有和没有G-CSF支持的难治性脑肿瘤的儿科患者分层以前的放疗。基于O 6-BG和亚硝基脲组合的体外和体内数据，O 6-BG和替莫唑胺的组合应增加替莫唑胺的治疗指数。然而，使用O 6-BG和替莫唑胺组合的最佳方案是未知的。拟议的研究与调整的时间表建立在最近结束的I期成人研究复发性恶性胶质瘤患者。研究受试者将在48小时O 6-BG输注开始后6小时接受单次替莫唑胺给药。将根据研究设计递增剂量，直至达到最大耐受剂量。将使用统计软件CRM确定最大耐受剂量（MTD）。将对分层1a和2a各至少18例患者进行研究，试验将继续进行，直至当前推荐剂量至少有6例患者被分配，最终推荐剂量为估计的MTD。将在接受联合药物治疗的患者中记录抗肿瘤应答。研究人员将评估肿瘤组织中MGMT酶和错配修复（MMR）蛋白水平与患者结局之间的可能相关性。

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. Temozolomide has been shown to produce responses in patients with high-grade gliomas. This study will provide the ability for physicians to characterize the pharmacokinetics of temozolomide and O6-benzylguanine (O6-BG) when used in combination, allowing the characterization of toxicities associated with the combination of these two drugs with and without G-CSF support. This foundation will provide guidelines for determining the maximum tolerated dose of temozolomide (Temodar) when administered with O6-BG, with and without G-CSF support to pediatric patients with refractory brain tumors stratified by previous radiotherapy. The combination of O6-BG and temozolomide should increase the therapeutic index of temozolomide based on in vitro and in vivo data with the combination of O6-BG and nitrosoureas. However, the optimal schedule for using O6-BG and temozolomide in combination is unknown. The proposed study with adapted schedule builds on a recently concluded Phase I adult study in patients with recurrent malignant gliomas. Study subjects will be given a single dose of temozolomide six hours after the start of a 48-hour O6-BG infusion. The dose will be escalated according to study design until the maximally tolerated dose has been reached. The maximum tolerated dose (MTD) will be determined using statistical software CRM. A minimum of eighteen patients on each of strata 1a and 2a will be studied and the trial will continue until the current recommended dose has at least six patients assigned to it and the final recommend dose is the estimated MTD. Anti-tumor response will be documented in patients treated with the combination drugs. The investigators will evaluate the possible correlation between levels of MGMT enzyme and mismatch repair (MMR) proteins in tumor tissue, and patient outcomes.