PBTC-025-A PHASE I PHARMACOPKINETIC AND SAFETY STUDY IN CHILDREN

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。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 摘要 这是一项针对复发性或难治性髓母细胞瘤儿童的多中心I期试验，旨在为随后的II期试验选择推荐基于药代动力学的GDC-0449每日剂量，以评估毒性并表征GDC-0449的药代动力学和生物制剂。 I. 假设 拟定的GDC 0449 I期类型研究将寻求描述药物在复发性或难治性髓母细胞瘤患者中的毒性和药代动力学特征。 福尔马林固定石蜡包埋组织和快速冷冻组织（如可用）的相关研究将寻求选择PTCH/SHH信号通路被激活的患者。 这些信息将用于后续的II期研究，以选择一组生物学上最适合这种靶向治疗的患者。 二. 具体目标 主要目的： 1.基于安全性和药代动力学，选择推荐用于复发性或难治性髓母细胞瘤儿童的后续PBTC II期试验的GDC 0449日剂量。 次要目的： 1.记录并描述与每日给药GDC-0449相关的毒性。 2.描述GDC-0449在难治性髓母细胞瘤儿童/青少年中的药代动力学（血浆和脑脊液）。 3.记录GDC-0449治疗复发性或难治性髓母细胞瘤患者的初步抗肿瘤活性。 4.记录鉴定PTCH/SHH通路激活的CNS肿瘤的病理学和基因组学方法。

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 This is a multi-center, phase I type trial for children with recurrent or refractory medulloblastoma to select recommend a pharmacokinetic based daily dose of GDC-0449 for a subsequent Phase II trial to evaluate toxicity and to characterize the pharmacokinetics and biologics of the GDC-0449. I. HYPOTHESIS The proposed phase I type study of GDC 0449 will seek to describe the toxicities and pharmacokinetic characteristics of the drug in patients with recurrent or refractory medulloblastoma. Correlative studies on formalin fixed paraffin embedded tissue and snap frozen tissue (when available) will seek to select patients in whom the PTCH/SHH signaling pathway is activated. This information will be used in subsequent Phase II study so as to select a group of patients that are biologically optimal for treatment with this targeted therapy. II. SPECIFIC AIMS Primary Objectives: 1. To select, based on safety and pharmacokinetics, a daily dose of GDC0449 to recommend for a subsequent PBTC Phase II trial of children with recurrent or refractory medulloblastoma. Secondary Objectives: 1. To document and describe toxicities associated with GDC-0449 administered on a daily schedule. 2. To characterize the pharmacokinetics (plasma and cerebrospinal fluid) of GDC-0449 in children/adolescents with refractory medulloblastoma. 3. To document preliminary antitumor activity in patients with recurrent or refractory medulloblastoma treated with GDC-0449. 4. To document pathologic and genomic methods to identify CNS tumors with activation of the PTCH/SHH pathway.