PHASE I & II STUDIES IN CHILDREN WITH SOLID TUMORS

项目5包括本项目的临床研究 项目补助金，并将测试两个假设：1），管理 喜树碱衍生物，全身暴露量相当于 在异种移植模型中产生客观反应，将产生 儿童中具有临床意义的抗肿瘤反应 神经母细胞瘤、髓母细胞瘤和横纹肌肉瘤， 毒性;和2）雷帕霉素类似物（WAY 1290327）将抑制 信号转导分子mTOR（雷帕霉素靶标）和阻滞剂 小儿肿瘤的生长。 每项临床试验均来自 我们实验室项目中的观察结果。 这些项目反过来 与我们的临床试验互动，并利用独特的病人 通过项目5提供的资源，以检验提出的假设 在实验室项目中。 目标1和2关注喜树碱 衍生物和衍生自项目2、3和4以及异种移植物 核心 在目标1中，我们将评估长期每日给药 根据异种移植物核心预测的拓扑替康给药方案 最佳活动。 试验将单独使用拓扑替康和联合使用， 定义毒性，确定影响药物处置的参数， 和肿瘤反应的生化标志物。 同样，在目标2中，我们 将评价伊立替康每日给药时间延长，定义 毒性，确定影响药物处置的参数， 肿瘤反应的生化标志物。 目标3直接扩展了 项目I中提出的研究，提供第一阶段的初步评估 的雷帕霉素类似物WAY 12932，评价毒性，确定 MTD和测量T细胞功能的恢复。 这个项目是关键 在将实验室发现转化为患有固体 恶性肿瘤，并提供临床信息， 继续进行实验室研究的适当指导。

Project 5 comprises the clinical research studies of this Program Project Grant, and will test two hypotheses: 1) that administration of camptothecin derivatives, at systemic exposures equivalent to those producing objective response in the xenograft model, will produce clinically important antitumor responses in children with neuroblastoma, medulloblastoma, and rhabdomyosarcoma with acceptable toxicity; and 2) that a rapamycin analog (WAY 1290327) will inhibit the signal transducing molecule mTOR (Target of Rapamycin) and retard growth of pediatric tumors. Each clinical trial is derived from observations in our laboratory projects. These projects in turn interact with our clinical trails and utilize the unique patient resources made available through Project 5 to test hypotheses proposed in the laboratory projects. Aims 1 and 2 focus on camptothecin derivatives and are derived from Projects 2, 3, and 4 and the Xenograft Core. In Aim 1, we will evaluate prolonged daily administration schedules of topotecan predicted from the Xenograft Core to have optimal activity. Trials will use topotecan alone and in combination, defining toxicity, determining parameters affecting drug disposition, and biochemical markers of tumor response. Similarly, in Aim 2, we will evaluate prolonged daily administration of irinotecan, defining toxicity, determining parameters affecting drug disposition and biochemical markers of tumor response. Aim 3 directly extends the studies proposed in Project I, providing the initial phase I evaluation of the rapamycin analog WAY 12932, evaluating toxicity, determining the MTD and measuring the recovery of T-cell function. This project is key in translating the laboratory discoveries to children with solid malignancies, and providing clinical information that defines appropriate directions for continued laboratory investigations.