PHASE I & II STUDIES IN CHILDREN WITH SOLID TUMORS

项目5包括本计划的临床研究 项目拨款，并将测试两个假设：1） 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 儿童临床上重要的抗肿瘤反应 神经母细胞瘤、髓母细胞瘤和横纹肌肉瘤，可接受 毒性； 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retard 小儿肿瘤的生长。 每个临床试验均源自 我们实验室项目中的观察结果。 这些项目依次 与我们的临床试验互动并利用独特的患者 通过项目 5 提供的资源来检验提出的假设 在实验室项目中。 目标 1 和 2 重点关注喜树碱 衍生品，源自项目 2、3 和 4 以及异种移植 核心。 在目标 1 中，我们将评估长期每日给药 从异种移植核心预测拓扑替康的时间表 最佳活动。 试验将单独或联合使用拓扑替康， 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 将评估伊立替康的长期每日给药，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。 目标 3 直接扩展了 项目 I 中提出的研究，提供初始第一阶段评估 雷帕霉素类似物 WAY 12932，评估毒性，确定 MTD 并测量 T 细胞功能的恢复情况。 这个项目是关键 将实验室的发现转化为患有固体疾病的儿童 恶性肿瘤，并提供定义的临床信息 继续实验室研究的适当指示。

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.