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.
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