PHASE I & II STUDIES IN CHILDREN WITH SOLID TUMORS

第一阶段

• 批准号: 6654028
• 负责人: Victor M. Santana
• 金额: $ 28.58万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-06 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654028
• 关键词: Wilms' tumor; adolescence (12-20); antineoplastics; camptothecin; child (0-11); clinical research; clinical trial phase I; combination cancer therapy; drug adverse effect; drug screening /evaluation; enzyme inhibitors; human subject; human therapy evaluation; irinotecan; medulloblastoma; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neuroblastoma; patient oriented research; pediatric neoplasm /cancer; pharmacokinetics; rhabdomyosarcoma; sirolimus; temozolomide; topotecan

DESCRIPTION (provided by applicant): Although contemporary treatment strategies have improved the survival of children with solid tumors, relapse or refractory disease still accounts for the leading cause of death in these children. New therapeutic strategies are needed and a further understanding of the biologic and biochemical processes that control tumor proliferation, differentiation and cell death to provide insights into how promising new chemotherapeutic and biologic agents can be incorporated into treatment regimens. This Project 10 comprises the clinical Phase I/II research studies of this Program Project Grant and focuses on 3 hypotheses: (1) that the rapamycin analogue CCI-779 will inhibit the signal transduction molecule mTOR (target of rapamycin) and retard the growth of pediatric tumors; (2) that an inhibitor of ErbB1 signaling (ZD1839) in combination with intravenous camptothecins will produce clinically meaningful responses in children with neuroblastoma and highgrade gliomas either through direct inhibition of ErbB1 in tumors expressing this receptor (glioblastomas) or through modulating ABC transporters such as BCRP and MRP in neuroblastoma; and (3) that 4-anilinoquinazolones such as ZD1839 may modulate the bioavailability of oral camptothecins and result in systemic exposures associated with response in pre-clinical xenograft models. Incorporated into selected clinical trials will be assessments of the expression of the ErbB family of receptors and BCRP/MRP, and mTOR inhibition and recovery. Each clinical trial is derived from observations in laboratory projects. Specific aim 1 focuses on evaluation of CCI-779 as a single agent or in combination defining toxicity, potential activity and markers of tumor response. In Specific aims 2 and 3, we will evaluate oral ZD1839 in combination with intravenous or oral camptothecins defining the MTD, bioavailability and tumor responses. Lastly, Specific aim 4 will focus on continued evaluation of a pharmacokinetically targeted approach to dosing of topotecan for relapsed Wilms tumor and combination studies of camptothecins with DNA damaging agents. This clinical project is fundamental in translating key laboratory discoveries into the treatment approaches for children with solid tumors, and providing direction for continued laboratory investigations.

描述（由申请人提供）：尽管当代的治疗策略已经改善了实体瘤儿童的生存率，但复发或难治性疾病仍然是这些儿童死亡的主要原因。需要新的治疗策略，并进一步了解控制肿瘤增殖、分化和细胞死亡的生物和生化过程，以深入了解如何将有前途的新型化疗和生物制剂纳入治疗方案。该项目10包括本项目资助的临床I/II期研究，重点关注3个假设：（1）雷帕霉素类似物CCI-779将抑制信号转导分子mTOR（雷帕霉素的靶点）并延缓细胞的生长。小儿肿瘤； (2) ErbB1 信号传导抑制剂 (ZD1839) 与静脉注射喜树碱联合使用，可通过直接抑制表达该受体的肿瘤（胶质母细胞瘤）中的 ErbB1 或通过调节 ABC 转运蛋白，对患有神经母细胞瘤和高级神经胶质瘤的儿童产生具有临床意义的反应，例如神经母细胞瘤中的 BCRP 和 MRP； (3) 4-苯胺基喹唑酮类药物如 ZD1839 可能会调节口服喜树碱的生物利用度，并导致与临床前异种移植模型反应相关的全身暴露。选定的临床试验将纳入 ErbB 受体家族和 BCRP/MRP 表达以及 mTOR 抑制和恢复的评估。每个临床试验都源自实验室项目的观察。具体目标 1 重点评估 CCI-779 作为单一药物或组合药物的毒性、潜在活性和肿瘤反应标志物。具体来说 目标 2 和 3，我们将评估口服 ZD1839 与静脉注射或口服喜树碱的组合，确定 MTD、生物利用度和肿瘤反应。最后，具体目标 4 将重点关注对复发性肾母细胞瘤拓扑替康给药的药代动力学靶向方法的持续评估以及喜树碱与 DNA 损伤剂的联合研究。该临床项目对于将关键实验室发现转化为儿童实体瘤的治疗方法至关重要，并为持续的实验室研究提供方向。