17-AAG IN PEDIATRIC PATIENTS WITH RECURRENT/REFRACTORY MALIGNANCIES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。这是一项在选定的复发性/难治性儿科恶性肿瘤患者中进行的17-N-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG，NSC#330507）多中心I期剂量递增试验。本研究的主要目的是确定17-AAG在选定的复发性/难治性儿科恶性肿瘤患者中的剂量限制性毒性（DLT）和最大耐受剂量（MTD），并确定以MTD给药的17-AAG，改变已知影响从特定儿科实体瘤患者收集的癌细胞增殖和存活的关键蛋白质的水平，白血病本研究中的患者必须患有尽管接受标准治疗仍进展的疾病，或没有已知的有效标准治疗。患者将在入组研究时根据诊断进行分层，分为实体瘤或白血病分层。剂量将递增，DLT和MTD将独立确定两个分层。 将在MTD时扩展分层，以便进行更深入的生物学相关研究。这些研究对于帮助确定HSP 90抑制在这些选定的肿瘤类型中的作用至关重要。患者将主要在门诊接受17-AAG治疗，但只要符合资格标准，就允许住院治疗。17-对于实体瘤患者，AAG将每周两次静脉内给药，持续2周，随后休息1周。根据成人白血病患者的经验，白血病患者将省略休息周;这些患者将每周接受两次治疗，连续3周。如果未观察到DLT且患者未出现疾病进展，则患者可继续接受给定剂量水平的治疗。对于疾病稳定或有客观缓解证据的患者，可以给予的周期数没有限制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a multicenter Phase I dose escalation trial of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG, NSC#330507) in patients with selected recurrent/refractory pediatric malignancies. The primary objectives of this study are to establish the Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD) of 17-AAG in patients with selected recurrent/refractory pediatric malignancies, and to determine the extent to which 17-AAG, administered at the MTD, alters the levels of key proteins known to influence proliferation and survival in cancer cells collected from patients with specific pediatric solid tumors and leukemias. Patients in this study must have disease that has progressed despite standard therapy or for which no effective standard therapy is known. Patients will undergo stratification by diagnosis at study entry to either a solid tumor or a leukemia stratum. Doses will be escalated, and the DLT and MTD will be determined independently for the two strata. The strata will be expanded at the MTD to allow for the conduct of more intensive biologic correlative studies. These studies are critical to help determine the role of HSP90 inhibition in these selected tumor types. Patients will be treated with 17-AAG primarily in the outpatient setting, although treatment as an inpatient is allowed as long as eligibility criteria are met. 17-AAG will be administered intravenously twice weekly for 2 weeks followed by a 1 week rest for patients with solid tumors. Based on experience in adult leukemia patients, the rest week will be omitted in patients with leukemia; these patients will be treated twice weekly for 3 consecutive weeks. Patients may continue to receive treatment at a given dose level if no DLTs are observed and if the patient does not have progressive disease. There will be no limitation on the number of cycles that may be administered to a patient who has stable disease or evidence of an objective response to this agent.