17-DIMETHYLAMINOETHYLAMINO-17DEMETHOXYGELDANAMYCIN IN ADVANCED SOLID TUMORS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项研究的主要目标是：1)确定在两种不同的计划--每天5天和每天3天，每3周重复一次--给予17-二甲基丙氨酸(17-Dimethylaminoethylamino-17-Demethoxygeldanamycin)的最大耐受量，2)评估17-二甲基氨基甲酸在晚期实体肿瘤患者中的安全性和毒性，3)为未来的研究建立推荐的第二阶段剂量，以及4)研究17-二甲基氨基甲酸在血液、尿液和肿瘤组织中的药代动力学和药效学。17-AAG(17-烯丙氨基-17-去甲氧基格尔达那霉素)和现在的17-DMAG是第一批进入临床试验的热休克蛋白90(Hsp90)调节剂。HSP90似乎在许多癌症的发病机制中起重要作用，HSP90导向的药物需要在临床试验中进行评估。17-DMAG的水溶性增加以及与17-AAG(17-烯丙氨基-17-去甲氧基格尔丹霉素)相比具有更好的临床前特征，这为这项人类研究首次提供了理论基础。这项研究的起始剂量是基于老鼠和狗的毒理学数据。治疗将在门诊基础上进行，但第一天患者将入院进行药代动力学采样的情况除外。A组每日静脉滴注17-DMAG 1小时，连续5天；B组每日静脉滴注17-DMAG 3天。治疗周后休息2周，共3周。受试者可以重复周期，除非有疾病进展或不可接受的副作用。在治疗的第一周，受试者将采集药代动力学血液和尿样，并在服药前后进行活组织检查。所有受试者将在前24小时(第1-2天)进行药代动力学血样采集，A组在第5天进行，B组在第3天进行。GCRC仅在研究治疗的第一周进行探视。这项研究将从3个参与中心中招募60名受试者-20名受试者预计在两年内进入这个地点。

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. The primary objectives of this study are: 1) to define the maximum tolerated dose of 17-DMAG (17-Dimethylaminoethylamino-17-Demethoxygeldanamycin) given on 2 different schedules--daily for 5 days and daily for 3 days, repeated every 3 weeks, 2) to evaluate the safety and toxicity of 17-DMAG in patients with advanced solid tumors, 3) to establish a recommended phase 2 dose for future studies, and 4) to study the pharmacokinetics and pharmacodynamics of 17-DMAG in blood, urine and tumor tissue. 17-AAG (17-allylamino-17-demethoxygeldanamycin) and now 17-DMAG are the first modulators of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 appears to be important in the pathogenesis of many cancers, and, Hsp90-directed agents need to be evaluated in clinical trials. The increased water solubility of 17-DMAG and a superior preclinical profile compared to 17 AAG (17-allylamino-17-demethoxygeldanamycin) provide the rationale for this first time in humans study. The starting dose for this study is based on rat and dog toxicology data. Treatment will be administered on an outpatient basis, except on the first day when patients will be admitted overnight for pharmacokinetic sampling. Patients will receive intravenous 1-hour infusions of 17-DMAG daily for 5 days in Group A or for 3 days in Group B. The treatment week is followed by two weeks of rest, composing a 3-week cycle. Subjects may repeat cycles unless there is disease progression or unacceptable side effects. In the first week of treatment, subjects will have pharmacokinetic blood and urine samples taken as well as a pre- and post-dose biopsy. Pharmacokinetic blood samples will be done over the first 24 hours (Days 1-2) for all subjects and on Day 5 for Group A/Day 3 for Group B. The GCRC will be involved for the visits during the first week of study treatment only. This study will enroll 60 subjects among 3 participating centers- 20 subjects are expected at this site over two years.