17-DIMETHYLAMINOETHYLAMINO-17DEMETHOXYGELDANAMYCIN IN ADVANCED SOLID TUMORS

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来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本研究的主要目的是：1）确定17-DMAG的最大耐受剂量（17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素）以2种不同的时间表给药-每天给药5天和每天给药3天，每3周重复，2）评价17-DMAG在晚期实体瘤患者中的安全性和毒性，3）建立用于未来研究的推荐的2期剂量，和4）研究17-DMAG在血液、尿液和肿瘤组织中的药代动力学和药效学。17-AAG（17-烯丙基氨基-17-去甲氧基格尔德霉素）和现在的17-DMAG是第一个进入临床试验的热休克蛋白90（Hsp 90）调节剂。Hsp 90在许多癌症的发病机制中起重要作用，因此，Hsp 90导向的药物需要在临床试验中进行评估。与17 AAG（17-烯丙基氨基-17-去甲氧基格尔德霉素）相比，17-DMAG的水溶性增加，临床前特征上级，这为首次进行人体研究提供了依据。本研究的起始剂量基于大鼠和犬毒理学数据。治疗将在门诊进行，但第一天除外，患者将在第一天住院过夜进行药代动力学采样。A组患者将接受17-DMAG静脉输注，每天1小时，持续5天，B组患者将接受17-DMAG静脉输注，持续3天。治疗周之后是两周的休息，组成一个3周的周期。受试者可以重复周期，除非出现疾病进展或不可接受的副作用。在治疗的第一周，将采集受试者的药代动力学血液和尿液样本以及给药前和给药后活检。将在前24小时（第1-2天）内采集所有受试者的药代动力学血样，A组在第5天采集，B组在第3天采集。GCRC将仅参与研究治疗第一周的访视。本研究将在3家参与研究中心入组60例受试者-预计该研究中心将在2年内入组20例受试者。

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.