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.
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