17-ALLYLAMINO-17 DEMETHOXYGELDANAMYCIN (17-AAG) W/PACLITAXEL IN ADV 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。这是一项I期多中心研究，旨在评估每周一次的紫杉醇联合17-烯丙氨基-17-去甲氧基格尔达霉素(17-AAG)治疗晚期实体肿瘤患者的疗效。假设是，从药效学的角度来看，每周一次的紫杉醇(4周中有3周给药)可能更适合与17-AAG联合使用，从而允许最大限度地接触这两种药物。本研究的目的是：1)确定在上述人群中17-AAG与紫杉醇每周剂量合用的II期研究的推荐剂量；2)确定与该药物组合有关的剂量限制毒性，并描述其他非剂量限制毒性；3)评估两种药物联合给药时的药代动力学相互作用；4)量化外周血单核细胞(PBMC)中Hsp90客户蛋白的变化，并确定该药物组合治疗时PBMC和口腔粘膜细胞微管结构的扰动程度和时间进程；5)比较治疗前后肿瘤组织中Hsp90及其客户蛋白的浓度；6)记录和描述联合方案治疗后患者的肿瘤反应。治疗将在门诊进行。每个治疗周期为28天。紫杉醇在每个周期的第1、8和15天给药，17-AAG在每个周期的第1、4、8、11、15和18天给药。每种药物都将作为60分钟的输液进行注射。在两种药物同时使用的日子里，紫杉醇的输注将在17-AAG输注之后立即进行。剂量递增将根据协议中的细节进行。用于药代动力学和药效学研究的血液样本将仅在第一周期内采集。这项研究的预计样本量为25-35名受试者(本网站预计有6名受试者)，为期3年。大约的应计费率为每月3-4名病人。6至12名患者将以第二阶段推荐剂量入选，以获得更多的安全性、药代动力学和相关科学数据。在周期1期间，仅在研究试剂、药代动力学和活组织检查后护理的情况下，才能在GCRC门诊看到该站点的受试者。

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. This is a phase I, multicenter study to evaluate the combination of weekly paclitaxel with 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) in patients with advanced solid malignancies. The hypothesis is that a weekly schedule of paclitaxel (administered for 3 out of 4 weeks) may be more suited to combine with 17-AAG from a pharmacodynamic standpoint, allowing for maximal exposure to both the agents. The objectives of this study are: 1) to determine the recommended doses for phase II studies of 17-AAG that can be administered in combination with weekly doses of paclitaxel in the above population; 2) to define the dose-limiting toxicities associated with this drug combination and to describe other non-dose-limiting toxicities; 3) to evaluate the pharmacokinetic interactions between the two drugs when given in combination; 4) to quantify changes in Hsp90 client proteins in peripheral blood mononuclear cells (PBMC) and to determine the extent and time-course of perturbations in microtubule architecture in PBMC and buccal mucosal cells upon treatment with this drug combination; 5) to compare concentrations of Hsp90 and its client proteins on tumor tissue pre- and post-treatment; 6) to document and describe the tumor responses of patients treated with the combination regimen. Treatment will be administered on an outpatient basis. Each treatment cycle consists of 28 days. Paclitaxel is administered on days 1,8, and 15 of each cycle, and 17-AAG will be administered on days 1,4, 8,11,15, and 18 of each cycle. Each agent will be administered as a 60-minute infusion. On days when both drugs are administered, the paclitaxel infusion will immediately follow the 17-AAG infusion. Dose escalation will proceed according to the details in the protocol. Blood samples for pharmacokinetic and pharmacodynamic studies will be drawn during Cycle 1 only. The estimated sample size for this study will be 25-35 subjects (6 subjects are expected at this site) over 3 years. The approximate accrual rate will be 3-4 patients/month. Six to 12 patients will be enrolled at the phase II recommended dose to obtain additional safety, pharmacokinetic and correlative science data. Subjects at this site will be seen at the GCRC on an outpatient basis during Cycle 1 only for administration of study agent, pharmacokinetics, and post biopsy care.