17-ALLYLAMINO-17 DEMETHOXYGELDANAMYCIN (17-AAG) W/PACLITAXEL IN ADV SOLID TUMORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一项I期多中心研究，旨在评估每周紫杉醇联合17-烯丙胺-17-去甲氧基格尔达霉素（17-AAG）治疗晚期实体恶性肿瘤的疗效。假设从药效学的角度来看，每周服用紫杉醇（4周中的3周）可能更适合与17-AAG联合使用，允许最大限度地暴露于这两种药物。本研究的目的是：1)确定17-AAG II期研究的推荐剂量，该剂量可与上述人群中每周剂量的紫杉醇联合给药；2)确定与该药物组合相关的剂量限制性毒性，并描述其他非剂量限制性毒性；3)评价两药合用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，并确定该药物联合治疗后PBMC和颊粘膜细胞微管结构的扰动程度和时间过程；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、15天给药，17-AAG在每个周期的第1、4、8、11、15、18天给药。每种药物将以60分钟的输注方式给药。在给予两种药物的日子里，紫杉醇输注将紧随17-AAG输注。剂量递增将根据方案中的细节进行。用于药代动力学和药效学研究的血液样本将仅在第1周期抽取。本研究的估计样本量为25-35名受试者（预计现场有6名受试者），为期3年。大约的累积率为3-4例/月。6 - 12名患者将以II期推荐剂量入组，以获得额外的安全性、药代动力学和相关科学数据。在第1周期，该地点的受试者将以门诊为基础在GCRC就诊，仅用于给药、药代动力学和活检后护理。

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.