17-ALLYLAMINO-17 DEMETHOXYGELDANAMYCIN (17-AAG) W/PACLITAXEL IN ADV 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。这是一项I期、多中心研究，旨在评价紫杉醇每周一次联合17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）治疗晚期实体恶性肿瘤患者的疗效。假设从药效学的角度来看，紫杉醇的每周给药方案（4周中给药3周）可能更适合于联合收割机与17-AAG联合使用，从而使两种药物的暴露量最大化。本研究的目的是：1）确定在上述人群中可与每周剂量紫杉醇联合给药的17-AAG II期研究的推荐剂量; 2）确定与该药物联合给药相关的剂量限制性毒性，并描述其他非剂量限制性毒性; 3）评价联合给药时两种药物之间的药代动力学相互作用; 4）定量外周血单核细胞（PBMC）中Hsp 90客户蛋白的变化，并确定在用该药物组合治疗后PBMC和口腔粘膜细胞中微管结构的扰动的程度和时程; 5）比较治疗前和治疗后肿瘤组织上Hsp 90及其客户蛋白的浓度; 6）记录和描述用组合方案治疗的患者的肿瘤反应。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将在每个周期的第1、4、8、11、15和18天给药。每种药物将以60分钟输注给药。在两种药物同时给药的当天，紫杉醇输注将在17-AAG输注后立即进行。剂量递增将根据方案中的详细信息进行。仅在第1周期采集用于药代动力学和药效学研究的血样。3年内，本研究的估计样本量为25-35例受试者（预计该研究中心有6例受试者）。大概的增加率为3-4例患者/月。将以II期推荐剂量入组6 - 12例患者，以获得额外的安全性、药代动力学和相关科学数据。该研究中心的受试者将在第1周期期间在GCRC门诊就诊，仅接受研究药物给药、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.