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

17-烯丙氨基-17 去甲氧基格尔德霉素 (17-AAG) 联合紫杉醇治疗 ADV 实体瘤

• 批准号: 7378069
• 负责人: Scot C Remick
• 金额: $ 0.33万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378069
• 关键词: 17; ALLYLAMINO; DEMETHOXYGELDANAMYCIN; AAG; PACLITAXEL

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.

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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。这是一项I期，多中心研究，旨在评估每周紫杉醇与17-乙酰胺-17-甲氧基甲氧苯甲霉素（17-AAG）的组合，以患有晚期固体恶性肿瘤的患者。假设是，从药效动力学的角度来看，紫杉醇的每周时间表（在4周内施用了3周）可能更适合与17-AAG结合，从而使两种药物的最大暴露率最大化。这项研究的目的是：1）确定可以与上述人群中每周剂量的紫杉醇结合使用的17-AAG II期研究的建议剂量； 2）定义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毒性； 3）当组合给药时，评估两种药物之间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PBMC和颊粘膜细胞在用这种药物组合治疗后微管结构中扰动的程度和时间顺序； 5）比较在治疗前后肿瘤组织上HSP90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。治疗将在门诊患者的基础上进行。每个治疗周期包括28天。紫杉醇在第1,8天进行，每个周期的15个紫杉醇将在每个周期的1,4、8,11,15和18天进行17-AAG。每个代理将作为60分钟的输注施用。在服用两种药物的日子里，紫杉醇输注将立即输注。剂量升级将根据协议中的详细信息进行。仅在周期1期间才能绘制用于药代动力学和药效学研究的血液样本。这项研究的估计样本量将在3年内为25-35名受试者（预计在此地点将有6个受试者）。大约应计率为每月3-4例患者。 II期建议的六到12名患者将招募以获取其他安全性，药代动力学和相关科学数据。该站点的受试者将在周期1期间在GCRC上在GCRC上观看，仅用于研究剂，药代动力学和活检后护理。