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 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。这是一项 I 期、多中心研究，旨在评估每周一次紫杉醇与 17-烯丙氨基-17-去甲氧基格尔德霉素 (17-AAG) 联合治疗晚期实体恶性肿瘤患者的效果。假设从药效学的角度来看，每周服用紫杉醇（4 周中的 3 周给药）可能更适合与 17-AAG 联合使用，从而最大限度地暴露于两种药物。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) 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性毒性； 3) 评价两种药物联合用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，并确定使用该药物组合治疗后 PBMC 和颊粘膜细胞中微管结构扰动的程度和时程； 5) 比较治疗前后肿瘤组织中Hsp90及其客户蛋白的浓度； 6) 记录和描述接受联合方案治疗的患者的肿瘤反应。治疗将在门诊进行。每个治疗周期由28天组成。紫杉醇在每个周期的第 1,8 和 15 天施用，17-AAG 将在每个周期的第 1,4、8、11、15 和 18 天施用。每种药物将通过 60 分钟输注给药。在同时施用两种药物的日子里，紫杉醇输注将在 17-AAG 输注之后立即输注。剂量递增将根据方案中的详细信息进行。仅在第 1 周期期间抽取用于药代动力学和药效学研究的血样。这项研究的估计样本量将是 25-35 名受试者（本地点预计有 6 名受试者），为期 3 年。大约的累积率为 3-4 名患者/月。将以 II 期推荐剂量入组 6 至 12 名患者，以获得额外的安全性、药代动力学和相关科学数据。该地点的受试者将在第 1 周期期间在 GCRC 门诊就诊，仅进行研究药物的给药、药代动力学和活检后护理。