PS 341 IN THE TREATMENT OF RECURRENT GLIOMAS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 长期目标是：1)确定PS-341在接受(A组)或不接受(B组)已知由P450肝酶复合体代谢的抗惊厥药物的成人复发性胶质瘤患者每周两次给药时的最大耐受量。2)通过测定蛋白酶体20S活性来描述PS-341的生物活性，并观察肝酶诱导剂如抗惊厥药物对PS-341生物活性的影响。3)检测15例受试者在MTD(B期)经PS-341治疗后肿瘤组织中蛋白酶体20S活性。蛋白小体抑制剂可以通过多种机制来抑制肿瘤生长、肿瘤扩散和血管生成。在A阶段，受试者每周服药两次，共4周，然后停药2周。研究药物将以3名受试者为一组，逐步升级。在接受抗惊厥药物治疗的受试者(A组)和未接受抗惊厥药物治疗的受试者(B组)中，剂量递增将独立进行。A组和B组受试者的研究药物将升级，直到发生DLT。仅在第1周期输液后24小时内，在筛查、基线和x4时抽取血样。B期受试者必须对其复发的胶质瘤进行手术减压，并在手术前立即接受1IV剂量的研究药物。将对肿瘤进行20S蛋白酶体分析。

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. Long-term objectives are 1) To determine the maximum tolerated dose of PS-341 when administered in a twice weekly regimen to adults with recurrent glioma, receiving (Group A) or not receiving (Group B) anticonvulsants known to be metabolized by the P450 hepatic enzyme complex. 2) To describe the biologic activity of PS-341 by this route of administration, by measurement of proteasome 20S activity, and to determine the effects of hepatic enzyme inducing drugs, such as the anticonvulsants on the biologic activity. 3) To determine proteasome 20S activity in tumor samples after treatment with PS-341 at the MTD in 15 subjects (Phase B). Proteosome inhibitors can act through multiple mechanisms to arrest tumor growth, tumor spread and angiogenesis. In Phase A subjects will be dosed twice weekly x 4 weeks, then off 2 weeks. Study drug will be escalated in a stepwise fashion in groups of 3 subjects. Dose escalations will proceed independently in subjects receiving anticonvulsant medication (Group A) and those not receiving anticonvulsant medications (Group B). Study drug will be escalated for subjects in Group A and B until a DLT occurs. Blood samples will be drawn at screening, baseline and x 4 during 1st 24 hours after infusion for cycle 1 only. Phase B subjects must need surgical decompression of their recurrent glioma and receive 1 IV dose of study drug immediately prior to surgery. Tumor will be analyzed for 20S proteasome analysis.