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.
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