This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.There are four primary objectives to this study. The first objective is to determine the maximum tolerated dose (MTD) of BAY 43-9006 when administered to adults with recurrent malignant glioma, receiving or not receiving anti-convulsants known to be metabolized by the P450 hepatic enzyme complex. The second objective is to assess and estimate the dose-related toxicities. Thirdly, to describe the pharmacokinetics of this route of administration, measuring BAY 43-9906, and to assess the pharmacokinetic difference between patients taking enzyme-inducing agents and those who are not. And lastly, to estimate overall survival. Malignant gliomas are characterized byalterations in mitogenic signaling pathways such as the EGFR (epidermal growth factor receptor) and the PDGFR (platelet derived growth factor receptor). The RAS/raf signaling pathway is an important mediator of responses to growth signals and angiogenic factors. This pathway is often aberrantly activated in human tumors due to presence of activated ras, mutant b-raf, or over expression of growth factor receptors. BAY 43-9006 is a potent inhibitor of c-raf, and wild-type and mutant b-raf in vitro. Additionally, further characterization of BAY 43-9006 tosylate revealed that this agent inhibits several receptor tyrosine kinases that are involved in tumor progression and p38a, a member of the MAPK family. Bay 43-9006 has been evaluated in multiple Phase I and Phase II studies in a variety of tumor types. To date, over 500 patients have been treated with single agent BAY 43-9006. BAY 43-9006 will be administered orally BID for 4 consecutive weeks. The 28-day period will represent one treatment cycle. The starting dose will be 200 mg BID. Patients will be stratified according to the use of cytochrome P450-inducing anticonvulsants in this study. Three patients per cohort in each arm of the study (3 from Group A and 3 from Group B) will be treated at the starting dose of 200 mg BID x 4 weeks until tumor progression. The dose will be escalatedin a stepwise fashion with an expansion to a total of 6 patients at the putative MTD.
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