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.A phase II study of bevacizumab in combination with irinotecan will be performed in children with recurrent malignant glioma and diffuse brain stem gliomas. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously on day 1 and day 15 followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of begacizumab to assess whether there is reduction in permeability since VEGF mediates tumor angiogenesis and vascular permeability and bevacizumab directly inhibits VEGF. The first dose of irinotecan will be given intravenously following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m^2 every two weeks for those on EIACDS. If the patient is not on an EIACD, the starting dose will be 125 mg/m^2. These doses are routinely used with irinotecan is administered as a single-agent for malignant glioma in adults and children. Treatment will continue on study until tumor progression, unacceptable toxicity, or for a maximum if two years. Standard MRI scan of brain +/- spine, rapid perfusion and diffusion MRI, and FDG-PET scans prior to treatment and at periodic intervals will be obtained to study the effects of bevacizumab + irinotecan in these tumors. In addition, biology correlates will be studied including serum pharmacokinetics of bevacizumab and the expression of vacular endothelial growth factor receptor-2 on peripheral blood mononuclear cells and the effect of bevacizumab on VEGF-R2 phosphorylation. The latter would be correlated with tumor responses and MR perfusion changes in tumor following bevacizumab therapy.
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