PBTC-005: TEMOZOLOMIDE & O6-BENZYLGUANINE IN CHILDREN WITH BRAIN TUMORS

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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. Temozolomide has been shown to produce responses in patients with high-grade gliomas. This study will provide the ability for physicians to characterize the pharmacokinetics of temozolomide and O6-benzylguanine (O6-BG) when used in combination, allowing the characterization of toxicities associated with the combination of these two drugs with and without G-CSF support. This foundation will provide guidelines for determining the maximum tolerated dose of temozolomide (Temodar) when administered with O6-BG, with and without G-CSF support to pediatric patients with refractory brain tumors stratified by previous radiotherapy. The combination of O6-BG and temozolomide should increase the therapeutic index of temozolomide based on in vitro and in vivo data with the combination of O6-BG and nitrosoureas. However, the optimal schedule for using O6-BG and temozolomide in combination is unknown. The proposed study with adapted schedule builds on a recently concluded Phase I adult study in patients with recurrent malignant gliomas. Study subjects will be given a single dose of temozolomide six hours after the start of a 48-hour O6-BG infusion. The dose will be escalated according to study design until the maximally tolerated dose has been reached. The maximum tolerated dose (MTD) will be determined using statistical software CRM. A minimum of eighteen patients on each of strata 1a and 2a will be studied and the trial will continue until the current recommended dose has at least six patients assigned to it and the final recommend dose is the estimated MTD. Anti-tumor response will be documented in patients treated with the combination drugs. The investigators will evaluate the possible correlation between levels of MGMT enzyme and mismatch repair (MMR) proteins in tumor tissue, and patient outcomes.