This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT: MK-0752 will be administered orally for 3 consecutive days of every 7 days for 28 days to children with recurrent or refractory central nervous system (CNS) malignancies. The starting dose is 200 mg/m2/day and inter-patient dose escalation or reduction will occur in set increments (to an estimated maximum of 400mg/m2/day). At the recommended MTD, we will treat a minimum of 6 evaluable patients who are 12 years of age. Although the dose escalation will be based on toxicities observed during the first course, any grade 3/4 toxicities that occur after the first course will be documented and may warrant a review of the treatment regimen. Therapy may continue for 6 courses. If patients are deriving benefit from the therapy and have at least clinical and radiographic stable disease at the end of course 6, patients may continue therapy for an additional 13 courses (for a total of 19 courses) with the prior approval of the study Chair and representatives from Merck and Co. I. HYPOTHESIS MK-0752 will have anti-tumor activity in children and adolescents with refractory primary CNS tumors. II.
SPECIFIC AIMS PRIMARY OBJECTIVES To estimate the MTD and recommend a Phase II dose of MK-0752 administered for 3 consecutive days of every 7 days for 28 days to children with recurrent or refractory central nervous system (CNS) malignancies. SECONDARY OBJECTIVES To characterize the pharmacokinetics of MK-0752 administered on this schedule. To document and describe toxicities associated with MK-0752 administrated on this schedule. To preliminarily define the antitumor activity of MK-0752 within the confines of a Phase I setting. To explore the incidence of NOTCH receptor and ligand expression and pathway activation in recurrent or refractory CNS tumor samples. To estimate the fraction of cancer stem cells and their association with the tumor vasculature in recurrent or refractory CNS tumor samples. To explore changes in correlative magnetic resonance imaging in children receiving MK-0752. Volumetric MR imaging findings may be combined across similar PBTC protocols to increase the power for detecting correlations among scans and associations with outcome. To explore the pharmacogenetic polymorphisms in MK-0752 metabolizing enzymes and relate these polymorphisms to MK-0752 pharmacokinetics. To explore the pharmacodynamic relationships between NOTCH-cleaved forms and NOTCH pathway target genes and MK-0752 pharmacokinetics.
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