A phase I trial of MK-0752 in children with recurrent or refractory CNS malignancies: A Pediatric Brain Tumor Consortium study.

9502 Background: The NOTCH pathway plays a central role in normal neural stem cell regulation and maintenance. Recent data indicate that most brain tumors including gliomas, medulloblastoma, and ependymoma are maintained by rare fractions of stem cell-like cancer cells. NOTCH signaling is important in medulloblastoma pathogenesis; NOTCH amplification has been identified in a subgroup of posterior fossa ependymomas, and high-levels of NOTCH ligand expression (Delta 1, Jagged 1 and 2) have been identified in high-grade gliomas. MK-0752 is an orally active inhibitor of gamma secretase which inhibits the cleavage of Notch with an IC50 of 55 nM. A phase I trial of MK0752 was conducted in children with recurrent or refractory CNS malignancies to estimate the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). We also assessed expression of NOTCH and HES proteins in peripheral blood mononuclear cells (PBMCs) prior to and following treatment with MK-0752. Methods: MK0752 was a...