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. This protocol is comprised of a dose-finding Phase I study, a Molecular Biology study and a Phase II study. The Phase I component of this protocol has two aims: (i) To estimate the maximum tolerated dose (MTD) and to describe the dose limiting toxicities (DLTs) of oral lapatinib (GW572016) administered twice daily for 28 consecutive days to children with recurrent or refractory malignant CNS tumors in two strata: a) Stratum 1: those who are not receiving steroids and b) Stratum 2: those who are receiving steroids; (ii) To characterize the effect of steroids on the lapatinib (GW572016) disposition in children. Lapatinib (GW572016) will be administered twice daily for 28 days at a starting dose of 300 mg/m 2/dose bid (~80% of the adult MTD). This defines one course of therapy. After the MTD is estimated in stratum 1, the molecular biology component of the study will commence concurrently with the phase II component of the study. The molecular biology study is designed to assess whether lapatinib (GW572016) administered at the MTD inhibits intratumoral ERBB receptor signaling. This question will be studied in children with recurrent or refractory medulloblastoma/PNET, high grade glioma or ependymoma who are undergoing a surgical resection of their tumor. The phase II trial will be conducted in children with recurrent or refractory medulloblastoma, malignant glioma or ependymoma who have measurable residual disease after the MTD is determined. Efficacy will be assessed independently in each of these histologically defined strata of patients. Patients with measurable residual disease enrolled on either the phase I trial and treated at the MTD or on the molecular biology trial will also be included in the phase II trial.
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