BACKGROUND: Steroid induced toxicities adversely affect the quality of life of children treated with brain tumors. Side effects include; mood changes, myopathy, weight gain, fluid retention, hypertension, moon faces, acne, etc. Alternatives to control peritumoral edema are needed. METHODS: Eligible patients included Pediatric patients less than 18 years of age on chronic corticosteroids who failed attempts to wean. A two part trial consisting of a Phase I dose escalation phase followed by a long-term (26 week) maintenance phase was undertaken. Patients were initially enrolled at a dose of 10 ug/kg divided BID, and in the absence of DLTs, were escalated to 20 ug/kg/day, 30 ug/kg/day, 40 ug/ kg/day and 60ug/kg/day of Xereceptw. If no DLT's were observed in cohorts of 3 subjects, subsequent patients were started at the next highest dose level with a plan to assess twelve patients at the highest tolerated dose. The study was designed to evaluate: toxicities of Xerecept, dexamethasone dose reduction, changes in steroid induced side effects and HRQoL. Dexamethasone dose reduction was allowed beginning after 7 days of Xerecept. RESULTS: 15 subjects were enrolled, 14 evaluable patients with recurrent DIPG(8), HGG (4) and ependymoma (2) received Xerecept. No patients experienced a DLT. All evaluable patients were able able to reduce dexamethasone. From a mean starting dose of 5.4 mg/day to a minimal dose of 1 mg/day in 87.5% of patients on treatment for at least 6 weeks. 4 patients weaned off completely despite progressive disease. QOL analysis revealed significant improvements in physical functioning, emotional functioning, and improvements in sleep/rest and fatigue scores for all evaluable patients at week 18. CONCLUSIONS: Xerecept at 60 ug/kg/day is safe and well tolerated. Even in this poor prognosis population, significant dose reduction of corticosteroids can occur with Xerecept. Patient QOL improved as evident by changes in emotional, physical and fatigue scores. Future efficacy trials with Xerecept are warranted, a Phase II/III trial is planned. SECONDARY CATEGORY: Pediatrics.