Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors. Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients. There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL x h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs 200 ng/mL x h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed. Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.