TY - JOUR
T1 - Phase I study of everolimus in pediatric patients with refractory solid tumors
AU - Fouladi, Maryam
AU - Laningham, Fred
AU - Wu, Jianrong
AU - O'Shaughnessy, Melinda A.
AU - Molina, Kristen
AU - Broniscer, Alberto
AU - Spunt, Sheri L.
AU - Luckett, Inga
AU - Stewart, Clinton F.
AU - Houghton, Peter J.
AU - Gilbertson, Richard J.
AU - Furman, Wayne L.
PY - 2007/10/20
Y1 - 2007/10/20
N2 - Purpose: 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. Patients and Methods: 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. Results: 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·h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs ≥ 200 ng/mL·h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed. Conclusion: 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.
AB - Purpose: 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. Patients and Methods: 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. Results: 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·h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs ≥ 200 ng/mL·h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed. Conclusion: 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.
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U2 - 10.1200/JCO.2007.11.4017
DO - 10.1200/JCO.2007.11.4017
M3 - Article
C2 - 17947729
AN - SCOPUS:36049023679
SN - 0732-183X
VL - 25
SP - 4806
EP - 4812
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 30
ER -
