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

Maryam Fouladi, Fred Laningham, Jianrong Wu, Melinda A. O'Shaughnessy, Kristen Molina, Alberto Broniscer, Sheri L. Spunt, Inga Luckett, Clinton F. Stewart, Peter J. Houghton, Richard J. Gilbertson, Wayne L. Furman

From the Departments of Oncology, Radiological Sciences, Biostatistics, Developmental Neurobiology, Pharmaceutical Sciences, Pathology, and Molecular Pharmacology, St Jude Children's Research Hospital; and Department of Pediatrics, The University of Tennessee School of Medicine, Memphis, TN

Address reprint requests to Maryam Fouladi, MD, Department of Oncology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; e-mail: maryam.fouladi{at}stjude.org

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.

Supported by Grants No. P30 CA21765 and P01 CA23099 from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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