• Rochelle Bagatell, Robin Norris, Ashish M Ingle, Charlotte Ahern, Stephan Voss, Elizabeth Fox, Anthony R Little, Brenda J Weigel, Peter C Adamson, and Susan Blaney.
• The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
• Pediatr Blood Cancer. 2014 May 1; 61 (5): 833-9.

BackgroundmTOR inhibitors have activity in pediatric tumor models. A phase I trial of the mTOR inhibitor temsirolimus (TEM) with irinotecan (IRN) and temozolomide (TMZ) was conducted in children with recurrent/refractory solid tumors, including central nervous system (CNS) tumors.MethodsEscalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21-day cycles. IRN (50 mg/m(2)/dose escalated to a maximum of 90 mg/m(2)/dose) and TMZ (100 mg/m(2)/dose escalated to a maximum of 150 mg/m(2)/dose) were administered orally (PO) on days 1-5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly.ResultsSeventy-one eligible pts (median age 10.9 years, range 1.0-21.5) with neuroblastoma (16), osteosarcoma (7), Ewing sarcoma (7), rhabdomyosarcoma (4), CNS (22) or other (15) tumors were enrolled. Dose-limiting hyperlipidemia occurred in two patients receiving oral corticosteroids. The protocol was subsequently amended to preclude chronic steroid use. The MTD was identified as TEM 35 mg/m(2) IV weekly, with IRN 90 mg/m(2) and TMZ 125 mg/m(2) PO on days 1-5. At higher dose levels, elevated serum alanine aminotransferase and triglycerides, anorexia, and thrombocytopenia were dose limiting. Additional ≥ grade 3 regimen-related toxicities included leukopenia, neutropenia, lymphopenia, anemia, and nausea/vomiting. Six patients had objective responses confirmed by central review; three of these had sustained responses through ≥ 14 cycles of therapy.ConclusionThe combination of TEM (35 mg/m(2)/dose IV weekly), IRN (90 mg/m(2)/dose days 1-5) and TMZ (125 mg/m(2)/dose days 1-5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing.© 2013 Wiley Periodicals, Inc.

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