Background: Inhibitors of mTOR have demonstrated activity in preclinical pediatric solid tumor models. A phase I trial to define the dose limiting toxicities (DLTs) associated with the mTOR inhibitor TEM in combination with IRN and TMZ was conducted in patients (pts) with refractory solid tumors. Methods: Escalating doses of TEM were administered intravenously on days (d) 1 and 8 of a 21-d cycle for a maximum of 1 year (y). IRN (50 mg/m²/dose) was administered orally on d1-5. TMZ (100 mg/m²/dose) was administered orally on d1-5. When the maximum planned dose of TEM was reached (35 mg/m²/dose), IRN was escalated stepwise from 50 to 90 mg/m²/dose. Pts were enrolled on 6 dose levels using the rolling-six design. Results: 46 eligible pts (30 male, median age 11y, range 1 – 21) were enrolled; 37 were fully evaluable for toxicity [neuroblastoma (9), osteosarcoma (4), Ewing sarcoma (3), rhabdomyosarcoma (3), CNS (10) or other (8) tumors]. 173 cycles, median 2 (range 1 – 17) have been delivered. Dose-limiting hyperlipidemia was observed during cycle 1 in 2 pts at dose level 3 (TEM 25 mg/m², IRN 50 mg/m², TMZ 100 mg/m²); both pts were on chronic corticosteroids. The protocol was amended to preclude chronic systemic steroid use and modify hyperlipidemia management. Dose-limiting hyperlipidemia was not observed in subsequent pts. Cycle 1 DLT (elevated GGT) was observed in 1 pt treated with TEM 35 mg/m², IRN 65 mg/m², TMZ 100 mg/m². DLT has not been observed in 4 of the first 6 pts treated at the highest planned dose level (TEM 35 mg/m², IRN 90 mg/m², TMZ 100 mg/m²). Additional ≥Grade 3 regimen-related toxicities occurring in >1 evaluable pt include neutropenia (12), lymphopenia (10), leukopenia (6), thrombocytopenia (4), anemia (2), nausea or vomiting (5), hypokalemia (4), hypophosphatemia (2), diarrhea (2), elevated transaminases (2), and infection (2). 1 pt had a Grade 3 allergic reaction to TEM. 1 pt had a confirmed partial response and 4 have remained on protocol therapy for ≥1 year. Conclusions: The combination of TEM (35 mg/m²/dose) d 1 and 8, IRN (90 mg/m²/dose) d 1-5, and TMZ (100 mg/m²/dose) d 1-5 of a 21-d cycle appears to be well tolerated in children with refractory solid tumors.