Background: mTOR 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. Methods: Escalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21-day cycles. IRN (50mg/m2/dose escalated to a maximum of 90mg/m2/dose) and TMZ (100mg/m2/dose escalated to a maximum of 150mg/m2/dose) were administered orally (PO) on days 1-5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly. Results: Seventy-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 35mg/m2 IV weekly, with IRN 90mg/m2 and TMZ 125mg/m2 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. Conclusion: The combination of TEM (35mg/m2/dose IV weekly), IRN (90mg/m2/dose days 1-5) and TMZ (125mg/m2/dose days 1-5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing. Pediatr Blood Cancer 2014;61:833-839.
- Phase 1
- Solid tumors