Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: A children's oncology group study

Rochelle Bagatell, Robin Norris, Ashish M. Ingle, Charlotte Ahern, Stephan Voss, Elizabeth Fox, Anthony R. Little, Brenda J. Weigel, Peter C. Adamson, Susan Blaney

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)833-839
Number of pages7
JournalPediatric Blood and Cancer
Volume61
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Phase 1
  • Solid tumors
  • Temsirolimus

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