title: 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.
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 (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.
  
  
  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 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Rochelle
authors.initials: R
authors.lastname: Bagatell
authors.forename: Robin
authors.initials: R
authors.lastname: Norris
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Ingle
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahern
authors.forename: Stephan
authors.initials: S
authors.lastname: Voss
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Little
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Susan
authors.initials: S
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D012074:Remission Induction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077204:Temozolomide; D055815:Young Adult
chemical_list: C401859:temsirolimus; D000077146:Irinotecan; D003606:Dacarbazine; D020123:Sirolimus; D002166:Camptothecin; D000077204:Temozolomide
keywords: phase 1; solid tumors; temsirolimus