title: A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report.
abstract: OBJECTIVE
  To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors.
  
  
  METHODS
  Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle.
  
  
  RESULTS
  Thirty-nine patients, median age 11.8 years (range, 1-21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m(2); (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m(2); (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m(2); and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m(2). Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m(2), the median temsirolimus AUC was 2,946 ng • h/mL (range, 937-5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245-3,675).
  
  
  CONCLUSIONS
  The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m(2), respectively.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. maryam.fouladi@cchmc.org.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: John P
authors.initials: JP
authors.lastname: Perentesis
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Wagner
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.affiliation: Children's Oncology Group Operations Center, Arcadia, California.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahern
authors.affiliation: University of Cincinnati, Cincinnati, Ohio.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: University of Cincinnati, Cincinnati, Ohio.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mercer
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Darcy A
authors.initials: DA
authors.lastname: Krueger
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.affiliation: Texas Children's Cancer Center/Baylor College of Medicine, Houston, Texas.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C557414:cixutumumab; C401859:temsirolimus; D020123:Sirolimus