title: Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Children's Oncology Group.
abstract: BACKGROUND
  The combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial.
  
  
  METHODS
  Cixutumumab 6 mg/kg and temsirolimus 8 mg/m(2) were administered intravenously once weekly in 4-week cycles to patients <30 years. Temsirolimus was escalated to 10 mg/m(2) for subsequent cycles in patients who did not experience unacceptable first-cycle toxicity. A two-stage design was used to identify a response rate <10 or >35% for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response.
  
  
  RESULTS
  Forty-three evaluable patients received a median of 2 cycles (range 1-7). No objective responses were observed, and 16% of patients were progression-free at 12 weeks. Dose-limiting toxicity was observed in 15 (16%) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers.
  
  
  CONCLUSIONS
  Despite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma.
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Wagner
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Atif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.forename: Brenda
authors.initials: B
authors.lastname: Weigel
authors.forename: Steven G
authors.initials: SG
authors.lastname: DuBois
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
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; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C557414:cixutumumab; C401859:temsirolimus; D020123:Sirolimus
keywords: Phase II; cixutumumab; pediatric sarcoma; temsirolimus