title: Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program.
abstract: BACKGROUND
  IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models.
  
  
  METHODS
  IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement" measure, and (2) a linear regression model for time-to-event to formally evaluate for sub- and supra-additivity for the combination compared to the agents used alone.
  
  
  RESULTS
  Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met.
  
  
  CONCLUSIONS
  The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective.
authors.affiliation: A.I. duPont Hospital for Children, Nemours Center for Childhood Cancer Research, Wilmington, Delaware 19803, USA. eakolb@nemours.org
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Amy W
authors.initials: AW
authors.lastname: Wozniak
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C557414:cixutumumab; D017526:Receptor, IGF Type 1; D020123:Sirolimus