A212

Background: SCH 717454 is a fully human antibody directed against the insulin-like growth factor 1 receptor (IGF-1R), which is implicated in the growth and metastatic phenotype of a broad range of malignancies. IGF-1R signaling may be of particular importance in the childhood cancer setting, with preclinical data supporting its role in the growth and survival of a number of pediatric cancers, including of neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, Wilms tumor, and osteosarcoma. The activity of SCH 717454 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP).
 Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. SCH 717454 was tested against the PPTP in vitro panel at concentrations ranging from 0.01nM to 100 nM and was tested against the PPTP in vivo panel at a dose of 0.5 mg per mouse administered twice weekly for four weeks via intraperitoneal injection. Three measures of antitumor activity were used: 1) response criteria modeled after the clinical setting; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (4-fold increase in tumor volume) measure based on the median EFS of treated and control lines (intermediate activity required EFS T/C > 2, and high activity additionally required a net reduction in median tumor volume at the end of the experiment).
 Results: SCH 717454 was ineffective at retarding growth of cell lines in the in vitro panel. SCH 717454 significantly increased event-free survival in 20 of 35 (57%) solid tumor xenograft models with tumor regressions in one Ewing sarcoma model (complete response) and 2 osteosarcoma models (maintained complete responses). Although objective responses were not noted in the neuroblastoma panel, tumor growth was well-controlled during the 4 weeks of SCH 717454 treatment for 3 of 6 evaluable neuroblastoma xenografts. Using the time to event activity measure, SCH 717454 had intermediate (n=9) or high (n=1) activity against 31 evaluable solid tumor xenografts, including xenografts from the rhabdoid tumor (1 of 3), Ewing (2 of 5), rhabdomyosarcoma (1 of 4), glioblastoma (1 of 4), ependymoma (1 of 1), neuroblastoma (2 of 5), and osteosarcoma panels (2 of 4). SCH 717454 showed little activity against the 8 xenografts of the acute lymphoblastic leukemia panel.
 Conclusions: SCH 717454 showed little in vitro activity against the PPTP’s in vitro panel, which may be related to the use of 20% fetal bovine serum and insulin in the growth media used for testing. SCH 717454 demonstrated broad antitumor activity against the PPTP’s in vivo solid tumor panels. Further characterization of the molecular predictors of response and of the activity of combinations of SCH 717454 with other anticancer agents are anticipated. (Supported by NCI NO1CM42216)

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA