Abstract 5265: Pediatric preclinical testing program (PPTP) stage 1 evaluation of BMS-754807 IGF-1 receptor inhibitor

Abstract

Abstract Background: Signaling through the type-1 insulin-like growth factor receptor (IGF-1R) is involved in autocrine or paracrine growth of many tumor types including childhood malignancies, and provides a strong anti-apoptotic signal that induces resistance to many forms of cellular stress. BMS-754807 is a potent inhibitor of IGF-1R and the insulin receptor that has entered phase 1 clinical trials. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing common types of childhood solid tumors and ALL. BMS-754807 was tested against the PPTP in vitro panel at concentrations from 1.0 nM to 10 μM and results were compared to those obtained with the anti-IGF-1R antibody mAb391 (50 μg/ml). In vivo testing used a dose of 25 mg/kg BID administered daily × 6 × 6 weeks by oral gavage. In vivo antitumor activity was primarily assessed by using response criteria modeled after the clinical setting and by using a time to event 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: The median EC50 for BMS-754807 against the in vitro panel was 0.62 μM (range, 0.07 - 4.96 μM). The median BMS-754807 EC50 value for the 5 cell lines with the greatest response to mAb391 was 0.12 μM compared to 1.1 μM for the 11 cell lines with the least response to mAb391 (p=0.0009). These results are consistent with a specific IGF-1R effect that has half-maximal response in the 0.1 μM range and with a non-IGF-1R effect that shows half-maximal response at approximately 1 μM. The mortality rate among treated mice was 6.5%, and 39 of 45 xenograft models were evaluable for efficacy. BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied. Criteria for intermediate activity for the time to event activity measure (EFS T/C > 2) were met in 7 of 27 solid tumor xenografts and were most commonly observed in the neuroblastoma (3 of 6) and rhabdomyosarcoma (2 of 6) panels. Objective responses (i.e., tumor regression) were not observed for any xenografts. The best response was PD2 (progressive disease with growth delay), which was observed in two or more xenografts in the rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing, and Wilms tumor panels. Conclusions: BMS-754807 showed broad tumor growth inhibition activity against the PPTP in vivo preclinical models. Future studies will focus on defining how pharmacokinetic and pharmacodynamic effects of BMS-754807 relate to tumor sensitivity and to evaluating combinations of BMS-754807 with standard cytotoxic agents. (Supported by NCI NO1CM42216) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5265.