Abstract C57: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of AZD8055 an inhibitor of mTOR Kinase

Abstract

Abstract Background: The serine/threonine kinase mTOR in the mTORC1 complex plays an important role in regulating cap-dependent translation and in the mTORC2 complex is required to fully activate Akt signaling. AZD8055 is a small molecule being evaluated in phase 1 clinical trials that selectively inhibits mTOR kinase in both complexes. The activity of AZD8055 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. AZD8055 was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 µM to determine the IC50 (concentration at which T/C% = 50%) and the minimum T/C%, and it was tested against the PPTP in vivo panel at a dose of 20 mg/kg daily by oral gavage for 4 consecutive weeks. 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: AZD8055 potently inhibited growth of the PPTP cell lines with a median IC50 value for the in vitro panel of 31.7 nM (range 2.6 nM to > 10 µM) and a minimum T/C% value of 6.2% (range 0.1% to 62.3%). AZD8055 was well tolerated in vivo (4.3% lethality), with only 3 of 45 tested xenograft models considered non-evaluable because of toxicity. AZD8055 induced significant differences in EFS distribution compared to control in 23 of 36 (64%) of the solid tumor xenografts and in 1 of 6 (17%) of the ALL xenografts. Criteria for intermediate activity for the time to event activity measure (i.e., EFS T/C > 2) were met in 5 of 32 (16%) solid tumor xenografts evaluable for this measure and were observed in the rhabdomyosarcoma panel (3 of 6) and Ewing sarcoma panel (2 of 5). Tumor regression was not observed at the 20 mg/kg daily dose, with the best response being stable disease, which was observed in 2 of 36 (5.6%) evaluable solid tumor xenografts. PD2 (progressive disease with growth delay) was observed in 20 of 36 (55.6%) evaluable solid tumor xenografts, including 4 of 5 Ewing sarcoma and 4 of 6 rhabdomyosarcoma xenografts. Conclusions: The activity observed for AZD8055 against the PPTP preclinical models is modest, although a subset of PPTP xenografts in the rhabdomyosarcoma and Ewing sarcoma panels showed greater tumor growth inhibition compared to other solid tumor xenografts. Future studies will focus on defining how the pharmacokinetics and the pharmacodynamic effects of AZD8055 relate to tumor sensitivity and on evaluating combinations of AZD8055 with standard cytotoxic agents. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C57.