Abstract C106: Pediatric Preclinical Testing Program (PPTP) Stage 1 evaluation of the PI3K inhibitor XL147 (SAR245408).

Abstract

Abstract Introduction: XL147 is a potent, orally bioavailable inhibitor of the class I PI3K family of lipid kinases with IC50 values in the nanomolar range in biochemical assays. XL147 inhibits phosphorylation of downstream effectors of PI3K in preclinical models as well as in surrogate tissues and tumors in adults with cancer. XL147 is under clinical evaluation for adults with cancer in combination with certain cytotoxic agents as well as with other cell signaling pathway inhibitors (e.g., the MEK inhibitor MSC1936369B). The activity of XL147 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical testing Program (PPTP). Methods: XL147 was tested against the PPTP's in vitro cell line panel at concentrations ranging from 10.0 nM to 100 μM using the PPTP's standard 96 hour exposure period. For in vivo testing, an XL147 dose of 100 mg/kg administered orally daily for 14 days with a total planned observation period of 6 weeks. Results: XL147 demonstrated cytotoxic activity, with Ymin values approaching 0% for all of the cell lines at the highest concentration tested (100 μM). The median relative IC50 value for the PPTP cell lines was 10.9 μM, with a range from 2.7 μM (CHLA-10) to 24.5 μM (TC-71). There were no significant differences by histotype in median relative IC50 values, though there was a trend for lower values for the rhabdomyosarcoma panel (median IC50 5.6 μM) and higher values for the neuroblastoma panel (median IC50 19.5 μM). XL147 was tested against 31 solid tumor xenografts and 7 acute lymphoblastic leukemia (ALL) xenografts. A dose of 100 mg/kg administered orally daily for 14 days for a total planned observation period of 6 weeks was utilized. XL147 was generally well tolerated, with a <1% toxicity rate in the treated groups, similar to that observed for control animals. XL147 induced significant differences in EFS distribution compared to control in 26 of 30 (87%) of the evaluable solid tumor xenografts and in 2 of 7 (29%) of the evaluable ALL xenografts. XL147 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 3 of 29 (10%) evaluable solid tumor xenografts (2 of 6 rhabdomyosarcoma and 1 of 5 neuroblastoma), and intermediate or high EFS T/C activity was observed for 2 of 7 (29%) evaluable ALL xenografts. Basal levels of activation of PI3K signaling, as assessed by phospho-AKT, levels did not correlate with in vivo response to XL147. Expression of PI3K isoforms at the RNA level was evaluated using Affymetrix U133 Plus 2.0 arrays, with the most striking observation being the pattern of expression of PIK3CD, which was virtually restricted to the ALL and lymphoma cell lines and xenografts, as would be expected from the hematopoietic cell specificity of this isoform in normal tissues. Conclusions: Under the conditions evaluated in this study, XL147 achieved modest single-agent activity against the PPTP preclinical models. Available data suggests that genomic activation of PI3K signaling (e.g., through PIK3CA mutation or PTEN deletion) is less common in the pediatric solid tumors setting compared to the adult cancer setting, which may explain the limited single agent activity. Preclinical evaluations of XL147 in combination with particular standard agents and with other pathway signaling inhibitors are planned. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C106.