Abstract 34: A phase I study of a p70S6 kinase inhibitor (LY2584702) in patients (pts) with solid tumors.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: LY2584702 is an inhibitor of p70S6 kinase, a downstream effector of the AKT pathway which is activated in multiple tumor types. Suppressing p70S6 kinase activity is expected to inhibit cell growth, cell proliferation, and possibly cell death. A phase 1 study was conducted to evaluate the safety and tolerability of LY2584702 in Japanese pts with solid tumors. Methods: Patients received a single oral dose of LY2584702 on Day1, followed by the same doses given twice daily (BID) from Day3 to Day30 (Cycle 1), and were evaluated for occurrence of dose limiting toxicity (DLT). Other measurements included safety, pharmacokinetics, pharmacodynamics (PD biomarkers) and efficacy. The first 3 pts were assigned to 50 mg BID LY2584702, and the following 6 pts assigned to 75 mg BID. Study treatment was repeated until progressive disease or intolerable toxicity occurred. Results: Cancer types included colon, gastric and esophagus cancers. All pts in the trial completed Cycle 1 without showing DLT. There were no serious adverse events or discontinuations due to adverse events during the study. Adverse events of Grade 3 were observed in 2 pts receiving 50 mg BID LY2584702: one with increased alkaline phosphatase, and another with increased bilirubin. Of these 9 pts, 5 had aPTT elongation and 4 had PT/INR elongation. After a single dose, the PK parameters showed relatively high variability; tmax, t1/2, and apparent clearance ranged from 5 to 8 h, 14.7 to 28.1 h, and 5.18 to 7.79 L/h, respectively. Accumulation ratio of exposure ranged from 1.41 to 2.07. While PD biomarkers (pS6RP, pAKT, and pPRAS40) showed no meaningful findings, a pattern in the kinetics of these biomarkers was observed after LY2584702 exposure; there was a reduction in the level of expression of pS6 positive cells from the entire epidermis, and 3 PD biomarkers in PBMCs showed the same kinetic pattern with consistent down-regulation. No complete or partial responses were observed, but 2 pts (colon and esophagus cancers) exhibited long-term stable disease (one for 183 days; the other 137 days). Conclusion: No remarkable safety concern was revealed during the phase 1 study of LY2584702 in Japanese solid tumor pts. Despite a limited number of pts and high variability, Cmax and AUC in this study were generally consistent with those in a previous US phase 1 study. Coagulation response was down-regulated after LY2584702 exposure, which would have opposite effects of everolimus. In addition, since a pattern of kinetics of PD biomarkers was observed in both PBMCs and skin biopsies after LY2584702 exposure, our PD marker analysis may encourage their future potential as biomarker candidates for PI3K-Akt pathway. Citation Format: Toshihiko Doi, Naoto Yoshizuka, Risa Sekiguchi, Risa Nasu, Akihiko Kido, Leslie H. Brail, Paul Matthew Westwood, Atsushi Ohtsu. A phase I study of a p70S6 kinase inhibitor (LY2584702) in patients (pts) with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 34. doi:10.1158/1538-7445.AM2013-34