First-in-human, first-in-class phase 1 study of a novel oral multi-AGC kinase inhibitor AT13148 in patients (pts) with advanced solid tumors.

2554 Background: Aberrant signaling through the AGC kinases is implicated as a critical driver of multiple cancers. AT13148 is a novel multi-AGC kinase inhibitor, which potently inhibits AKT, P70S6K, PKA and ROCKI/II. Following promising in vivoantitumor activity through mechanisms distinct from specific AKT inhibitors, a phase I trial was initiated. Methods: Pts with advanced solid tumors were enrolled onto study using a standard 3+3 dose escalation strategy. AT13148 was given orally on days (D) 1, 3 and 5 of every week, in 28-day cycles. The starting dose was 5mg, with a 4-week dose limiting toxicity (DLT) period. Pharmacokinetic (PK) parameters were assessed after a run-in dose (D1-7) and at cycle (C)2 D1. Pharmacodynamic (PD) biomarkers for AKT signaling were analyzed in tumor, platelet rich plasma (PRP) and hair follicles at multiple timepoints. Results: 14 pts were treated with AT13148 (7M: 7F; 4 ECOG 0, 10 ECOG 1). Median age 57y. Median duration of treatment was 40 days (range 25-76). AT13148 was ...