A First-in-Human Phase I Study of the ATP-Competitive Akt Inhibitor Ipatasertib (GDC-0068) Demonstrates Robust and Safe Targeting of Akt in Patients with Solid Tumors.

Activation of Akt signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers but targeting Akt has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of Akt. Ipatasertib (GDC‑0068) is a novel selective ATP-competitive small molecule inhibitor of Akt that preferentially targets active phosphorylated Akt and is potent in cell lines with evidence of Akt activation. In this Phase I study, ipatasertib was well-tolerated; most adverse events were gastrointestinal and Grade 1-2 in severity. The exposures of ipatasertib ≥ 200 mg QD in patients correlated with preclinical TGI90, and pharmacodynamic studies confirmed that multiple targets (i.e., PRAS40, GSK3β, and mTOR) were inhibited in paired on-treatment biopsies. Preliminary antitumor activity was observed; 16 of 52 patients (30%), with diverse solid tumors and who progressed on prior therapies, had radiographic stable disease, and many of their tumors had activation of Akt.