A first-in-human phase I study of the ATP-competitive AKT inhibitor Ipatasertib demonstrates Robust and safe targeting of AKT in patients with solid tumors

Cristina Saura, Desamparados Roda, Susana Roselló, Mafalda Oliveira, Teresa Macarulla, José Alejandro Pérez-Fidalgo, Rafael Morales-Barrera, Juan Manuel Sanchis-García, Luna Musib, Nageshwar Budha, Jin Zhu, Michelle Nannini, Wai Y. Chan, Sandra M. Sanabria Bohórquez, Raymond D. Meng, Kui Lin, Yibing Yan, Premal Patel, José Baselga, Josep TaberneroAndrés Cervantes

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74 Citations (Scopus)

Abstract

© 2016 American Association for Cancer Research. Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been diffi cult 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 (pAKT) 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 daily in patients correlated with preclinical TGI90, and pharmacodynamic studies confi rmed 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.
Original languageEnglish
Pages (from-to)102-113
JournalCancer Discovery
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

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