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Ref Type Journal Article
PMID (31835495)
Authors Schneeweiss A, Hess D, Joerger M, Varga A, Moulder S, Tsimberidou AM, Ma C, Hurvitz SA, Rentzsch C, Rudolph M, Thiele S, Boix O, Wilkinson G, Lagkadinou E, Ocker M
Title Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer-Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy.
Journal Vol Issue Date Pages Journal Short Title
Cancers 11 12 2019 Dec 10 Cancers (Basel)
URL
Abstract Text This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the AKT1E17K mutation, was performed at the recommended phase 2 dose (R2D) of 60 mg BID. Dose-limiting toxicities (Grades 3-4) were increased in transaminases, γ-glutamyltransferase (γ-GT), and alkaline phosphatase in four patients in both schedules and stomach pain in one patient. Of the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. AKT1E17K mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BAY1125976 BAY1125976 9 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
BAY1125976 BAY 1125976|BAY-1125976 Akt1 Inhibitor 6 Akt2 Inhibitor 2 BAY1125976 inhibits the activity of AKT1/2, which may result in reduced tumor cell proliferation and decreased growth of tumors with activated PI3K/AKT/mTOR signaling (PMID: 27699769, PMID: 31835495).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References