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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

Andreas Schneeweiss, Dagmar Hess, Markus Joerger, Andrea Varga, Stacy Moulder, Apostolia M Tsimberidou, Cynthia Ma, Sara A Hurvitz, Christine Rentzsch, Marion Rudolph, Silke Thiele, Oliver Boix, Gary Wilkinson, Eleni Lagkadinou & Matthias Ocker

abstract 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 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. 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.
   
citation Schneeweiss A, Hess D, Joerger M, Varga A, Moulder S, Tsimberidou A M, Ma C, Hurvitz S A, Rentzsch C, Rudolph M, Thiele S, Boix O, Wilkinson G, Lagkadinou E, Ocker M. 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. Cancers (Basel) 2019; 11:.
   
type journal paper/review (English)
date of publishing 10-12-2019
journal title Cancers (Basel) (11/12)
ISSN print 2072-6694
PubMed 31835495
DOI 10.3390/cancers11121987