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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

1
National Center for Tumor Diseases, University Hospital Heidelberg and German Cancer Research Center, 69120 Heidelberg, Germany
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Kantonsspital St. Gallen, 9001 St. Gallen, Switzerland
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Institut Gustave Roussy, 94800 Villejuif, France
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MD Anderson Cancer Center, Houston, TX 77030, USA
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Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
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Bayer AG, 13353 Berlin, Germany
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(12), 1987; https://doi.org/10.3390/cancers11121987
Received: 25 November 2019 / Revised: 5 December 2019 / Accepted: 7 December 2019 / Published: 10 December 2019
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. View Full-Text
Keywords: AKT inhibitor; biomarker; breast cancer; pharmacokinetics; phase 1 AKT inhibitor; biomarker; breast cancer; pharmacokinetics; phase 1
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MDPI and ACS Style

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 2019, 11, 1987. https://doi.org/10.3390/cancers11121987

AMA Style

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. 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. 2019; 11(12):1987. https://doi.org/10.3390/cancers11121987

Chicago/Turabian Style

Schneeweiss, Andreas, 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, and Matthias Ocker. 2019. "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 11, no. 12: 1987. https://doi.org/10.3390/cancers11121987

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