First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors Timothy A. Yap, Li Yan, Amita Patnaik, Ivy Fearen, David Olmos, Kyriakos Papadopoulos, Richard D. Baird, Liliana Delgado, Adekemi Taylor, Lisa Lupinacci, Ruth Riisnaes, Lorna L. Pope, Simon P. Heaton, George Thomas, Michelle D. Garrett, Daniel M. Sullivan, Johann S. de Bono, and Anthony W. Tolcher See accompanying article doi: 10.1200/JCO.2011.37.4751 Author affiliations appear at the end of this article. Submitted March 4, 2011; accepted August 3, 2011; published online ahead of print at www.jco.org on October 24, 2011. Supported by Merck. The Drug Develop- ment Unit, Royal Marsden National Health Service (NHS) Foundation Trust, and The Institute of Cancer Research supported in part by a program grant from Cancer Research UK. Also supported by Experi- mental Cancer Medicine Centre (to The Institute of Cancer Research) and National Institute for Health Research Biomedical Research Centre (jointly to the Royal Mars- den NHS Foundation Trust and The Insti- tute of Cancer Research). Presented in part at the 45th Annual Meet- ing of the American Society of Clinical Oncology (ASCO), May 29-June 2, 2009, Orlando, FL; 2009 Annual Meeting of the American Association for Cancer Research–National Cancer Institute (NCI)– European Organisation for the Research and Treatment of Cancer (EORTC), November 15-19, 2009, Boston, MA; 101st Annual Meeting of the American Associa- tion for Cancer Research, April 17-21, 2010, Washington, DC; 46th Annual Meet- ing of ASCO, June 4-8, 2010, Chicago, IL; and ASCO-NCI-EORTC Annual Meeting on Molecular Markers in Cancer, October 18-20, 2010, Hollywood, FL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Johann S. de Bono, MB, ChB, FRCP, MSc, PhD, Professor of Experimental Cancer Medi- cine, Drug Development Unit, Royal Marsden NHS Foundation Trust, Divi- sion of Clinical Studies, The Institute of Cancer Research, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: johann.de-bono@icr.ac.uk. © 2011 by American Society of Clinical Oncology 0732-183X/11/2999-1/$20.00 DOI: 10.1200/JCO.2011.35.5263 A B S T R A C T Purpose AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacoki- netics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy. Patients and Methods Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss. Results Thirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approxi- mately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses. Conclusion MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy. J Clin Oncol 29. © 2011 by American Society of Clinical Oncology INTRODUCTION AKT, also known as protein kinase B (PKB), is a serine-threonine kinase that comprises a family of three different protein isoforms: AKT1, AKT2, and AKT3. 1 AKT is a key regulator of phosphatidyli- nositide 3-kinase (PI3K) –AKT–mammalian target of rapamycin (mTOR) signaling, with PI3K- dependent activation resulting in increased cellular survival, proliferation, growth, and metabolism. 1 Hyperactivation of this pathway is an important driver of malignant progression and chemoresis- tance and may occur through different mechanisms, including upstream stimulation by receptor tyrosine kinases, PIK3CA and AKT mutations or amplifica- tions, and loss of phosphatase and tensin ho- molog (PTEN) function. 1 In view of the key role of the PI3K-AKT-mTOR pathway in cancer, mul- tiple strategies have been developed in recent years to target critical components of this signal- ing cascade. 2,3 Several chemical classes of small-molecule AKT inhibitors with varying potencies and specific- ities for the different AKT isoforms have been devel- oped. 2,3 Adenosine triphosphate (ATP)– competitive AKT inhibitors have been reported to have a higher likelihood of off-target effects; therefore, allosteric AKT inhibitors have been designed in an attempt to JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T © 2011 by American Society of Clinical Oncology 1 http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.35.5263 The latest version is at Published Ahead of Print on October 24, 2011 as 10.1200/JCO.2011.35.5263 Copyright 2011 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on November 8, 2012. 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