| First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors. | |
| | |
MedLine Citation:
|
PMID: 22025163 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
PURPOSEAKT 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), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy. PATIENTS AND METHODSPatients 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.ResultsThirty-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 approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses. CONCLUSIONMK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy. |
| | |
Authors:
|
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; Anthony W Tolcher |
Related Documents
:
|
9518263 - Effects of conformationally restricted synthetic retinoids on ovarian tumor cell growth. 7558443 - Malignant transformation of human fibroblast strain msu-1.1 by v-fes requires an additi... 280183 - Temperature-dependent growth and regression of epidermal tumors in the european eel (an... |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2011-10-24 |
Journal Detail:
|
Title: Journal of clinical oncology : official journal of the American Society of Clinical Oncology Volume: - ISSN: 1527-7755 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
|
Created Date: 2011-10-25 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 8309333 Medline TA: J Clin Oncol Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
|
Timothy A. Yap, David Olmos, Richard D. Baird, and Johann S. de Bono, Royal Marsden National Health Service Foundation Trust; Timothy A. Yap, David Olmos, Ruth Riisnaes, Lorna L. Pope, Simon P. Heaton, George Thomas, and Michelle D. Garrett, The Institute of Cancer Research, Sutton, Surrey, United Kingdom; Li Yan, Ivy Fearen, Liliana Delgado, Adekemi Taylor, and Lisa Lupinacci, Merck, North Wales, PA; Amita Patnaik, Kyriakos Papadopoulos, and Anthony W. Tolcher, South Texas Accelerated Research Therapeutics, San Antonio, TX; and Daniel M. Sullivan, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody t...
Next Document: Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival.