Cancer Therapy : Clinical The Safety , Tolerability , Pharmacokinetics , and Pharmacodynamics of Single Oral Doses of CH 4987655 in Healthy Volunteers : Target Suppression Using a Biomarker

Purpose:CH4987655 (RO4987655) is an orally active and highly selective small-molecule MEK inhibitor. It potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC50 of 5.2 nmol/L for inhibition of MEK1/2. Single-agent oral administration of CH4987655 resulted in complete tumor regressions in xenograft models. Experimental Design: All 40 subjects received a single oral dose followed by 72 hrs of pharmacokinetic, pharmacodynamic, and safety/tolerability assessments. The pharmacodynamics were measured by changes in phosphorylated extracellular signalregulated kinase (pERK) levels in a surrogate tissue peripheral blood mononuclear cells ex vivo stimulated by PMA. Results: Doses of 0.5, 1, 2, 3, and 4 mg were safe and well tolerated. No clinically significant safety event was observed. A total of 26 adverse events (n = 15) were reported: 21 mild, 5 moderate, and none severe. Moderate adverse events were experienced by one subject at 1 mg (autonomic nervous system imbalance) and three subjects at 4 mg (diarrhea, abdominal pain, autonomic nervous system and acne). CH4987655 was rapidly absorbed with a tmax of ∼1 h. Exposures were dose proportional from 0.5 to 4 mg. The disposition was biphasic with a terminal t1/2 of ∼25 hr. Intersubject variability was low, 9% to 23% for Cmax and 14% to 25% for area-under-the-curve (AUC). pERK inhibition was exposure dependent and was greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship was characterized by an inhibitory Emax model (Emax ∼100%; IC50 40.6 ng/mL) using nonlinear mixed-effect modeling. Conclusions: A significant extent of pERK inhibition was achieved for a single dose that was considered to be safe and well tolerated in healthy volunteers. (Clin Cancer Res 2009;15(23):7368–74) The Ras/Raf/MEK/ERK [mitogen-activated protein kinase (MAPK)] pathway represents one of the best-characterized signaling pathways involved in the development and progression of human cancers. This pathway, through the Ras/Raf/MEK/ERK signal cascade, is responsible for transmitting and amplifying mitogenic signals from the cell surface to the nucleus where activated transcription factors regulate gene expression and determine cell fate. The constitutive activation of this pathway is sufficient to induce cellular transformation. Deregulation of the MAPK pathway, due to aberrant receptor tyrosine kinase activation and Ras and/or B-Raf mutations (frequently found in human cancers), represents a major factor in determining abnormal cell growth control (1). Oncogenic Ras mutations can be found in ∼30% of all human cancers. The highest incidences Authors' Affiliations: Clinical Pharmacology, Discovery Oncology, Clinical Drug Safety, Modelling and Simulation, Drug Metabolism and Pharmacokinetics, Hoffman-La Roche, Nutley, New Jersey, Roche Diagnostics GmbH, Penzberg, Germany; Clinical Pharmacology and Clinical Research and Early Development, Chugai Pharmaceuticals, Tokyo, Japan; Preclinical Pharmacokinetic-Pharmacodynamics, Chugai Pharmaceut ica ls , Kamakura , Japan; Drug Metabol ism and Pharmacokinetics, Chugai Pharmaceuticals, Gotemba, Japan; Clinical Pharmacology, Roche Products Ltd., and Clinical Research and Early Development, Hoffman-La Roche, Welwyn, United Kingdom, Clinical Research and Early Development, Hoffman-La Roche, Basel, Switzerland; HistoGeneX, Antwerp, Belgium; and Institute of Translational and Experimental Medicine, Hoffman-La Roche, Strasbourg, France Received7/1/09; revised8/11/09; accepted8/17/09; publishedOnlineFirst 11/24/09. The costs of publicationof this articlewere defrayed inpart by thepayment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Lucy Lee, Clinical Pharmacology, Hoffman-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110. Phone: 973-6150177; Fax: 9732353377; E-mail: lucy.lee@roche.com. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1696 7368 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals.org Research. on July 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-09-1696