www.thelancet.com/oncology Vol 13 August 2012 773 Articles Lancet Oncol 2012; 13: 773–81 Published Online July 16, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70270-X See Articles page 782 See Comment page 744 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA (J R Infante MD, J C Bendell MD, H A Burris III MD); University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA (L A Fecher MD, K Flaherty MD); University of Texas MD Anderson Cancer Center, Houston, TX, USA (G S Falchook MD, Prof R Kurzrock MD); University of Colorado Cancer Center, Aurora, CO, USA (S Nallapareddy MD, G Eckhardt MD, W A Messersmith MD); Pinnacle Oncology Hematology, Scottsdale, AZ, USA (M S Gordon MD); Texas Oncology-Baylor Charles A Sammons Cancer Center, Dallas, TX, USA (C Becerra MD); GlaxoSmithKline, Oncology, Philadelphia, PA, USA (D J DeMarini PhD, D S Cox PhD, Y Xu MS, S R Morris MD, V G R Peddareddigari MD, N T Le MD); and Sarah Cannon Research Institute/Florida Cancer Specialists, Fort Myers, FL, USA (L Hart MD) Correspondence to: Dr Jeffrey R Infante, 250 25th Avenue, Suite 200, Nashville, TN 37203, USA jinfante@tnonc.com Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial Jeffrey R Infante, Leslie A Fecher, Gerald S Falchook, Sujatha Nallapareddy, Michael S Gordon, Carlos Becerra, Douglas J DeMarini, Donna S Cox, Yanmei Xu, Shannon R Morris, Vijay G R Peddareddigari, Ngocdiep T Le, Lowell Hart, Johanna C Bendell, Gail Eckhardt, Razelle Kurzrock, Keith Flaherty, Howard A Burris III, Wells A Messersmith Summary Background Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. Methods We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. Findings We enrolled 206 patients (median age 58·5 years, range 19–92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half- life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. Interpretation The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side- effects. Trametinib’s inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. Funding GlaxoSmithKline. Introduction The MAPK pathway incorporates the enzymes RAS, RAF, ERK, and MEK. In this pathway, membrane-bound receptors signal to proteins that regulate cell proliferation and survival. The MAPK pathway is constitutively activated in many tumour types, including those BRAF V600 mutations and some RAS mutations. 1–3 MEK has emerged as a key anticancer target because inhibition of this enzyme blocks cell proliferation and induces apoptosis. 4–7 Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 (also known as MAP2K1 and MAP2K2) activation and kinase activity, with a half-maximum inhibitory concentration (IC 50 ) of 0·7–0·9 nmol/L. 8 In enzymatic and cellular studies, trametinib inhibited kinase activity of MEK1 and MEK2, prevented RAF-dependent MEK phosphorylation, and prolonged inhibition of phosphorylated ERK (a substrate of MEK). 8 In-vitro studies undertaken in 94 different cancer cell lines showed cytotoxic responses in seven of ten BRAF V600 -mutant cells lines at nanomolar concentrations. 8 Cell lines and mouse xenograft models with activating mutations in RAS were also sensitive to trametinib. 6 Pharmacokinetic profiling in mice indicated a mean effective half life (t 1/2 ) of 33 h, with a low peak:trough ratio (around 1·6–2·8) after single or repeat dosing of trametinib. 8 We undertook an open-label phase 1 study to ascertain the maximum tolerated dose of trametinib in human beings for the first time, and to define the recommended phase 2 dose and regimen of this agent for patients with advanced solid tumours. We also aimed to establish pharmacokinetic, pharmacodynamic, and efficacy data for trametinib in selected tumour types. Methods Study design We undertook this phase 1 study in three parts (appendix, p 1). In part one, we identified the maximum tolerated dose of trametinib by safety, pharmacokinetic, and See Online for appendix