• The lancet oncology · Aug 2012

    Multicenter Study Webcasts

    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, and Wells A Messersmith.
    • Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA. jinfante@tnonc.com
    • Lancet Oncol. 2012 Aug 1; 13 (8): 773-81.

    BackgroundInhibition 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.MethodsWe 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.FindingsWe 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.InterpretationThe 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.FundingGlaxoSmithKline.Copyright © 2012 Elsevier Ltd. All rights reserved.

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