Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
JR Infante, LA Fecher, GS Falchook… - The lancet …, 2012 - thelancet.com
JR Infante, LA Fecher, GS Falchook, S Nallapareddy, MS Gordon, C Becerra, DJ DeMarini…
The lancet oncology, 2012•thelancet.comBackground 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 …
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 …
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.
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