A Phase IB Trial of the Oral MEK Inhibitor Trametinib (GSK1120212) in Combination With Everolimus in Patients With Advanced Solid Tumors
Mené sur 67 patients atteints d'une tumeur solide de stade avancé, cet essai de phase 1b évalue la dose maximale recommandée et la toxicité du trametinib, un inhibiteur de MEK, en combinaison avec l'everolimus
Background : This phase 1b trial investigated the safety, tolerability, and recommended phase 2 dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic characterization and evaluation of clinical activity. Patients and methods : A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3+3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. Pharmacokinetics samples were collected pre-dose, as well as 1, 2, 4, and 6 hours post-dose on day 15 of the first treatment cycle. Results : Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). Pharmacokinetic assessment did not suggest drug-drug interactions between these 2 agents. Of the 67 enrolled patients, 5 (7%) achieved partial response to treatment and 21 (31%) displayed stable disease. Among the 21 patients with pancreatic cancer, partial response was observed in 1 patient (5%) and stable disease in 6 patients (29%). Conclusion : This study was unable to identify a recommended phase 2 dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.
Annals of Oncology 2014