Abstract CT307: Phase I, placebo-controlled, patient (pt)-blinded study to evaluate the effect of repeat oral dosing of the MEK inhibitor trametinib on cardiac repolarization in pts with solid tumors
Authors: Rasco Drew , Patnaik Amita , Tolcher Anthony W. , Papadopoulos Kyriakos P. , Beeram Muralidhar , Chambers Glenda , Werner Theresa L. , Bauman John W. , Scheuber Anita , Cox Donna , Zhou YanYan , Hamid Mohammed , Schramek Daniel , Criscitiello Peggy , Sharma Sunil 
Published: August 2015

Abstract
Trametinib is a reversible, selective inhibitor of the MAPKs, MEK1, and MEK2. Trametinib cardiotoxicity is an infrequent, but potentially life-threatening, adverse event (AE); elevated blood pressure (BP), and decreased left ventricular ejection fraction and heart rate have been seen with trametinib. Prolongation of the QT interval due to delayed cardiac repolarization increases the risk of developing a potentially fatal cardiac arrhythmia. Risk of trametinib inducing QT prolongation at supratherapeutic exposure was evaluated. (ClinicalTrials.gov NCT01658553).
In this 2-wk study, pts with histologically/cytologically confirmed solid tumors received placebo on Day 1, followed by once-daily trametinib 2mg doses on Days 2-14. On Day 15 all pts received a single 3mg trametinib dose. The regimen was expected to achieve supratherapeutic dosing for QTc measurement on Day 15. ECG was monitored by 12-lead ambulatory continuous 24-hr Holter monitoring pre-study, and on Days 1 and 15. Pharmacokinetic (PK) and pharmacodynamic (PD) parameters were also measured.
32/35 pts completed the study. There was no effect of trametinib compared to time-matched placebo on the change from baseline in QTcF (Table), QTcB or QTci. Mean AUC0-24 and Cmax following trametinib 2mg repeat doses were 364ng*hr/mL and 22.9ng/mL, respectively, consistent with those previously reported; the values for 3mg were 454ng*hr/mL and 29.2ng/mL. Median Tmax was approximately 2 hrs for both trametinib doses. There was no relationship between QTcF interval and trametinib plasma concentrations, as supported by statistical analysis and PK/PD modeling. Trametinib had no effect on ambulatory BP. 33/35 pts (94%) reported at least one AE; these were consistent with AEs previously reported. No ECG abnormalities were reported as AEs.
This study showed no statistical difference between trametinib and placebo. Trametinib has no significant effect on QT prolongation at the supratherapeutic dose. Trametinib PK parameters were consistent with those previously reported. No new safety signals were seen.
Results of Repeated Measures Statistical Analysis of QTcF Change from BaselinePlanned TimeLSmean (msec)Treatment difference (SE) [90% confidence intervals]PlaceboTrametinibTrametinib - Placebo1 hr post-dose2.461.88-0.58 (2.666) [-5.05, 3.88]2 hrs post-dose0.902.651.75 (2.847) [-3.01, 6.51]3 hrs post-dose1.374.803.43 (3.061) [-1.70, 8.55]4 hrs post-dose-0.782.923.70 (2.828) [-1.03, 8.43]6 hrs post-dose-2.71-0.672.04 (2.874) [-2.77, 6.84]8 hrs post-dose-7.47-6.041.44 (2.367) [-2.52, 5.39]10 hrs post-dose-8.66-3.145.53 (2.468) [1.40, 9.65]24 hrs post-dose-2.15-2.83-0.68 (2.704) [-5.20, 3.84]hr(s), hour(s); LS, least squares; msec, milliseconds; SE, standard error
Citation Format: Drew Rasco, Amita Patnaik, Anthony W. Tolcher, Kyriakos P. Papadopoulos, Muralidhar Beeram, Glenda Chambers, Theresa L. Werner, John W. Bauman, Anita Scheuber, Donna Cox, YanYan Zhou, Mohammed Hamid, Daniel Schramek, Peggy Criscitiello, Sunil Sharma. Phase I, placebo-controlled, patient (pt)-blinded study to evaluate the effect of repeat oral dosing of the MEK inhibitor trametinib on cardiac repolarization in pts with solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT307. doi:10.1158/1538-7445.AM2015-CT307