Clinically significant cardiovascular disease including: \r\n* Myocardial infarction within  months \r\n* Uncontrolled angina within  months\r\n* Congestive heart failure New York Heart Association (NYHA) class  or  in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) >  msec\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension (systolic blood pressure <  millimeters of mercury or bradycardia with a heart rate of <  beats per minute on any ECG taken at the screening visit\r\n* Bradycardia with a heat rate of <  beats per minutes in the screening ECG, unless pharmaceutically induced and reversible\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg at the screening visit
Clinically significant cardiovascular disease including: ) myocardial infarction within  months of screening visit; ) uncontrolled angina within  months of screening visit; ) congestive heart failure New York Heart Association (NYHA) class  or , or subjects with history of congestive heart failure NYHA class  or  in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the Screening visit results in a left ventricular ejection fraction that is >= %. ) history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes). ) prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) >  msec. ) history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. ) hypotension (systolic blood pressure <  mmHg or bradycardia with a heart rate of <  beats per minute on the screening ECG., unless pharmaceutically induced and thus reversible (i.e. beta blockers).
No clinically significant cardiovascular disease including:\r\n* Myocardial infarction (MI) within  months\r\n* Uncontrolled angina within  months\r\n* Chronic heart failure (CHF) with New York Heart Association (NYHA) class  or , or patients with NYHA class  or  in the past, unless a screening echo or multigated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > % \r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsades de pointes)\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension (systolic blood pressure [BP] <  mmHg) or bradycardia (<  beat per minute [bpm]) at screening\r\n* Uncontrolled hypertension (systolic BP > mmHg or diastolic BP > mmHg at screening)
Known clinically significant heart disease as evidenced by:\r\n* Myocardial infarction within  months of enrollment\r\n* Uncontrolled angina within  months of enrollment\r\n* Congestive heart failure New York Heart Association (NYHA) class III or IV, or a history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within  months results in a left ventricular ejection fraction >= %\r\n* Clinically significant ventricular arrhythmias\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Bradycardia as indicated by a heart rate <  beats per minute at screening visit\r\n* Hypotension as indicated by systolic blood pressure (SBP) =<  on  consecutive measurements at screening visit\r\n* Uncontrolled hypertension as indicated by SBP >  mmHg or diastolic blood pressure (DBP) >  mmHg on  consecutive measurements at screening visit
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within  months prior to screening\r\n* Uncontrolled angina within  months prior to screening\r\n* Congestive heart failure New York Heart Association (NYHA) class  or , or subjects with history of congestive heart failure NYHA class  or  in the past, unless a screening echocardiogram or multi-gated acquisition (MUGA) scan performed within  months results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure >  mm Hg or diastolic blood pressure >  mm Hg at screening; patients with initially elevated systolic blood pressure >  mm Hg or diastolic blood pressure >  mm Hg are eligible if they undergo medical management and are re-screened
Clinically significant cardiovascular disease including:\r\n* Acute coronary syndrome within  months of screening visit\r\n* Hypotension defined as a systolic blood pressure <  mmHg\r\n* Bradycardia defined as a heart rate of <  beats per minute, unless pharmaceutically induced and thus reversible (i.e. beta blockers)\r\n* Uncontrolled angina (requiring escalating doses of nitrates) within  months of screening visit\r\n* Congestive heart failure New York Heart Association (NYHA) class III or IV or subjects with a history of congestive heart failure NYHA class III or IV, unless screening echocardiogram (ECHO) results in left ventricular ejection fraction that >= %\r\n* History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening electrocardiogram (EKG) >  msec\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
Clinically significant heart disease defined as:\r\n* Myocardial infarction within  months of screening visit\r\n* Uncontrolled angina within  months of screening visit\r\n* Congestive heart failure New York Heart Association (NYHA) class  or , or subjects with history of congestive heart failure NYHA class  or  in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the screening visit results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes)\r\n* Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) >  msec\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension (systolic blood pressure <  mmHg) or bradycardia with a heart rate of <  beats per minute on the screening ECG, unless pharmaceutically induced and thus reversible (i.e. beta blockers) or known, chronic asymptomatic baseline heart rate\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg at the screening visit
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within  months\r\n* Uncontrolled angina within  months\r\n* Congestive heart failure New York Heart Association (NYHA) class  of , or patients with history of congestive heart failure NYHA class  or  in the past, unless screening echocardiogram or multi-gated acquisition scan performed within  months results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension as indicated by systolic blood pressure <  millimeters of mercury (mmHg) at the screening visit\r\n* Bradycardia as indicated by a heart rate of <  beats per minute on the screening electrocardiogram (ECG)\r\n* Uncontrolled hypertension as indicated by systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg
Clinically significant cardiovascular disease, including:\r\n* Myocardial infarction within  months of enrollment\r\n* Uncontrolled angina within  months of enrollment\r\n* Congestive heart failure New York Heart Association (NYHA) class  or , or history of congestive heart failure NYHA class  or  in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within  months results in a left ventricular ejection fraction >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension as indicated by systolic blood pressure <  mmHg on  consecutive measurements at the screening visit\r\n* Bradycardia as indicated by a heart rate <  beats per minute at the screening visit;\r\n* Uncontrolled hypertension as indicated by systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg on  consecutive measurements at the screening visit;\r\n* Electrocardiogram (EKG) demonstrating equal to or greater than grade III toxicity according the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version .
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within  months of screening visit\r\n* Uncontrolled angina within  months of screening visit\r\n* Congestive heart failure New York Heart Association (NYHA) class  or , or subjects with history of congestive heart failure NYHA class  or  in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the screening visit results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes)\r\n* Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) >  msec\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension (systolic blood pressure <  mmHg or bradycardia with a heart rate of <  beats per minute on the screening ECG, unless pharmaceutically induced and thus reversible [i.e. beta blockers])\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg at the screening visit
No clinically significant cardiovascular disease including:\r\n* Myocardial infarction (MI) within  months\r\n* Uncontrolled angina within  months\r\n* Congestive heart failure (CHF) with New York Heart Association (NYHA) class  or , or patients with NYHA class  or  in the past, unless a screening echocardiogram (echo) or multi gated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension (systolic blood pressure [BP] <  mmHg) or bradycardia (<  beats per minute [bpm]) at screening \r\n* Uncontrolled hypertension (systolic BP >  mmHg or diastolic BP >  mmHg at screening)
Clinically significant heart disease as evidenced by:\r\n* Myocardial infarction within  months of enrollment\r\n* Uncontrolled angina within  months of enrollment\r\n* Congestive heart failure New York Heart Association (NYHA) class III or IV, or a history of congestive heart failure NYHA class III or IV in the past, unless a screening echocardiogram (ECHO) or multigated acquisition scan (MUGA) within  months results in a left ventricular ejection fraction >= %\r\n* Clinically significant ventricular arrhythmias\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Bradycardia as indicated by a heart rate <  beats per minute at screening visit\r\n* Hypotension as indicated by systolic blood pressure (SBP) =<  on  consecutive measurements\r\n* Uncontrolled hypertension as indicated by SBP >  mmHg or diastolic blood pressure (DBP) >  mmHg on  consecutive measurements at screening visit
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within  months prior to screening;\r\n* Uncontrolled angina within  months prior to screening;\r\n* Congestive heart failure New York Heart Association (NYHA) class  or , or patients with history of congestive heart failure NYHA class  or  in the past, unless a screening echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) performed within  months results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Hypotension as indicated by systolic blood pressure <  mmHg at the screening visit\r\n* Bradycardia as indicated by a heart rate of <  beats per minute at the screening visit \r\n* Uncontrolled hypertension as indicated by systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg at the screening visit
Clinically significant cardiovascular disease as evidenced by: myocardial infarction within  months of screening; uncontrolled angina within  months of screening; New York Heart Association (NYHA) class  or  congestive heart failure; clinically significant ventricular arrhythmia; Mobitz II/nd degree/or rd degree heart block without a pacemaker in place; uncontrolled hypertension (HTN) (systolic >  mmHg or diastolic >  mmHg at screening)
Clinically significant cardiovascular disease within  months of study treatment including:\r\n* Severe or unstable angina\r\n* Myocardial infarction\r\n* Symptomatic congestive heart failure\r\n* New York Heart Association (NYHA) (class II-IV heart disease)\r\n* Arterial or venous thromboembolic events (such as pulmonary embolism cerebrovascular accident including transient ischemic attacks)\r\n* History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening electrocardiogram (EKG) >  msec\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place\r\n* Uncontrolled hypertension (systolic blood pressure >=  mmHg or diastolic blood pressure >=  mmHg); participants with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within six months prior to screening\r\n* Uncontrolled angina within three months prior to screening\r\n* Congestive heart failure New York Heart Association (NYHA) class  or , or subjects with history of congestive heart failure NYHA class  or  in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within  months results in a left ventricular ejection fraction that is >= %\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
Clinically significant cardiovascular disease including:\r\n* GROUP  (trametinib arm): LVEF < LLN\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within  months\r\n* Uncontrolled angina within  months\r\n* GROUP  and GROUP  (non-trametinib arms): Congestive heart failure New York Heart Association (NYHA) class  or , or patients with history of congestive heart failure NYHA class  or  in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within  months results in a left ventricular ejection fraction that is >= %\r\n* GROUP  (trametinib arm): Any history of congestive heart failure of any NYHA class for patients assigned to Group  (trametinib arm)\r\n* History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)\r\n* Patients with intra-cardiac defibrillators or permanent pacemakers\r\n* Hypotension as indicated by systolic blood pressure <  millimeters of mercury (mmHg) at the screening visit\r\n* Bradycardia as indicated by a heart rate of <  beats per minute on the screening electrocardiogram (ECG)\r\n* Treatment refractory hypertension defined as a blood pressure of systolic >  mmHG and/or diastolic >  mmHG which cannot be controlled by anti-hypertensive therapy\r\n* Corrected QT interval (QTC) >=  milliseconds\r\n* Known cardiac metastases