No cardiovascular disorders including:\r\n* Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening\r\n* Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days prior to registration\r\n* Any of the following within 6 months prior to registration:\r\n** Unstable angina pectoris\r\n** Clinically-significant cardiac arrhythmias\r\n** Stroke (including transient ischemic attack [TIA], or other ischemic event)\r\n** Myocardial infarction
Significant cardiovascular or cerebrovascular disease including:\r\n* Uncontrolled hypertension (systolic blood pressure [SBP] >= 150; diastolic blood pressure [DBP] >= 90)\r\n* History of myocardial infarction within 6 months\r\n* Unstable angina\r\n* New York Heart Association functional classification II, III or IV\r\n* Baseline ejection fraction =< 50% as assessed by echocardiogram or multi-gated acquisition (MUGA)\r\n* Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within 6 months\r\n* Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or peripheral arterial thrombosis) within 6 months
Known cardiopulmonary disease defined as having one or more of the following:\r\n* Uncontrolled high blood pressure (i.e. systolic > 180 mmHg or diastolic > 95 mmHg);\r\n* Cardiomyopathy\r\n* Ischemic heart disease; patients with acute coronary syndrome, myocardial infarction, and/or revascularization (e.g. coronary artery bypass graft, stent) within 6 months of first dose of study drug are excluded; patients with a history of ischemic heart disease who have had revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll\r\n* Arrhythmia (e.g. history of polymorphic ventricular fibrillation or torsade de pointes); patients with symptomatic atrial fibrillation (Afib) incompletely controlled medically, or controlled by device (e.g. pacemaker) or by ablation are excluded; however, patients with stable, asymptomatic AFib for a period of at least 6 months, whose Afib is controlled with medication, or who have a history of paroxysmal AFib are permitted to enroll\r\n* Implantable cardioverter defibrillator\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV; or class II with a recent decompensation requiring hospitalization or referral to a heart failure clinic within 4 weeks before screening)\r\n* Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing); mild regurgitation is not excluded\r\n* Pulmonary hypertension
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction or uncontrolled angina within 6 months\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
Patients with clinically significant cardiovascular disease including: uncontrolled hypertension defined as systolic > 150 mm Hg or diastolic > 90 mm Hg; unstable angina or who have had a myocardial infarction within the past six months prior to registration; New York Heart Association (NYHA) grade II or greater congestive heart failure; serious cardiac arrhythmia requiring medication (this does not include asymptomatic atrial fibrillation with controlled ventricular rate); or CTCAE v4.0, grade 2 or greater peripheral vascular disease (peripheral ischemia), defined as having at least brief (< 24 hour) episodes of ischemia managed non-surgically and without permanent deficit
Heart disease including congestive heart failure (New York Heart Association [NYHA] grade II or greater); unstable angina; prior myocardial infarction (non-ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]) within 6 months prior to study enrollment; hypertension with a systolic blood pressure of > 150 mm Hg or diastolic blood pressure of >100 mm Hg while on antihypertensive medication
Current symptomatic congestive heart failure (New York Heart Association classification >= grade III), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100 mmHg); or any of the following occurring within 6 months (180 days) prior to first dose of study treatment: myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack; use of antihypertensive medication to control blood pressure is allowed
Clinically significant, uncontrolled heart diseases\r\n* Unstable angina within 6 months prior to screening\r\n* Myocardial infarction within 6 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without antihypertensive medication; initiation or adjustment of antihypertensive medication (s) is allowed prior to screening\r\n* Ventricular arrhythmias\r\n* Supraventricular and nodal arrhythmias not controlled with medication\r\n* Other cardiac arrhythmia not controlled with medication\r\n* Fridericia's correction formula (QTcF) > 480 msec
Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n* History or presence of serious uncontrolled ventricular arrhythmias\r\n* Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE)\r\n* Uncontrolled hypertension (defined as systolic blood pressure [SBP] >= 160 mm Hg or diastolic blood pressure [DBP] >= 100 mm Hg while on anti-hypertensive medications)
Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: \r\n* Impaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n** History or presence of serious uncontrolled ventricular arrhythmias\r\n** Clinically significant resting bradycardia\r\n** Left ventricular ejection fraction (LVEF) assessed by 2-dimensional (2-D) echocardiogram (ECHO) < 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan (MUGA), < 45% or lower limit of normal (whichever is higher)\r\n** Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE)\r\n** Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication(s)\r\n* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) \r\n* Cirrhosis, chronic active hepatitis or chronic persistent hepatitis \r\n* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)\r\n* Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin; full-dose anti-coagulation with low molecular weight heparin is permitted\r\n* Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
Current symptomatic congestive heart failure (New York Heart Association > class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100mmHg). Or any of the following occurring within 6 months (180 days) prior to first dose of study drugs: myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack. (Use of antihypertensive medication to control blood pressure is allowed.)
Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to:\r\n* Any medical condition requiring a higher dose of corticosteroid than 10mg prednisone/prednisolone once daily\r\n* History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents\r\n* Uncontrolled hypertension (systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment (systolic BP <160 mmHg or diastolic BP <95 mmHg)\r\n* Active or symptomatic viral hepatitis or chronic liver disease\r\n* Known active human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection. (HIV testing is not mandatory)\r\n* History of pituitary or adrenal dysfunction\r\n* Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < 50% at baseline, or clinically significant ventricular arrhythmias within 6 months prior to treatment start.\r\n* History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness =< 1 year prior to treatment start; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)\r\n* Uncontrolled diabetes mellitus\r\n* History of inflammatory bowel disease\r\n* Baseline moderate and severe hepatic impairment (Child Pugh class B & C)
Significant medical history or unstable medical comorbidities, including but not limited to:\r\n* Heart disease including congestive heart failure (New York Heart Association [NYHA] grade II or greater); unstable angina; prior myocardial infarction (non-ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]) within 6 months prior to study enrollment; hypertension with a systolic blood pressure of > 150 mm Hg or diastolic blood pressure of > 100 mm Hg while on antihypertensive medication\r\n* Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval\r\n* Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease\r\n* Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses\r\n* Active infection or ongoing antiviral medication for viral infections including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). Screening for chronic conditions is not required. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with osimertinib\r\n* Ongoing use of warfarin (injectable low-molecular weight heparins are permitted). Patients must be off warfarin for > 7 days prior to enrollment
Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ?3 hypertension (diastolic blood pressure ?100 mmHg or systolic blood pressure ?160 mmHg) despite antihypertensive therapy.
Clinically significant cardiovascular disease including: \r\n* Myocardial infarction within 6 months \r\n* Uncontrolled angina within 6 months\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4 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 >= 45%\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) > 470 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 < 86 millimeters of mercury or bradycardia with a heart rate of < 50 beats per minute on any ECG taken at the screening visit\r\n* Bradycardia with a heat rate of < 50 beats per minutes in the screening ECG, unless pharmaceutically induced and reversible\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
Known cardiopulmonary disease defined as one of the following:\r\n* Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)\r\n* Cardiomyopathy or history of ischemic heart disease\r\n* Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de pointes); however, patients with < grade 3 atrial fibrillation (a fib) for a period of at least 6 months may enroll; grade 3 a fib is symptomatic and\r\nincompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation; patients with paroxysmal a fib are permitted to enroll\r\n* Implantable cardioverter defibrillator\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV; or class II with a recent decompensation requiring hospitalization or referral to a heart failure clinic within 4 weeks before screening), myocardial infarction and/or revascularization (eg, coronary artery bypass graft, stent) within 6 months of first dose of study drug\r\n* Patients who had ischemic heart disease who have had acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll\r\n* Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)\r\n* Pulmonary hypertension
Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to the first planned dose of study drugs), myocardial infarction (< 6 months prior to the first planned dose of study drugs), unstable angina, congestive heart failure (New York Heart Association Classification class >= II), serious cardiac arrhythmia, or uncontrolled hypertension (systolic blood pressure [SBP] > 170/ diastolic blood pressure [DBP] > 105)
Participants may not have uncontrolled inter-current illness; this includes, but is not limited to: ongoing or active infection; symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV); unstable angina pectoris or new onset angina that began within the last 3 months; cardiac ventricular arrhythmias requiring anti-arrhythmic therapy; or thrombotic/embolic events such as cerebrovascular accident, including transient ischemic attacks within the past 6 months; uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management; known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C; known grade 3 or 4 neurotoxicity
Patients with clinically significant, uncontrolled cardiovascular disease, such as:\r\n* Unstable angina within 6 months prior to screening\r\n* Myocardial infarction within 6 months prior to screening\r\n* Patients with a history of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Peripheral vascular disease\r\n* Patients with uncontrolled hypertension defined as a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication; initiation or adjustment of antihypertensive medication(s) is allowed prior to screening\r\n* Ventricular arrhythmias\r\n* Supraventricular and nodal arrhythmias not controlled with medication\r\n* Other cardiac arrhythmia not controlled with medication\r\n* Patients with corrected QT (QTc) >= 450 ms (male patients) or >= 460 ms (female patients) using Fridericia correction (QTcF) on the screening electrocardiogram (ECG)\r\n* Patients with history of congenital long QT syndrome or history of torsade de pointes
Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA) class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, uncontrolled hypertension (defined as an average systolic blood pressure [SBP] over 140 or a diastolic blood pressure [DBP] over 90 despite antihypertensive agents), clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant; NOTE: there is no lower limit of left ventricular ejection fraction below which patients are excluded from participation
History of serious systemic disease, including myocardial infarction or unstable angina within the last 12 months, history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (blood pressure of > 140/90 mmHg) at the time of enrollment, New York Heart Association (NYHA) grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), significant vascular disease or symptomatic peripheral vascular disease
Cardiac conditions as follows: uncontrolled hypertension (resting blood pressure [BP] ?150/95 millimeters of mercury [mmHg] despite optimal therapy), heart failure New York Heart Association (NYHA) Class II or above, prior or current cardiomyopathy, atrial fibrillation with heart rate >100 beats per minute (bpm). Unstable ischemic heart disease (myocardial infarction within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly)
Have significant, uncontrolled or active cardiovascular disease, specifically including but restricted to:\r\n* Myocardial infarction (MI) within 6 months of trial enrollment\r\n* Unstable angina within 6 months of trial enrollment\r\n* Congestive heart failure (CHF) with 6 months prior to trial enrollment\r\n* Any history of ventricular arrhythmia\r\n* Cerebrovascular accident or transient ischemic attack within 6 months of D1 of treatment\r\n* Clinically significant atrial arrhythmia or severe baseline bradycardia defined as resting heart rate < 50 beat per minute\r\n* Uncontrolled hypertension defined as baseline systolic blood pressure (SBP) > 160 and diastolic blood pressure (DBP) > 100 on 3 separate clinic visits or past history of hypertensive urgency, emergency or encephalopathy
Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:\r\n* Unstable angina within 6 months prior to screening?\r\n* Myocardial infarction within 6 months prior to screening?\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV);\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without antihypertensive medication.\r\n* Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening?\r\n* Ventricular arrhythmias\r\n* Supraventricular and nodal arrhythmias not controlled with medication?\r\n* Other cardiac arrhythmia not controlled with medication?\r\n* Corrected QT (QTcF) > 470 ms using Fridericia’s correction on the screening electrocardiography (ECG)
Any other serious illness or medical condition or social circumstance that might interfere with the subject’s participation in the trial or interfere with the interpretation of the results, including, but not limited to:\r\n* Any uncontrolled infection\r\n* New York Heart Association (NYHA) class III or class IV heart failure \r\n* Unstable angina\r\n* Myocardial infarction within the 6 months prior to study entry\r\n* Uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg despite 2 antihypertensive medications) \r\n* Chronic obstructive pulmonary disease (COPD) requiring hospital admission in the year prior to study entry\r\n* Diabetes mellitus requiring hospital admission in the year prior to study entry \r\n* Chronic liver disease\r\n* Hypothyroidism (thyroid-stimulating hormone [TSH] level > 3.0 mIU/L)\r\n* Substance abuse
No clinically significant cardiovascular disease including:\r\n* Myocardial infarction (MI) within 6 months\r\n* Uncontrolled angina within 3 months\r\n* Chronic heart failure (CHF) with New York Heart Association (NYHA) class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a screening echo or multigated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > 45% \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] < 86 mmHg) or bradycardia (< 50 beat per minute [bpm]) at screening\r\n* Uncontrolled hypertension (systolic BP >170 mmHg or diastolic BP >105 mmHg at screening)
Patients with significant cardiac history including:\r\n* Severe or unstable angina pectoris\r\n* Uncontrolled hypertension (defined as systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg;. Note - patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment\r\n* Atrial fibrillation or other cardiac arrhythmia requiring therapy.\r\n* Heart disease as evidenced by myocardial infarction, or aterial thrombotic events in the past 6 months\r\n* Class II-IV heart failure (as defined by New York Heart Association) or a cardiac ejection fraction measurement of less than 50% at baseline
Known cardiopulmonary disease defined as one of the following:\r\n* Unstable angina\r\n* Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg)\r\n* Cardiomyopathy or history of ischemic heart disease\r\n* Arrhythmia (eg, history of polymorphic ventricular fibrillation or torsade de pointes); permanent atrial fibrillation (a fib) defined as a fib >= 6 months; persistent a fib defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening; however, patients with < grade 3 atrial fibrillation (a fib) for a period of at least 6 months may enroll; grade 3 a fib is symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation; patients with paroxysmal a fib are permitted to enroll\r\n* Implantable cardioverter defibrillator\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV; or class II with a recent decompensation requiring hospitalization or referral to a heart failure clinic within 4 weeks before screening),\r\n* Myocardial infarction and/or revascularization (eg, coronary artery bypass graft, stent) within 6 months of first dose of study drug\r\n* Patients who had ischemic heart disease who have had ACS, MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll\r\n* Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)\r\n* Pulmonary hypertension
Current symptomatic congestive heart failure (New York Heart Association >= class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100 mmHg); or any of the following occurring within 6 months (180 days) prior to first dose of avelumab: myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or serious cardiac arrhythmia requiring medication; (use of antihypertensive medication to control blood pressure is allowed)
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator, including, but not limited to:\r\n* Myocardial infarction or arterial or venous thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease\r\n* History of documented congestive heart failure (New York Heart Association functional classification III or IV)\r\n* Documented history of cardiomyopathy\r\n* Uncontrolled hypertension (systolic blood pressure [SBP] > 160/diastolic blood pressure [DBP] > 100 despite medical intervention)\r\n* History of myocarditis of any etiology\r\n* History of cardiac surgery\r\n* History of ventricular arrhythmias
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator, including, but not limited to:\r\n* Myocardial infarction or arterial or venous thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease\r\n* History of documented congestive heart failure (New York Heart Association functional classification III or IV)\r\n* Documented history of cardiomyopathy\r\n* Uncontrolled hypertension defined by: systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood Pressure (DBP) > 100 mmHg\r\n* History of myocarditis of any etiology\r\n* History of cardiac surgery\r\n* History of ventricular arrhythmias
Significant cardiovascular disease, including myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism, within 6 months prior to start of study therapy; symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; uncontrolled Grade ?3 hypertension (diastolic blood pressure ?100 mmHg or systolic blood pressure ?160 mmHg) despite antihypertensive therapy; or history of congenital prolonged QT syndrome.
Significant cardiac history:\r\n* History of myocardial infarction or ischemic heart disease within 1 year before first study drug administration;\r\n* Uncontrolled arrhythmia;\r\n*History of congenital QT prolongation;\r\n* New York Heart Association class III or IV cardiac disease;\r\n* Uncontrolled hypertension: blood pressure consistently greater than 150 mm Hg systolic and 100 mm Hg diastolic in spite of antihypertensive medication
Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:\r\n* Clinically significant cardiac diseases, including any of the following:\r\n** History or presence of serious uncontrolled ventricular arrhythmias \r\n** Clinically significant resting bradycardia\r\n** Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE)\r\n** Uncontrolled hypertension defined by a systolic blood pressure (SBP) ? 160 mmHg and/or diastolic blood pressure (DBP) ? 100 mm Hg, with or without anti-hypertensive medication(s)\r\n* Cirrhosis, chronic active hepatitis or chronic persistent hepatitis\r\n* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)\r\n* Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy; usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted; for questions, please consult the study chair\r\n* Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
History of coronary artery disease, with or without angina pectoris or myocardial infarction, symptomatic congestive heart failure (New York Heart Association > Class II), uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100 mmHg) or cardiac arrhythmias requiring anti-arrrhythmic therapy.
Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:\r\n* Unstable angina\r\n* Myocardial infarction\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without antihypertensive medication\r\n* Ventricular arrhythmias, or supraventricular/nodal arrhythmias not controlled with medications; other cardiac arrhythmias not controlled with medications\r\n* Left ventricular ejection fraction < 20% corrected QT (QTcF) > 470 ms using Fridericia’s correction on the screening electrocardiogram (ECG)\r\n* Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening
CAPMATINIB EXCLUSION CRITERIA: Cardiovascular disorders including:\r\n* Symptomatic congestive heart failure (New York Heart Association class III or IV)\r\n* Personal or family history of congenital long QT syndrome\r\n* Corrected QTc > 480 msec using Fridericia correction on screening electrocardiography (ECG)\r\n* Uncontrolled hypertension (systolic pressure >= 160 mmHg or diastolic pressure >= 100 mmHg on repeated measurement) despite optimal medical management; initiation or adjustment of anti-hypertensive medications are allowed prior to screening
Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:\r\n* Unstable angina within 6 months prior to screening\r\n* Myocardial infarction within 6 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without antihypertensive medication \r\n** Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening\r\n* Ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled with medication\r\n* Other cardiac arrhythmia not controlled with medication\r\n* Corrected QT (QTcF) > 470 ms using Fridericia’s correction on the screening electrocardiogram (ECG)
Known clinically significant heart disease as evidenced by:\r\n* Myocardial infarction within 6 months of enrollment\r\n* Uncontrolled angina within 6 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 3 months results in a left ventricular ejection fraction >= 45%\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 < 50 beats per minute at screening visit\r\n* Hypotension as indicated by systolic blood pressure (SBP) =< 85 on 2 consecutive measurements at screening visit\r\n* Uncontrolled hypertension as indicated by SBP > 170 mmHg or diastolic blood pressure (DBP) > 105 mmHg on 2 consecutive measurements at screening visit
Uncontrolled intercurrent illness including, but not limited to:\r\n* Ongoing or active infection requiring parenteral antibiotics\r\n* Impairment of lung function (chronic obstructive pulmonary disease [COPD] > grade 2, lung conditions requiring oxygen therapy) or current dyspnea at rest\r\n* Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)\r\n* Known left ventricular ejection fraction (LVEF) < 50%\r\n* Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months\r\n* Uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg, found on two consecutive measurements separated by a 1 or 2-week period despite adequate medical support)\r\n* Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute-Common Terminology Criteria for Adverse Events, version 4.0, grade 3])\r\n* Corrected QT using the Fridericia correction formula (QTcF) >= 480 msec on screening electrocardiogram (EKG)\r\n* Known history of QT/correct QT (QTc) prolongation or Torsades de Pointes (TdP)\r\n* ST depression or elevation of >= 1.5 mm in 2 or more leads\r\n* Diarrhea of any cause >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2\r\n* Active autoimmune disease that is not controlled by nonsteroidal or steroidal (< 10 mg of prednisone per day) anti-inflammatory drugs or active inflammatory disease, including small or large intestine inflammation such as active Crohn’s disease or ulcerative colitis, which requires immunosuppressive therapy\r\n* Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary\r\n* Known history of chronic liver disease including cirrhosis, current alcohol abuse, or infection with hepatitis B virus or hepatitis C virus (active or carrier) or renal failure\r\n* Known history of chronic pancreatitis\r\n* Conditions that affect lymphocyte counts, such as human immunodeficiency virus (HIV) infection or immunosuppressive therapy
Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as: \r\n* Unstable angina within 6 months prior to screening\r\n* Myocardial infarction within 6 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mmHg and/or diastolic blood pressure (DBP) >= 100 mmHg, with or without antihypertensive medication - initiation or adjustment of antihypertensive medication(s) is allowed prior to screening\r\n* Ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled with medication\r\n* Other cardiac arrhythmia not controlled with medication\r\n* Corrected QT interval (QTc) > 450 msec using Fridericia correction on the screening electrocardiogram (ECG)
Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:\r\n* Unstable angina within 6 months prior to screening\r\n* Myocardial infarction within 6 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without antihypertensive medication \r\n* Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening\r\n* Ventricular arrhythmias\r\n* Supraventricular and nodal arrhythmias not controlled with medication\r\n* Other cardiac arrhythmia not controlled with medication\r\n* Corrected QTcF > 470 msec using Fridericia correction on the screening electrocardiogram (ECG)
Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study; impaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n* Unstable angina within 6 months prior to screening\r\n* Myocardial infarction within 6 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III - IV)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without antihypertensive medication\r\n* Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening\r\n* Ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled with medication\r\n* Other cardiac arrhythmia not controlled with medication\r\n* Corrected QT (QTc) > 450 msec using Fridericia correction on the screening electrocardiogram (ECG)
History of serious systemic disease, including myocardial infarction or unstable angina within the last 12 months, history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (blood pressure of > 140/90 mmHg) at the time of enrollment, New York Heart Association (NYHA) grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication (patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular tachycardia are eligible), significant vascular disease or symptomatic peripheral vascular disease
Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n* History or presence of serious uncontrolled ventricular or significant arrhythmias\r\n* Any of the following within 6 months prior to registration: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE)\r\n* Uncontrolled hypertension (defined by a systolic blood pressure [SBP] >= 160 mmHg or diastolic blood pressure [DBP] >= 100 mmHg while on anti-hypertensive medications) or history of hypertensive crisis or hypertensive encephalopathy, stroke, TIA, symptomatic peripheral vascular disease, or grade 2 CHF
The subject has serious intercurrent illness as determined by the treating physician, that would compromise either patient safety or study outcomes such as:\r\n* Hypertension (two or more blood pressure [BP] readings performed at screening of > 150 mmHg systolic or > 100 mmHg diastolic) despite optimal treatment\r\n* Non-healing wound, ulcer, or bone fracture\r\n* Clinically significant cardiac arrhythmias\r\n* Untreated hypothyroidism\r\n* Uncontrolled systemic infection\r\n* Symptomatic congestive heart failure or unstable angina pectoris within 3 months prior study drug\r\n* Myocardial infarction, stroke, transient ischemic attack within 6 months\r\n* Known active malignancy (other than their glioma) except non-melanoma skin cancer or carcinoma in-situ in the cervix
Uncontrolled hypertension, blood pressure of > 150 mmHg systolic and > 100 mmHg diastolic, or history of hypertensive encephalopathy; subjects with any known uncontrolled inter-current illness including ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] grade [Gr.] 2 or >), myocardial infarction, unstable angina pectoris within the past 12 months
Ponatinib\r\n* History of acute pancreatitis within 1 year of study or history of chronic pancreatitis\r\n* History of alcohol abuse\r\n* Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)\r\n* Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:\r\n** Any history of myocardial infarction, stroke, or revascularization\r\n** Unstable angina or transient ischemic attack within 6 months prior to start of study treatment\r\n** Congestive heart failure within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to enrollment\r\n** History of clinically significant (as determined by the treating physician) atrial arrhythmia\r\n** Any history of ventricular arrhythmia\r\n** Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism\r\n* Uncontrolled hypertension (diastolic blood pressure > 90 mm Hg; systolic > 140 mm Hg); patients with hypertension should be under treatment on study entry to effect blood pressure control; taking medications that are known to be associated with torsades de pointes\r\n* Taking any medications or herbal supplements that are known to be strong inhibitors of CYP3A4 within at least 14 days before the first dose of ponatinib\r\n* Ocular toxicity present as measured during a comprehensive eye exam
Cardiac conditions as follows:\r\n* Uncontrolled hypertension (blood pressure [BP] >=150/95 mmHg despite medical therapy)\r\n* Left ventricular ejection fraction < 55% measured by echocardiography\r\n* Atrial fibrillation with a ventricular rate > 100 beats per minute (bpm) on electrocardiogram (ECG) at rest\r\n* Symptomatic heart failure (New York Heart Association [NYHA] grade II-IV)\r\n* Prior or current cardiomyopathy\r\n* Severe valvular heart disease\r\n* Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy)\r\n* Acute coronary syndrome =< 6 months prior to registration
Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication. Subjects with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry.
Known cardiopulmonary disease defined as one of the following:\r\n* Unstable angina\r\n* Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mm Hg )\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV)\r\n* Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as a (acute chest syndrome [ACS]), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll)\r\n* Cardiomyopathy\r\n* Clinically significant arrhythmia: 1) History of polymorphic ventricular fibrillation or torsade de pointes, 2) Permanent atrial fibrillation [a fib], defined as continuous a fib for >= 6 months, 3) Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening, 4) grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and 5) Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen\r\n* Implantable cardioverter defibrillator\r\n* Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)\r\n* Pulmonary hypertension\r\n* Prolong rate corrected QT (QTc) interval >= 500 msec. calculated according to institutional guidelines\r\n* Left ventricular ejection fraction (LVEF) ? 50% as assessed by echocardiogram or radionuclide angiography
Active cardiac conditions, including any of the following:\r\n* Uncontrolled hypertension (blood pressure [BP] > 150/95 mmHg despite medical therapy)\r\n* Acute coronary syndrome within 6 months prior to starting treatment\r\n* Uncontrolled angina despite medical therapy\r\n* Symptomatic heart failure (New York Heart Association [NYHA] class II-IV despite medical therapy)\r\n* Baseline left ventricular ejection fraction (LV EF) < 50% measured by either echocardiography or multigated acquisition (MUGA) scan\r\n* Severe valvular heart disease\r\n* Atrial fibrillation with ventricular rate > 100 beats per minute (bpm) on electrocardiogram (EKG) at rest
Cardiac conditions as follows:\r\n* Active coronary artery disease, unstable or newly diagnosed angina or myocardial infarction less than 12 months prior to first study drug administration\r\n* Class II-IV New York Heart Association (NYHA) congestive heart failure\r\n* Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg and diastolic BP > 90 mmHg for 24 hours) despite optimal medical management; blood pressure must be below 140/90 mmHg at screening; subjects with a history of hypertension who are receiving treatment with calcium channel blockers that are cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates should be changed to an alternative antihypertensive medication prior to first study drug administration\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Corrected QT (QTc) (Frederica) prolongation > 480 msec\r\n* Subjects with valvular heart disease Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) grade 2\r\n* Known left ventricular ejection fraction (LVEF) < 50%
Patients with significant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure [BP] > 115 mmHg), unstable angina, congestive heart failure (> New York Heart Association [NYHA] class II), poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty or myocardial infarction within the last 6 months, or uncontrolled atrial or ventricular cardiac arrhythmias
No clinically significant cardiovascular disease, defined as one of the following:\r\n* Uncontrolled hypertension (blood pressure > 150/100 mm/Hg at the time of enrollment); patients with hypertension and blood pressure =< 150/100 mm Hg on stable antihypertensive regimen are eligible\r\n* History of myocardial infarction or unstable angina < 24 weeks prior to randomization\r\n* New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris\r\n* Grade II or greater peripheral vascular disease
Significant medical co-morbidities as described below:\r\n* Cardiac disease:\r\n** Congestive heart failure > class II New York Heart Association (NYHA)\r\n** Unstable angina (anginal symptoms at rest), or new-onset angina (begun within the last 3 months), or myocardial infarction within the 6 months prior to enrollment, or\r\n** Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy\r\n** Known history of QTc prolongation or torsades de pointes\r\n* Grade 3 hypertension (systolic blood pressure [SBP] >= 160 mm Hg and/or diastolic blood pressure [DBP] >= 100 mm Hg despite maximal medical therapy)\r\n* Thrombotic, embolic, venous, or arterial events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months\r\n* Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C\r\n* Previous or concurrent cancer that is distinct in primary site or histology from breast cancer within 5 years prior to enrollment EXCEPT cervical cancer in situ, treated non-melanoma skin cancers, superficial bladder tumors (Ta and Tis)
Uncontrolled hypertension (systolic blood pressure [BP] greater than [>] 150 millimeters of mercury [mmHg] and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure of any New York Heart Association classification, serious cardiac arrhythmia that requires treatment with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia, and history of myocardial infarction within 6 months of enrollment
No cardiac risk factors including:\r\n* Uncontrolled high blood pressure (systolic blood pressure > 150)\r\n* Unstable angina\r\n* History of documented myocardial infarction or cerebrovascular accident\r\n* New York Heart Association class III or IV heart failure
Uncontrolled hypertension (sustained systolic > 150 mmHg and/or diastolic > 100 mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including: myocardial infarction or unstable angina within =< 6 months prior to the first study treatment; New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF); serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia); significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior of study enrollment; prior history of hypertensive crisis or hypertensive encephalopathy
Patients with any of the following cardiovascular diseases are excluded:\r\n* History of myocardial infarction within six months\r\n* Unstable angina\r\n* Angina pectoris that requires the use of anti-anginal medication\r\n* History of documented congestive heart failure (New York Heart Association [NYHA] classification of III or IV) or documented cardiomyopathy\r\n* Valvular disease with documented compromise in cardiac function\r\n* If cardiac function assessment is clinically indicated or performed: left ventricular ejection fraction (LVEF) less than normal per institutional guidelines, or < 55%, if threshold for normal not otherwise specified by institutional guidelines; patients with the following risk factor should have a baseline cardiac function assessment:\r\n** Prior treatment with anthracyclines\r\n* Any prior history of hypertensive crisis or hypertensive encephalopathy\r\n* Patients may not have any evidence of pre-existing inadequately controlled hypertension (defined as a systolic blood pressure [BP] of > 140 mmHg or a diastolic BP of > 90 mmHg), and must have a normal blood pressure (=< 140/90 mmHg) taken in the clinic setting by a medical professional within 2 weeks prior to starting study\r\n* Clinically significant peripheral vascular disease\r\n* Vascular disease including aortic aneurysm or dissection\r\n* History of stroke, transient ischemic attack or subarachnoid hemorrhage\r\n* Ventricular arrhythmias except for benign premature ventricular contractions\r\n* Cardiac conduction abnormality requiring a pacemaker\r\n* Known history of QT/corrected QT interval (QTc) prolongation or torsades de pointes\r\n* QTc prolongation > 470 msec or other significant electrocardiogram (ECG) abnormality noted during screening
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within 6 months prior to screening\r\n* Uncontrolled angina within 3 months prior to screening\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition (MUGA) scan performed within 3 months results in a left ventricular ejection fraction that is >= 45%\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 > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening; patients with initially elevated systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg are eligible if they undergo medical management and are re-screened
Significant cardiac disease or risk factors as indicated by MUGA or echocardiogram performed =< 60 days prior to registration and/or by presence of any of the following:\r\n* History of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) grade >= 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria class >= II\r\n* Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease\r\n* High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 [Mobitz 2] or third degree AV-block])\r\n* Significant symptoms (grade >= 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia\r\n* Myocardial infarction within 12 months prior to randomization\r\n* Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure >100 mmHg)\r\n* Evidence of transmural infarction on electrocardiogram (ECG)\r\n* Requirement for oxygen therapy
Patients with clinically significant cardiovascular disease; this includes:\r\n* Poorly controlled hypertension (> 140 mm Hg and > 90 mm Hg for systolic and diastolic blood pressure [BP]) are ineligible\r\n* Myocardial infarction or unstable angina within 6 months prior to registration; New York Heart Association (NYHA) grade II or greater congestive heart failure \r\n* Cardiac arrhythmia requiring medication
Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol including:\r\n* History of myocardial infarction in the past year or unstable, severe cardiovascular disease including angina or congestive heart failure (CHF) with symptoms at rest, or clinically significant abnormalities on the electrocardiogram (ECG)\r\n* Clinically significant and/or unstable pulmonary, gastrointestinal, hepatic, or renal disease\r\n* Insulin-requiring diabetes or uncontrolled diabetes mellitus,\r\n* Uncontrolled hypertension (systolic blood pressure [BP] > 170 or diastolic blood pressure [BP] > 100)
Cardiac risk factors including: 1) uncontrolled high blood pressure (systolic blood pressure > 150); 2) unstable angina; 3) history of documented myocardial infarction or cerebrovascular accident; 4) New York Heart Association class III or IV heart failure
Clinically significant heart disease defined as:\r\n* Myocardial infarction within 6 months of screening visit\r\n* Uncontrolled angina within 3 months of screening visit\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 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 >= 45%\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) > 470 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 < 86 mmHg) or bradycardia with a heart rate of < 50 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 > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
Other medical conditions including but not limited to:\r\n* History of liver disease such as cirrhosis, chronic active hepatitis, chronic persistent hepatitis or hepatitis B or C\r\n* Active infection requiring parenteral antibiotics\r\n* Poorly controlled high blood pressure (>= 150 mmHg systolic and/or 100 mmHg diastolic) despite treatment\r\n* New York Heart Association class II-IV congestive heart failure\r\n* Serious cardiac arrhythmia requiring medication\r\n* Myocardial infarction or unstable angina =< 6 months prior to registration/randomization\r\n* Clinically significant peripheral vascular disease\r\n* Deep venous thrombosis or pulmonary embolus =< 1 year of registration/randomization\r\n* Ongoing need for full-dose oral or parenteral anticoagulation\r\n* Ongoing anti-platelet treatment other than low-dose aspirin (i.e., aspirin 81 mg by mouth daily)\r\n* Active bleeding or pathological conditions that carry high risk of bleeding (e.g., known esophageal varices, etc.)\r\n* Serious, non-healing wound (including wounds healing by secondary intention), ulcer or bone fracture\r\n* History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess =< 6 months prior to registration/randomization\r\n* History of central nervous system (CNS) disease (e.g., vascular abnormalities, etc.), clinically significant stroke or transient ischemic attack (TIA) =< 6 months prior to registration/randomization, seizures not controlled with standard medical therapy\r\n* Radiographically documented tumor invading major blood vessels\r\n* History of hypertensive crisis or hypertensive encephalopathy
The patient has cardiac conditions as follows: uncontrolled hypertension (blood pressure [BP] > 160/100) despite optimal therapy, uncontrolled angina, ventricular arrhythmias, congestive heart failure (New York Heart Association class II or above), baseline left ventricular ejection fraction (LVEF) =< 50%, prior or current cardiomyopathy, atrial fibrillation with heart rate > 100 beats per minute (bpm), unstable ischemic heart disease (myocardial infarction [MI] within 6 months prior to starting treatment or angina requiring use of nitrates more than once weekly)
Patients with clinically significant cardiovascular disease, including: \r\n* Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg\r\n* Myocardial infarction or unstable angina < 6 months prior to registration\r\n* New York Heart Association (NYHA) class II or higher congestive heart failure \r\n* Serious cardiac arrhythmia requiring medication\r\n* Cancer Therapy Evaluation Program (CTEP) CTCAE version 4.0, grade 2 or higher peripheral ischemia (brief [< 24 hours (hrs)] episode of ischemia managed non-surgically and without permanent deficit) \r\n* Corrected QT (QTc) interval > 470 msec (CTCAE grade 2 or greater)
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within 6 months\r\n* Uncontrolled angina within 3 months\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 of 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is >= 45%\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 < 86 millimeters of mercury (mmHg) at the screening visit\r\n* Bradycardia as indicated by a heart rate of < 50 beats per minute on the screening electrocardiogram (ECG)\r\n* Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg
Clinically significant cardiovascular disease, including:\r\n* Myocardial infarction within 3 months of enrollment\r\n* Uncontrolled angina within 3 months of enrollment\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction >= 45%\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 < 86 mmHg on 2 consecutive measurements at the screening visit\r\n* Bradycardia as indicated by a heart rate < 50 beats per minute at the screening visit;\r\n* Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 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 4.0
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within 6 months of screening visit\r\n* Uncontrolled angina within 3 months of screening visit\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 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 >= 45%\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) > 470 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 < 86 mmHg or bradycardia with a heart rate of < 50 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 > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
No clinically significant cardiovascular disease including:\r\n* Myocardial infarction (MI) within 6 months\r\n* Uncontrolled angina within 3 months\r\n* Congestive heart failure (CHF) with New York Heart Association (NYHA) class 3 or 4, or patients with NYHA class 3 or 4 in the past, unless a screening echocardiogram (echo) or multi gated acquisition scan (MUGA) performed within three months demonstrates an ejection fraction (EF) > 45%\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] < 86 mmHg) or bradycardia (< 50 beats per minute [bpm]) at screening \r\n* Uncontrolled hypertension (systolic BP > 170 mmHg or diastolic BP > 105 mmHg at screening)
Clinically significant heart disease as evidenced by:\r\n* Myocardial infarction within 6 months of enrollment\r\n* Uncontrolled angina within 6 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 3 months results in a left ventricular ejection fraction >= 45%\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 < 50 beats per minute at screening visit\r\n* Hypotension as indicated by systolic blood pressure (SBP) =< 85 on 2 consecutive measurements\r\n* Uncontrolled hypertension as indicated by SBP > 170 mmHg or diastolic blood pressure (DBP) > 105 mmHg on 2 consecutive measurements at screening visit
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within 6 months prior to screening;\r\n* Uncontrolled angina within 3 months prior to screening;\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is >= 45%\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 < 86 mmHg at the screening visit\r\n* Bradycardia as indicated by a heart rate of < 50 beats per minute at the screening visit \r\n* Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the screening visit
Significant cardiovascular disease, including\r\n* Uncontrolled hypertension: systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg documented on 2 consecutive measurements taken at least 24 hours apart\r\n* Myocardial infarction, severe angina, or unstable angina within 6 months prior to administration of first dose of study drug\r\n* History of class III or IV congestive heart failure, as defined by the New York Heart Association\r\n* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation)\r\n* Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well-controlled with anti-arrhythmic medication; and/or\r\n* Coronary or peripheral artery bypass graft within 6 months of screening
Active cardiac disease\r\n* Any prior myocardial infarction (asymptomatic changes on electrocardiogram [EKG] suggestive of old myocardial infarction [MI] is not an exclusion)\r\n* Documented congestive heart failure (CHF)\r\n* Current use of any therapy specifically for CHF\r\n* Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)\r\n* Clinically significant pericardial effusion
Uncontrolled intercurrent illness including, but not limited to:\r\n* Ongoing or active infection requiring parenteral antibiotics\r\n* Impairment of lung function (chronic obstructive pulmonary disease [COPD] > grade 2, lung conditions requiring oxygen therapy)\r\n* Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)\r\n* Known / previously documented left ventricular ejection fraction (LVEF) < 50% within 6 months of trial enrollment\r\n* Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months\r\n* Uncontrolled hypertension within 2 weeks of study initiation (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg, found on two consecutive measurements separated by a 1 or 2-week period despite adequate medical support)\r\n* Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse Events, version 4.0, grade 3])\r\n* QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 480 msec on screening electrocardiogram (EKG)\r\n* Known history of QT/corrected QT interval (QTc) prolongation or torsades de pointes (TdP)\r\n* ST depression or elevation of >= 1.5 mm in 2 or more leads\r\n* Diarrhea of any cause >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2\r\n* Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary\r\n* Patients with symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment)\r\n* Patients with known history of chronic liver or renal failure\r\n* Patients with known history of chronic or acute pancreatitis
Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to:\r\n* Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated\r\n* Severe hepatic impairment (Child-Pugh class C)\r\n* History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents\r\n* Uncontrolled hypertension (systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment\r\n* Active or symptomatic viral hepatitis or chronic liver disease\r\n* History of pituitary or adrenal dysfunction\r\n* Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < 50 % at baseline\r\n* Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy\r\n* Uncontrolled diabetes mellitus\r\n* Active psychiatric condition
Clinically significant cardiovascular disease including myocardial infarction within 6 months, uncontrolled angina within 3 months, congestive heart failure New York Heart Association (NYHA) class 3 or 4, uncontrolled hypertension as indicated by systolic blood pressure > 160 mmHg or diastolic blood pressure > 95 mmHg at the screening visit
Uncontrolled hypertension (sustained systolic > 150 mmHg and/or diastolic > 100 mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including:\r\n* Myocardial infarction or unstable angina within =< 6 months prior to the first study treatment\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF)\r\n* Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia)\r\n* Peripheral vascular disease > grade 3 (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)
Any contra-indications to bevacizumab which include but are not limited to recent\r\n* Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 3\r\n* Severe uncontrolled hypertension (systolic blood pressure >= 150 mmHg and/or diastolic blood pressure >= 100 mmHg)\r\n* Cardiovascular disease including stroke of myocardial infarction =< 6 months prior to study enrollment, New York Heart Association grade 2 or greater congestive heart failure, serious cardiac arrhythmia uncontrolled by medication\r\n* Hemorrhagic brain metastases; asymptomatic (not requiring escalating doses of steroids) brain metastases are acceptable\r\n* History of severe proteinuria (urine dipstick >= 2+ or 24 hour [hr] urine > 2 gm/24 hr)\r\n* Prior history of hypertensive crisis or hypertensive encephalopathy\r\n* History of a central nervous system disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy\r\n* Significant vascular disease (e.g. aortic aneurysm requiring surgical repair) =< 6 months prior to study enrollment\r\n* History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) within the last 3 months\r\n* Evidence of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)\r\n* Current or recent (within 10 days of study drug start) use of aspirin (> 325 mg daily), clopidogrel (> 75 mg daily)\r\n* Recent initiation of full dose oral or parental anticoagulants that have not been in place for at least 2 weeks\r\n* Tumor invading or abutting major blood vessels\r\n* Tumor histology classified by squamous cell histology\r\n* Any history of abdominal fistula or gastrointestinal tract (GI) perforation within 6 months of study enrollment
Patients with clinically significant cardiovascular disease. This includes: 1) Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm Hg; 2) Myocardial infarction or unstable angina < 6 months prior to registration; 3) New York Heart Association (NYHA) Grade II or greater congestive heart failure; 4) Serious cardiac arrhythmia requiring medication. This does not include asymptomatic, atrial fibrillation with controlled ventricular rate
Evidence of current uncontrolled cardiovascular conditions, including sustained hypertension (systolic blood pressure [SBP] > 150 mmHg on two or more readings one week apart without normalization in between), clinically significant uncontrolled cardiac arrhythmias, symptomatic class III-IV New York Heart Association (NYHA) congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
Clinically significant cardiovascular disease, defined as any of the following conditions: i. Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) ii. Prior history of hypertensive crisis or hypertensive encephalopathy iii. Myocardial infarction within 6 months iv. Unstable angina v. New York heart association grade II or greater congestive heart failure (Appendix C) vi. Serious cardiac arrhythmia requiring medication vii. LVEF < 50% or below institutional limit of normal f) History of stroke of TIAs within 6 months prior to Day 1 g) Grade II or greater peripheral vascular disease within 1 year prior to study entry or other significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 h) Serious, non-healing wound, active ulcer, or untreated bone fracture i) History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 j) Known hypersensitivity to any component of bevacizumab k) Known CNS disease, except for stable or regressing brain metastases. l) Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) m) Psychiatric illness/social situations that would limit compliance with study requirements. n) Significant ocular issues including history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration. The risk factors for RVO are listed below. Patients should be excluded if they have the following conditions:
SELUMETINIB ARM: Cardiac conditions as follows:\r\n* Uncontrolled hypertension (blood pressure [BP] >= 150/95 despite optimal therapy)\r\n* Heart failure NYHA class II or above\r\n* Prior or current cardiomyopathy\r\n* Baseline left ventricular ejection fraction (LVEF) =< 50%\r\n* Atrial fibrillation with heart rate > 100 bpm\r\n* Unstable ischemic heart disease (myocardial infarction [MI] within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly)
Recent (< 6 months) myocardial infarction, unstable angina, coronary artery bypass surgery (CABG) or stent placement in the last 2 years, difficult-to-control congestive heart failure, uncontrolled hypertension (systolic blood pressure > 160 mm or a diastolic blood pressure [BP] > 110 mm under normal conditions and while on appropriate anti-hypertensive medications), or difficult-to-control cardiac arrhythmias
Clinically significant cardiac disease (class III, or IV of the New York Heart Association classification; unstable angina pectoris, myocardial infarction within 6 months or is post angioplasty or stenting within 6 months; clinically significant cardiac arrhythmia, or uncontrolled hypertension (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 90 mmHg) despite anti-hypertensive medication;
Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension (persistent systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg on antihypertensive medications) or arrhythmia, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or myocardial infarction within 6 months prior to the first dose of study treatment
Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:\r\n* Impaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n** History or presence of serious uncontrolled ventricular arrhythmias\r\n** Clinically significant resting bradycardia\r\n** Left ventricular ejection fraction (LVEF) assessed by 2-dimensional (D) echocardiogram (ECHO) =< 50% or lower limit of normal (whichever is higher) or multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (whichever is higher)\r\n** Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE)\r\n** Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication(s)\r\n* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)\r\n* Cirrhosis, chronic active hepatitis or chronic persistent hepatitis\r\n* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)\r\n* Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin\r\n* Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
Patients with clinically significant cardiovascular or cerebrovascular disease:\r\n* History of cerebrovascular accident or transient ischemic attack within past 6 months\r\n* Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg or systolic blood pressure (BP) > 180 mm Hg if diastolic blood pressure < 90 mm Hg, on at least 2 repeated determinations on separate days within past 3 months\r\n* Myocardial infarction, coronary artery bypass graft (CABG) or unstable angina within the past 6 Months\r\n* New York Heart Association grade III or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris within past 6 months\r\n* Clinically significant peripheral vascular disease within past 6 months\r\n* Pulmonary embolism, deep vein thrombosis (DVT), or other thromboembolic event within past 6 months
Preexisting cardiovascular disease. The only exception being well controlled essential hypertension with a sitting blood pressure (B.P.) of < 160 systolic and < 90 diastolic without any evidence of structural heart disease or one episode of myocardial infarction > 8 months ago. A past history of any of the following conditions is considered as exclusions to study participation:
Uncontrolled intercurrent illness including, but not limited to,\r\n* Ongoing or active infection\r\n* Psychiatric illness/social situations that would limit compliance with study requirements\r\n* Clinically significant cardiac disease including any of the following:\r\n** Congestive heart failure requiring treatment (New York Heart Association grade >= 2), left ventricular ejection fraction (LVEF) < 50% as determined by multi gated acquisition scan (MUGA) scan or echocardiogram\r\n** Uncontrolled hypertension (defined as systolic blood pressure [BP] >= 160 mmHg OR diastolic BP >= 100 mmHg despite maximal anti-hypertensive medications: refer to World Health Organization [WHO]-International Society of Hypertension [ISH] guidelines)\r\n** History or presence of clinically significant ventricular arrhythmias, atrial fibrillation, resting bradycardia, or conduction abnormality\r\n** Unstable angina pectoris or acute myocardial infarction < 3 months prior to starting study treatment\r\n** Corrected QT using the Fredericia's formula (QTcF) > 450 msec (males); > 470 msec (females)\r\n** History of congenital long QT syndrome
Impaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n* History or presence of serious uncontrolled ventricular arrhythmias\r\n* Clinically significant resting bradycardia\r\n* Ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected QTc interval to > 480 msec\r\n•\t* Left ventricular ejection fraction (LVEF) assessed by 2-dimensional (2-D) echocardiogram (ECHO) < 50% or lower limit of normal (whichever is the higher), or 2-D multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (whichever is the higher)\r\n* Any of the following =< 180 days prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA)\r\n* Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic (D)BP >= 100 mm Hg, with or without anti-hypertensive medication(s); initiation or adjustment of antihypertensive medication(s) is allowed prior to study entry
Clinically significant cardiovascular disease as evidenced by: myocardial infarction within 6 months of screening; uncontrolled angina within 3 months of screening; New York Heart Association (NYHA) class 3 or 4 congestive heart failure; clinically significant ventricular arrhythmia; Mobitz II/2nd degree/or 3rd degree heart block without a pacemaker in place; uncontrolled hypertension (HTN) (systolic > 180 mmHg or diastolic > 105 mmHg at screening)
Clinically significant cardiovascular disease within 6 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) > 470 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 >= 140 mmHg or diastolic blood pressure >= 90 mmHg); participants with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive therapy
Significant cardiovascular disease precluding an exercise program, including recent (within 6 months) myocardial infarction or stroke, pulmonary edema, myocarditis, pericarditis, unstable angina, pulmonary embolism/deep venous thrombosis (PE/DVT), uncontrolled hypertension (systolic blood pressure [SBP] > 200; diastolic blood pressure [DBP] > 110), uncontrolled arrhythmia, heart failure; or
Patients must not have cardiovascular risk factors including unstable angina, history of documented myocardial infarction or cerebrovascular accident, coronary artery bypass surgery, or New York Heart Association class III or IV heart failure; patients must not have known uncontrolled hyperlipidemia (defined as low-density lipoprotein cholesterol [LDL-C] >= 190 mg/dL or triglycerides >= 500 mg/dL) within the last 3 years prior to registration or uncontrolled high blood pressure (systolic blood pressure > 150 mm Hg) within 28 days prior to registration
Active cardiac disease including any of the following:\r\n* Severe congestive heart failure (class IV in accordance with the classification of the New York Heart Association)\r\n* Unstable angina\r\n* Severe arrhythmia (i.e. ventricular tachycardia, flutter fibrillation; ventricular premature complexes occurring close to the preceding T- wave, multifocal complexes)\r\n* Myocardial infarction within 14 days prior to the date of proposed Definity administration\r\n* Uncontrolled systemic hypertension (systolic blood pressure [BP] > 180 mm Hg and/or diastolic BP > 100 mm Hg) despite optimal medical management
Active cardiac disease including any of the following:\r\n* Severe congestive heart failure (class IV in accordance with the classification of the New York Heart Association)\r\n* Unstable angina\r\n* Severe arrhythmia (i.e. ventricular tachycardia, flutter fibrillation; ventricular premature complexes occurring close to the preceding T-wave, multifocal complexes)\r\n* Myocardial infarction within 1 year prior to the date of proposed Definity administration\r\n* Uncontrolled systemic hypertension (systolic blood pressure [BP] > 150 mmHg and/or diastolic BP > 90 mmHg despite optimal medical management)
Any medical condition that in the opinion of the investigator puts the patient at risk of potentially serious complications while on this therapy; specifically, uncontrolled hypertension (systolic > 150 and/or diastolic > 100), unstable angina, congestive heart failure of any New York Heart Association (NYHA) classification, serious cardiac arrhythmia requiring treatment (exception: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment
History or evidence of cardiovascular risk including any of the following: \r\n* Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina\r\n* History of serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia)\r\n* History of myocardial infarction within 6 months of day 1 of dosing \r\n* History of congestive heart failure (CHF) of New York Heart Association (NYHA) criteria
Potentially life-threatening arrhythmia; myocardial infarct within the previous 3 months; unstable angina, or angina at rest; congestive heart failure (New York Heart Association Functional Classification class II or worse), uncontrolled hypertension (systolic blood pressure [BP] > 160 or diastolic BP > 100)
Uncontrolled hypertension (systolic blood pressure [BP] > 150 millimeters of mercury [mmHg] and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure (CHF) of any New York Heart Association (NYHA) classification (Class II or greater), serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment
Clinically significant cardiovascular disease including:\r\n* GROUP 2 (trametinib arm): LVEF < LLN\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months\r\n* Uncontrolled angina within 3 months\r\n* GROUP 1 and GROUP 3 (non-trametinib arms): Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is >= 45%\r\n* GROUP 2 (trametinib arm): Any history of congestive heart failure of any NYHA class for patients assigned to Group 2 (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 < 86 millimeters of mercury (mmHg) at the screening visit\r\n* Bradycardia as indicated by a heart rate of < 40 beats per minute on the screening electrocardiogram (ECG)\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 160 mmHG and/or diastolic > 95 mmHG which cannot be controlled by anti-hypertensive therapy\r\n* Corrected QT interval (QTC) >= 480 milliseconds\r\n* Known cardiac metastases