Patient history: patients who have any of the following are NOT eligible:\r\n* Central nervous system (CNS): Symptomatic, untreated, or uncontrolled brain metastases present\r\n* Heme: Active bleeding or bleeding diathesis\r\n* Gastrointestinal (GI):\r\n** Abdominal fistula, GI perforation, or intra-abdominal abscess within  days prior to registration\r\n** Acute GI bleed within  days of registration\r\n* Diabetes mellitus: Patients with diabetes mellitus with inadequate control, based on either a glycosylated hemoglobin (Hgb Ac) of > . or fasting blood glucose above or equal to  mg/dL\r\n* Cardiac and vascular disorders:\r\n** History of congenital long QT syndrome or torsades de pointes\r\n** Any arrhythmia that is currently not rate-controlled (rate between  and )\r\n** Prolongation of corrected QT interval via Fridericias formula (QTcF) >  msec\r\n** Ongoing unstable angina\r\n** Symptomatic peripheral vascular disease\r\n** Arterial thrombosis within  days of registration including transient ischemic attack (TIA), cerebrovascular accident (CVA), myocardial infarction (MI)\r\n** Patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) must be on a stable dose of anticoagulation for  days prior to registration\r\n** Uncontrolled hypertension, defined as blood pressure (BP) > /\r\n** Multi gated acquisition scan (MUGA) with ejection fraction (EF), % or echocardiogram (echo) with low EF\r\n** Class III or IV congestive heart failure (CHF) within  days of registration
Significant cardiovascular or cerebrovascular disease including:\r\n* Uncontrolled hypertension (systolic blood pressure [SBP] >= ; diastolic blood pressure [DBP] >= )\r\n* History of myocardial infarction within  months\r\n* Unstable angina\r\n* New York Heart Association functional classification II, III or IV\r\n* Baseline ejection fraction =< % as assessed by echocardiogram or multi-gated acquisition (MUGA)\r\n* Cerebral vascular accident (CVA) or transient ischemic attack (TIA) within  months\r\n* Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or peripheral arterial thrombosis) within  months
Known cardiopulmonary disease defined as having one or more of the following:\r\n* Uncontrolled high blood pressure (i.e. systolic >  mmHg or diastolic >  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  months of first dose of study drug are excluded; patients with a history of ischemic heart disease who have had revascularization greater than  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  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  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  months\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\r\n* Uncontrolled hypertension as indicated by a resting systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg at the screening visit
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 >  mmHg or diastolic >  mmHg); or any of the following occurring within  months ( 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
Patients with clinically significant cardiovascular disease are excluded\r\n* Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] >  mmHg and/or diastolic blood pressure [DBP] >  mmHg despite antihypertensive medication)\r\n* History of cerebrovascular accident (CVA) within  months\r\n* Myocardial infarction or unstable angina within  months\r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
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 >  mmHg or diastolic > mmHg). Or any of the following occurring within  months ( 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 mg 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] >=  mmHg or diastolic BP >=  mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment (systolic BP < mmHg or diastolic BP < 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  months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of < % at baseline, or clinically significant ventricular arrhythmias within  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 =<  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 cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within  months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class  or  congestive heart failure; or uncontrolled Grade ? hypertension (diastolic blood pressure ? mmHg or systolic blood pressure ? mmHg) despite antihypertensive therapy.
Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:\r\n* Cardiovascular disorders:\r\n** Uncontrolled hypertension defined as sustained blood pressure (BP) >  mmHg systolic or >  mmHg diastolic despite optimal antihypertensive treatment\r\n** Congestive heart failure New York Heart Association class  or , unstable angina pectoris, serious cardiac arrhythmias\r\n** Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within  months before first dose\r\n* Any history of congenital long QT syndrome\r\n* Presence of a non-healing wound\r\n* Other clinically significant disorders that would preclude safe study participation including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, psychiatric conditions with active suicidal ideation within the past year; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
Known cardiopulmonary disease defined as:\r\n* Unstable angina pectoris\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV)\r\n* Myocardial infarction within  months prior to first dose (patients who had ischemic heart disease such as acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization more than  months prior to enrollment and who are without cardiac symptoms may enroll)\r\n* Cardiomyopathy\r\n* Clinically significant cardiac arrhythmia\r\n** History of polymorphic ventricular fibrillation or Torsade de Pointes\r\n** Permanent atrial fibrillation (a fib), defined as continuous a fib for ?  months\r\n** Persistent a fib, defined as sustained a fib lasting >  days and/or requiring cardioversion in the  weeks before screening\r\n** Grade  a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker) or ablation\r\n** Patients with Paroxysmal a fib or < grade  a fib for a period of at least  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
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; in addition, subjects will be excluded for any of the following:\r\n* Myocardial infarction or arterial or venous thromboembolic events within  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] > /diastolic blood pressure [DBP] >  despite medical intervention)\r\n* History of myocarditis of any etiology\r\n* History of cardiac surgery\r\n* History of ventricular arrhythmias
Known cardiopulmonary disease defined as one of the following:\r\n* Uncontrolled high blood pressure (ie, systolic blood pressure >  mm Hg, diastolic blood pressure >  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  atrial fibrillation (a fib) for a period of at least  months may enroll; grade  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  weeks before screening), myocardial infarction and/or revascularization (eg, coronary artery bypass graft, stent) within  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  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 (<  months prior to the first planned dose of study drugs), myocardial infarction (<  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] > / diastolic blood pressure [DBP] > )
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  months; cardiac ventricular arrhythmias requiring anti-arrhythmic therapy; or thrombotic/embolic events such as cerebrovascular accident, including transient ischemic attacks within the past  months; uncontrolled hypertension defined as systolic blood pressure >  mmHg or diastolic pressure >  mmHg, despite optimal medical management; known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C; known grade  or  neurotoxicity
Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA) class  or  congestive heart failure, myocardial infarction within the previous  months, unstable angina pectoris, uncontrolled hypertension (defined as an average systolic blood pressure [SBP] over  or a diastolic blood pressure [DBP] over  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  months, history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (blood pressure of > / 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] ?/ 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 > beats per minute (bpm). Unstable ischemic heart disease (myocardial infarction within  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  months of trial enrollment\r\n* Unstable angina within  months of trial enrollment\r\n* Congestive heart failure (CHF) with  months prior to trial enrollment\r\n* Any history of ventricular arrhythmia\r\n* Cerebrovascular accident or transient ischemic attack within  months of D of treatment\r\n* Clinically significant atrial arrhythmia or severe baseline bradycardia defined as resting heart rate <  beat per minute\r\n* Uncontrolled hypertension defined as baseline systolic blood pressure (SBP) >  and diastolic blood pressure (DBP) >  on  separate clinic visits or past history of hypertensive urgency, emergency or encephalopathy
Serious intercurrent illness such as:\r\n* Hypertension (two or more blood pressure readings performed at screening of >  mmHg systolic or >  mmHg diastolic) despite optimal treatment\r\n* Non-healing wound or ulcer\r\n* Uncontrolled life threatening cardiac arrhythmias\r\n* Untreated hypothyroidism\r\n* Uncontrolled active infection\r\n* Symptomatic congestive heart failure or unstable angina pectoris within  months prior to study drug\r\n* Myocardial infarction, stroke, transient ischemic attack within  months\r\n* Gastrointestinal perforation, abdominal fistula, intra-abdominal abscess within  year
Any other serious illness or medical condition or social circumstance that might interfere with the subjects 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  months prior to study entry\r\n* Uncontrolled hypertension (systolic blood pressure [BP] >  mmHg despite  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 > . mIU/L)\r\n* Substance abuse
Patients with significant cardiac history including:\r\n* Severe or unstable angina pectoris\r\n* Uncontrolled hypertension (defined as systolic blood pressure [BP] >=  mmHg or diastolic BP >=  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  months\r\n* Class II-IV heart failure (as defined by New York Heart Association) or a cardiac ejection fraction measurement of less than % 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 >  mm Hg, diastolic blood pressure >  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 >=  months; persistent a fib defined as sustained a fib lasting >  days and/or requiring cardioversion in the  weeks before screening; however, patients with < grade  atrial fibrillation (a fib) for a period of at least  months may enroll; grade  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  weeks before screening),\r\n* Myocardial infarction and/or revascularization (eg, coronary artery bypass graft, stent) within  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  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 >  mmHg or diastolic >  mmHg); or any of the following occurring within  months ( 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 patients 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  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] > /diastolic blood pressure [DBP] >  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 patients 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  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) >  mmHg and/or diastolic blood Pressure (DBP) >  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  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  or  congestive heart failure; uncontrolled Grade ? hypertension (diastolic blood pressure ? mmHg or systolic blood pressure ? mmHg) despite antihypertensive therapy; or history of congenital prolonged QT syndrome.
Participant has a clinically significant cardiovascular disease including:\r\n* Uncontrolled hypertension, defined as systolic >  mmHg or diastolic >  mmHg\r\n* Myocardial infarction or unstable angina within  months prior to enrollment\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure \r\n* Participant has a grade II or greater peripheral vascular disease\r\n* Participant has a clinically significant peripheral artery disease (e.g. those with claudication, within  months)
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 >  mmHg or diastolic >  mmHg) or cardiac arrhythmias requiring anti-arrrhythmic therapy.
Cardiac conditions as follows: \r\n Uncontrolled hypertension (BP ? / mmHg, despite medical therapy) \r\n Left ventricular ejection fraction (LVEF) < %, measured by echocardiography \r\n Atrial fibrillation with a ventricular rate >  bpm on ECG at rest \r\n Symptomatic heart failure (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 within  months prior to starting treatment
History of serious systemic disease, including myocardial infarction or unstable angina within the last  months, history of hypertensive crisis or hypertensive encephalopathy, uncontrolled hypertension (blood pressure of > / 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  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] >=  mmHg or diastolic blood pressure [DBP] >=  mmHg while on anti-hypertensive medications) or history of hypertensive crisis or hypertensive encephalopathy, stroke, TIA, symptomatic peripheral vascular disease, or grade  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 >  mmHg systolic or >  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  months prior study drug\r\n* Myocardial infarction, stroke, transient ischemic attack within  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 >  mmHg systolic and >  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.]  or >), myocardial infarction, unstable angina pectoris within the past  months
Patients with clinically significant cardiovascular disease are excluded\r\n* Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] >  mmHg and/or diastolic blood pressure [DBP] >  mmHg despite antihypertensive medication)\r\n* History of cerebrovascular accident (CVA) within  months (see additional requirement for adjuvant protocols)\r\n* Myocardial infarction or unstable angina within  months (see additional requirement for adjuvant protocols)\r\n* New York Heart Association grade II or greater congestive heart failure \r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
Cardiac conditions as follows:\r\n* Uncontrolled hypertension (blood pressure [BP] >=/ mmHg despite medical therapy)\r\n* Left ventricular ejection fraction < % measured by echocardiography\r\n* Atrial fibrillation with a ventricular rate >  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 =<  months prior to registration
Known cardiopulmonary disease defined as:\r\n* Unstable angina\r\n* Congestive heart failure (New York Heart Association class III or IV)\r\n* Myocardial infarction (MI) within  months prior to first dose of pevonedistat (patients who had ischemic heart disease resulting in MI and/or revascularization greater than  months before treatment and who are without cardiac symptoms may enroll)\r\n* Cardiomyopathy\r\n* Left ventricular ejection fraction < % as assessed by echocardiogram or radionuclide angiography\r\n* Clinically significant arrhythmia:\r\n** History of polymorphic ventricular fibrillation or torsade de pointes\r\n** Permanent atrial fibrillation [a fib], defined as continuous a fib for >=  months\r\n** Persistent a fib, defined as sustained a fib lasting >  days and/or requiring cardioversion in the  weeks before screening\r\n** Grade  a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and \r\n** Patients with paroxysmal a fib or < grade (Gr)  a fib for period of at least  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
Known cardiopulmonary disease defined as one of the following:\r\n* Unstable angina\r\n* Uncontrolled high blood pressure (ie, systolic blood pressure >  mmHg, diastolic blood pressure >  mm Hg )\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV)\r\n* Myocardial infarction (MI) within  months prior to first dose (patients who had ischemic heart disease such as a (acute chest syndrome [ACS]), MI, and/or revascularization greater than  months before screening and who are without cardiac symptoms may enroll)\r\n* Cardiomyopathy\r\n* Clinically significant arrhythmia: ) History of polymorphic ventricular fibrillation or torsade de pointes, ) Permanent atrial fibrillation [a fib], defined as continuous a fib for >=  months, ) Persistent a fib, defined as sustained a fib lasting >  days and/or requiring cardioversion in the  weeks before screening, ) grade  a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and ) Patients with paroxysmal a fib or < grade (Gr)  a fib for period of at least  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 >=  msec. calculated according to institutional guidelines\r\n* Left ventricular ejection fraction (LVEF) ? % as assessed by echocardiogram or radionuclide angiography
Active cardiac conditions, including any of the following:\r\n* Uncontrolled hypertension (blood pressure [BP] > / mmHg despite medical therapy)\r\n* Acute coronary syndrome within  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) < % measured by either echocardiography or multigated acquisition (MUGA) scan\r\n* Severe valvular heart disease\r\n* Atrial fibrillation with ventricular rate >  beats per minute (bpm) on electrocardiogram (EKG) at rest
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator; systolic blood pressure higher than  millimeter of mercury (mmHg) or diastolic blood pressure higher than  mmHg found on  separate occasions separated by  week, despite adequate therapy, will be defined as uncontrolled hypertension; uncontrolled diabetes mellitus (despite therapeutic, compliance intervention) as defined by a hemoglobin Ac (HbAc) level more than % and/or occurrence of more than  episodes of ketoacidosis in the  months prior to the first dose of study drug.
The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:\r\n* 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) >  mmHg systolic, or >  mmHg diastolic despite optimal antihypertensive treatment within  days of the first dose of study treatment\r\n** Any history of congenital long QT syndrome\r\n** Any of the following within  months before the first dose of study treatment:\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\r\n*** Thromboembolic event requiring therapeutic anticoagulation (note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)
Cardiac conditions as follows:\r\n* Active coronary artery disease, unstable or newly diagnosed angina or myocardial infarction less than  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] >  mmHg and diastolic BP >  mmHg for  hours) despite optimal medical management; blood pressure must be below / mmHg at screening; subjects with a history of hypertension who are receiving treatment with calcium channel blockers that are cytochrome P, family , subfamily A, polypeptide  (CYPA) 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 >  msec\r\n* Subjects with valvular heart disease Common Terminology Criteria for Adverse Events (CTCAE) (version .) grade \r\n* Known left ventricular ejection fraction (LVEF) < %
Patients with clinically significant cardiovascular disease; this includes:\r\n* Uncontrolled hypertension, defined as systolic greater than  mmHg or diastolic greater than  mmHg\r\n* Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry\r\n* Congenital long QT syndrome or baseline QTc greater than  milliseconds\r\n* Myocardial infarction or unstable angina within  months prior to registration\r\n* New York Heart Association (NYHA) class III or greater congestive heart failure\r\n* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate\r\n* Patients who have received prior treatment with an anthracycline (including doxorubicin, excluding liposomal doxorubicin) must have an echocardiogram or multigated acquisition scan (MUGA) assessment and are excluded if they have an ejection fraction less than %\r\n* CTCAE v.. grade  or greater peripheral vascular disease (at least brief less than  hours [hrs]) episodes of ischemia managed non-surgically and without permanent deficit\r\n* History of cardiac angioplasty or stenting within  months prior to registration; history of coronary artery bypass graft surgery within  months prior to registration\r\n* Arterial thrombosis within  months prior to registration
Uncontrolled hypertension (systolic blood pressure [BP] greater than [>]  millimeters of mercury [mmHg] and/or diastolic BP >  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  months of enrollment
No cardiac risk factors including:\r\n* Uncontrolled high blood pressure (systolic blood pressure > )\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
Other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension (blood pressure ? / mmHg).
Uncontrolled hypertension (sustained systolic >  mmHg and/or diastolic >  mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including: myocardial infarction or unstable angina within =<  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  months prior of study enrollment; prior history of hypertensive crisis or hypertensive encephalopathy
Patients with clinically significant cardiovascular disease are excluded\r\n* Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] >=  mmHg and/or diastolic blood pressure [DBP] >=  mmHg despite antihypertensive medication)\r\n* History of cerebrovascular accident (CVA) within  months\r\n* Myocardial infarction or unstable angina within  months\r\n* New York Heart Association class II or greater congestive heart failure \r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
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 < %, 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 >  mmHg or a diastolic BP of >  mmHg), and must have a normal blood pressure (=< / mmHg) taken in the clinic setting by a medical professional within  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 >  msec or other significant electrocardiogram (ECG) abnormality noted during screening
The subject has serious intercurrent illness, such as:\r\n* Hypertension (two or more blood pressure [BP] readings performed at screening of >  mmHg systolic or >  mmHg diastolic) despite optimal treatment\r\n* Non-healing wound, ulcer, or bone fracture\r\n* Significant cardiac arrhythmias\r\n* Untreated hypothyroidism\r\n* Uncontrolled active infection\r\n* Symptomatic congestive heart failure or unstable angina pectoris within  months prior study drug\r\n* Myocardial infarction, stroke, transient ischemic attack within  months\r\n* Gastrointestinal perforation, abdominal fistula, intra-abdominal abscess within  year\r\n* History or clinical evidence of pancreatitis within  years
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] >  or diastolic blood pressure [BP] > )
Patient with impaired cardiac function or any clinically significant uncontrolled cardiac disease, and/or, cardiac repolarization abnormality, including any of the following: Clinically significant heart disease such as CHF requiring treatment (NYH grade ? ), history of angina pectoris, myocardial infarction, symptomatic pericarditis, or coronary artery bypass graft (CABG) within  months prior to study entry, documented cardiomyopathy, or left ventricular ejection fraction (LVEF) < % as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO). Uncontrolled systolic blood pressure (SBP) ? mmHg and/or diastolic blood pressure (DBP) ? mmHg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to screening, Systolic blood pressure (SBP) < mmHg Standard -lead ECG values defined as the mean of the triplicate ECGs and assessed by central laboratory
Cardiac risk factors including: ) uncontrolled high blood pressure (systolic blood pressure > ); ) unstable angina; ) history of documented myocardial infarction or cerebrovascular accident; ) New York Heart Association class III or IV heart failure
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 (>=  mmHg systolic and/or  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 =<  months prior to registration/randomization\r\n* Clinically significant peripheral vascular disease\r\n* Deep venous thrombosis or pulmonary embolus =<  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  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 =<  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) =<  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] > /) despite optimal therapy, uncontrolled angina, ventricular arrhythmias, congestive heart failure (New York Heart Association class II or above), baseline left ventricular ejection fraction (LVEF) =< %, prior or current cardiomyopathy, atrial fibrillation with heart rate >  beats per minute (bpm), unstable ischemic heart disease (myocardial infarction [MI] within  months prior to starting treatment or angina requiring use of nitrates more than once weekly)
Unstable angina, congestive heart failure (New York Heart Association (NYHA) > class II), uncontrolled hypertension (diastolic blood pressure >  mmHg), or recent (within  year) myocardial infarction
Patients who have any severe and/or uncontrolled medical conditions or other\r\nconditions that could affect their participation in the study such as:\r\n* Known cardiopulmonary disease defined as:\r\n** Unstable angina\r\n** Congestive heart failure (New York Hear Association [NYHA] class III or IV\r\n** Myocardial infarction (MI) within  months prior to first dose (patients who had ischemic heart disease such as acute chest syndrome [ACS], MI and/or revascularization greater than  months before screening and who are without cardiac symptoms may enroll)\r\n** Cardiomyopathy\r\n** Clinically significant arrhythmia:\r\n*** Polymorphic ventricular fibrillation or torsade de pointes\r\n*** Permanent atrial fibrillation [a fib], defined as continuous a fib >=  months\r\n*** Persistent a fib, defined as sustained a fib lasting >  days and/or requiring cardioversion in the  weeks before screening\r\n*** Grade  a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation\r\n*** Patients with paroxysmal a fib or < grade (Gr)  a fib for period of at least  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** Symptomatic pulmonary hypertension\r\n* Active infection requiring IV antibiotic, antiviral, or anti-fungal medications within  weeks of starting study drug\r\n* Known history of human immunodeficiency virus (HIV) seropositivity
Unstable angina, congestive heart failure (New York Heart Association (NYHA) > Class II), uncontrolled hypertension (diastolic blood pressure > mmHg), or recent (within  year) myocardial infarction
Significant cardiovascular disease, including\r\n* Uncontrolled hypertension: systolic blood pressure >  mmHg and/or diastolic blood pressure >  mmHg documented on  consecutive measurements taken at least  hours apart\r\n* Myocardial infarction, severe angina, or unstable angina within  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  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 >  mmHg or systolic >  mmHg)\r\n* Clinically significant pericardial effusion
Clinically significant cardiovascular disease, such as:\r\n* Inadequately controlled hypertension (HTN) (for adults: systolic blood pressure [SBP] >  mmHg and/or diastolic blood pressure [DBP] >  mmHg despite antihypertensive medication; for children: please refer to \Grading and management of hypertension for adults and for children  through  years old\ for age-appropriate values indicating >= grade )\r\n* History of cerebrovascular accident (CVA) within  months\r\n* Myocardial infarction or unstable angina within  months\r\n* New York heart association grade II or greater congestive heart failure\r\n* Serious and inadequately controlled cardiac arrhythmia\r\n* Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular disease
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] >=  mmHg or diastolic BP >=  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  months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of <  % 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  months, uncontrolled angina within  months, congestive heart failure New York Heart Association (NYHA) class  or , uncontrolled hypertension as indicated by systolic blood pressure >  mmHg or diastolic blood pressure >  mmHg at the screening visit
Uncontrolled hypertension (sustained systolic >  mmHg and/or diastolic >  mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including:\r\n* Myocardial infarction or unstable angina within =<  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  (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 \r\n* Severe uncontrolled hypertension (systolic blood pressure >=  mmHg and/or diastolic blood pressure >=  mmHg)\r\n* Cardiovascular disease including stroke of myocardial infarction =<  months prior to study enrollment, New York Heart Association grade  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 >= + or  hour [hr] urine >  gm/ 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) =<  months prior to study enrollment\r\n* History of hemoptysis (>= / teaspoon of bright red blood per episode) within the last  months\r\n* Evidence of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)\r\n* Current or recent (within  days of study drug start) use of aspirin (>  mg daily), clopidogrel (>  mg daily)\r\n* Recent initiation of full dose oral or parental anticoagulants that have not been in place for at least  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  months of study enrollment
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the last  months), cardiac arrhythmia, history of cerebrovascular accident (CVA) within  months, hypertension (defined as blood pressure of >  mmHg systolic and/or >  mmHg diastolic on medication) history of peripheral vascular disease, or psychiatric illness/social situations that would limit compliance with study requirements
Evidence of current uncontrolled cardiovascular conditions, including sustained hypertension (systolic blood pressure [SBP] >  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  months
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Association class II, III, or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (less than the last  months), cardiac arrhythmia, history of cerebrovascular accident (CVA) within  months; no uncontrolled hypertension (defined as blood pressure of > / mmHg) on medication or, history of peripheral vascular disease
Clinically significant cardiovascular disease, defined as any of the following conditions: i. Uncontrolled hypertension (defined as systolic blood pressure >  mmHg and/or diastolic blood pressure >  mmHg) ii. Prior history of hypertensive crisis or hypertensive encephalopathy iii. Myocardial infarction within  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 < % or below institutional limit of normal f) History of stroke of TIAs within  months prior to Day  g) Grade II or greater peripheral vascular disease within  year prior to study entry or other significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within  months prior to Day  h) Serious, non-healing wound, active ulcer, or untreated bone fracture i) History of abdominal fistula or gastrointestinal perforation within  months prior to Day  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] >= / 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) =< %\r\n* Atrial fibrillation with heart rate >  bpm\r\n* Unstable ischemic heart disease (myocardial infarction [MI] within  months prior to starting treatment, or angina requiring use of nitrates more than once weekly)
Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension (persistent systolic blood pressure >  mmHg and/or diastolic blood pressure >  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  months prior to the first dose of study treatment
Preexisting cardiovascular disease. The only exception being well controlled essential hypertension with a sitting blood pressure (B.P.) of <  systolic and <  diastolic without any evidence of structural heart disease or one episode of myocardial infarction >  months ago. A past history of any of the following conditions is considered as exclusions to study participation:
Significant cardiovascular disease precluding an exercise program, including recent (within  months) myocardial infarction or stroke, pulmonary edema, myocarditis, pericarditis, unstable angina, pulmonary embolism/deep venous thrombosis (PE/DVT), uncontrolled hypertension (systolic blood pressure [SBP] > ; diastolic blood pressure [DBP] > ), uncontrolled arrhythmia, heart failure; or
Subjects with congestive heart failure are not eligible, nor are subjects with myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack (TIA) within the past  months, uncontrolled hypertension (systolic blood pressure [BP] >  or diastolic BP > ), uncontrolled or symptomatic arrhythmia, or grade  or greater peripheral vascular disease
In addition, subjects with any contraindications to exercise testing according to American Heart Association guidelines will not be enrolled; nonetheless, the cardiovascular magnetic resonance (CMR) cardiologist supervising the research portion of the exam will also evaluate each subject for evidence of any contra-indications; the absolute contra-indications include acute myocardial infarction, high-risk unstable angina, uncontrolled cardiac arrhythmias, active endocarditis, symptomatic severe aortic stenosis, decompensated symptomatic heart failure, acute pulmonary embolus or pulmonary infarction, acute non-cardiac disorder that may be aggravated by exercise, acute myocarditis or pericarditis, physical disability that would preclude safe and adequate test performance, and inability to provide consent; the relative contra-indications include left main coronary stenosis, moderate stenotic valvular heart disease, electrolyte abnormalities, tachyarrhythmias or bradyarrhythmias, atrial fibrillation with uncontrolled ventricular rate, hypertrophic cardiomyopathy, and high-degree atrioventricular node block; subjects with uncontrolled hypertension and resting blood pressure exceeding / mmHg will be excluded
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  year prior to the date of proposed Definity administration\r\n* Uncontrolled systemic hypertension (systolic blood pressure [BP] >  mmHg and/or diastolic BP >  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 >  and/or diastolic > ), 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  months of enrollment
History or evidence of cardiovascular risk including any of the following: \r\n* Current uncontrolled hypertension (systolic >  mmHg and/or diastolic >  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  months of day  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  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] >  or diastolic BP > )
Uncontrolled hypertension (systolic blood pressure [BP] >  millimeters of mercury [mmHg] and/or diastolic BP >  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  months of enrollment