History or evidence of cardiovascular risk including any of the following:\r\n* LVEF < LLN (lower limit of normal range)\r\n* A QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators\r\n* Known cardiac metastasesXx_NEWLINE_xXParticipants with any of the following:\r\n* History of myocardial infarction within six months\r\n* Unstable angina\r\n* History of cerebrovascular accident (CVA) within 6 months\r\n* New York Heart Association grade II or greater congestive heart failure\r\n* Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)\r\n* Clinically significant peripheral vascular diseaseXx_NEWLINE_xXHistory of cardiac disease: congestive heart failure (CHF) > New York Heart Association (NYHA) Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).Xx_NEWLINE_xXPatients who have the following risk factors are considered to be at increased risk for cardiac toxicity and must have documented left ventricular ejection fraction (LVEF) by echocardiogram greater than institution’s lower limit of normal (or 55% if threshold for normal not otherwise specified by institutional guidelines) obtained within 3 months\r\n* Prior treatment with anthracyclines\r\n* Prior treatment with trastuzumab\r\n* A New York Heart Association (NYHA) classification of II controlled with treatment\r\n* Prior central thoracic radiation therapy (RT), including RT to the heart.\r\n* History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded)Xx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXPatients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomizationXx_NEWLINE_xXPatients must not have any clinical evidence of congestive heart failure (CHF) (specifically, New York Heart Association [NYHA] class III [moderate] or class IV [severe]) at the time of registration; baseline echocardiogram within 28 days of registration must demonstrate an ejection fraction (EF) >= 50%; patients must have corrected QT (QTc) interval < 500 msec on prestudy electrocardiogram (EKG) and no known history of congenital long QT syndrome; patients must not have experienced unstable angina pectoris, clinically significant cardiac arrhythmias, or stroke (transient ischemic attack [TIA] or other ischemic event) within 3 months prior to registration and not have experienced myocardial infarction or thromboembolic event requiring anticoagulation within 6 months of registration; prestudy EKG must be obtained within 28 days prior to registrationXx_NEWLINE_xXNo 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 infarctionXx_NEWLINE_xXMyocardial infarction or arterial thrombotic event within 6 months, heart failure of New York Heart Association class II or higher, uncontrolled angina, severe uncontrolled ventricular arrhythmiaXx_NEWLINE_xXSubjects with any of the following cardiovascular conditions within the past 6 months\r\n* Cerebrovascular accident (CVA) or transient ischemic attack (TIA)\r\n* Cardiac arrhythmia\r\n* Admission for unstable angina\r\n* Cardiac angioplasty or stenting\r\n* Coronary artery bypass graft surgery\r\n* Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks\r\n* Arterial thrombosis\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; a subject who has a history of class II heart failure and is asymptomatic on treatment may be considered eligibleXx_NEWLINE_xXAny of the following cardiac conditions:\r\n* Documented New York Heart Association (NYHA) class III or IV congestive heart failure\r\n* Myocardial infarction within 6 months prior to randomization\r\n* Unstable angina within 6 months prior to randomization\r\n* Symptomatic arrhythmiaXx_NEWLINE_xXAdequate cardiac function, defined as:\r\n* No electrocardiogram (EKG) evidence of acute ischemia\r\n* No EKG evidence of active, clinically significant conduction system abnormalities\r\n* No EKG evidence of > grade 2 (> 480 ms) corrected QT (QTc) prolongation \r\n* Prior to study entry, any EKG abnormality at screening not felt to put the patient at risk has to be documented by the investigator as not medically significant\r\n* No uncontrolled angina or severe ventricular arrhythmias\r\n* No clinically significant pericardial disease\r\n* No history of myocardial infarction within 6 months prior to registration\r\n* No class 3 or higher New York Heart Association congestive heart failureXx_NEWLINE_xXPatient must not have significant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction within 3 months prior to initiation of treatment, unstable arrhythmias, or unstable angina given the higher risks associated with surgical resectionXx_NEWLINE_xXNew York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 monthsXx_NEWLINE_xXPatient has, in the opinion of the treating investigator, any intercurrent conditions that could pose an undue medical hazard or interfere with the interpretation of the study results; these conditions include, but not limited to: congestive heart failure (New York Heart Association (NYHA) Class III or IV), unstable angina, cardiac arrhythmia requiring treatment, recent (within the prior 6 months) myocardial infarction, acute coronary syndrome or stroke, severe obstructive pulmonary disease, hypertension requiring more than 2 medications for adequate control, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 12 monthsXx_NEWLINE_xXHave the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.Xx_NEWLINE_xXSignificant history of uncontrolled cardiac disease defined as uncontrolled arrhythmias, unstable angina, myocardial infarction within the last 4 months, and uncontrolled congestive heart failure or any class 2 - 4 New York Heart Association classification cardiac diseaseXx_NEWLINE_xXHistory or evidence of increased cardiovascular risk including any of the following: \r\n* Left ventricular ejection fraction (LVEF) < institutional lower limit of normal\r\n* A QT interval corrected for heart rate using the Bazett’s formula >= 480 msec\r\n* Current clinically significant uncontrolled arrhythmias\r\n** Exception: subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* Current >= class II congestive heart failure as defined by New York Heart Association\r\n* Patients with intra-cardiac defibrillators\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on studyXx_NEWLINE_xXPatients must not have clinically significant cardiovascular disease (New York Heart Association class III or IV heart failure), uncontrolled clinically significant atrial or ventricular cardiac arrhythmias, or any of the following within the past 6 months: myocardial infarction, new evidence of transmural infarction on electrocardiogram (ECG), unstable angina, coronary angioplastyXx_NEWLINE_xXPatients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: coronary artery bypass graft, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association Grade ?2, supraventricular arrhythmias including atrial fibrillation, which are uncontrolled, haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other central nervous system bleeding.Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXPatients with a history of any one or more of the following cardiovascular conditions within the past 6 months prior to study enrollment are NOT eligible for participation:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart AssociationXx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXELIGIBILITY CRITERIA - PHASE I (ARMS A, B, C): Patients with New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia may not be enrolledXx_NEWLINE_xXELIGIBILITY CRITERIA - PHASE II (ARM D): Patients with NYHA class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia may not be enrolledXx_NEWLINE_xXMyocardial infarction within six months prior to enrollment or has New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities prior to study entryXx_NEWLINE_xXPatients with active heart disease (New York Heart Association [NYHA] class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months)Xx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXSignificant cardiovascular disease (New York Heart Association Class II or greater), myocardial infarction within the 6 months prior to study entry, unstable angina, or cerebral vascular accident / stroke (< 6 months prior to enrollment), or serious uncontrolled cardiac arrhythmia requiring medication / active intervention, corrected QT interval [QTc] prolongation of > 470ms and/or prior diagnosis of congenital long QT syndrome.Xx_NEWLINE_xXHistory within 6 months prior to treatment of myocardial infarction, severe/unstable angina pectoris, coronary artery bypass grafting (CABG), New York Heart Association (NYHA) class III or IV congestive heart failure (CHF), stroke or transient ischemic attack (TIA)Xx_NEWLINE_xXKnown 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 hypertensionXx_NEWLINE_xXAny of the following cardiac abnormalities:\r\n* Unstable angina pectoris\r\n* Congestive heart failure >= New York Heart Association class 3\r\n* Corrected QT interval (QTc) >= 470 milliseconds calculated using Fridericia‘s correction\r\n* Current or history of pericardial effusion causing hemodynamic compromiseXx_NEWLINE_xXNew York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECGXx_NEWLINE_xXClinically significant cardiac disease, including: NYHA Class III or IV congestive heart failure, unstable angina, acute myocardial infarction within six months of planned first dose, arrhythmia requiring therapy (including torsades de pointes, with the exception of extrasystoles, minor conduction abnormalities, or controlled and well treated chronic atrial fibrillation)Xx_NEWLINE_xXHistory of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to day 1 of protocol therapyXx_NEWLINE_xXReceived treatment for unstable angina within the prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.Xx_NEWLINE_xXKnown history of symptomatic congestive heart failure (New York Heart Association III-IV), symptomatic or poorly controlled cardiac arrhythmia, complete left bundle branch block, bifascicular block, or any clinically significant ST segment and/or T-wave abnormalities, QTcF > 450 msec prior to randomization.Xx_NEWLINE_xXThe subject has an uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure (New York Heart Association class III or IV), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe malnutritionXx_NEWLINE_xXClinically 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 visitXx_NEWLINE_xXActive angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 months of the first dose of study drug, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by medicationXx_NEWLINE_xXHistory of any of the following cardiovascular conditions within 12 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart AssociationXx_NEWLINE_xXActive coronary artery disease requiring treatment, myocardial infarction within the prior year, New York Heart Association grade III or greater congestive heart failure, cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > Class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiographic (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXCongestive heart failure (CHF) New York (NY) Heart Association class III or IV; unstable coronary artery disease (myocardial infarction [MI] more than 6 months prior to study entry is permitted); or serious cardiac arrhythmiaXx_NEWLINE_xXCongestive heart failure (New York Heart Association Class III or IV), myocardial infarction within 12 months before starting study treatment, or unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris.Xx_NEWLINE_xXCongestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris. Previous history of myocardial infarction within 1 year prior to study entry, uncontrolled hypertension or uncontrolled arrhythmiasXx_NEWLINE_xXSignificant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment (including oral anticoagulation)Xx_NEWLINE_xXRecent (within 6 months) history of second degree (Type II) or third degree atrioventricular (AV) block cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting; Class II, III, or IV heart failure, or symptomatic pericarditis.Xx_NEWLINE_xXClinically significant, uncontrolled heart disease and/or recent events including any of the following:\r\n* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening;\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV);\r\n* Documented cardiomyopathy;\r\n* Patient has a left ventricular ejection fraction < 50% as determined by multi-gated acquisition (MUGA) scan or echocardiography\r\n(ECHO) at screening;\r\n* History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrthymias, or conduction abnormality within 12 months of screening;\r\n* Bradycardia (heart rate < 50 at rest), by electrocardiography (ECG) or pulse, at screening;\r\n* Congenital long QT syndrome or family history of long QT syndrome;\r\n* Systolic blood pressure (SBP) > 160 or < 90 mm HgXx_NEWLINE_xXPatients who have a significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmias within 6 months of registration (New York Heart Association [NYHA] classification III-IV)Xx_NEWLINE_xXSignificant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure greater than 115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, or myocardial infarction within 6 months prior to screening, or uncontrolled atrial or ventricular cardiac arrhythmias.Xx_NEWLINE_xXUnstable angina, congestive heart failure [NYHA (New York Heart Association) >class II], uncontrolled hypertension [diastolic > 100 mmHg], uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction, uncontrolled diabetes mellitusXx_NEWLINE_xXHistory of significant cardiovascular disease unless the disease is well-controlled or history of myocardial infarction in the past 6 months; significant cardiac diseases includes second/third degree heart block; significant conduction abnormalities, significant ischemic heart disease; corrected QT (QTc) interval > 480 msec at baseline (using Bazett’s formula and read by local cardiologist); poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea) and inability to tolerate intravenous hydration necessary for study therapy administrationXx_NEWLINE_xXUncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within six months prior to study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease or cardiac amyloidosis.Xx_NEWLINE_xXA history or evidence of cardiovascular risk including any of the following:\r\n* A QT interval corrected for heart rate using the Bazett's formula (QTc) >= 480 msec\r\n* A history or evidence of current clinically significant uncontrolled arrhythmias\r\n** Exception: subjects with atrial fibrillation controlled for > 30 days prior to study day 1\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study day 1\r\n* A history or evidence of current >= class I congestive heart failure as defined by the New York Heart Association (NYHA) guidelines\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators or permanent pacemakers\r\n* Known cardiac metastasesXx_NEWLINE_xXEvidence of New York Heart Association (NYHA) class III or IV cardiac disease, or presence of unstable life-threatening arrhythmia, or history of myocardial infarction during the past 6 monthsXx_NEWLINE_xXUnstable angina or myocardial infarction within 6 months prior cycle 1, day 1, New York Heart Association (NYHA) class III or IV heart failure, left ventricular ejection fraction (LVEF) < 40%, uncontrolled angina, history of severe coronary artery disease, history of torsade de pointes, history of symptomatic pulmonary hypertension, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, corrected QT (QTc) prolongation > 450 msec, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or Qtc >480 msecXx_NEWLINE_xXFor Parts F and H: Cardiac disease including myocardial infarction within 6 months, unstable angina, or New York Heart Association (NYHA) Grade II or greater functional impairment.Xx_NEWLINE_xXHistory of serious organ dysfunction or disease involving the heart (left ventricular ejection fraction < 50%; unstable angina, acute myocardial infarction within 6 months prior to randomization, congestive heart failure New York Heart Association [NYHA] III-IV, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities)Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* A QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec on screening electrocardiography (ECG)\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on studyXx_NEWLINE_xXClinically significant cardiac disease (New York [NY] Heart Association class III or IV), including chronic arrhythmia, or pulmonary diseaseXx_NEWLINE_xXPatients with significant cardiovascular disease are excluded, including:\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 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)\r\n* Coronary or peripheral artery bypass graft within 6 months of screening\r\n* History of class III or IV congestive heart failure, as defined by the New York Heart AssociationXx_NEWLINE_xXPatients 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 deficitXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months prior to randomizationXx_NEWLINE_xXCongestive heart failure (NYHA class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six months prior to first dose.Xx_NEWLINE_xXHistory of symptomatic congestive heart failure ([CHF]; New York Heart Association [NYHA] Classes II-IV), ventricular arrhythmia requiring treatment, current unstable angina, or history of myocardial infarction within 6 months prior to study entryXx_NEWLINE_xXPatient must not have a history of the following within 6 months prior to cycle 1 day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorderXx_NEWLINE_xXThe participant has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, severe malnutrition or psychiatric illness/social situations that would limit compliance with study requirementsXx_NEWLINE_xXThe subject has an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutritionXx_NEWLINE_xXHistory of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification >= 3), angina, myocardial infarction or ventricular arrhythmia.Xx_NEWLINE_xXNew York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.Xx_NEWLINE_xXUncontrolled or significant cardiovascular disease, including any of the following:\r\n* Symptomatic congestive heart failure (>= New York Heart Association Classification class II)\r\n* Cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), or unstable angina\r\n* Uncontrolled hypertension or uncontrolled cardiac arrhythmiaXx_NEWLINE_xXPHASE II EXCLUSION CRITERIA: Uncontrolled or significant cardiovascular disease, including any of the following:\r\n* Symptomatic congestive heart failure (>= New York Heart Association Classification class II)\r\n* Cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), or unstable angina\r\n* Uncontrolled hypertension or uncontrolled cardiac arrhythmiaXx_NEWLINE_xXAny clinically-significant cardiac disease defined as New York Heart Association class III or IV within the past 6 months of Screening, unless, in the opinion of the Investigator, the disease is well-controlledXx_NEWLINE_xXHistory of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following:\r\n* Unstable angina or myocardial infarction\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV)\r\n* Uncontrolled clinically significant arrhythmias.Xx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV cardiac disease, myocardial infarction, within the past 6 months, unstable arrhythmia, or known pericardial disease.Xx_NEWLINE_xXSubject has clinically significant cardiac disease, including significant ischemic coronary disease, congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 6 months before randomization, a history of additional risk factors for torsades de pointes (eg, electrolyte abnormalities, family history of long QT syndrome), or a family history of sudden cardiac death before age 40Xx_NEWLINE_xXSignificant cardiovascular impairment within 6 months prior to the first dose of study drug; history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke, or cardiac arrhythmia associated with significant cardiovascular impairmentXx_NEWLINE_xXSignificant medical history or unstable medical comorbidities, including:\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 important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), e.g. complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval > 250 msec, mean resting corrected QT value (QTc) of > 470 msec\r\n* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, 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 the prolong the QT interval that a patient is unable to stop\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* Active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol\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 ineligibleXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina.Xx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, severe or unstable angina, myocardial infarction, symptomatic congestive heart failure (defined as New York Heart Association grade II or greater), arterial or venous thromboembolic events (e.g., pulmonary embolism), or clinically significant ventricular arrhythmias, significant vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease within 6 months prior to registrationXx_NEWLINE_xX10. Those with New York Heart Association functional classification II, III or IV; active cardiac conditions including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia.Xx_NEWLINE_xXActive cardiac disease defined as symptomatic congestive heart failure, history of New York Heart Association (NYHA) class III or IV heart failure, uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, active angina pectoris, myocardial infarction or coronary intervention within 6 months of registrationXx_NEWLINE_xXSubject had a myocardial infarction within 6 months of enrollment, heart failure (New York Heart Association (NYHA) Class III or IV), uncontrolled angina, severe uncontrolled ventricular arrhythmias, left ventricular ejection fraction (LVEF) ? 40% or evidence of acute ischemia or active conduction system abnormalities.Xx_NEWLINE_xXCurrent 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 allowedXx_NEWLINE_xXThe participant has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, severe malnutrition or psychiatric illness/social situations that would limit compliance with study requirementsXx_NEWLINE_xXHistory of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea).Xx_NEWLINE_xXPatients with known cardiac disease per the New York Heart Association definition such as myocardial infarction, severe or unstable angina, peripheral vascular disease, or congestive heart failure or peripheral vascular disease are not eligibleXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable anginaXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.Xx_NEWLINE_xXNo history of any of the following =< 6 months of registration:\r\n* Myocardial infarction or unstable angina\r\n* New York Heart Association grade III or greater congestive heart failure \r\n* Cerebrovascular accident \r\n* Grade 3 or 4 peripheral ischemia\r\n* Grade 3 or 4 thromboembolic eventXx_NEWLINE_xXHistory of cardiac disease: congestive heart failure (CHF) > New York Heart Association (NYHA) Class II; active coronary artery disease, myocardial infarction or coronary stenting within 6 months prior to randomization; unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).Xx_NEWLINE_xXSevere, active co-morbidity defined as follows:\r\n* Chronic or current active infectious disease requiring systemic antibiotics, antifungal or antiviral treatment\r\n* Known brain or central nervous system metastases or history of uncontrolled seizures\r\n* Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from enrollment, New York Heart Association class III or IV congestive heart failure, and serious arrhythmia requiring medication (this does not include asymptomatic atrial fibrillation with controlled ventricular rate)\r\n* Partial or complete gastrointestinal obstructionXx_NEWLINE_xXAny of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) >= class 2\r\n* Unstable angina pectoris\r\n* Congestive heart failure\r\n* Acute myocardial infarction\r\n* Conduction abnormality not controlled with pacemaker or medication\r\n* Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)\r\n* AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarctionXx_NEWLINE_xXHistory of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), untreated coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), myocardial infarction or atrial thrombotic events within the past 6 months, severe unstable angina, New York Heart Association Class III and IV heart disease or depressed left ventricular ejection fraction (LVEF; previously documented LVEF < 50% without documentation of recovery), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndromeXx_NEWLINE_xXParticipant has had a myocardial infarction within 6 months prior to registration or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.Xx_NEWLINE_xXThe participant has an uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure (New York Heart Association class III or IV), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe malnutritionXx_NEWLINE_xXHistory of significant cardiovascular disease unless the disease is well controlled. Significant cardiac disease includes second/third degree heart block; significant ischemic heart disease; poorly controlled hypertension; congestive heart failure of the New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary activity results in fatigue, palpitation or dyspnea)Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXUncontrolled or significant cardiovascular disease, including any of the following:\r\n* Corrected QT (QTc) interval > 480 msec (mean value and manually verified) at 3 or more time points within a 24 hour period if necessary\r\n* Diagnosed or expected congenital long QT syndrome\r\n* Concurrent congestive heart failure, prior history of class III/IV cardiac disease (New York Heart Association)\r\n* Left ventricular ejection fraction < 50%\r\n* Prior history of cardiac ischemia or cardiac arrhythmia within the last 6 months; coronary angioplasty or stenting in the previous 12 months\r\n* Any history of second or third degree heart block (may be eligible if the subject currently has a pacemaker)\r\n* Uncontrolled hypertension defined as inability to maintain blood pressure below the limit of 140/90 mmHg\r\n* Known pulmonary hypertensionXx_NEWLINE_xXUncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months before study treatment, New York Heart Association Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease or cardiac amyloidosis.Xx_NEWLINE_xXCongestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic cardiac ischemia, unstable angina or myocardial infarction in the previous 6 months prior to first dose, or with a known left ventricular ejection fraction (LVEF) <40%, cardiomyopathy, pericardial disease, clinically relevant cardiac arrhythmia (CTCAE version 4.03 Grade 2 or higher), clinically significant ECG abnormalities, or screening 12-lead ECG showing a baseline prolonged QT interval (baseline QT interval as corrected by Fridericia's formula > 470 msec).Xx_NEWLINE_xXSubjects with the following cardiac risk factors must be excluded: transmural myocardial infarction (MI) within prior 6 months, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack (TIA) or seizure disorder within 6 months prior to study drug administration; in addition, patients with New York Heart Association (NYHA) class III or IV heart failure will be excludedXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXCardiac abnormalities:\r\n* Mean QTc interval >= 480 msec at screening\r\n* Acute coronary syndrome (ACS)/acute myocardial infarction (AMI) –within 24 weeks prior to screening\r\n* Percutaneous coronary intervention (PCI)/percutaneous transluminal coronary angioplasty (PTCA) –within 24 weeks prior to screening\r\n* Symptomatic heart failure – New York Heart Association (NYHA) class >= II symptomsXx_NEWLINE_xXActive coronary artery disease requiring treatment, myocardial infarction within the prior year, New York Heart Association grade III or greater congestive heart failure, cerebro-vascular attack within the prior year, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.Xx_NEWLINE_xXClass III or IV heart failure as defined by the New York Heart Association (NYHA), history of cardiac angioplasty or stenting, documented myocardial infarction or unstable angina within 6 months prior to enrollment, cardiac ejection fraction of < 45%, or other clinically significant cardiac diseaseXx_NEWLINE_xXHave clinically significant cardiac disease (New York Heart Association class III or IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial infarction one year prior to study entry, or grade 2 or higher compromised left ventricular ejection fractionXx_NEWLINE_xXHistory 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: History of immune deficiencies or autoimmune disease; Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval > 470 msec; Uncontrolled hypertension or diabetes mellitus; Another known malignancy that is progressing or requires active treatment; Active infection requiring systemic therapy; Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.Xx_NEWLINE_xXThe patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure [Appendix 1], uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).Xx_NEWLINE_xXWithin 6 months prior to study drug administration, clinically significant cardiovascular/cerebrovascular disease defined as follows: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association classification class >= II), bleeding or pulmonary embolism or cardiac arrhythmias that was severe enough to cause hemodynamic compromiseXx_NEWLINE_xXCongestive heart failure (New York Heart Association Class III or IV), myocardial infarction within 12 months before starting study treatment, or unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris.Xx_NEWLINE_xXSignificant cardiovascular disease (New York Heart Association Class [NYHA] class II or greater); myocardial infarction within 3 month prior to randomization, unstable arrhythmias, unstable angina or a patient with a known left ventricular ejection fraction (LVEF) < 40%Xx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to registrationXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (angina symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina\r\n* Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriateXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure-New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXNew York Heart Association classification III or IV congestive heart failure, known symptomatic coronary artery disease, symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or supraventricular tachycardia [SVT])Xx_NEWLINE_xXPatients with uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to start of study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis may not be enrolled.Xx_NEWLINE_xXNew York Heart Association classification III or IV cardiovascular disease or recent myocardial infarction or unstable angina pectoris or cardiac arrhythmia (< 30 days)Xx_NEWLINE_xXPatients who had had a myocardial infarction within 6 months of enrollment or have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollmentXx_NEWLINE_xXClinically significant heart failure (New York Heart Association [NYHA] > 2), recent myocardial infarction, or symptomatic atrial fibrillationXx_NEWLINE_xXPatients with a serious cardiac condition, such as congestive heart failure; New York Heart Association class III/IV heart disease; unstable angina pectoris; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant despite medical intervention; or arrhythmias that are symptomatic or refractory to medical interventionXx_NEWLINE_xXPatients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:\r\n* New York Heart Association class III or IV cardiac disease, including pre-existing clinically significant arrhythmia, congestive heart failure, or cardiomyopathy\r\n* Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac diseaseXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within four months prior to enrollmentXx_NEWLINE_xXCardiac abnormalities as evidenced by any of the following: History or current clinically significant uncontrolled arrhythmias or hypertension; Clinically significant conduction abnormalities or arrhythmias, subjects with Bundle Branch Block; Presence of cardiac pacemaker; History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA); History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months.Xx_NEWLINE_xXEvidence of current uncontrolled cardiovascular conditions (New York Heart Association [NYHA] class III or IV), including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction within the past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)Xx_NEWLINE_xXClinically significant cardiac dysfunction defined as a history of >= New York Heart Association (NYHA) class II symptoms, angina, congestive heart failure, myocardial infarction, arrhythmias or cardiac dysfunction requiring treatment or discontinuation of chemotherapyXx_NEWLINE_xXHave a history of New York Heart Association (NYHA) Class ?3, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug administrationXx_NEWLINE_xXIf they have New York Heart Association (NYHA) class 3 or 4: myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEphB4HSA or places the patient at undue risk for treatment related complicationsXx_NEWLINE_xXSignificant cardiovascular disease with New York Heart Association (NYHA) class II, III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmiaXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke < 6 months prior to enrollment, myocardial infarction < 6 months prior to enrollment, unstable angina, congestive heart failure (>= New York Heart Association [NYHA] III) or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXNo clinically significant cardiac event such as myocardial infarction; New York Heart Association (NYHA) classification of heart disease >= 2 within 3 months prior to registration for protocol therapyXx_NEWLINE_xXSignificant cardiovascular disease or condition including:\r\n* Congestive heart failure (CHF) currently requiring therapy.\r\n* Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) functional criteria.\r\n* Need for antiarrhythmic medical therapy for a ventricular arrhythmia.\r\n* Severe conduction disturbance (e.g. 3rd degree heart block).\r\n* Unstable angina pectoris (i.e. last episode =< 6 months prior to first dose of protocol-indicated treatment).\r\n* Uncontrolled (per investigator judgment) hypertension.\r\n* Myocardial infarction within 6 months prior to starting trial treatment.\r\n* Fridericia's correction formula (QTcF) > 450 ms in men, or > 470 ms in women.Xx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication.Xx_NEWLINE_xXCurrent 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.)Xx_NEWLINE_xXCongestive heart failure (New York Heart Association class III or IV), myocardial infarction within 12 months before starting study treatment, or unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectorisXx_NEWLINE_xXEXCLUSION - PARTICIPANT: Clinically significant cardiac disease or impaired cardiac function, including any of the following: \r\n* Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade >= 2) uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment\r\n* Fridericia's correction formula (QTcF) > 470 msec for females, or > 450 msec for males, on screening electrocardiography (ECG) or congenital long QT syndrome\r\n* Acute myocardial infarction or unstable angina pectoris < 6 months prior to screeningXx_NEWLINE_xXClinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association classification class > II), or serious cardiac arrhythmia.Xx_NEWLINE_xXClinically significant, uncontrolled heart disease and/or recent events including any of the following:\r\n* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting\r\n* Coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathy\r\n* Patient has a left ventricular ejection fraction < 40% as determined by multigated acquisition (MUGA) scan or echocardiography (ECHO) (MUGA and ECHO are not required prior to enrollment)Xx_NEWLINE_xXNew York Heart Association class 3 or 4 heart failure; myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis, or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEPHB4-HSA or places the patient at undue risk for treatment related complicationsXx_NEWLINE_xXSubject has a history of a major adverse cardiac event, including cerebrovascular accident or myocardial infarction within the prior 6 months, or uncontrolled congestive heart failure (New York Heart Association class 3 or 4) at Screening.Xx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseaseXx_NEWLINE_xXPatient 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* Cardiac arrhythmias not controlled with medication;\r\n* Corrected QT (QTcF) > 470 ms at baselineXx_NEWLINE_xXSignificant cardiac disease as determined by the investigator including:\r\n* Known or suspected cardiac amyloidosis\r\n* Congestive heart failure of class III or IV of the New York Heart Association (NYHA) classification\r\n* Uncontrolled angina, hypertension or arrhythmia\r\n* Myocardial infarction in the past 6 months\r\n* Any uncontrolled or severe cardiovascular disease\r\n* Corrected QT Interval (QTc) > 470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECGXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication; patients with stable rate-controlled atrial fibrillation will be allowed to participateXx_NEWLINE_xXClinically significant cardiac illness including New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or >= grade 3 cardiac arrhythmias noted =< 14 days prior to registrationXx_NEWLINE_xXSubject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:\r\n* New York Heart Association heart failure > class 2\r\n* Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemiaXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease, for example cerebrovascular accidents =< 6 months prior to study enrollment, myocardial infarction =< 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment.Xx_NEWLINE_xXClinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification class >= II), or serious cardiac arrhythmiaXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (class III or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable anginaXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association functional classificationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any ECG abnormality at screening has to be documented by the Investigator as not medically relevantXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease including unstable or newly diagnosed angina or myocardial infarction within 6 months prior to study entry\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Corrected QT interval (QTc) (Fridericia) > 450 msec on two consecutive electrocardiograms (ECGs) (baseline ECG should be repeated if QTc is found to be > 450 msec)Xx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, uncontrolled arrhythmias, unstable angina, non-compensative congestive heart failure, or clinically significant pericardial effusion)Xx_NEWLINE_xXClinically significant cardiovascular/ cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification class > II), or serious cardiac arrhythmia.Xx_NEWLINE_xXSignificant 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 enrollmentXx_NEWLINE_xXAny significant medical conditions, laboratory abnormality, or psychiatric illness that would exclude the subject from participation or interfere with study treatment, monitoring and compliance such as:\r\n* Unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association [NYHA] III or IV), myocardial infarction ? 6 months prior to first study drug, clinically significant and uncontrolled cardiac arrhythmia (e.g. atrial fibrillation/flutter ventricular cardiovascular physiology is allowed), cerebrovascular accidents ? 6 months before study drug start\r\n* Severely impaired lung functionXx_NEWLINE_xXParticipants must not have had uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: \r\n* Myocardial infarction or stroke/transient ischemic attack within the past 6 months\r\n* Uncontrolled angina within the past 3 months\r\n* Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)\r\n* History of other clinically significant heart disease (eg, cardiomyopathy, congestive heart failure with New York Heart Association functional classification III to IV, pericarditis, significant pericardial effusion, or myocarditis)\r\n* Cardiovascular disease-related requirement for daily supplemental oxygen therapyXx_NEWLINE_xXSignificant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drugXx_NEWLINE_xXClinically significant heart disease as evidenced by myocardial infarction, arterial thrombotic events in the past 6 months, severe or unstable angina, class III-IV New York Heart Association heart failureXx_NEWLINE_xXSignificant cardiovascular disease (i.e. New York Heart Association [NYHA] class 3 congestive heart failure; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)Xx_NEWLINE_xXUncontrolled, 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) > 140 mmHg systolic or > 90 mmHg diastolic despite optimal antihypertensive treatment\r\n** Congestive heart failure New York Heart Association class 3 or 4, 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 6 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 studyXx_NEWLINE_xXActive and uncontrolled comorbidities including active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, clinically significant and uncontrolled arrhythmia as judged by the treating physicianXx_NEWLINE_xXCardiac risk factors including:\r\n* Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent\r\n* Patients with a New York Heart Association classification of III or IVXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: acute cerebral vascular accident/stroke (< 6 months prior to enrollment) excluding transient ischemic attack (TIA), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication.Xx_NEWLINE_xXResearch participants with a known history of congestive heart failure (CHF) or cardiac symptoms consistent with New York Heart Association (NYHA) classification III-IV within 6 months prior to Day 1 of protocol treatment, cardiomyopathy, myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications or with clinical history suggestive of the above must have an electrocardiogram (EKG) and echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatmentXx_NEWLINE_xXDocumented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV (see Appendix 12.4) within 6 months prior to their first dose of study drug.Xx_NEWLINE_xXDocumented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of enfortumab vedotin.Xx_NEWLINE_xXUnstable angina, new-onset angina within last 3 months, myocardial infarction within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as New York Heart Association Class II or higherXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening will be documented by the investigator as not medically relevant.Xx_NEWLINE_xXCongestive heart failure (New York Heart Association Class III or IV) or unstable angina pectoris. Previous history of myocardial infarction within 1 year prior to study entry, uncontrolled hypertension or uncontrolled arrhythmiasXx_NEWLINE_xXSignificant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure; myocardial infarction, unstable angina and/or stroke; or LVEF <40% by echocardiogram (ECHO), or by other methods according to institutional practice, obtained within 28 days prior to the start of study treatmentXx_NEWLINE_xXParticipant has a cardiovascular disability status of New York Heart Association Class > 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.Xx_NEWLINE_xXHad any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)Xx_NEWLINE_xXImpaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant cardiac disease including the following: a) New York Heart Association grade III or IV congestive heart failure, b) myocardial infarction within the last 6 monthsXx_NEWLINE_xXCardiac conditions: congestive heart failure, New York Heart Association class 3-4 heart failure, baseline left ventricular ejection fraction (LVEF) < 50%, transmural myocardial infarction, uncontrolled hypertension, angina pectoris requiring medication, clinically significant valvular disease, high-risk arrhythmia in the past 12 monthsXx_NEWLINE_xXSignificant cardiovascular diseases (i.e., uncontrolled hypertension, unstable angina, history of infarction within the past 3 months prior to start of study treatment, congestive heart failure > New York Heart Association (NYHA) II, serious cardiac arrhythmia)Xx_NEWLINE_xXUncontrolled, significant concurrent or recent illness including, but not limited to, the following conditions: a. Cardiovascular disorders including i. congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening ii. concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment iii. any history of congenital long QT syndrome or iv. any of the following within 6 months before the first dose of study treatment: unstable angina pectoris, clinically-significant cardiac arrhythmias, stroke (including transient ischemic attack [TIA], or other ischemic event) within 90 days of the first dose of study treatment, myocardial infarction, clinically significant thromboembolic event within 42 days of randomization requiring therapeutic anticoagulation.Xx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXUncontrolled 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 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 arrhythmiasXx_NEWLINE_xXHistory of myocardial infarction or stroke within 6 months, congestive heart failure greater than New York Heart Associate (NYHA) class II, unstable angina pectoris, unexplained recurrent syncope, cardiac arrhythmia requiring treatment or family history of sudden death from cardiac-related causesXx_NEWLINE_xXSignificant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 months prior to initiation of study treatment, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatmentXx_NEWLINE_xXHistory of myocardial infarction, New York Heart Association (NYHA) class III or IV congestive heart failure, arrhythmia requiring therapy, unstable angina, cardiac or other vascular stenting, angioplasty, or surgery within 6 months prior to the start of study drugXx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseaseXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classification, or history of myocardial infarction within 6 months prior to first dose with study drugXx_NEWLINE_xXKnown 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 hypertensionXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association classification III or IV cardiovascular disease, myocardial infarction =< 6 months prior to registration, unstable angina pectoris or cardiac arrhythmia =< 3 months prior to registration, or cardiac arrhythmiaXx_NEWLINE_xXSignificant cardiovascular disease (New York Heart Associate [NYHA] class II or greater); myocardial infarction within 3 month prior to randomization, unstable arrhythmias, unstable angina or a patient with a known LVEF (left ventricular ejection fraction) < 40%Xx_NEWLINE_xXClinically 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)Xx_NEWLINE_xXParticipants 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 neurotoxicityXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (? New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXNot eligible for more intensive cytotoxic chemotherapy or consolidative autologous stem cell transplant based on one or more of the following:\r\n* Clinically significant heart or lung comorbidities, as reflected by at least 1 of the following:\r\n** Left ventricular ejection fraction (LVEF) =< 50%\r\n** Chronic stable angina or congestive heart failure controlled with medication\r\n** New York Heart Association (NYHA) class III or IV heart failure\r\n** Symptomatic chronic pulmonary disease or requirement for intermittent or continuous oxygen therapy\r\n* Presence of other medical comorbidity or limitation in functional status which the investigator judges to be incompatible with an acceptable risk to the subject with the use of intensive chemotherapy; the associated comorbidity or functional limitation must be clearly documented in the medical record at the time of enrollment ORXx_NEWLINE_xXHistory of myocardial infarction =< 12 months prior to registration, severe/unstable angina, systematic congestive heart failure (CHF) New York Heart Association classification III or IV or CHF requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmiasXx_NEWLINE_xXClinically significant cardiac disease defined by any of the following criteria: a.) New York Heart Association (NYHA) class IV heart failure b.) N-terminal prohormone of brain natriuretic peptide (NT-ProBNP) > 8500 ng/L c.) Symptomatic orthostatic hypotension with supine systolic blood pressure < 90 mm Hg d.) Unstable cardiac arrhythmia e.) Unstable angina f.) Myocardial infarction within the past 6 monthsXx_NEWLINE_xXClinically significant cardiovascular disease including: 1) myocardial infarction within 6 months of screening visit; 2) uncontrolled angina within 3 months of screening visit; 3) 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 >= 50%. 4) history of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes). 5) prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the screening electrocardiogram (ECG) > 470 msec. 6) history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. 7) 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).Xx_NEWLINE_xXSignificant cardiovascular diseases within the past 6 months including uncontrolled congestive heart failure (> New York Heart Association [NYHA] class II), myocardial infarction, unstable angina, or uncontrolled arrhythmiaXx_NEWLINE_xXHas known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension.Xx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), congestive heart failure (>= New York Heart Association [NYHA] class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXCardiovascular disease including unstable angina; therapy for life-threatening cardiac arrhythmia, myocardial infarction, stroke; or NYHA Class III or IV congestive heart failure within the last 3 months prior to initiation of study treatmentXx_NEWLINE_xXMedically 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 participationXx_NEWLINE_xXHas a clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within ?180 days prior to start of study treatment, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXSevere, active co-morbidity defined as follows:\r\n* Chronic or current active infectious disease requiring systemic antibiotics, antifungal or antiviral treatment (with the exception of uncomplicated urinary tract infection [UTI])\r\n* Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from enrollment, New York Heart Association class Ill or IV congestive heart failure, and serious arrhythmia requiring medication (this does not include asymptomatic atrial fibrillation with controlled ventricular rate)\r\n* Partial or complete gastrointestinal obstructionXx_NEWLINE_xXClinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association classification class >= II), serious cardiac arrhythmia, clinically significant bleeding or clinically significant pulmonary embolismXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* LVEF< LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula (QTcB) >= 480 msec;\r\n* History or evidence of current clinically significant uncontrolled arrhythmias\r\n* Clarification: Subjects with atrial fibrillation controlled (defined as not requiring change in cardiac drug dosing, emergency room visit, or hospital admission) for > 30 days prior to dosing are eligible\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study enrollment\r\n* History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy;\r\n* Patients with intra-cardiac defibrillatorsXx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to registration, New York Heart Association (NYHA) class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXHistory 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 diseaseXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication.Xx_NEWLINE_xXHistory of pericarditis or pericardial effusion that had required medical or surgical intervention in the last 6 months, or myocardial infarction or arterial thromboembolic events within 6 months, or experiencing severe or unstable angina, or New York Heart Association (NYHA) class III or IV disease, or a corrected QC (QTc) interval > 0.47 secondsXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, or unstable angina; patients with known left ventricular ejection fraction (LVEF) < 40% will be excluded; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50%, must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriateXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.Xx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (? New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXPatients who are medically unstable, patients who are seriously or terminally ill, and patients whose clinical course is unpredictable; for example:\r\n* Patients on life support or in a critical care unit\r\n* Patients with unstable occlusive disease (e.g., crescendo angina)\r\n* Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia\r\n* Patients with uncontrolled congestive heart failure (New York heart Association [NYHA] class IV)Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association functional classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment on the studyXx_NEWLINE_xXAny significant diseases medical condition, laboratory abnormality, or psychiatric illness that would exclude the subject from participate or interfere with study treatment, monitoring and compliance such as:\r\n* Unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association [NYHA] III or IV), myocardial infarction =< 6 months prior to first study drug, clinically significant and uncontrolled cardiac arrhythmia (e.g. atrial fibrillation/flutter ventricular cardiovascular physiology is allowed), cerebrovascular accidents =< 6 months before study drug start\r\n* Severely impaired lung functionXx_NEWLINE_xXImpaired cardiac function or clinically significant cardiac disease including the following:\r\n* New York Heart Association grade III or IV congestive heart failure\r\n* Myocardial infarction within the last 12 months.\r\n* Subjects with impaired left ventricular ejection fraction (LVEF) (< 50%)Xx_NEWLINE_xXClinically significant (i.e. active) cardiovascular disease: cerebral vascular accident (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXClinically significant cardiovascular abnormalities such as:\r\n* Corrected QT interval (QTc) >= 470 msec\r\n* Angina not well-controlled by medication\r\n* Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac/vascular stenting within 6 months of enrollment\r\n* Symptomatic or documented congestive heart failure that meets New York Heart Association (NYHA) class III to IV definitions\r\n* History of stroke within the last 6 months prior to screeningXx_NEWLINE_xXHistory of clinically significant cardiovascular disease including, but not limited to:\r\n* Myocardial infarction or unstable angina =< 6 months prior to treatment initiation.\r\n* Clinically significant cardiac arrhythmia.\r\n* Deep vein thrombosis, pulmonary embolism, stroke =< 6 months prior to treatment initiation.\r\n* Congestive heart failure (New York Heart Association class III-IV).\r\n* Pericarditis/clinically significant pericardial effusion.\r\n* Myocarditis.\r\n* Endocarditis.Xx_NEWLINE_xXMyocardial infarction within ONE months prior to enrollment or has New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.Xx_NEWLINE_xXCongestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months before first doseXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXCardiac 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)Xx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to:\r\n* Ongoing or active infection\r\n* Left ventricular ejection fraction (LVEF) < 50% as determined by either multigated acquisition (MUGA) scan or echocardiogram (Echo)\r\n* Edema > grade 1\r\n* Documented myocardial infarction or unstable/uncontrolled cardiac disease (e.g., unstable angina, severe arrhythmias, congestive heart failure [New York Heart Association [NYHA] > class II]) within 6 months of study entry\r\n* Arterial thrombosis or vascular ischemic events, such as transient ischemic attack, cerebral infarction, within 6 months prior to study entry\r\n* Serious or non-healing wound\r\n* History of any medical condition including cardiovascular disease or chronic obstructive pulmonary disease (COPD), that in the opinion of the investigator, may increase the risks associated with study participation or study treatments or may interfere with the conduct of the study or interpretation of study results\r\n* Psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirementsXx_NEWLINE_xXSignificant cardiovascular disease, such as:\r\n* New York Heart Association congestive heart failure class II or greater\r\n* Myocardial infarction, unstable angina or unstable arrhythmias within 3 months of enrollment\r\n* History of stroke or TIA within 3 months of enrollment\r\n* Other clinically significant arterial vascular disease within 6 months of enrollment (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis); prior history of adequately treated venous thromboembolism > 7 days prior to cycle 1 day 1 (C1D1) on stable dose of therapeutic anticoagulation is permitted\r\n* Subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriateXx_NEWLINE_xXFOR ALL PHASES (Ib AND II): History of significant cardiac disease:\r\n* Congestive heart failure > New York Heart Association (NYHA) class 2\r\n* Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) \r\n* Myocardial infarction less than 6 months before start of test drug\r\n* Anti-arrhythmic therapy (beta blockers or digoxin are permitted)Xx_NEWLINE_xXSignificant cardiovascular disease such as New York Heart Associate Class III/IV, cardiac failure, myocardial infarction within 6 months prior to enrolment, unstable arrhythmia, or evidence of ischemia on ECG.Xx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to enrollmentXx_NEWLINE_xXClinically-significant cardiac disease:\r\n* Recent myocardial infarction (=< 6 months prior to day 1)\r\n* Unstable angina pectoris\r\n* Uncontrolled congestive heart failure (New York Heart Association > class II)\r\n* Uncontrolled hypertension (>= Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03 grade 3)\r\n* Prior history of hypertensive crisis or hypertensive encephalopathy\r\n* Uncontrolled cardiac arrhythmias\r\n* Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm)\r\n* Severe aortic stenosis\r\n* Clinically significant peripheral vascular disease\r\n* >= Grade 3 cardiac toxicity following prior chemotherapy\r\n* Corrected QT interval (QTc) > 470 for females and > 450 for malesXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Suspected long QT syndrome defined as corrected QT (QTc) interval > 500 milliseconds at baseline\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXParticipant had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class II, III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities, or treatment refractory hypertension defined as a blood pressure of systolic > 140mmHg and/ or diastolic > 90 mmHg which cannot be controlled by anti–hypertensive therapy; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXA history or evidence of cardiovascular risk including any of the following:\r\n* A QT interval corrected for heart rate using the Bazett’s formula (QTcB) >= 480 msec;\r\n* A history or evidence of current clinically significant uncontrolled arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible\r\n* A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to alternate assignment\r\n* A history or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines;\r\n* Patients with intra-cardiac defibrillators;\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapyXx_NEWLINE_xXPatients with following cardiac conditions will be excluded:\r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure\r\n* Myocardial infarction =< 6 months prior to enrollment\r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration =< 6 months prior to enrollment\r\n* History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Left ventricular ejection fraction (LVEF) < LLN\r\n* A QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to -enrollment are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 150 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Known cardiac metastasesXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXClinically significant cardiovascular disease including cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), congestive heart failure with New York Heart Association (NYHA) class II or greater or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXPatients with following cardiac conditions will be excluded:\r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure\r\n* Myocardial infarction =< 6 months prior to enrollment\r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration\r\n* History of severe non-ischemic cardiomyopathyXx_NEWLINE_xXSubject has clinically significant cardiac disease, including: myocardial infarction within 1 year before cycle 1, day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association class III-IV); cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] version 4.03 grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities; screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msecXx_NEWLINE_xXUncontrolled concurrent disease or illness including but not limited to: symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV) per the NYHA classification, unstable angina pectoris, clinically significant cardiac arrhythmia; unstable or untreated cardiac conditions or ejection fraction of < 50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA); diabetes mellitus (i.e. fasting blood glucose > 220 despite acceptable chronic diabetes therapy); psychiatric illness that would limit compliance with study requirements, as determined by the investigator.Xx_NEWLINE_xXConcurrent illness including, but not limited to, ongoing uncontrolled infection, symptomatic New York Heart Association (NYHA) class 3 or 4 congestive heart failure, unstable angina pectoris, or cardiac arrhythmiaXx_NEWLINE_xXPresence of cardiac impairment defined as:\r\n* Prior history of cardiovascular disease including heart failure that meets New York Heart Association (NYHA) class III and IV definitions; OR \r\n* History of myocardial infarction/active ischemic heart disease within one year of study entry; OR \r\n* Uncontrolled dysrhythmias; OR \r\n* Poorly controlled anginaXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXImpaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant cardiac disease including the following: a) New York Heart Association grade III or IV congestive heart failure, b) myocardial infarction within the last 6 monthsXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXPatients with unstable or severe intercurrent medical conditions such as severe heart (New York Heart Association class 3 or 4) or lung (forced expiratory volume in 1 second [FEV1] < 50%) disease, uncontrolled diabetes mellitusXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXNew York Heart Association classification III or IV cardiovascular disease or recent myocardial infarction or unstable angina pectoris or cardiac arrhythmia =< 30 days prior to registrationXx_NEWLINE_xXAny 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 abuseXx_NEWLINE_xXPatients with any of the following cardiac conditions:\r\n* Symptomatic restrictive cardiomyopathy\r\n* Unstable angina within 4 months prior to enrollment\r\n* New York Heart Association functional class III-IV heart failure on active treatment\r\n* Symptomatic pericardial effusionXx_NEWLINE_xXClinically significant (i.e. active) cardiovascular disease (e.g., myocardial infarction or arterial thromboembolic events =< 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, grade II or greater congestive heart failure, or serious cardiac arrhythmia, or a corrected QT (QTc) interval > 470 msec)Xx_NEWLINE_xXPre-existing cardiac conditions as outlined below:\r\n* Congestive heart failure >= New York Heart Association (NYHA) class 2\r\n* Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months); myocardial infarction less than 6 months before the start of study treatment\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)Xx_NEWLINE_xXClinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within =<180 days prior to registration, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome =< 6 months prior to pre-randomizationXx_NEWLINE_xXHas the any of the following cardiac history:\r\n* Active heart disease including myocardial infarction within previous 3 months\r\n* Symptomatic coronary artery disease\r\n* Arrhythmias not controlled by medication\r\n* Unstable angina pectoris\r\n* Uncontrolled or symptomatic congestive heart failure (New York Heart Association [NYHA] class III and IV)Xx_NEWLINE_xXHistory of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac diseases within 12 months of enrollmentXx_NEWLINE_xXMyocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalitiesXx_NEWLINE_xXNew York Heart Association class II - IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.Xx_NEWLINE_xXSignificant cardiovascular disease such as New York Heart Association (NYHA) class III or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 45% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriateXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec (calculated using Friderica's formula: QT/RR0.33) at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.Xx_NEWLINE_xXHas active angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 6 months of randomization, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, or arrhythmias not controlled by medication.Xx_NEWLINE_xXPatients who have the following risk factors are considered to be at increased risk for cardiac toxicities, and must have documented left ventricular ejection fraction (LVEF) by echocardiogram greater than institution’s lower limit of normal (or 55% if threshold for normal not otherwise specified by institutional guidelines) obtained within 3 months\r\n* Prior treatment with anthracyclines\r\n* Prior treatment with trastuzumab\r\n* A New York Heart Association (NYHA) classification of II controlled with treatment\r\n* Prior central thoracic radiation therapy (RT), including RT to the heart\r\n* History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded from the study)Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXClinically significant cardiovascular disease with uncontrolled arrhythmia, New York Association class 3 or 4 congestive heart failure, history of myocardial infarction within 6 months, or prolonged corrected QT (QTc) > 500 msecXx_NEWLINE_xXClinically significant cardiac illness including New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or >= grade 3 cardiac arrhythmias noted =< 14 days prior to registrationXx_NEWLINE_xXMust not have had any unstable angina or myocardial infarction within 4 months prior to enrollment to treatment, New York Heart Association Class (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXClinically significant heart disease, including the following:\r\n* Active severe angina pectoris prior to registration\r\n* Acute myocardial infarction prior to registration\r\n* New York Heart Association classification IV cardiovascular disease or symptomatic class III disease\r\n* Note: patients with any of the above may be allowed after discussion amongst the investigators including the principal investigatorXx_NEWLINE_xXUnstable cardiac disease as defined by one of the following:\r\n* Cardiac events such as myocardial infarction (MI) within the past 6 months\r\n* NYHA (New York Heart Association) heart failure class III-IV\r\n* Uncontrolled atrial fibrillation or hypertensionXx_NEWLINE_xXUncontrolled intercurrent medical condition including, but not limited to:\r\n* Uncontrolled infection\r\n* Symptomatic congestive heart failure (New York Heart Association [NYHA] class III-IV)\r\n* Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening\r\n* Uncontrolled cardiac arrhythmia or arrhythmia requiring medication other than beta blocker\r\n* Psychiatric illness/social situations that would limit compliance with study requirements\r\n* Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, etc.)Xx_NEWLINE_xXCurrent 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)Xx_NEWLINE_xXNew York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECGXx_NEWLINE_xXCardiovascular disease or cerebrovascular disease, for example cerebrovascular accidents or myocardial infarction ? 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or with the potential to interfere with protocol treatment;Xx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of >= 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 monthsXx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication.Xx_NEWLINE_xXSevere co-morbidity that would confer excess risk of surgery, radiation or chemotherapy, defined as follows:\r\n* Unstable angina and/or congestive heart failure within the last 6 months\r\n* Transmural myocardial infarction within the last 6 months\r\n* Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiography (EKG) performed within 14 days of registration\r\n* New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registration\r\n* History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months\r\n* Serious and inadequately controlled cardiac arrhythmiaXx_NEWLINE_xXSubject has clinically significant cardiac disease, including:\r\n* Myocardial infarction within 1 year before cycle 1 day 1, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association class III-IV)\r\n* Uncontrolled cardiac arrhythmia (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4 grade 2:2) or clinically significant electrocardiogram (ECG) abnormalities\r\n* Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msecXx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 50% at baselineXx_NEWLINE_xXHas significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examinationXx_NEWLINE_xXHistory 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 arrhythmiasXx_NEWLINE_xXActive and uncontrolled disease/(active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association [NYHA] class III/IV, clinically significant and uncontrolled arrhythmia) as judged by the treating physicianXx_NEWLINE_xXClinically significant cardiovascular disease with uncontrolled arrhythmia, New York Association class 3 or 4 congestive heart failure, history of myocardial infarction within 6 months, or prolonged corrected QT (QTc) > 500 msecXx_NEWLINE_xXImpaired cardiac function or clinically significant cardiac disease including the following:\r\n* New York Heart Association class III or IV congestive heart failure\r\n* Myocardial infarction within the last 12 months\r\n* Subjects known to have impaired left ventricular ejection fraction (LVEF) according to institutional standardsXx_NEWLINE_xXHistory 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 arrhythmiasXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association functional classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to start of first study treatmentXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXNew York Heart Association class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG)Xx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXPatients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or New York Heart Association class II–IV congestive heart failureXx_NEWLINE_xXCardiac abnormalities as evidenced by any of the following: clinically significant uncontrolled arrhythmias or uncontrolled hypertension; history or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA); history of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months; baseline Corrected QT (QTc) interval using Fridericia's formula >450 milliseconds (msec) or >480 msec in subjects with Bundle Branch Block. QTc value based on single or average of triplicate ECGs obtained over a brief recording periodXx_NEWLINE_xXSignificant cardiovascular disease (i.e. New York Heart Association [NYHA] class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)Xx_NEWLINE_xXPresence of concurrent conditions that, in the opinion of the Investigator and/or Medical Monitor, may compromise the participant's ability to tolerate study treatment or interfere with any aspect of study conduct or interpretation of results. This includes, but is not limited to, unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled and sustained hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality (eg, QTcF >470 msec)Xx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months of initiating therapy on trial, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXPatients with unstable angina, new onset angina within the last 3 months, myocardial infarction within the last 6 months, and current congestive heart failure New York Heart Association class III or higherXx_NEWLINE_xXCardiac conditions as follows:\r\n* Uncontrolled hypertension (blood pressure [BP] >= 170/100 despite optimal therapy)\r\n* Heart failure New York Heart Association (NYHA) class II or above\r\n* If NYHA class I heart failure, left ventricular ejection fraction (LVEF) by multi-gated acquisition scan (MUGA) or echocardiogram (ECHO) is less than 50%\r\n* Unstable ischemic heart disease (myocardial infarction within 6 months prior to starting treatment, or angina requiring use of nitrates more than once weekly)\r\n* Mean resting corrected QT (QTc) interval using the Fridericia formula (QTcF) > 450 msec/male and > 470 msec/female (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome\r\n* Patients with significant ventricular or supraventricular arrhythmias and patients with cardiac conduction abnormalities that are not controlled (e.g. with a pacemaker or medication)Xx_NEWLINE_xXSignificant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > New York heart association ([NYHA] II, serious cardiac arrhythmia, pericardial effusion)Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollmentXx_NEWLINE_xXPatients with a history of New York Heart Association class 3 or 4 heart failure, or history of myocardial infarction, unstable angina, or cerebrovascular accident (CVA) within 6 months of protocol registrationXx_NEWLINE_xXAny life-threatening illness, severe and/or uncontrolled medical condition, or organ system dysfunction, laboratory abnormality, psychiatric illness or other condition which, in the Investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, put the study outcomes at undue risk or affect their participation in the study such as\r\n* Symptomatic, or history of documented congestive heart failure New York Heart Association (NYHA) functional classification III-IV (NYHA) \r\n* Corrected QT interval using Fridericia's formula (QTcF) > 470 msec (unless related to pacemaker) on echocardiogram (EKG) within 21 days of initiation of treatment\r\n* Angina not well-controlled by medication\r\n* Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months prior to enrollmentXx_NEWLINE_xXNo history of myocardial infarction =< 6 months prior to pre-registration or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXParticipant has a clinically significant cardiovascular disease including:\r\n* Uncontrolled hypertension, defined as systolic > 150 mmHg or diastolic > 90 mmHg\r\n* Myocardial infarction or unstable angina within 6 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 6 months)Xx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 2 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXPatients with cardiac disease defined as one of the following are not eligible:\r\n* Congestive heart failure > class II New York Heart Association (NYHA)\r\n* Unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months)\r\n* Myocardial infarction within the past 6 monthsXx_NEWLINE_xXHistory of cardiac disease, including: (a) myocardial infarction within 6 months of the start of study, (b) history of QTc prolongation or QTc >= 450 msec on screening EKG, history of additional risk factors for torsade de pointes (e.g., heart failure, hyperkalemia), and family history of long QT syndrome; (c) use of concomitant drugs that prolong QT/QTc interval; (d) New York Heart Association class III or IV heart disease, (e), active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically signification cardiac arrhythmia requiring therapyXx_NEWLINE_xXActive or clinically significant cardiac disease including any of the following:\r\n* Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment\r\n* Myocardial infarction within 6 months prior to initiating study treatment\r\n* New York Heart Association (NYHA) class III or IV congestive heart failureXx_NEWLINE_xXHistory of myocardial infarction within 6 months before study entry, unstable congestive heart failure (New York Heart Association, NYHA Stage III-IV), angina pectoris, or transient ischemic attack or cardiac arrhythmia requiring medical therapyXx_NEWLINE_xXSignificant active cardiac disease within the previous 6 months including: New York Heart Association (NYHA) class 4 congestive heart failure (CHF), unstable angina, myocardial infarctionXx_NEWLINE_xXSubjects with a history of a cardiovascular illness including: congestive heart failure (New York Heart Association grade III or IV); unstable angina or myocardial infarction within the previous 6 months; or symptomatic cardiac arrhythmia despite medical managementXx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than that related to the primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically significant pericardial effusion)Xx_NEWLINE_xXPatients who have significant cardiac disease, including but not limited to history of congestive heart failure (New York Heart Association Class III/IV; see Appendix 7), unstable angina, or uncontrolled cardiac arrhythmia.Xx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically significant pericardial effusion)Xx_NEWLINE_xXHave New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (> 30 seconds) ventricular tachyarrhythmiasXx_NEWLINE_xXPatients who currently have or have a history of the following within 6 months preceding study entry are not eligible: unstable angina (UA), myocardial infarction (MI), transient ischemic attack (TIA), stroke, deep vein thrombosis (DVT), acute peripheral or pulmonary arterial thromboembolism (PE); clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsades de pointes); New York Heart Association class III or IV heart failureXx_NEWLINE_xXPresence of concurrent conditions that, in the opinion of the Investigator and/or Medical Monitor, may compromise the participant's ability to tolerate study treatment or interfere with any aspect of study conduct or interpretation of results. This includes, but is not limited to, unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled and sustained hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality (eg, QTcF >470 msec)Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXSignificant cardiovascular disease, including:\r\n* Cardiac failure New York Heart Association (NYHA) class III or IV\r\n* Myocardial infarction, severe or unstable angina within 6 months prior to study day 1\r\n* History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation)\r\n* Ventricular cardiac arrhythmias requiring anti-arrhythmic medications\r\n* Known left ventricular ejection fraction (LVEF) =< 50%Xx_NEWLINE_xXHistory of the following within the prior 6 months: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorderXx_NEWLINE_xXHistory 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.Xx_NEWLINE_xXHistory of myocardial infarction (MI) or New York Heart Association (NYHA) Class II-IV congestive heart failure within 6 months of the administration of the first dose of ARQ 751 (MI occurring > 6 months of the first dose of ARQ 751 will be permitted); Grade 2 or worse conduction defect (e.g., right or left bundle branch block)Xx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to start of treatment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXMyocardial infarction or unstable angina within 6 months prior to enrollment or has New York Hospital Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 2 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXPatients with clinically significant cardiovascular disease; this includes:\r\n* Myocardial infarction or unstable angina < 6 months prior to registration\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure\r\n* Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rateXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXHave the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.Xx_NEWLINE_xXActive or clinically significant (or symptomatic) cardiac disease, including active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin within the last 3 months, unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before study day 0Xx_NEWLINE_xXHas New York Heart Association (NYHA) class 3 or 4, myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEphB4HSA or pembrolizumab (MK-3475) or places the patient at undue risk for treatment related complicationsXx_NEWLINE_xXActive or severe hepatic, cardiovascular, or cerebrovascular disease, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, or unstable angina; history of other clinically significant cardiac disease that, in the opinion of the PI or designee, is a contraindication to lymphodepleting chemotherapy, JCAR014 infusion, or durvalumab infusion is also excludedXx_NEWLINE_xXHistory of New York Heart Association class 3-4 congestive heart failure or patients with history myocardial infarction within 6 months of starting study treatmentXx_NEWLINE_xXClinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes), New York Heart Association (NYHA) class III-IV heart disease or cardiac ejection fraction measurement of < 40% at baselineXx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medicationXx_NEWLINE_xXSignificant active cardiac disease within the previous 6 months, including: New York Heart Association (NYHA) class III or IV congestive heart failure; unstable angina or angina requiring surgical or medical intervention, and/or; myocardial infarctionXx_NEWLINE_xXPatient has a clinically significant cardiac disease or impaired cardiac function, such as: \r\n* The presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association class III/IV congestive heart failure, or uncontrolled hypertension \r\n* Documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments) \r\n* Major abnormalities documented by echocardiography (ECHO) with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular [LV] ejection fraction < 50%, evaluation based on the institutional lower limit of normal) \r\n* Predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by computed tomography [CT] scan/magnetic resonance imaging [MRI] with contrast)Xx_NEWLINE_xXClinically significant heart disease, including the following:\r\n* Active severe angina pectoris within 3 months prior to registration\r\n* Acute myocardial infarction within 3 months prior to registration\r\n* New York Heart Association classification IV cardiovascular disease or symptomatic class III disease\r\n** Note: patients with any of the above may be allowed after discussion amongst the investigators including the principal investigatorXx_NEWLINE_xXSerious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IVXx_NEWLINE_xXKnown cardiac disease including any of the following:\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure\r\n* History of myocardial infarction or unstable angina within 6 months prior to day 1\r\n* History of stroke or transient ischemic attack within 6 months prior to day 1Xx_NEWLINE_xXSignificant cardiac disease as determined by the investigator including:\r\n* Known or suspected cardiac amyloidosis\r\n* Congestive heart failure of class III or IV of the New York Heart Association (NYHA) classification\r\n* Uncontrolled angina, hypertension or arrhythmia\r\n* Myocardial infarction in the past 6 months\r\n* Any uncontrolled or severe cardiovascular diseaseXx_NEWLINE_xXEjection fraction (EF) ? 50%; no uncontrolled angina or active cardiac symptoms consistent with congestive heart failure (class III or IV), by the New York Heart Association criteria; no symptomatic ventricular arrhythmias, or electrocardiogram (ECG) evidence of active ischemia; no evidence by echocardiography of severe valvular stenosis or regurgitationXx_NEWLINE_xXPatients must not have significant cardiac co-morbidity including: history of acute coronary syndromes (including myocardial infarction and unstable angina) within 12 months; coronary angioplasty or stenting within 6 months; history or evidence of current >/= class III congestive heart failure as defined by the New York Heart Association (NYHA); patients with intra-cardiac defibrillators or permanent pacemakersXx_NEWLINE_xXSignificant history of uncontrolled cardiac disease including uncontrolled hypertension, unstable angina, cerebrovascular accidents or myocardial infarction within the last 6 months, and New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medicationXx_NEWLINE_xXAny serious medical condition including but not limited to uncontrolled hypertension, uncontrolled congestive heart failure within past 6 months prior to screening (class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification), uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (LVEF) less than 40%, renal failure, active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form; patients with history of cardiac arrhythmias should have cardiac evaluation and clearanceXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, QT prolongation or familial history of QT prolongation, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXNYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry, and/or serious arrhythmia requiring anti-arrhythmic therapyXx_NEWLINE_xXActive or clinically significant cardiac disease including any of the following:\r\n* Unstable angina (e.g., anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment\r\n* Myocardial infarction within 6 months prior to initiating study treatment\r\n* Ventricular arrhythmias requiring anti-arrhythmic therapy other than beta blockers\r\n* New York Heart Association (NYHA) class III or IV congestive heart failureXx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 35 % at baseline, if doneXx_NEWLINE_xXPatients with a history of serious cardiac events defined as: New York Heart Association class 3 or 4 heart failure, or history of myocardial infarction, unstable angina or cerebrovascular accident (CVA) within 6 months of protocol registrationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiography (ECG) abnormality at screening has to be documented by the investigator as not medically relevant\r\n* ECG =< 450 msec for males and =< 470 msec for females required on screening ECGXx_NEWLINE_xXCurrent uncontrolled cardiac disease such as angina or myocardial infarction, congestive heart failure including New York Heart Association functional classification of 3, or arrhythmia requiring treatmentXx_NEWLINE_xXSubjects must have evidence of adequate cardiac function, as defined by the following: absence of New York Heart Association (NYHA) class II, III, or IV congestive heart failure; absence of uncontrolled angina or hypertension; absence of myocardial infarction in the previous 6 months; absence of clinically significant bradycardia, or other uncontrolled cardiac arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0Xx_NEWLINE_xXClinically 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 II-IV heart diseaseXx_NEWLINE_xXClinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment or left ventricular ejection fraction (LVEF) < 50%;Xx_NEWLINE_xXSubjects must not have New York Heart Association (NYHA) class III or IV heart failure, unstable angina, or a history of recent (within 6 months) myocardial infarction or sustained (> 30 seconds) ventricular tachyarrhythmiasXx_NEWLINE_xXPatients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure New York Heart Association [NYHA] class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the studyXx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medicationXx_NEWLINE_xXPatients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure New York Heart Association [NYHA] class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the studyXx_NEWLINE_xXClinically significant heart disease (i.e., active), stroke or myocardial infarction within 6 months prior to enrollment, unstable angina pectoris, congestive heart failure of grade > II according to the New York Heart Association (NYHA), or cardiac arrhythmia requiring specific treatment during the study and that may interfere with the follow-up of the study treatment or poorly controlled by treatmentXx_NEWLINE_xXSignificant cardiac conduction abnormalities, including a history of long QTc syndrome and/or pacemaker, or impaired cardiovascular function such as New York Heart Association classification score >2.Xx_NEWLINE_xXHave clinically significant cardiac disease (New York Heart Association, class III or IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial infarction 1 year prior to study entry, or a known history of grade 2 or higher compromised left ventricular ejection fractionXx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association (NYHA) criteria unstable angina pectoris, or myocardial infarction within 6 months of registration; patients with a history of myocardial infarction or irregular heart rate within 6 months prior to registration should be evaluated by a cardiologist prior to registrationXx_NEWLINE_xXActive or clinically significant cardiac disease including: Congestive heart failure-New York Heart Association (NYHA) > class II, Active coronary artery disease, Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, Unstable angina (anginal symptoms at rest), new onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXClinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4 angina, not well controlled by medication, or myocardial infarction within 6 months)Xx_NEWLINE_xXCardiac syncope, uncompensated New York Heart Association (NYHA) class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, severe orthostatic hypotension, or clinically important autonomic diseaseXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; if for some reason an electrocardiogram is obtained before study enrollment, any abnormalities detected should be documented as clinically irrelevantXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* LVEF < LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators \r\n* Known cardiac metastasesXx_NEWLINE_xXAny of the following cardiac conditions: \r\n* Clinically significant heart disease (New York Heart Association [NYHA] class III or IV) or symptomatic congestive heart failure \r\n* Myocardial infarction =< 6 months prior to enrollment \r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration \r\n* History of severe non-ischemic cardiomyopathy with ejection fraction =< 20%Xx_NEWLINE_xXPatients must not have any of the following: New York Heart Association (NYHA) class 3 or 4 congestive heart failure; myocardial infarction within the past 12 months, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contra-indicates treatment with sEphB4HSA or places the patient at undue risk for treatment related complicationsXx_NEWLINE_xXSignificant cardiac event (eg, myocardial infarction), New York Heart Association (NYHA) classification of heart disease >= 2 within 12 weeks before starting treatment, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmiaXx_NEWLINE_xXKnown 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 visitXx_NEWLINE_xXPHASE II STUDY METASTATIC CASTRATE-RESISTANT PROSTATE CANCER COHORT 4 ELIGIBILITY CRITERIA (MEDI+O ONLY):\r\nThe patient 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 BP >140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal anti-hypertensive treatment (BP must be controlled at screening)\r\n** Any history of congenital long QT syndrome\r\n** Any of the following within 6 months before the first dose of study treatment:\r\n*** Unstable angina pectoris\r\n*** Clinically-significant cardiac arrhythmias with the exception of asymptomatic atrial fibrillation controlled on therapy\r\n*** Stroke (including TIA, or other ischemic event)\r\n*** Myocardial infarction\r\n*** Thromboembolic event requiring therapeutic anti-coagulation (Note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)\r\n*** Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s correction or other significant ECG abnormality noted within 14 days of treatment\r\n* Other clinically significant disorders such as:\r\n** Active infection requiring intravenous treatment within 7 days of starting protocol treatment\r\n** Serious non-healing wound/ulcer/bone fracture (excluding stable compression fracture) within 28 days before the first dose of study treatmentXx_NEWLINE_xXSerious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients’ risk for toxicityXx_NEWLINE_xXHistory of myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of ARQ 092 (MI that occurred > 6 months prior to the first dose of ARQ 092 will be permitted)Xx_NEWLINE_xXActive or clinically significant cardiac disease including any of the following:\r\n* Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment\r\n* Myocardial infarction within 6 months prior to initiating study treatment\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers\r\n* New York Heart Association (NYHA) class III or IV congestive heart failureXx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXPatients with history of serious cardiac events defined as: New York Heart Association class 3 or 4 heart failure, history of myocardial infarction, unstable angina, or cardiovascular accident (CVA) within 6 months of protocol registration; history of PR prolongation or atrioventricular (AV) blockXx_NEWLINE_xXSubject has a clinically significant cardiovascular disease including:\r\n* Uncontrolled hypertension\r\n* Myocardial infarction or unstable angina within 6 months prior to enrollment\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXHave moderate or severe cardiovascular disease:\r\n* Has the presence of cardiac disease, including a myocardial infarction within six months prior to study entry, unstable angina pectoris, New York Heart Association class III/IV congestive heart failure, or uncontrolled hypertension\r\n* Has documented clinically significant electrocardiography (ECG) abnormalities (not responding to medical treatments) or not clinically stable for at least 6 months\r\n* Has major abnormalities documented by echocardiogram (ECHO) with Doppler (for example, moderate or severe heart valve function defect) that is not stable for at least 6 months; Note: left ventricular [LV] ejection fraction < 50% is allowed only if clinically stable for at least 6 months (evaluation based on the institutional lower limit of normal)\r\n* Has predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by computed tomography [CT] scan/magnetic resonance imaging [MRI] with contrast)Xx_NEWLINE_xXPatients with any of the following:\r\n* History of myocardial infarction within six months\r\n* Unstable angina\r\n* Resting electrocardiogram (ECG) with clinically significant abnormal findings\r\n* New York Heart Association (NYHA) classification of III or IVXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 2 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classificationXx_NEWLINE_xXPatients with significant atherosclerotic disease, as defined by: a) myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; b) symptomatic congestive heart failure; c) claudication limiting activity and; d) history of cerebrovascular events within the last year (including transient ischemic attack [TIA]); e) unstable anginaXx_NEWLINE_xXPatients with active heart disease (New York Heart Association [NYHA] class 3-4 as assessed by history and physical examination, unstable angina/stroke/myocardial infarction within the last 6 months)Xx_NEWLINE_xXSignificant cardiovascular disease (New York Heart Association class II or greater); myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, unstable angina or a patient with a known left ventricular ejection fraction (LVEF) < 40%Xx_NEWLINE_xXSignificant cardiac disease (New York Heart Association classes III or IV) or unstable angina despite medicationXx_NEWLINE_xXActive and uncontrolled disease/(active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association [NYHA] class III/IV, clinically significant and uncontrolled arrhythmia) as judged by the treating physicianXx_NEWLINE_xXActive heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, or uncontrolled congestive heart failure (New York Heart Association class III and IV)Xx_NEWLINE_xXEvidence of current uncontrolled cardiovascular conditions, including uncontrolled cardiac conditions such as hypertension, or cardiac arrhythmias, or New York Heart Association stage III and IV congestive heart failure, or unstable angina or myocardial infarction within the past 6 monthsXx_NEWLINE_xXPatients with clinically significant cardiovascular disease: history of ischemic or hemorrhagic stroke within past 6 months; uncontrolled hypertension, on at least 2 repeated determinations on separate days within past 3 months; myocardial infarction or unstable angina within past 6 months; New York Heart Association grade III or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris within past 6 months; clinically significant peripheral vascular disease within past 6 months; pulmonary embolism, deep vein thrombosis (DVT), or other thromboembolic event within past 6 months; diagnosed congenital long QT syndrome; any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes); prolonged QTc interval on pre-entry electrocardiogram (> 450 msec); subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administrationXx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollmentXx_NEWLINE_xXHistory of significant cardiac disease defined as:\r\n* Symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] classes III-IV)\r\n* High-risk uncontrolled arrhythmias; i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia or higher-grade atrioventricular (AV) block (second degree AV-block type 2 [mobitz 2] or third degree AV-block)\r\n* Prolongation of QT interval > 480 msecs\r\n* History of myocardial infarction within last 12 months\r\n* Clinically significant valvular heart disease\r\n* Angina pectoris requiring anti-angina treatment\r\n* Current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg); initiation or adjustment of anti-hypertensive medication is permitted prior to study entryXx_NEWLINE_xXClinically significant cardiac disease, including major cardiac dysfunction, such as uncontrolled angina, clinical congestive heart failure with New York Heart Association (NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy, recent (within 6 months) myocardial infarction or unstable coronary artery diseaseXx_NEWLINE_xXPatient 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)Xx_NEWLINE_xXClinically significant atherosclerotic cardiovascular disease including patients with New York Heart class II/III/IV congestive heart failure (CHF), ventricular arrhythmias requiring medication, myocardial infarction, cerebrovascular accident, transient ischemic attack, coronary artery bypass grafting, angioplasty, cardiac or other vascular stenting within the past 6 monthsXx_NEWLINE_xXMyocardial infarct or unstable angina within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, valvular disease with documented compromise in cardiac function, or electrocardiographic evidence of acute ischemic or active conduction system abnormalitiesXx_NEWLINE_xXPatients with active unstable angina, concomitant clinically significant active arrhythmias, myocardial infarction within 6 months, or congestive heart failure New York Heart Association class III-IV; patients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are excludedXx_NEWLINE_xXUnstable angina or myocardial infarction within 6 months prior to enrollment, NYHA class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* A QT interval corrected for heart rate using the Bazett’s correction formula (QTcB) >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with controlled atrial fibrillation for > 30 days prior to taking study drug are eligible\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to taking study drug\r\n* History or evidence of current >= class II congestive heart failure as defined by New York Heart Association\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by antihypertensive therapy\r\n* Patients with intra-cardiac defibrillators\r\n* Known cardiac metastases\r\n* Subjects with abnormal left ventricular ejection fraction (< 50%) on echocardiogram or multiple-gated acquisition scan (MUGA)Xx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXUnstable cardiovascular function defined as symptomatic ischemia, uncontrolled clinically significant conduction abnormalities (i.e.: ventricular tachycardia on antiarrhythmics are excluded and first [1st] degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXHistory 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 diseaseXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure as defined by the New York Heart AssociationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXCardiac dysfunction defined as myocardial infarction within 6 months of study entry, New York Heart Association Class III or IV heart failure, uncontrolled dysrhythmias or poorly controlled angina.Xx_NEWLINE_xXPatients with any of the following cardiac conditions:\r\n* Symptomatic restrictive cardiomyopathy\r\n* Unstable angina within 4 months prior to enrollment\r\n* New York Heart Association functional class III-IV heart failure on active treatment\r\n* Symptomatic pericardial effusionXx_NEWLINE_xXSevere cardiac insufficiency (New York Heart Association [NYHA] III or IV), with uncontrolled and/or unstable cardiac or coronary artery diseaseXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Left ventricular ejection fraction (LVEF) < LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula (QTcB) >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators\r\n* Known cardiac metastasesXx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXPatients with pre-existing cardiovascular disease requiring ongoing treatment; this includes: a) congestive heart failure class III/IV congestive heart failure (CHF) per New York Heart Association (NYHA) criteria; b) cardiomyopathy; c) uncontrolled cardiac arrhythmia; d) unstable angina pectoris; e) recent myocardial infarction (MI) (within 6 months)Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* An average of the three most recent QT intervals corrected for heart rate using the Bazett’s formula QTcB >= 460 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study\r\n* Prior placement of an implantable defibrillator\r\n* History of or identification on screening imaging of intracardiac metastasesXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Left ventricle ejection fraction (LVEF) < LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to enrollment are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Known cardiac metastases\r\n* Patients with intra-cardiac defibrillatorsXx_NEWLINE_xXNo significant cardiac disease, including the following: unstable angina, New York Heart Association class II-IV congestive heart failure, myocardial infarction within six months prior to study enrollmentXx_NEWLINE_xXPatients with clinically significant cardiovascular co-morbidities including: congestive heart failure (New York Heart Association class III-IV heart disease), unstable angina pectoris, cardiac arrhythmias requiring medication or a pacemaker; myocardial infarction within the past six months; stroke within the past 6 months; or hypertension requiring more than 2 medications for blood pressure control.Xx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXEvidence or history of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)Xx_NEWLINE_xXPatients have clinically significant cardiovascular disease, including any of the following: \r\n* History of acute coronary syndrome including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting < 6 months prior to screening\r\n* Symptomatic chronic heart failure (New York Heart Association criteria, class II-IV)\r\n* Evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening except atrial fibrillation (AF) and paroxysmal supraventricular tachycardia (PSVT)Xx_NEWLINE_xXSignificant cardiovascular disease (i.e. New York Heart Association [NYHA] class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)Xx_NEWLINE_xXMyocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemiaXx_NEWLINE_xXMust not have had any unstable angina or myocardial infarction within 4 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.Xx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia or conduction abnormalities uncontrolled by conventional interventions; myocardial infarction within 6 months of study entryXx_NEWLINE_xXStroke, transient ischemic attack, unstable angina, myocardial infarction or congestive heart failure (New York Heart Association grade II or greater) within the past 12 months; unstable or severe intercurrent medical conditions, chronic renal disease, or uncontrolled diabetes mellitusXx_NEWLINE_xXSerious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, coronary artery disease, myocardial infarction within the past 3 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients’ risk for toxicityXx_NEWLINE_xXPatients must not have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemiaXx_NEWLINE_xXRANDOMIZED PHASE II (ARMS K AND L): Patients must not have NYHA class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemiaXx_NEWLINE_xXRelapsed/refractory MCL: Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months at the time of consent or any class 3 (moderate) or 4 (severe) cardiac disease defined by the New York Heart Association classificationXx_NEWLINE_xXNewly diagnosed MCL: Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months at the time of consent or any class 3 (moderate) or 4 (severe) cardiac disease defined by the New York Heart Association ClassificationXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular accident or myocardial infarction within 6 months prior to randomization), unstable angina, congestive heart failure (New York Heart Association class >= II) or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with administration of study treatmentXx_NEWLINE_xXClinically significant cardiac disease, including major cardiac dysfunction, such as uncontrolled angina, clinical congestive heart failure with New York Heart Association (NYHA) class III or higher, ventricular arrhythmias requiring antiarrhythmic therapy, recent (within 6 months) myocardial infarction or unstable coronary artery diseaseXx_NEWLINE_xXCongestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six monthsXx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within 4months prior to Day 1, unstable arrhythmia or symptomatic peripheral arterial vascular diseaseXx_NEWLINE_xXPatients with any of the following:\r\n* Uncontrolled angina at time of consent OR\r\n* > New York Heart Association (NYHA) class II congestive heart failure at time of consent OR\r\n* Myocardial infarction (MI) within 6 months prior to start of study treatmentXx_NEWLINE_xXPatients with clinically significant cardiovascular disease; this includes: uncontrolled hypertension (greater than 140/90); myocardial infarction or unstable angina within 6 months prior to registration; New York Heart Association (NYHA) grade II or greater congestive heart failure; serious cardiac arrhythmia requiring medication; grade II or greater peripheral vascular disease; patients with clinically significant peripheral artery disease, e.g., those with claudication, within 6 months of first date of treatment on this studyXx_NEWLINE_xXPatients with pre-existing cardiovascular disease requiring ongoing treatment; this includes: congestive heart failure III/IV as defined by New York Heart Association (NYHA); uncontrolled cardiac arrhythmia; unstable angina pectoris; and recent myocardial infarction (MI) (within 6 months)Xx_NEWLINE_xXAdult patients (>= 18 years old) with the following cardiac conditions will be excluded: \r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure \r\n* Myocardial infarction =< 6 months prior to enrollment\r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration\r\n* History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%Xx_NEWLINE_xXImpaired cardiac function or clinically significant cardiac diseases, including any of the following:\r\n* Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia\r\n* Known history of congenital QT prolongation or Torsade de pointes (TdP)\r\n* Complete left bundle branch or bifascicular block\r\n* QTc interval > 450 ms for men or > 470 ms for women\r\n* Persistent or history of clinically meaningful ventricular arrhythmias or atrial fibrillation\r\n* Unstable pectoris or myocardial infarction =< 3 months prior to starting study treatment\r\n* Uncontrolled hypertension (blood pressure >= 160/95 mmHg)\r\n* Other clinically significant heart disease such as congestive heart failure requiring treatmentXx_NEWLINE_xXThose with New York Heart Association functional classification II, III or IV active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia.Xx_NEWLINE_xXClinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association [NYHA] grade ? 2), uncontrolled hypertension or clinically significant arrhythmia currently requiring medical treatmentXx_NEWLINE_xXCardiac 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 registrationXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXActive cardiac disease including any of the following:\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure\r\n* History of myocardial infarction or unstable angina within 6 months prior to day 1\r\n* History of stroke or transient ischemic attack within 6 months prior to day 1 of FOLFIRI + bevacizumab initiationXx_NEWLINE_xXUncontrolled inter-current illness including, but not limited to ongoing or active infection (> grade 2 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version 4.0), congestive heart failure (> New York Heart Association (NYHA) class 2), active coronary artery disease (CAD), cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin), uncontrolled hypertension and any condition which could jeopardize the safety of the patient and his/her compliance in the study; myocardial infarction more than 6 months prior to screening is permittedXx_NEWLINE_xXHistory of significant cardiac disease, particularly uncompensated congestive heart failure New York Heart Association (NYHA) grade 2 or more or left ventricular ejection fraction (LVEF) < 40% on any prior assessment; (assessment of LVEF prior to therapy is not required in the absence of other clinical indicators of heart disease); patients with a prior LVEF < 40% will require-evaluation prior to study entryXx_NEWLINE_xXPatients with following cardiac conditions will be excluded: \r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure\r\n* Myocardial infarction =< 6 months prior to enrollment\r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration\r\n* History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%Xx_NEWLINE_xXPatient has clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina, New York Heart Association Grade 3 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident (CVA)) within 6 months of enrollment.Xx_NEWLINE_xXUncontrolled 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.Xx_NEWLINE_xXCongestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to administration of first dose of study drug.Xx_NEWLINE_xXHistory or evidence of cardiovascular (CV) risk including any of the following: a) Recent (within the past 6 months) history of serious uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third degree atrioventricular block. b) Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before enrollment. c) Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association (NYHA) functional classification system. d) Recent (within the past 6 months) history of symptomatic pericarditis.Xx_NEWLINE_xXHas uncontrolled clinically significant cardiac disease, including myocardial infarction within 6 months before date of study entry or unstable or uncontrolled angina, congestive heart failure, New York Heart Association (NYHA) Class III-IV, uncontrolled cardiac arrhythmia (Grade 2 or higher).Xx_NEWLINE_xXClinically significant (i.e. active) cardiovascular disease for example cerebro vascular accidents (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, New York Heart Association (NYHA) grade II or higher, congestive heart failure, serious cardiac arrhythmia requiring medication.Xx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association [NYHA] class >= II), or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXCriteria 8 Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant electrocardiogram (ECG) abnormalities, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomizationXx_NEWLINE_xXPatients with New York Heart Association Class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50%, or significant uncontrolled cardiac disease, current diagnosis of unstable angina, uncontrolled congestive heart failure, new myocardial infarction, or ventricular arrhythmia requiring medication;Xx_NEWLINE_xXClinically significant cardiovascular disease including:\r\n* LVEF < 45% measured by echocardiogram\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* New York Heart Association (NYHA) class III or IV congestive heart failure\r\n* Clinically significant abnormality on EKG\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 pacemakersXx_NEWLINE_xXSubject has had myocardial infarction within 6 months prior to enrollment , or NYHA(New York Hospital Association) Class III or IV heart failure (see APPENDIX VI), Ejection Fraction < 35%, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalities.Xx_NEWLINE_xXHave unstable angina, clinically significant cardiac arrhythmia, New York Heart Association Class 3 or 4 congestive heart failure, or prolonged QT interval corrected wave of greater than 470 ms.Xx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to randomization, New York Heart Association (NYHA) class III or IV heart failure, left ventricular ejection fraction (LVEF) < 40%, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias including uncontrolled chronic atrial fibrillation/atrial flutter, history of torsades de pointe, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXHistory of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, including New York Heart Association functional classification of threeXx_NEWLINE_xXPatients who have had any of the following cardiac conditions are NOT eligible for participation (unless otherwise noted):\r\n* Unstable angina or myocardial infarction within 4 months prior to registration\r\n* New York Heart Association (NYHA) class III or IV heart failure\r\n* Uncontrolled angina\r\n* A history of severe coronary artery disease\r\n* Severe, uncontrolled ventricular arrhythmias\r\n* Sick sinus syndrome\r\n* Electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities UNLESS the patient has a pacemakerXx_NEWLINE_xXPatient had a myocardial infarction within 6 months of enrollment or has NYHA Class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.Xx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function\r\n* Other clinically significant heart disease such as congestive heart failure requiring treatment (New York Heart Association [NYHA] Class III or IV) or uncontrolled hypertension (please refer to World Health Organization-International Society of Hypertension [WHO-ISH] guidelines)\r\n* Documented cardiomyopathyXx_NEWLINE_xXPatients with clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to enrollment, congestive heart failure (New York Heart Association [NYHA ] III-IV), and arrhythmia unless controlled by therapy (with the exception of extra systoles or minor conduction abnormalities), are NOT eligibleXx_NEWLINE_xXPatient with grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e. congestive heart failure, myocardial infarction within 6 months before baseline) Patient with any condition that the physician judges could be detrimental to subjects participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical events Previous treatmentXx_NEWLINE_xXSignificant cardiac disease including heart failure that meets New York Heart Association (NYHA) class III and IV definitions; history of myocardial infarction within one year of study entry; uncontrolled dysrhythmias; or poorly controlled angina.Xx_NEWLINE_xXCardiac disease, specifically restrictive cardiomyopathy, unstable angina within the last 6 months prior to enrollment, New York Heart Association functional class III-IV heart failure on active treatment with normalized LVEF on therapy, and symptomatic pericardial effusionXx_NEWLINE_xXEvidence of cardiovascular risk including any of the following: Corrected QT interval Fridericia (QTcF) interval >=470 milliseconds (msecs); Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block; History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening; Class III or IV heart failure as defined by the New York Heart Association functional classification system (NYHA); Uncontrolled hypertension.Xx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseaseXx_NEWLINE_xXAny of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) >= class 2\r\n* Unstable angina pectoris\r\n* Congestive heart failure\r\n* Acute myocardial infarction\r\n* Conduction abnormality not controlled with pacemaker or medication\r\n* Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)Xx_NEWLINE_xXIf they have New York Heart Association (NYHA) class 3 or 4; myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEphB4-HSA or places the patient at undue risk for treatment related complicationsXx_NEWLINE_xXEvidence of cardiovascular risk including any of the following: a. Corrected QT (QTc) interval >=470 millisecond (msec); Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block; History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening; Class III or IV heart failure as defined by the New York Heart Association functional classification system; Uncontrolled hypertension.Xx_NEWLINE_xXHistory or current condition of an uncontrolled cardiovascular disease including congestive heart failure NYHA > Class 2, unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months) or myocardial infarction within past 6 months and cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted).Xx_NEWLINE_xXHas significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability, significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogramXx_NEWLINE_xXA cardiovascular disability status of New York Heart Association Class ? 2, defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina painXx_NEWLINE_xXSymptomatic arterial peripheral vascular disease or significant cardiovascular disease or condition including:\r\n* Congestive heart failure (CHF) currently requiring therapy\r\n* Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) functional criteria\r\n* Need for antiarrhythmic medical therapy for a ventricular arrhythmia\r\n* Severe conduction disturbance (e.g. third [3rd] degree heart block)\r\n* Unstable angina pectoris (i.e. last episode =< 6 months prior to first dose of protocol-indicated treatment)\r\n* Uncontrolled (per investigator judgment) hypertension\r\n* Myocardial infarction within 6 months prior to starting trial treatment\r\n* Corrected QT interval by Fridericia (QTcF) > 450 ms in men, or > 470 ms in womenXx_NEWLINE_xXSevere or unstable medical condition, such as congestive heart failure (New York Heart Association [NYHA] Class III or IV), ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an uncontrolled cardiac arrhythmia requiring medication (?grade 2, according to NCI CTCAE v4.03), myocardial infarction within 6 months prior to starting study treatment, or any other significant or unstable concurrent medical illness that in the opinion of the investigator would preclude protocol therapy.Xx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 35 % at baselineXx_NEWLINE_xXSubject has any one of the following:\r\n* Clinically significant abnormal electrocardiogram (ECG) finding at screening\r\n* Congestive heart failure (New York Heart Association class III or IV)\r\n* Myocardial infarction within 12 months prior to starting study treatment\r\n* Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectorisXx_NEWLINE_xXSerious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IVXx_NEWLINE_xXHistory of any of the following cardiovascular conditions within 6 months of enrollment: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, class III or IV congestive heart failure as defined by the New York Heart Association, symptomatic peripheral vascular disease, cerebrovascular accident, or transient ischemic attackXx_NEWLINE_xXSignificant cardiac disease (New York Heart Association classes III or IV) or unstable angina despite medication;Xx_NEWLINE_xXAny of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) >= class 2. a. Unstable angina pectoris; b. Congestive heart failure; c. Acute myocardial infarction; d. Conduction abnormality not controlled with pacemaker or medication; e. Significant ventricular or supraventricular arrhythmias (patients with chronic rate- controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).Xx_NEWLINE_xXPatients who have significant cardiovascular diseases are not eligible; these are:\r\n* Uncontrolled hypertension\r\n* Unstable angina\r\n* History of infarction within the past 12 months prior to start of study treatment\r\n* Congestive heart failure > New York Heart Association (NYHA) II\r\n* Serious uncontrolled cardiac arrhythmia\r\n* Pericardial effusionXx_NEWLINE_xXUncontrolled or significant cardiovascular disease including, but not limited to, any of the following:\r\n* Myocardial infarction or stroke/transient ischemic attack within the past 6 months\r\n* Uncontrolled angina within the past 3 months\r\n* Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)\r\n* QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation > 480 msec\r\n* History of other clinically significant heart disease (e.g. cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, or myocarditis)Xx_NEWLINE_xXRENAL & BLADDER: History of clinically significant cardiovascular disease including, but not limited to:\r\n* Myocardial infarction or unstable angina ? 6 months prior to treatment initiation \r\n* Clinically significant cardiac arrhythmia\r\n* Deep vein thrombosis, pulmonary embolism, stroke ? 6 months prior to treatment initiation\r\n* Congestive heart failure (New York Heart Association class III-IV)\r\n* Pericarditis/clinically significant pericardial effusion\r\n* Myocarditis\r\n* EndocarditisXx_NEWLINE_xXHistory or current evidence of uncontrolled cardiovascular disease including, but not limited to, the following conditions:\r\n* Congestive heart failure of New York Heart Association (NYHA) class III or IV\r\n* Unstable angina (symptoms of angina at rest) or new-onset angina =< 6 months before the start of anetumab ravtansineXx_NEWLINE_xXMyocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) grade III or IV heart failure.Xx_NEWLINE_xXHistory of any of the following cardiovascular conditions within the past 6 months:\r\n* Class III or IV congestive heart failure as defined by the New York Heart Association Criteria\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Symptomatic peripheral vascular disease or other clinically significant cardiac diseaseXx_NEWLINE_xXPatients with cardiovascular (CV) disease conditions including New York Heart Association class 3 or 4 congestive heart failure, unstable angina pectoris, or clinically important cardiac arrhythmias OR a recent (< 3 months) CV event, including myocardial infarction, unstable angina pectoris, or stroke.Xx_NEWLINE_xXPatients with history of myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.Xx_NEWLINE_xXUnstable cardiac disease as defined by one of the following:\r\n* Cardiac events such as myocardial infarction (MI) within the past 6 months\r\n* NYHA (New York Heart Association) heart failure class III-IV\r\n* Uncontrolled atrial fibrillation or hypertensionXx_NEWLINE_xXActive 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 restXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months at the time of consent or any class 3 (moderate) or 4 (severe) cardiac disease defined by the New York Heart Association classification.Xx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months at the time of consent or any class 3 (moderate) or 4 (severe) cardiac disease defined by the New York Heart Association classification.Xx_NEWLINE_xXSubject has clinically significant cardiac disease, including: 1) myocardial infarction within 1 year before study enrollment, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association class III-IV); 2) uncontrolled cardiac arrhythmia or clinically significant electrocardiography (ECG) abnormalities; 3) screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msecXx_NEWLINE_xXOther 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* New York Heart Association class II-IV congestive heart failure (serious cardiac arrhythmia requiring medication)\r\n* Myocardial infarction or unstable angina =< 6 months prior to registration\r\n* Congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias\r\n* Clinically significant peripheral vascular disease\r\n* History of CNS disease (e.g., primary brain tumor, vascular abnormalities, etc.), clinically significant stroke or transient ischemic attack (TIA) =< 6 months prior to registration, seizures not controlled with standard medical therapy\r\n* Neuropathy ? grade 3Xx_NEWLINE_xXHas a history of cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent; subjects with a New York Heart Association classification of III or IVXx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to uncontrolled infection, psychiatric illness that would limit compliance with study requirements, or active heart disease including confirmed myocardial infarction within previous 3 months, symptomatic coronary artery disease, clinically significant arrhythmias not controlled by medication, or uncontrolled congestive heart failure New York (NY) Heart Association class III or IVXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease (e.g., cerebrovascular accident or myocardial infarction [MI] within 6 months prior to randomization), unstable angina, congestive heart failure (CHF) (New York Heart Association [NYHA] class >= NII), or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with administration of study treatmentXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXSignificant cardiovascular impairment (e.g., New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia)Xx_NEWLINE_xXCardiac abnormalities as evidenced by any of the following: Baseline QT interval corrected for heart rate by Fridericia's formula (QTcF) interval >=450 milliseconds (msec), clinically significant conduction abnormalities or arrhythmias, such as subjects with second degree (Type II) or third degree atrio-ventricular block, history or evidence of current ?Class II congestive heart failure as defined by New York Heart Association (NYHA), history of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months. Subjects with a history of stent placement requiring ongoing anti-coagulant therapy (e.g., clopidogrel, prasugrel) will not be permitted to enroll, known cardiac metastasis.Xx_NEWLINE_xXParticipant has a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class (NYHA) III - IV within 6 months prior to their first dose of study drug.Xx_NEWLINE_xXParticipant has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infarction within the last 6 months prior to start of study drug, documents by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function\r\n* History of documents congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathy\r\n* Congenital long QT syndromeXx_NEWLINE_xXNew York Heart Association class III or IV cardiac disease or myocardial infarction within the past 12 monthsXx_NEWLINE_xXPatient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association [NYHA] class 3 or 4); unstable angina; cardiac arrhythmia; recent (within the preceding 6 months) myocardial infarction or stroke; hypertension requiring > 2 medications for adequate control; diabetes mellitus with > 2 episodes of ketoacidosis in the preceding 12 months; or chronic obstructive pulmonary disease (COPD) requiring > 2 hospitalizations in the preceding 12 monthsXx_NEWLINE_xXThe 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) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment\r\n** Any history of congenital long QT syndrome\r\n** Any of the following within 6 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)Xx_NEWLINE_xXActive angina or Class III or IV Congestive Heart Failure (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 6 months of the first dose of study drug, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by medicationXx_NEWLINE_xXSignificant cardiovascular disease with NYHA Class III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia.Xx_NEWLINE_xXPatients with a significant history of cardiovascular disease or procedures within the preceding 6 months (e.g., myocardial infarction [MI], coronary artery bypass graft placement, angioplasty, vascular stent, angina pectoris, ventricular arrhythmias requiring continuous therapy, congestive heart failure New York Heart Association [NYHA] grade >= 2, thrombotic or thromboembolic event)Xx_NEWLINE_xXHistory of any of the following cardiovascular conditions within 12 months of screening:\r\n* Myocardial infarction\r\n* Unstable angina pectoris\r\n* Cardiac angioplasty or stenting\r\n* Coronary/peripheral artery bypass graft\r\n* Class III or IV congestive heart failure per New York Heart Association\r\n* Cerebrovascular accident or transient ischemic attackXx_NEWLINE_xXClinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association [NYHA] class 3 or 4, congestive heart failure, uncontrolled or unstable angina, history of myocardial infarction or stroke within 6 months prior to study entry, or clinically significant arrhythmias not controlled by medication)Xx_NEWLINE_xXSubjects with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure (New York Heart Association [NYHA] class 3), myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligibleXx_NEWLINE_xXMyocardial infarction within the last 12 months, severe/unstable angina, symptomatic congestive heart failure New York Heart Association (NYHA) class III or IVXx_NEWLINE_xXCurrently active clinically significant cardiovascular disease, such as uncontrolled arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease, as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drugXx_NEWLINE_xXPatients with any of the following:\r\n* History of myocardial infarction within six months\r\n* Unstable angina\r\n* Resting electrocardiogram (ECG) with clinically significant abnormal findings\r\n* New York Heart Association functional classification of III or IVXx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXHistory within 6 months prior to treatment of myocardial infarction, severe/unstable angina pectoris, coronary artery bypass graft (CABG), New York Heart Association (NYHA) class III or IV congestive heart failure (CHF), stroke or transient ischemic attack (TIA)Xx_NEWLINE_xXHistory or evidence of cardiovascular risks, except stable ECD cardiac lesion, including any of the following:\r\n* QT interval corrected for heart rate using the Bazett’s formula (QTcB) >= 480 msec\r\n* History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization\r\n* History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Intra-cardiac defibrillators\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study\r\n* History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapyXx_NEWLINE_xXSignificant cardiac event (e.g., myocardial infarction), superior vena cava syndrome, New York Heart Association (NYHA) classification of heart disease >= 2 within 12 weeks, or presence of cardiac disease that in the opinion of the investigator increases the risk of ventricular arrhythmiaXx_NEWLINE_xXCurrently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction unstable angina, or acute coronary syndrome within 6 months prior to enrollment in the studyXx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, ongoing or active infection, severe or unstable angina, myocardial infarction, symptomatic congestive heart failure (defined as New York Heart Association grade II or greater), arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks) or clinically significant ventricular arrhythmias within 6 months prior to randomization; or significant vascular disease (e.g., aortic aneurysm, aortic dissection), symptomatic peripheral vascular diseaseXx_NEWLINE_xXPatient has abnormal cardiac status, evidenced by any of the following:\r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure (CHF)\r\n* Myocardial infarction within the previous 6 months\r\n* Symptomatic cardiac arrhythmia requiring treatment or persisting despite treatmentXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)Xx_NEWLINE_xXPatients with uncontrolled hypertension (> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congestive heart failure (CHF) (> New York Heart Association [NYHA] class II), or myocardial infarction within 6 months of enrollmentXx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)Xx_NEWLINE_xXPatients who have congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollmentXx_NEWLINE_xXClinically significant cardiac disease, including:\r\n* >= Grade 2 myocardial infarction within 6 months prior to day 1 of protocol therapy\r\n* Unstable or uncontrolled disease condition relating to or affecting cardiac function (e.g. unstable angina, congestive heart failure, New York Heart Association Class III-IV) within 6 months prior to day 1 of protocol therapy\r\n* >= Grade 2 uncontrolled cardiac arrhythmiaXx_NEWLINE_xXClinically evident congestive heart failure > class II of the New York Heart Association (NYHA) guidelines, unstable angina or myocardial infarction within the previous 6 monthsXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (angina symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXPatients who have congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction (MI) within 6 months of study registrationXx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXSubjects who have a history or current evidence of uncontrolled cardiovascular disease including but not limited to the following conditions:\r\n* Congestive heart failure of New York Heart Association (NYHA) class III or IV\r\n* Unstable angina (symptoms of angina at rest) or new-onset angina within < 3 months before the start of study treatment\r\n* Arterial thrombosis, deep vein thrombosis, or pulmonary embolism within < 3 months before the start of study treatment\r\n* Myocardial infarction or stroke within < 3 months before the start of study treatment\r\n* Pericarditis (any CTCAE grade), pericardial effusion (CTCAE grade >= 2) or pleural effusion (CTCAE grade >= 2)\r\n* Cardiac arrhythmia requiring anti-arrhythmic therapy; subjects receiving digoxin, calcium channel blockers except verapamil, or beta-adrenergic blockers except propranolol are eligible at the investigator’s discretion if the dose has been stable for at least 2 weeks before the start of study treatment; subjects with sinus arrhythmia and infrequent premature ventricular contractions are eligible at the investigator’s discretionXx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXPatients has any of the following cardiac abnormalities:\r\n* Symptomatic congestive heart failure\r\n** History of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy\r\n** Left ventricular ejection fraction < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) \r\n* Myocardial infarction =< 6 months prior to enrollment \r\n* Unstable angina pectoris\r\n* Serious uncontrolled cardiac arrhythmia\r\n* Symptomatic pericarditis\r\n* Corrected QT interval using Fridericia's formula (QTcF) > 480 msec on the screening electrocardiogram (ECG) (using the QTcF formula)Xx_NEWLINE_xXClinically significant, uncontrolled heart disease and/or a recent events including any of the following:\r\n* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathy\r\n* Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening\r\n* History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, conduction abnormality in the previous 12 months of screening\r\n* Congenital long QT syndrome or family history of long QT syndrome\r\n* Sustained systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening; must be corrected or controlled prior to starting study\r\n* Bradycardia (heart rate < 50 at rest) by electrocardiogram (ECG) or pulse, at screening\r\n* On screening inability to determine the QTcF interval on the ECG (i.e.: unreadable or not interpretable) or QTcF > 480 msec (using Fridericia’s correction); all as determined by screening ECG (mean of triplicate ECGs)Xx_NEWLINE_xXClinically significant, uncontrolled heart disease and/ or a history of cardiac dysfunction including any of the following:\r\n* History of unstable angina pectoris, symptomatic pericarditis, myocardial infarction, coronary artery bypass grafting or coronary angioplasty within 12 months prior to study entry\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathy\r\n* Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)\r\n* History of clinically significant ventricular arrhythmia and/or conduction delays within 12 months of screening\r\n* Systolic blood pressure > 160 mmHg or < 90 mmHg\r\n* Congenital long QT syndrome or family history of long QT syndrome\r\n* Bradycardia (heart rate < 50 at rest) by electrocardiogram (ECG) or pulse at screening.Xx_NEWLINE_xXUnstable cardiovascular function: \r\n* Electrocardiography (ECG) abnormalities requiring treatment, or   \r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3 \r\n* Myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillatorsXx_NEWLINE_xXClinically significant cardiac disease, including major cardiac dysfunction, such as uncontrolled angina, clinical congestive heart failure with New York Heart Association (NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapyXx_NEWLINE_xXSignificant cardiovascular disease, including:\r\n* Cardiac failure New York Heart Association (NYHA) class III or IV\r\n* Myocardial infarction, severe or unstable angina within 6 months prior to study day 1\r\n* History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation)\r\n* Cardiac arrhythmias requiring anti-arrhythmic medicationsXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXUnstable angina or myocardial infarction within 6 months prior to randomization, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, uncontrolled or persistent atrial fibrillation/flutter, history of ventricular fibrillation, ventricular tachycardia/torsade de pointes, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* LVEF < lower limit of normal (LLN)\r\n* A QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to registration are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to registration\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators\r\n* Known cardiac metastasesXx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia; myocardial infarction within 6 months prior to enrollmentXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction or acute coronary syndrome (within the last 6 months)Xx_NEWLINE_xXHistory or evidence of cardiovascular risks including any of the following:\r\n* History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization\r\n* History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Intra-cardiac defibrillators\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study\r\n* History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapyXx_NEWLINE_xXHistory or evidence of cardiovascular risks including any of the following:\r\n* QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization\r\n* History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Intra-cardiac defibrillators\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study\r\n* History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapyXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* LVEF < LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula (QTcB) >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to registration are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to registration\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators or permanent pacemakers\r\n* Known cardiac metastasesXx_NEWLINE_xXPatients must not have clinically significant illness including uncontrolled, active infection requiring intravenous antibiotics, New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, or >= grade 3 cardiac arrhythmiasXx_NEWLINE_xXSerious medical illness, such as significant cardiac disease (e.g. symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, pericardial disease or New York Heart Association class III or IV), or severe debilitating pulmonary disease, that would potentially increase patients’ risk for toxicityXx_NEWLINE_xXSubjects with any of the following cardiovascular conditions within the past 6 months\r\n* Cerebrovascular accident (CVA) or transient ischemic attack (TIA)\r\n* Admission for unstable angina\r\n* Myocardial infarction\r\n* Cardiac angioplasty or stenting\r\n* Coronary artery bypass graft surgery\r\n* Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks\r\n* Arterial thrombosis\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; a subject who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible\r\n* Active cardiac arrhythmia (except sinus arrhythmia, atrial fibrillation, asymptomatic premature ventricular contractions [PVCs])\r\n* Ejection fraction < institutional lower limit of normal (LLN) and/or history of cardiomyopathyXx_NEWLINE_xXClinically significant cardiac pathology: myocardial infarction within 6 months prior to enrollment, class III or IV heart failure according to New York Heart Association (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or acute conduction system abnormalities; specifically, any history of cardio-vascular pathology or symptoms, not clearly fitting this exclusion criterion will prompt an evaluation by a Clinical Center Cardiologist and eligibility will be considered on a case-by-case basis; should the cardiologist deem the patient’s findings on work-up to be not clinically significant pathology, the patient will have met this exclusion criterionXx_NEWLINE_xXPatients with significant intercurrent medical illness (including New York Heart Association [NYHA] class III or IV heart disease, significant arrhythmias requiring medication, symptomatic coronary artery disease, myocardial infarction) within the previous 6 monthsXx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function\r\n* History of or documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXPatients 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 arrhythmiasXx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXClinically significant cardiac pathology: myocardial infarction within 6 months prior to enrollment, class III or IV heart failure according to New York Heart Association (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXPatients with any of the following cardiovascular conditions within the past 6 months:\r\n* Cerebrovascular accident (CVA) or transient ischemic attack (TIA)\r\n* Admission for unstable angina\r\n* Myocardial Infarction\r\n* Cardiac angioplasty or stenting\r\n* Coronary artery bypass graft surgery\r\n* Pulmonary embolism, untreated deep venous thrombosis (DVT), or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks\r\n* Arterial thrombosis\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; Note: a patient who has a history of class III heart failure and is asymptomatic on treatment may be considered eligible for the studyXx_NEWLINE_xXMyocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalitiesXx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXParticipant with clinical signs of heart or coronary failure, or evidence of left ventricular ejection fraction (LVEF) < 40%; participant with myocardial infarction within 6 months prior to enrollment or have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXPatients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50%Xx_NEWLINE_xXPatients who have a significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmias within 6 months of registration (New York Heart Association [NYHA] classification III-IV)Xx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure - New York Heart Association (NYHA) > class II\r\n* Coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina or new-onset angina within 3 months before randomization, or myocardial infarction (MI) within 6 months before randomizationXx_NEWLINE_xXPatients must not have New York Heart Association class III or IV heart failure at the time of screening; patients must not have any thromboembolic event, unstable angina pectoris, myocardial infarction, or serious uncontrolled cardiac arrhythmia within 6 months prior to registration (Note: Patients with congenital long AT syndrome, congestive heart failure, frequent electrolyte abnormalities, and patients taking drugs known to prolong the QT interval may be at increased risk)Xx_NEWLINE_xXThis criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with clinically significant cardiovascular disease; this includes: \r\n* Patients with significant cardiac conduction abnormalities, i.e. PR interval > 0.24 seconds (sec) or 2nd or 3rd degree atrioventricular (AV) block\r\n* Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg\r\n* Myocardial infarction, cardiac arrhythmia or unstable angina < 6 months prior to registration\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure\r\n* Serious cardiac arrhythmia requiring medication\r\n* Grade II or greater peripheral vascular disease (exception: episodes of ischemia < 24 hours [hrs] in duration, that are managed non-surgically and without permanent deficit)\r\n* History of cerebrovascular attack (CVA) within six monthsXx_NEWLINE_xXDocumented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to their first dose of study drugXx_NEWLINE_xXNew York Heart Association Class III or IV (Appendix D) cardiac disease or myocardial infarction within the past 12 months before screening, or preexisting atrial fibrillation.Xx_NEWLINE_xXSignificant cardiovascular impairment: congestive heart failure > class II according to the New York Heart Association (NYHA), unstable angina or myocardial infarction within 6 months of enrollment, or serious cardiac arrhythmia (> grade 2)Xx_NEWLINE_xXHistory of the following within 6 months prior to first administration of a study drug: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder.7. Treatment with any investigational product within 28 days prior to signing Informed Consent Form.Xx_NEWLINE_xXClinically significant or uncontrolled cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that requires therapy.Xx_NEWLINE_xXClinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ? II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ?2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.Xx_NEWLINE_xXParticipant who had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure - New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Left ventricular function < 50%\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization\r\n* Patients who have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy\r\n* Patients who are receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents; once-daily aspirin (maximum dose 325 mg/day) is permittedXx_NEWLINE_xXClinically significant cardiac disease or impaired cardiac function, such as:\r\n* Baseline left ventricular ejection fraction (LVEF) < 50% on baseline echocardiogram or multi gated acquisition scan (MUGA)\r\n* Congestive heart failure requiring treatment (e.g., New York Heart Association class II, III or IV) within 6 months prior to screening\r\n* Acute coronary syndromes < 3 months prior to screening (including myocardial infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting)\r\n* Uncontrolled arterial hypertension defined by blood pressure > 140/100 mm Hg at rest (average of 3 consecutive readings)\r\n* History or current evidence of unstable, clinically significant cardiac arrhythmias\r\n* Patients that require medications with a narrow therapeutic window\r\n* Clinically significant conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete atrioventricular (AV)-blockage\r\n* Corrected QT interval (QTc) > 480 msec on screening electrocardiogram (ECG)Xx_NEWLINE_xXSignificant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure >115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, myocardial infarction within 6 months prior to Screening, or uncontrolled atrial or ventricular cardiac arrhythmias.Xx_NEWLINE_xXMyocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failureXx_NEWLINE_xXNYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry, and/or serious arrhythmia requiring anti-arrhythmic therapyXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)Xx_NEWLINE_xXUncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) grade II or higher, or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure as defined by the New York Heart AssociationXx_NEWLINE_xXMedically 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, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.Xx_NEWLINE_xXNew York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.Xx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable anginaXx_NEWLINE_xXPatients with a history or evidence of cardiovascular risk, including any of the following:\r\n* Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN)\r\n* Bazett's corrected QT (QTcB) >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias\r\n* Exception: Subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible\r\n* History of (within 6 months prior to randomization) acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting\r\n* History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators or permanent pacemakers\r\n* Known cardiac metastasesXx_NEWLINE_xXPatients must not have any grade III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmiaXx_NEWLINE_xXAny serious medical condition that places the subject at an unacceptable risk if he or she participates in this study. Examples of such a medical condition are, but are not limited to, subject with unstable cardiac disease as defined by: cardiac events such as myocardial infarction (MI) within the past 6 months, NYHA (New York Heart Association) heart failure class III-IV, uncontrolled atrial fibrillation or hypertension; subjects with conditions requiring chronic steroid or immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and lupus, that likely need additional steroid or immunosuppressive treatments in addition to the study treatmentXx_NEWLINE_xXSignificant cardiovascular impairment: History of (a) congestive heart failure greater than New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction, (d) stroke, or (e) cardiac arrhythmia associated with impairment within 6 months of the first dose of study drug.Xx_NEWLINE_xXMyocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of Cycle 1 Day 1Xx_NEWLINE_xXMyocardial infarction or arterial thromboembolic events within 6 months prior to Baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTcB (corrected according to Bazett's formula) interval > 470 msecXx_NEWLINE_xXHistory of myocardial infarction and unstable angina within 6 months before study drug treatment; symptomatic congestive heart failure (Congestive Heart Failure New York Heart Association Class III or IV); congenital long QT syndrome; or ventricular arrhythmias defined as grade ?2 according to NCI CTCAE, v4Xx_NEWLINE_xXMyocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failure.Xx_NEWLINE_xXActive angina or Class III or IV Congestive Heart Failure (CHF) (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by outpatient medicationXx_NEWLINE_xXHad a myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalitiesXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic untreated arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc > 480 msec at screening. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.Xx_NEWLINE_xXOther uncontrolled illness or medical condition, such as active infection, symptomatic heart failure (New York Heart Association class III or IV; moderate to severe objective evidence of cardiovascular disease), unstable angina pectoris, myocardial infarction or stroke within last 6 months, psychiatric illness that may limit compliance with study requirement or interfere with the understanding and giving of informed consent;Xx_NEWLINE_xXPatients who have class III or IV heart failure (as defined by the New York Heart Association), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities are not eligibleXx_NEWLINE_xXMyocardial infarction within 6 months of study initiation, active cardiac ischemia or New York Heart Association (NYHA) Grade III or IV heart failureXx_NEWLINE_xXSignificant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable anginaXx_NEWLINE_xXAny of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart Association (NYHA) Class III or IV.Xx_NEWLINE_xXClinically significant (that is, active) cardiovascular disease: cerebral vascular accident / stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXHistory of any one or more of the following cardiac conditions within the past 6 months: Cardiac angioplasty or stenting; Myocardial infarction; Unstable angina; History of Class III or IV congestive heart failure according to New York Heart Association classificationXx_NEWLINE_xXActive co-morbidity, defined as follows:\r\n* Chronic liver disease with cirrhosis (Child-Pugh B or C) or active hepatitis B or C\r\n* History of pituitary or adrenal dysfunction\r\n* Poorly controlled diabetes mellitus (A1c > 9% or history of complications including peripheral neuropathy, end organ damage, hospitalization, amputation)\r\n* Poorly controlled glaucoma\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-IV heart disease or known cardiac ejection fraction measurement of < 50% at baseline\r\n* Clinical evidence of active infection of any type, including active or symptomatic viral hepatitis\r\n* Known immune deficiency and/or human immunodeficiency virus (HIV)-positive patients\r\n* Any medical condition that warrants long-term corticosteroid use in excess of study doseXx_NEWLINE_xXCardiac abnormalities as evidenced by any of the following: History or current \untreated\ clinically significant uncontrolled arrhythmias; Clinically significant conduction abnormalities or arrhythmias, subjects with Bundle Branch Block; Presence of cardiac pacemaker; History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA); History of acute coronary syndromes (including unstable angina and myocardial infarction ), coronary angioplasty, or stenting within the past 3 months.Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXNo 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 failureXx_NEWLINE_xXSignificant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure greater than 115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, or myocardial infarction within 6 months prior to screening, or uncontrolled atrial or ventricular cardiac arrhythmias.Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Function Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to screeningXx_NEWLINE_xXClinically significant cardiac disease defined by CHF New York Heart Association (NYHA) Class > 1; uncontrolled clinically significant arrhythmia in last 6 months; Acute Coronary Syndrome (ACS) (angina or MI) in last 6 months.Xx_NEWLINE_xXAbnormal ECGs that are clinically significant such as QT prolongation (QTc > 480 msec), clinically significant cardiac enlargement or hypertrophy, new bundle branch block or existing left bundle branch block, or signs of new, active ischemia a. Patients with evidence of prior infarction who are New York Heart Association (NYHA) functional class II, III, or IV are excluded, as are patients with marked arrhythmia such as Wolff Parkinson White pattern or complete atrioventricular (AV) dissociationXx_NEWLINE_xXUncontrolled hypertension, unstable angina, New York Heart Association grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication, or clinically significant peripheral vascular disease (grade II or greater)Xx_NEWLINE_xXFor patients enrolling onto Arm A (Gemcitabine with nab-Paclitaxel) a. Known hypersensitivity to Gemcitabine or taxanes. i. Patients with history of Gemcitabine toxicity in the adjuvant setting requiring more than 1 dose level reduction are excluded. b. Significant cardiac disease, including the following: unstable angina, New York Heart Association class III-IV congestive heart failure, myocardial infarction within six months prior to study enrollment. c. History of hemolytic-uremic syndrome. d. History of posterior reversible encephalopathy syndrome. e. Known infection with Human Immunodeficiency Virus (HIV), and/or active infection with hepatitis B, or hepatitis C. f. History of active Peripheral Artery Disease (treated peripheral artery disease that is stable for at least 6 months is allowed).Xx_NEWLINE_xXSignificant cardiac disease, including the following: unstable angina, New York Heart Association class II-IV congestive heart failure, myocardial infarction within six months prior to study enrollment.Xx_NEWLINE_xXNo history of a congestive heart failure, myocardial infarction, unstable angina, uncontrolled arrhythmia, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification in the last 6 monthsXx_NEWLINE_xXCurrently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXActive or clinically significant cardiac disease including: \r\n* Congestive heart failure - New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXPatients must not have clinically significant illness including uncontrolled, active infection requiring intravenous antibiotics, New York Heart Association (NYHA) class III or class IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled >= grade 3 cardiac arrhythmias, uncontrolled hypertension, or uncontrolled diabetes mellitus; patients must have undergone an electrocardiogram (EKG) within 28 days prior to registrationXx_NEWLINE_xXKnown contraindications to sorafenib including allergic reaction, pill-swallowing difficulty, evidence of severe or systemic diseases, uncontrolled hypertension or history of cardiac arrhythmias (requiring anti-arrhythmic therapy or pace maker), congestive heart failure . New York Heart Association class 2, myocardial infarct within 6 months, prolonged QT/QTc >450ms, or laboratory finding that in the view of the investigator makes it undesirable for the patient to participate in the trial, significant GI bleed within 30 days, metastatic brain disease, renal failure requiring dialysisXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiographic (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable anginaXx_NEWLINE_xXMyocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of C1D1Xx_NEWLINE_xXPatients not suitable for cardiac MRI; contraindications include:\r\n* Intracranial metal, pacemakers, defibrillators, functioning neurostimulator devices, or other implanted electronic devices\r\n* Ferromagnetic cerebral aneurysm clips, or other intraorbital/intracranial metal\r\n* Allergy to gadolinium or other severe drug allergies\r\n* Claustrophobia\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV)\r\n* Significant valvular disease, or significant pulmonary disease requiring supplemental oxygen therapyXx_NEWLINE_xXUncontrolled 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 encephalopathyXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on studyXx_NEWLINE_xXSignificant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment (including oral anticoagulation).Xx_NEWLINE_xXKnown cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association [NYHA] Class III or IV) and/or myocardial infarction within 6 months prior to first dose, or severe pulmonary hypertension. As an example, well controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion.Xx_NEWLINE_xXGrade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., subjects with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), symptomatic pulmonary embolism within 3 months, unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia as determined by the treating physician.Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXDocumented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association class III-IV within 6 months prior to their first dose of the study drugsXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXActive and uncontrolled disease/(active uncontrolled infection, uncontrolled hypertension despite adequate medical therapy, active and uncontrolled congestive heart failure New York Heart Association [NYHA] class III/IV, clinically significant and uncontrolled arrhythmia) as judged by the treating physicianXx_NEWLINE_xXClinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4, angina not well controlled by medication, or myocardial infarction within 6 months)Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medicationXx_NEWLINE_xXPatients have clinically significant cardiovascular disease, including any of the following \r\n* Any history of acute coronary syndrome including myocardial infarction, stable or unstable angina, coronary artery bypass grafting (CABG), coronary angioplasty or stenting, or known obstructive coronary artery disease\r\n* Symptomatic chronic heart failure (New York Heart Association criteria, class II-IV) \r\n* Evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening except atrial fibrillation (AF) and paroxysmal supraventricular tachycardia (PSVT)Xx_NEWLINE_xXSignificant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > New York Heart Association [NYHA] II, serious cardiac arrhythmia, pericardial effusion)Xx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXAny clinically significant pericardial effusion, congestive heart failure (CHF) (New York [NY] Heart Association grade II-IV) or cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study; this determination will be made by a cardiologist if cardiac issues are suspectedXx_NEWLINE_xX? Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 monthsXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXPatients with cardiovascular disease including congestive heart failure grade III or IV according to the New York Heart Association (NYHA) classification, left ventricular ejection fraction of < 50%, myocardial infarction within previous 6 months or poorly controlled hypertensionXx_NEWLINE_xXSignificant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at ScreeningXx_NEWLINE_xXUncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.Xx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXUnstable angina and/or congestive heart failure in the last 6 months, transmural myocardial infarction within the last 6 months, New York Heart Association grade II or higher congestive heart failure requiring hospitalization within 12 months prior to registration, evidence of recent (within 14 days of registration) myocardial infarction by electrocardiogram (EKG) (only required if clinically indicated), serious or inadequately controlled cardiac arrhythmia, significant vascular and peripheral vascular disease, evidence of bleeding diathesis or coagulopathyXx_NEWLINE_xXPatients must not have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemiaXx_NEWLINE_xXPatients with history of myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXActive grade III-IV cardiac failure as defined by the New York Heart Association criteria, uncontrolled angina or myocardial infarction (MI) within 6 monthsXx_NEWLINE_xXClinically significant cardiac disease (New York Heart Association class III/IV) or severe debilitating pulmonary diseaseXx_NEWLINE_xXConcomitant medical condition that precludes adequate study treatment compliance or assessment, or increases subject risk, in the opinion of the investigator, such as but not limited to:\r\n* Myocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, or a QTCB (corrected according to Bazett's formula) interval > 470 msec; serious uncontrolled cardiac arrhythmia grade II or higher according to NYHA; uncontrolled hypertension (systolic > 150 and/or diastolic > 100 mm Hg)\r\n* Acute and chronic active infectious disorders and non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy\r\n* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)Xx_NEWLINE_xXPatients with any of the following: History of myocardial infarction within 6 months prior to starting treatment; Unstable angina; Resting electrocardiogram (ECG) with clinically significant abnormal findings; New York Heart Association functional classification of III or IVXx_NEWLINE_xXHistory of significant cardiovascular disease, defined as: congestive heart failure greater than New York Heart Association (NYHA) class II according to the NYHA functional classification; unstable angina or myocardial infarction within 6 months of enrollment; or serious cardiac arrhythmiaXx_NEWLINE_xXClinically significant, uncontrolled heart disease and/or recent events including any of the following:\r\n* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathy\r\n* Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening\r\n* History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening\r\n* Congenital long QT syndrome or family history of long QT syndrome\r\n* Bradycardia (heart rate <50 at rest), by electrocardiography (ECG) or pulse, at screening\r\n* Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screeningXx_NEWLINE_xXHave clinically significant cardiac disease (NYHA Class III or IV); clinically significant arrhythmia i.e. ventricular tachycardia, ventricular fibrillation, or \Torsade de Pointes\. Myocardial infarction with uncontrolled angina within 6 months, congestive heart failure, or clinical significant cardiomyopathyXx_NEWLINE_xXClinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association grade ?2), uncontrolled hypertension or clinically significant arrhythmia currently requiring medical treatmentXx_NEWLINE_xXPatients have clinically significant cardiovascular disease, including any of the following:\r\n* History of acute coronary syndrome including myocardial infarction, unstable angina, coronary artery bypass surgery (CABG), coronary angioplasty or stenting < 6 months prior to screening\r\n* Symptomatic chronic heart failure (New York Heart Association Criteria, class II-IV)\r\n* Evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening except atrial fibrillation (AF) and paroxysmal supraventricular tachycardia (PSVT)Xx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXSignificant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 6 months prior to start of study treatment, congestive heart failure > New York Heart Association [NYHA] II, serious cardiac arrhythmia, pericardial effusion)Xx_NEWLINE_xXPatients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:\r\n* Coronary artery bypass graft\r\n* Angioplasty\r\n* Vascular stent\r\n* Myocardial infarction\r\n* Angina pectoris\r\n* Congestive heart failure New York Heart Association grade >= 2 (ventricular arrhythmias requiring continuous therapy)\r\n* Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled\r\n* Hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding\r\n* History of drug abuse or alcohol abuse, as judged by the investigatorXx_NEWLINE_xXHave experienced any arterial thrombotic event or arterial thromboembolic event, including myocardial infarction, unstable angina (history or evidence of current clinically relevant coronary artery disease of current ?Class III as defined by Canadian Cardiovascular Society Angina Grading Scale or congestive heart failure of current ?Class III as defined by the New York Heart Association), cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment.Xx_NEWLINE_xXActive or clinically significant cardiac disease including: \r\n* Congestive heart failure - New York Heart Association (NYHA) > class II \r\n* Active coronary artery disease that is not medically treated\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before registration, or myocardial infarction within 6 months before registrationXx_NEWLINE_xXPatient has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification, left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO), unstable angina pectoris, symptomatic pericarditis, corrected QT Fridericia's formula (QTcF) > 480 msec on the screening electrocardiogram (ECG) (using the QTcF formula)Xx_NEWLINE_xXPatients with history of myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure or symptoms suspicious for congestive heart failure are not eligible unless a Left ventricular ejection fraction (LVEF) in the past 6 months is documented to be 50% or greater; patients who have had a LVEF (performed for any reason) that is less than 50% in the past 6 months are ineligibleXx_NEWLINE_xXMyocardial infarction within the last 12 months, severe/unstable angina, symptomatic congestive heart failure, New York Heart Association (NYHA) class III or IVXx_NEWLINE_xXPatients with any of the following conditions or complications are NOT eligible for participation:\r\n* Gastrointestinal (GI) tract disease resulting in an inability to take oral medication\r\n* Malabsorption syndrome\r\n* Require IV alimentation\r\n* History of prior surgical procedures affecting absorption\r\n* Uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis)\r\n* Hypersensitivity of any of the components of eribulin or lenvatinib\r\n* History of significant neurological (no neuropathy more than grade 2) or psychiatric disorders\r\n* Significant non neoplastic liver disease (cirrhosis, active chronic hepatitis)\r\n* Immunocompromised subjects, including patients with human immunodeficiency virus\r\n* Significant non neoplastic renal disease\r\n* Active infection requiring systemic therapy\r\n* Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment\r\n* Prolongation of corrected QT interval (QTc) to more than 480 milliseconds when electrolyte balance is normal\r\n* Major surgery within 4 weeks prior to first dose of the study drugXx_NEWLINE_xXCardiac abnormalities as evidenced by any of the following: History of or current \untreated\ clinically significant uncontrolled arrhythmias, Clinically significant conduction abnormalities or arrhythmias, Presence of cardiac pacemaker, History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA), History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months. Subjects with a history of stent placement requiring ongoing antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be permitted to enroll.Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screeningXx_NEWLINE_xXPatients with any other known concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes; cardiovascular disease including congestive heart failure New York Heart Association class [NYHA] class III or IV, myocardial infarction within 6 months, and poorly controlled hypertension; chronic renal failure; or active uncontrolled infection) which, in the opinion of the investigator could compromise participation in the studyXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class III or IV cardiac disease as defined by the New York Heart Association (NYHA) functional classificationXx_NEWLINE_xXNo significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > [New York Heart Association NYHA] II, serious cardiac arrhythmia, pericardial effusion)Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXParticipant has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.Xx_NEWLINE_xXhave the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.Xx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional classificationXx_NEWLINE_xXDocumented unstable angina or myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities (unless subject has a pacemaker), left ventricular ejection fraction (LVEF) < 40%, history of torsade de pointeXx_NEWLINE_xXSerious medical comorbidities such as New York Heart Association class III/IV cardiac disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12 monthsXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 2 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association functional classificationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities in the opinion of the Investigator. Prior to study entry any known abnormality on an electrocardiogram (ECG) must be determined and documented by the Investigator to be not clinically significant to the patient participation in this study.Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXA cardiovascular disability status of New York Heart Association class >= 2, defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina painXx_NEWLINE_xXUnstable cardiovascular function:\r\n* Symptomatic ischemia, or\r\n* Uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or\r\n* Myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] Class III or IV, refer to Appendix F), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollmentXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXNew York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.Xx_NEWLINE_xXKnown significant cardiac abnormalities including:\r\n* Congestive heart failure, New York Heart Association (NYHA) class III or IV\r\n* Uncontrolled angina, arrhythmia or hypertension\r\n* Myocardial infarction within the past six months\r\n* Any other uncontrolled or severe cardiovascular condition\r\n* Prior cerebrovascular event with residual neurologic deficitXx_NEWLINE_xXSubject has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.Xx_NEWLINE_xXHistory of cardiac disease: congestive heart failure New York Heart Association (NYHA) class >II, unstable angina (anginal symptoms at rest), new-onset angina (within the past 3 months before study entry), myocardial infarction within the past 3 months before study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers, calcium channel blockers, and digoxin are permitted).Xx_NEWLINE_xXSignificant cardiovascular disease defined as:\r\n* Myocardial infarction within 6 months of screening\r\n* Unstable angina pectoris\r\n* Uncontrolled or clinically significant arrhythmia grade >= 2\r\n* Left ventricular ejection fraction (LVEF) below institutional limits at screening\r\n* Congestive heart failure New York Heart Association (NYHA) class III or IV\r\n* Presence of clinically significant valvular heart diseaseXx_NEWLINE_xXParticipants with any of the following:\r\n* History of myocardial infarction within six months\r\n* Unstable angina\r\n* New York Heart Association (NYHA) classification of III or IVXx_NEWLINE_xXNo myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification, or congenital long QT syndrome, or QT interval corrected for heart rate, using Fridericia formula (QTcF) at Screening greater than (>) 470 milliseconds (ms)Xx_NEWLINE_xXSubjects who have a history of major cardiac or neurologic disease including, but not limited to, angina pectoris, symptomatic coronary artery disease, uncontrolled hypertension (at time of study entry), New York Heart Association (NYHA) Class III or IV congestive heart failure, confirmed significant cardiac conduction abnormalities (including QTc > 0.45 sec) or arrhythmias, myocardial infarction within 12 months, cerebrovascular accidents, or transient ischemic attacks.Xx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm)Xx_NEWLINE_xXNo myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXClass III or Class IV myocardial disease as described by the New York Heart Association; a recent history (within 6 months) of myocardial infarction, or symptomatic arrhythmia at the time of randomization. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. Such patients are comfortable at rest. Less than ordinary physical activity that causes fatigue, palpitation, dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to perform any physical activity without discomfort. Symptoms of cardiac insufficiency or anginal syndrome may be present even at rest.Xx_NEWLINE_xXSignificant cardiovascular disease, including:\r\n* Cardiac failure New York Heart Association (NYHA) class III or IV\r\n* Myocardial infarction, severe or unstable angina within 6 months prior to study day 1\r\n* History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation)\r\n* Cardiac arrhythmias requiring anti-arrhythmic medicationsXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* A corrected QT interval using the Bazett’s formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias or patients that require medications with a narrow therapeutic window, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete atrioventricular (AV)-blockage (exception: patients with chronic atrial fibrillation with heart rate less than 100 for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting within 6 months prior to randomization\r\n* Current class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 150 mmHg and/or diastolic > 90 mmHg despite adequate attempts at anti-hypertensive therapyXx_NEWLINE_xXUnstable angina and/or decompensated congestive heart failure in the last 6 months, transmural myocardial infarction within the last 6 months, New York Heart Association functional class II or higher congestive heart failure requiring hospitalization within 12 months prior to registration, serious or inadequately controlled cardiac arrhythmia, significant vascular and peripheral vascular disease, evidence of bleeding diathesis or coagulopathyXx_NEWLINE_xXAny severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:\r\n* Symptomatic, or history of documented congestive heart failure (New York [NY] Heart Association functional classification III-IV)\r\n* Corrected QT interval using Fridericia's formula (QTcF) > 470 msec\r\n* Angina not well-controlled by medication\r\n* Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting in the past 6 monthsXx_NEWLINE_xXCardiac 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 failureXx_NEWLINE_xXClinically significant cardiovascular disease including:\r\n* Acute coronary syndrome within 6 months of screening visit\r\n* Hypotension defined as a systolic blood pressure < 86 mmHg\r\n* Bradycardia defined as a heart rate of < 50 beats per minute, unless pharmaceutically induced and thus reversible (i.e. beta blockers)\r\n* Uncontrolled angina (requiring escalating doses of nitrates) within 3 months of screening visit\r\n* Congestive heart failure New York Heart Association (NYHA) class III or IV or subjects with a history of congestive heart failure NYHA class III or IV, unless screening echocardiogram (ECHO) results in left ventricular ejection fraction that >= 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 screening electrocardiogram (EKG) > 470 msec\r\n* History of Mobitz II second degree or third degree heart block without a permanent pacemaker in placeXx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)Xx_NEWLINE_xXSignificant cardiac disease as determined by the investigator including:\r\n* Known or suspected cardiac amyloidosis\r\n* Congestive heart failure of class III or IV of the New York Heart Association (NYHA) classification\r\n* Uncontrolled angina, hypertension or arrhythmia\r\n* Myocardial infarction in past 6 months\r\n* Any uncontrolled or severe cardiovascular disease\r\n* Prior cerebrovascular event with persistent neurologic deficitXx_NEWLINE_xXPatient has clinically significant heart disease (such as uncontrolled angina, myocardial infarction within the last 3 months or congestive heart failure of New York Heart Association III or IV)Xx_NEWLINE_xXPatients who have any severe and/or uncontrolled cardiac disease within =< 6 months prior to start of everolimus, including: unstable angina pectoris, symptomatic congestive heart failure of New York Heart Association class III or IV, myocardial infarction, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac diseaseXx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, New York Heart Association (NYHA) functional classification of 3, unstable angina or poorly controlled arrhythmia; myocardial infarction within 6 month prior to the study entryXx_NEWLINE_xXActive or clinically significant cardiac disease including: \r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina < 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec.Xx_NEWLINE_xXPatients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: a) coronary artery bypass graft; b) angioplasty; c) vascular stent; d) myocardial infarction; e) angina pectoris; f) congestive heart failure New York Heart Association grade >= 2; g) ventricular arrhythmias requiring continuous therapy; h) supraventricular arrhythmias including atrial fibrillation, which are uncontrolled; i) hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleedingXx_NEWLINE_xXClinically 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 visitXx_NEWLINE_xXMyocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalitiesXx_NEWLINE_xXNormal cardiac function\r\n* No active coronary artery disease\r\n* No New York Heart Association class II, III or IV disease\r\n* No arrhythmia requiring treatment\r\n* Baseline echocardiogram with a shortening fraction of >= 27% or an ejection fraction >= 50%Xx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or LVEF < 40%Xx_NEWLINE_xXUnstable cardiovascular function:\r\n* Symptomatic ischemia, or\r\n* Uncontrolled clinically significant conduction abnormalities (e.g.: ventricular tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or\r\n* Myocardial infarction (MI) within 3 months of cycle 1 day 1 doseXx_NEWLINE_xXOther concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection, New York Heart Association class III or IV congestive heart failure, uncontrolled cardiac arrhythmia) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocolXx_NEWLINE_xXActive angina or Class III or IV Congestive Heart Failure (CHF) (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 months of the first dose of study drug, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by outpatient medicationXx_NEWLINE_xXHistory of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2; patients must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 monthsXx_NEWLINE_xXSubjects with acute coronary syndrome within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities are not eligible; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXOther 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 encephalopathyXx_NEWLINE_xXPatients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or New York Heart Association class II–IV congestive heart failureXx_NEWLINE_xXThe 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)Xx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalitiesXx_NEWLINE_xXImpaired cardiac function or clinically significant heart disease, including any one of the following:\r\n* Angina pectoris within 3 months\r\n* Acute myocardial infarction within 3 months\r\n* Corrected Fridericia's QT (QTcF) > 450 msec for males and > 470 msec for females on the screening electrocardiogram (ECG)\r\n* A past medical history of clinically significant ECG abnormalities or a family history of prolonged QT-interval syndrome\r\n* New York Heart Association classification IV cardiovascular disease or symptomatic class III disease \r\n* Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)Xx_NEWLINE_xXPatients 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)Xx_NEWLINE_xXUnstable cardiovascular function:\r\n* Symptomatic ischemia, or\r\n* Uncontrolled clinically significant conduction abnormalities (e.g.: ventricular tachycardia on antiarrhythmics are excluded and first (1st) degree atrioventricular (AV) block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded)\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or\r\n* Myocardial infarction (MI) within 3 months of initiation of therapyXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months, or myocardial infarction within 6 monthsXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or LVEF > 50%Xx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure - New York Heart Association (NYHA) > class II;\r\n* Active coronary artery disease that is not medically treated;\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to the first day of treatment, the New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXPatients with clinically significant cardiovascular disease: \r\n* History of cerebrovascular accident (CVA) within 6 months \r\n* Myocardial infarction or unstable angina within 6 months \r\n* Unstable angina pectoris\r\n* New York Heart Association class III or greater congestive heart failureXx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXAny history of unstable angina, myocardial infarction, New York Heart Association (NYHA) class III or IV heart failure, and/or pulmonary hypertensionXx_NEWLINE_xXNo patients with a history of cardiac disease: congestive heart failure > class II New York Heart Association (NYHA); active coronary artery disease (CAD) (myocardial infarction or unstable angina within 6 months prior to study entry)Xx_NEWLINE_xXClinically 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 mmHgXx_NEWLINE_xXPatients with significant cardiac disease including heart failure that meets New York Heart Association (NYHA) class III and IV definitions, history of myocardial infarction within six months of study entry, uncontrolled dysrhythmias, or QTc greater than or equal to 450 msecXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication (atrial fibrillation is permitted)Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; before study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXCardiovascular 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 > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment\r\n* Any of the following within 6 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)Xx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) ? 40%.Xx_NEWLINE_xXClinically 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 4.0Xx_NEWLINE_xXClinically 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 baselineXx_NEWLINE_xXHistory of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapyXx_NEWLINE_xXHistory of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapyXx_NEWLINE_xXNo unstable angina or myocardial infarction within 4 months prior to cycle 1 day 1, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXHistory of any significant cardiac event (e.g. myocardial infarction), superior vena cava syndrome, New York Heart Association (NYHA) classification of heart disease >= 2 within 12 weeks before starting treatment, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmiaXx_NEWLINE_xXUnstable angina, congestive heart failure (New York Heart Association (NYHA) > class II), uncontrolled hypertension (diastolic blood pressure > 100 mmHg), or recent (within 1 year) myocardial infarctionXx_NEWLINE_xXA cardiovascular disability status of New York Heart Association Class >/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal painXx_NEWLINE_xXUncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosisXx_NEWLINE_xXCongestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months before first doseXx_NEWLINE_xXClinically 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-IV heart disease or cardiac ejection fraction measurement of < 50% at baselineXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Corrected QT using Fridericia's formula (QTcF) >= 480 msec (>= 500 msec for subject with bundle branch block)\r\n* History or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with controlled atrial fibrillation for > 30 days prior to randomization are eligible\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)Xx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 12 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXClinically 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 visitXx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following: Acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrolment; clinically significant uncontrolled arrhythmias; however, subjects with controlled atrial fibrillation for >30 days prior to enrollment are eligible; class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) criteria; left ventricular ejection fraction (LVEF) below the institutional LLN. If a LLN does not exist at an institution, then use LVEF <50%; abnormal cardiac valve morphology (?Grade 2) documented by ECHO; however, subjects with Grade 1 abnormalities (i.e., mild regurgitation/stenosis) may be entered on study but subjects with moderate valvular thickening should NOT be enrolled; corrected QT (QTc) interval for heart rate using Bazett-corrected QT interval (QTcB) >=480 msec; intracardiac defibrillator; treatment-refractory hypertension defined as a blood pressure (BP) >140/90 mmHg which may not be controlled by anti-hypertensive medication(s) and/or lifestyle modificationsXx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia; myocardial infarction within 6 months prior to study entryXx_NEWLINE_xXSignificant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, ejection fraction (EF) =< 40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed during screening evaluationXx_NEWLINE_xXSignificant cardiovascular impairment within 6 months as defined as (1) congestive heart failure greater than New York Heart Association Class II, (2) unstable angina, (3) myocardial infarction; (4) stroke, (5) symptomatic cardiac arrhythmiaXx_NEWLINE_xXHas significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia.Xx_NEWLINE_xXActive uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmiaXx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseaseXx_NEWLINE_xXHas significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, ejection fraction (EF) =< 40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination; echocardiogram will be performed during screening evaluationXx_NEWLINE_xXParticipant has active, uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of >= 2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmiaXx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to registration, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXClinically 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 visitXx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 50% at baselineXx_NEWLINE_xXClinically 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 visitXx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXPatients with any of the following cardiac conditions:\r\n* Restrictive cardiomyopathy\r\n* Unstable angina within 6 months prior to enrollment\r\n* New York Heart Association functional class III-IV heart failure \r\n* Symptomatic pericardial effusionXx_NEWLINE_xXHistory or evidence of cardiovascular risks including any of the following:\r\n* QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization\r\n* History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Intra-cardiac defibrillators\r\n* Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study\r\n* History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti- hypertensive therapyXx_NEWLINE_xXHistory of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; or history of known cardiac arrhythmias unless it has been stably controlledXx_NEWLINE_xXActive or severe hepatic, cardiovascular, or cerebrovascular disease, including myocardial infarction within 6 months prior to enrollment, have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXPatients must not have a history of acute coronary syndromes (including unstable angina), myocardial infarction within 6 months, coronary angioplasty, or stenting within the past 24 weeks; class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; or history of known cardiac arrhythmias (such as atrial fibrillation) unless it has been stably controlled for > 30 days prior to registration; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; subjects with moderate valvular thickening are not eligibleXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure-New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before treatment, or myocardial infarction within 6 months before treatmentXx_NEWLINE_xXUnstable angina, congestive heart failure (New York Heart Association (NYHA) > Class II), uncontrolled hypertension (diastolic blood pressure > 100mmHg), or recent (within 1 year) myocardial infarctionXx_NEWLINE_xXNew York Heart Association class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as active angina pectoris, clinically significant cardiac arrhythmia that requires therapy in the opinion of the treating physician or PI, uncontrolled hypertension (blood pressure > 160 systolic and > 110 diastolic not responsive to antihypertensive medication), uncontrolled diabetes mellitus in the opinion of the treating physician or PI, or uncontrolled congestive heart failure in the opinion of the treating physician or PIXx_NEWLINE_xXCurrently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or any class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina or acute coronary syndrome within 6 months prior to on-study registrationXx_NEWLINE_xXSignificant 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 screeningXx_NEWLINE_xXSignificant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.Xx_NEWLINE_xXClinically significant cardiac disease or impaired cardiac function, such as:\r\n* Congestive heart failure requiring treatment (e.g., New York Heart Association class II, III or IV)\r\n* Acute coronary syndromes < 3 months prior to screening (including myocardial infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting)\r\n* Uncontrolled arterial hypertension defined by blood pressure > 140/100 mm Hg at rest (average of 3 consecutive readings)\r\n* History or current evidence of unstable, clinically significant cardiac arrhythmias or patients that require medications with a narrow therapeutic window, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-grade/complete atrioventricular (AV) blockage\r\n* Corrected QT interval (QTc) > 480 msec on screening electrocardiogram (ECG)Xx_NEWLINE_xXActive cardiac disease including any of the following:\r\n* Congestive heart failure (New York Heart Association [NYHA]) >= class 2\r\n* Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months); myocardial infarction less than 6 months before start of day 1 of irinotecan\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)Xx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before study entryXx_NEWLINE_xXImpaired cardiac function including any of the following:\r\n* Screening electrocardiogram (ECG) with a corrected QT interval (QTc) > 450 msec \r\n* Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm)\r\n* Right bundle branch block + left anterior hemiblock (bifascicular block)\r\n* Patients with myocardial infarction or unstable angina < 3 months prior to starting study drug\r\n* Congestive heart failure (CHF) New York (NY) Heart Association class III or IVXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment, or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; NOTE: Prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXSignificant cardiac disease:\r\n* Congestive heart failure > class II New York Heart Association (NYHA)\r\n* Myocardial infarction within 6 months prior to study entry\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Serious myocardial dysfunction, defined as scintigraphically (multi gated acquisition scan [MUGA], myocardial scintigram) or echocardiogram determined absolute left ventricular ejection fraction (LVEF) below normal (< 50%)Xx_NEWLINE_xXNew York(NY) Heart Association Class III or IV cardiac disease or Myocardial infarction within the past 12 months.Xx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXClinically significant cardiovascular impairment (history of congestive heart failure greater or equal to New York Heart Association [NYHA] class II, unstable/active angina or myocardial infarction [MI] =< 6 months before day 1 of this study, or serious cardiac arrhythmia)Xx_NEWLINE_xXCardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association Class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months).Xx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXCardiovascular disability status of New York Heart Association Class greater than or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain.Xx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 50% at baselineXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Corrected QT (QTc) > 500 ms\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXHistory of myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association classification within 6 months of the first dose of ARQ 087 (MI occurring >6 months of the first dose of ARQ 087 will be permitted)Xx_NEWLINE_xXSignificant 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 conditionXx_NEWLINE_xXSignificant cardiovascular disease defined as congestive heart failure (New York Heart Association class III or IV cardiac disease), angina pectoris requiring nitrate therapy or recent myocardial infarction (=< 6 months prior to registration)Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Corrected QT using Bazett's method (QTcB) >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with controlled atrial fibrillation for > 30 days prior to enrollment are eligible\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrollment\r\n* History or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators\r\n* Cardiac metastasesXx_NEWLINE_xXPatients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities, including but not limited to atrial fibrillation, atrioventricular (AV) block, QT prolongation, sick sinus syndrome, ventricular tachycardiaXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities (not including 1st degree atrioventricular [AV]-block, Wenckebach type 2nd degree heart block, or left bundle branch block; 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 participationXx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalitiesXx_NEWLINE_xXHistory of any of the following coronary conditions within 90 days of planned tadalafil administration:\r\n* Myocardial Infarction\r\n* Coronary artery bypass graft surgery\r\n* Percutaneous coronary intervention (for example, angioplasty or stent placement)\r\n* Any evidence of heart disease (New York Heart Association [NYHA] >= class III) within 6 months of planned tadalafil administrationXx_NEWLINE_xXPatients who have had a myocardial infarction within 6 months of enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXUncontrolled, current significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities\r\n* Patients with history of cardiac disease, such as coronary disease, arrhythmia or congestive heart failure that are on appropriate medical therapy and without evidence of current decompensation are eligibleXx_NEWLINE_xXPatient must not have had a myocardial infarction within 6 months prior to enrollment or have New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXUncontrolled intercurrent illness including but not limited to: ongoing or active infection, systemic congestive heart failure class III or IV by New York Heart Association (NYHA) criteria, unstable angina pectoris, or cardiac arrhythmia, or in patients status post allogeneic transplantation with uncontrolled graft versus host disease (GVHD)Xx_NEWLINE_xXUncontrolled 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)Xx_NEWLINE_xXActive heart disease including myocardial infarction within previous 6 months, symptomatic coronary artery disease, clinically significant arrhythmias not controlled by medication, atrial fibrillation (whether active or known past history), uncontrolled angina, or uncontrolled congestive heart failure (New York Heart Association Class III or IV).Xx_NEWLINE_xXNo previous evidence of class 3 or greater New York Heart Association cardiac insufficiency or coronary artery diseaseXx_NEWLINE_xXSubject has a cardiovascular disability status of New York Heart Association Class greater or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.Xx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalitiesXx_NEWLINE_xXHistory of myocardial infarction or other evidence of arterial thrombotic disease (angina), symptomatic congestive heart failure (New York Heart Association >= grade 2), unstable angina pectoris, or cardiac arrhythmia; Note: allowed only if patient has no evidence of active disease for at least 6 months prior to randomizationXx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalitiesXx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and arrhythmia unless controlled by therapy, with the exception of extrasystoles or minor conduction abnormalitiesXx_NEWLINE_xXSubjects with any of the following cardiovascular conditions within the past 6 months:\r\n* Cerebrovascular accident (CVA) or transient ischemic attack (TIA)\r\n* Cardiac arrhythmia\r\n* Admission for unstable angina\r\n* Cardiac angioplasty or stenting\r\n* Coronary artery bypass graft surgery\r\n* Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks\r\n* Arterial thrombosis\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; a subject who has a history of Class II heart failure\tand is asymptomatic on treatment may be considered eligibleXx_NEWLINE_xXMyocardial infarction within 6 months prior to signing consent or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiograph (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXImpaired cardiac function or clinically significant cardiac diseases, including any one of the following: history or presence of sustained ventricular tachyarrhythmia; any history of ventricular fibrillation or torsade de pointes; bradycardia defined as heart rate (HR) < 50 beats per minute (bpm); patients with pacemakers are eligible if heart rate (HR) >= 50 bpm; screening ECG with a corrected QT using Fridericia's formula (QTcF) > 450 msec, right bundle branch block + left anterior hemiblock (bifascicular block), patients with myocardial infarction or unstable angina =< 6 months prior to starting study drug, other clinically significant heart disease (e.g., congestive heart failure [CHF] New York Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)Xx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months: \r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina \r\n* Coronary artery bypass graft surgery \r\n* Symptomatic peripheral vascular disease \r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXPatients with following cardiac conditions will be excluded:\r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure\r\n* Myocardial infarction =< 6 months prior to enrollment\r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration\r\n* History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%Xx_NEWLINE_xXUncontrolled illnesses including symptomatic congestive heart failure (class III or IV as per New York Heart Association functional classification system), unstable angina pectoris, cardiac arrhythmia requiring therapy, myocardial infarction within the past 6 months, cardiac angioplasty or stenting within last 3 months, arterial or venous thrombi (including cerebrovascular accident), or active infectionXx_NEWLINE_xXClinically significant cardiac disease (New York [NY] Heart Association class III or IV), including chronic arrhythmias, or pulmonary diseaseXx_NEWLINE_xXClinically significant cardiovascular disease, defined as myocardial infarction (or unstable angina) within 6 months of registration, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management; however, treated and controlled or stable/not clinically significant cardiovascular disease is allowed per evaluation by cardiologistXx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXA history or evidence of cardiovascular risk including any of the following: Corrected QT (QTc) interval >=480 msecs History of acute coronary syndromes (including myocardial infarction or unstable angina) within 6 months prior to first dose of study treatment Coronary angioplasty, or stenting within the past 24 weeks; A history or evidence of current Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy; Abnormal cardiac valve morphology ( >=Grade 2) documented by echocardiogram (subjects with Grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study; Patients with intra-cardiac defibrillators A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to randomization are eligible. Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, etc.), psychological, familial, sociological, or geographical conditions that interfere with the subject's safety or obtaining informed consent or do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol;Xx_NEWLINE_xXSubject has a cardiovascular disability status of New York Heart Association Class greater or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.Xx_NEWLINE_xXE 10. Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack.Xx_NEWLINE_xXHistory of cardiac dysfunction including any one of the following:\r\n* Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricle (LV) function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXActive cardiac disease including any of the following: \r\n* Congestive heart failure (New York Heart Association [NYHA]) >= class 2\r\n* Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months); myocardial infarction less than 6 months before start of day 1 of FOLFIRI\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)\r\n* Uncontrolled hypertension; (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)Xx_NEWLINE_xXPatients who have congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollmentXx_NEWLINE_xXAny of the following in previous 6 months: New York Heart Association (NYHA) class III/IV congestive heart failure, unstable angina, cerebrovascular accident (including transient ischemic attack), pulmonary embolism or myocardial infarction (by ECG or serologic criteria)Xx_NEWLINE_xXHave the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertensionXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class IIIB or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities (not including 1st degree atrioventricular (AV)-block, Wenckebach type 2nd degree heart block, or left bundle branch block; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be evaluted by the investigator or an authorized physician sub-investigator); note: there is no lower limit of left ventricular ejection fraction below which patients are excluded from participationXx_NEWLINE_xXPatients with clinically significant cardiovascular disease: history of cerebrovascular accident (CVA) within 6 months; myocardial infarction or unstable angina within 6 months; unstable angina pectoris; New York Heart Association class > IIXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXNYHA Class III or IV heart disease. History of active unstable angina, congestive heart disease, severe uncontrolled cardiac arrhythmia, electrocardiographic evidence of acute ischemia, active conduction system abnormalities or myocardial infarction within 6 months prior to enrollment. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.Xx_NEWLINE_xXSubject has a clinically significant cardiovascular disease including: uncontrolled hypertension; myocardial infarction or unstable angina within 6 months prior to registration; New York Heart Association (NYHA) Grade II or greater congestive heart failureXx_NEWLINE_xXMyocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of ARQ 087 (MI that occurred > 6 months prior to the first dose of ARQ 087 will be permitted)Xx_NEWLINE_xXThe patient has a serious cardiac condition, such as congestive heart failure; New York Heart Association class II/ III/IV heart disease; unstable angina pectoris, cardiac stenting within 6 months of enrollment; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatmentXx_NEWLINE_xXMyocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, or a corrected QT (QTc) interval > 470 msecXx_NEWLINE_xXMyocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, or a corrected QT (QTc) interval > 470 msecXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (<6 months before enrollment), myocardial infarction (<6 months before enrollment), unstable angina, congestive heart failure (New York Heart Association class ?II), or serious uncontrolled cardiac arrhythmia requiring medication.Xx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from day 1 of study administration, New York Heart Association class III or IV congestive heart failure, or symptomatic uncontrolled arrhythmias, prolonged corrected QT interval > 480 msec, treatment refractory hypertension, presence of a cardiac defibrillatorXx_NEWLINE_xXHas significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.Xx_NEWLINE_xXa. Class I and above myocardial ischemia or myocardial infarction, cardiac arrhythmia and Class 2 or above congestive heart failure classified according to New York Heart Association (NYHA)Xx_NEWLINE_xXHas a clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within ?180 days prior to start of study treatment, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association > class 2), unstable angina, uncontrolled hypertension, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXHas active or clinically significant cardiac disease including:\r\n* Congestive heart failure - New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before initiation, or myocardial infarction within 6 months before initiationXx_NEWLINE_xXHas significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, ejection fraction (EF) =< 40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination; echocardiogram will be performed during screening evaluationXx_NEWLINE_xXSignificant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction, cerebrovascular accident, or cardiac arrhythmia associated with hemodynamic instability. The following is also excluded: left ventricular ejection fraction below the institutional normal range as determined by multiple-gated acquisition scan or echocardiogramXx_NEWLINE_xXPatients with clinically significant cardiovascular disease: myocardial infarction or unstable angina pectoris within the last 6 months, class III/IV New York Heart Association (NYHA) heart failureXx_NEWLINE_xXPatients 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 rateXx_NEWLINE_xXPatients with following cardiac conditions will be excluded: \r\n* New York Heart Association (NYHA) stage III or IV congestive heart failure \r\n* Myocardial infarction =< 6 months prior to enrollment \r\n* History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration \r\n* History of severe non-ischemic cardiomyopathy with ejection fraction (EF) =< 20%Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment, or New York Hospital Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXSignificant cardiac disease as defined as: unstable angina, New York Heart Association (NYHA) grade II or greater, congestive heart failure, history of myocardial infarction within 6 monthsXx_NEWLINE_xXPatients with significant atherosclerotic disease, as defined by: a) Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia or active conduction system abnormalities. Any prior ECG abnormality at Screening has to be documented by the investigator as not medically relevant. b) Symptomatic congestive heart failure. c) Claudication limiting activity and d) History of cerebrovascular events within the last year (including TIA).Xx_NEWLINE_xXNew York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems reviewXx_NEWLINE_xXNo myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction or arterial thromboembolic events within 6 months prior to baseline or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTcB (corrected according to Bazett's formula) interval > 470 msec; serious uncontrolled cardiac arrhythmia grade II or higher according to NYHA; uncontrolled hypertension (systolic > 150 and/or diastolic > 100 mm Hg)Xx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification would be exclusion for ibrutinib therapy but idelalisib would be an optionXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXCongestive heart failure > New York Heart Association (NYHA) class 2: unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before study registration; cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted); uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).Xx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseaseXx_NEWLINE_xXUncontrolled or severe concurrent medical condition including cardiovascular disease (e.g., myocardial infarct, unstable angina, New York Heart Association (NYHA) Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, cardiac amyloidosis, transient ischemic attacks, CVA, coronary artery or other vascular stents).Xx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXAny of the following concurrent medical conditions or history: \t   \r\n* Uncontrolled hypertension, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) class 2 or greater, clinically significant peripheral vascular disease, serious cardiac arrhythmia requiring medication\r\n* History of myocardial infarction (MI) or stroke within 6 months before enrollment\r\n* History of intra-abdominal abscess within 4 weeks before enrollment, abdominal fistula, gastrointestinal perforation, or active peptic ulcer disease\r\n* Evidence of bleeding diathesis or coagulopathy\r\n* Serious non-healing wound, ulcer or bone fractureXx_NEWLINE_xXSignificant cardiovascular disease (New York Heart Association class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of medication to control heart rate in patients with atrial fibrillation is allowed, if stable medication for at least last month prior to randomization and medication not listed as causing torsade de pointes), or evidence of acute ischemia on electrocardiogram (ECG)Xx_NEWLINE_xXParticipant with myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to the first dose of study treatment, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina. Patient with known coronary artery disease, congestive heart failure not meeting the above criteria, or known left ventricular ejection fraction less than 50% must be on a stable medical regimen that is optimized in the opinion of the treating physicianXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXHistory of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months.Xx_NEWLINE_xXUnstable cardiovascular function that includes and may not be limited to:\r\n* Symptomatic myocardial ischemia, or\r\n* Uncontrolled clinically significant conduction abnormalities (e.g., ventricular tachycardia on antiarrhythmics are excluded and first [1st] degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class 3, or\r\n* Myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXMyocardial infarction within 6 months prior to C1D1 treatment, and/or prior diagnoses of congestive heart failure (New York Heart Association Class III or IV), unstable angina, unstable cardiac arrhythmia requiring medication; and/or the participant is at risk for polymorphic ventricular tachycardia (eg, hypokalemia, family history or long QT syndrome)Xx_NEWLINE_xXHistory of myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure (New York Heart Failure [NYHA] class III or IV congestive heart failure) within 6 months prior to study enrollment or left ventricular ejection fraction (LVEF) < 50%Xx_NEWLINE_xXDocumented myocardial infarction or unstable/uncontrolled cardiac disease (eg, unstable angina, congestive heart failure [New York Heart Association > Class III]) within 6 months or enrollmentXx_NEWLINE_xXMyocardial infarction within 6 months prior to C1D1, and/or prior diagnoses of congestive heart failure (New York Heart Association Class III or IV), unstable angina, unstable cardiac arrhythmia requiring medication; and/or the subject is at risk for polymorphic ventricular tachycardia (eg, hypokalemia, family history or long QT syndrome)Xx_NEWLINE_xXHistory of clinically significant cardiac dysfunction, including the following:\r\n* Current unstable angina\r\n* Symptomatic congestive heart failure of New York Heart Association (NYHA) class 2 or higher \r\n* History of congenital long QT syndrome or mean QT interval using the Fridericia correction formula (QTcF) > 450 msec at baseline or uncorrectable electrolyte abnormalities\r\n* Uncontrolled hypertension >= grade 2 (patients with a history hypertension controlled with anti-hypertensives to =< grade 1 are eligible)\r\n* Patients with left ventricular ejection fraction (LVEF) as measured by echocardiogram or multiple gated acquisition (MUGA) scan below institutional lower limit of normal or below 50%, whichever is lower, will be excluded from the study\r\n* Uncontrolled arrhythmias\r\n* Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 monthsXx_NEWLINE_xXNo uncontrolled inter-current illness including, but 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 therapyXx_NEWLINE_xXSignificant cardiac disease including myocardial infarction or unstable angina within 6 months, uncontrolled hypertension despite medical therapy (defined as blood pressure > 160/110 in spite of adequate medical therapy), active and uncontrolled congestive heart failure New York Heart Association (NYHA) class III/IV, stroke within preceding 6 monthsXx_NEWLINE_xXHas acute myocardial infarction within 6 months before starting study drug, current or history of New York Heart Association Class III or IV heart failure; evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiogram (ECG) evidence of acute ischemia or active conduction system abnormalities; Fridericia's corrected QT interval > 475 milliseconds (msec) (males) or > 450 msec (females) on a 12-lead ECG during the Screening period; or abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and intervals that in the opinion of the investigator are considered to be clinically significant.Xx_NEWLINE_xXHistory of cardiac disease including congestive heart failure New York Heart Association (NYHA) Class >II (Section 14.7), unstable angina (anginal symptoms at rest) or new-onset angina (within the last 6 months) or myocardial infarction within the past 6 months and cardiac arrhythmias requiring anti-arrhythmic therapy except for beta-blockers and digoxin; evidence for uncontrolled coronary artery disease (eg angina pectoris, myocardial infarction within 6 months prior to study entry, major regional wall motion abnormalities upon baseline echocardiography)Xx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.Xx_NEWLINE_xXNew York Heart Assoc Class III or IV cardiac disease, myocardial infarction within the past 12 months before screening, or pre-existing atrial fibrillation.Xx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically significant pericardial effusion)Xx_NEWLINE_xXPatient has a history of cardiac dysfunction including any of the following:\r\n* Myocardial infraction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXEvidence 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 monthsXx_NEWLINE_xXUnstable cardiovascular function:\r\n* Electrocardiogram (ECG) abnormalities requiring treatment, or\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3\r\n* Myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure-New York Heart Association (NYHA) > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXHistory of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 monthsXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXSubject has a history of a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or electrocardiogram (ECG) abnormality, cerebrovascular accident, transient ischemic attack, seizure disorder or clinically significant cardiac dysrhythmia or electrocardiogram (ECG) abnormality, within 6 months prior to Cycle 1 Day 1.Xx_NEWLINE_xXSignificant cardiovascular disease (i.e. New York Heart Association [NYHA] class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)Xx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXMajor cardiac abnormalities as defined but not limited to the following: uncontrolled angina or unstable life-threatening arrhythmias, history of myocardial infarction within 12 weeks prior to Baseline, Class 3 or higher New York Heart Association (NYHA) congestive heart failure, or severe cardiac insufficiency, persistent (3 consecutive electrocardiograms (ECGs) performed ? 5 minutes apart) prolongation of the QTc (Fridericia) interval to > 480 msec.Xx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association (NYHA) > class II\r\n* Uncontrolled cardiac arrhythmias despite optimal management\r\n* Unstable angina (anginal symptoms at rest), new-onset angina, myocardial infarction within 3 months of initiation of treatment on trialXx_NEWLINE_xXUncontrolled 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 6 months), cardiac arrhythmia, history of cerebrovascular accident (CVA) within 6 months; no uncontrolled hypertension (defined as blood pressure of > 160/90 mmHg) on medication or, history of peripheral vascular diseaseXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension (blood pressure >= 160 systolic and >= 110 diastolic not responsive to antihypertensive medication), uncontrolled diabetes mellitus, or congestive heart failureXx_NEWLINE_xXPatients with a cardiac ejection fraction (as measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 45% are excluded; currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drugXx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class II, III, or IV congestive heart failure, and arrhythmia requiring therapy.Xx_NEWLINE_xXCurrent uncontrolled cardiac disease such as angina or myocardial infarction, congestive heart failure including New York Heart Association functional classification of 3, or arrhythmia requiring treatment.Xx_NEWLINE_xXHistory of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment), New York Heart Association Classification III or IV.Xx_NEWLINE_xXSignificant or uncontrolled intercurrent condition including, but not limited to:\r\n* Infection other than HIV, hepatitis B, or hepatitis C that is symptomatic or requires systemic treatment\r\n* Opportunistic infection within 60 days prior to enrollment\r\n* Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infection within 6 months prior to enrollment\r\n* History of stroke or intracranial hemorrhage within 6 months prior to enrollment\r\n* History of class B or class C cirrhosis, per the modified Child-Pugh classification\r\n* Psychiatric illness that would limit complianceXx_NEWLINE_xXCardiac exclusion criteria: History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months prior to first dose of study drug; QTcF> 450 milliseconds (msec); Uncontrolled arrhythmias. Subjects with rate controlled atrial fibrillation for >1 month prior to first dose of study drug may be eligible; Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.Xx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXPatients with New York Health Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities, including but not limited to atrial fibrillation, atrioventricular (AV) block, QT prolongation, sick sinus syndrome, ventricular tachycardiaXx_NEWLINE_xXHave congestive heart failure classified as New York Heart Association Class 2 or higher.Have had unstable angina (angina symptoms at rest) or new-onset angina ? 3 months prior to screening. Have had a myocardial infarction < 6 months prior to initiation of study treatment.Xx_NEWLINE_xX11. Uncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association Class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease, or cardiac amyloidosis.Xx_NEWLINE_xXHistory or evidence of cardiac disease: congestive heart failure; New York Heart Association class 2 or greater; active coronary artery disease; unstable angina, cardiac arrhythmias requiring anti-arrhythmic therapy, atrio-ventricular block of second or third degree, or uncontrolled hypertension, patients with recent (less than 6 months) myocardial infarction (MI) or coronary revascularizationXx_NEWLINE_xXPatient has any of the following cardiac abnormalities:symptomatic congestive heart failure, history of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy, Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); myocardial infarction ? 6 months prior to enrolment, unstable angina pectoris, serious uncontrolled cardiac arrhythmia, symptomatic pericarditis, QTcF > 480 msec on the screening ECG (using the QTcF formula);Xx_NEWLINE_xXHistory of cardiac disease: congestive heart failure defined as class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); previously diagnosed bradycardia or other cardiac arrhythmia defined as >= grade 2 according to NCI-CTCAE (version 4.0), or uncontrolled hypertension; myocardial infarction occurred within 6 months prior to study entry (myocardial infarction occurred > 6 months prior to study entry is permitted)Xx_NEWLINE_xXClinically significant (that is [i.e.] active) cardiovascular disease (For example [e.g.] cerebrovascular accident or myocardial infarction within 6 months prior to randomization), unstable angina, congestive heart failure (New York Heart Association Class >/= II) or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with the administration of the study treatmentXx_NEWLINE_xXSerious illness including, significant ongoing or active infection, New York Heart Association (NYHA) grade III or IV congestive heart failure, unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within past 3 months; serious medical or psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirementsXx_NEWLINE_xXCongestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXClinically 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:Xx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (New York Heart Association [NYHA] III-IV), and uncontrolled symptomatic arrhythmiaXx_NEWLINE_xXPatients with uncontrolled hypertension (> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congestive heart failure (CHF) (> New York Heart Association [NYHA] class II), or myocardial infarction within 6 months of study will be excludedXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXSELUMETINIB 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)Xx_NEWLINE_xXCardiac related illnesses including, but not limited to:\r\n* Symptomatic congestive heart failure including participants with grade III/IV cardiac disease as defined by the New York Heart Association functional criteria\r\n* Unstable angina pectoris\r\n* Cardiac arrhythmiaXx_NEWLINE_xXClinically significant cardiac disease (New York Heart Association class III/IV) or severe debilitating pulmonary diseaseXx_NEWLINE_xXPatients with myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled cardiac arrhythmias, or electrocardiographic evidence of acute ischemiaXx_NEWLINE_xXCardiovascular 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) > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment\r\n* The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization; Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard\r\n* Any history of congenital long QT syndrome\r\n* Any of the following within 6 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** CardiomyopathyXx_NEWLINE_xXClinically significant cardiac disease (New York Heart Association class III/IV) or severe debilitating pulmonary diseaseXx_NEWLINE_xXHave a history of New York Heart Association (NYHA) Class ?3, QTc interval > 480 milliseconds (ms) on screening electrocardiogram (ECG) per Friderica's formula, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug administration.Xx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiography (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXCardiac disease: congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXClinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, unstable atrial fibrillation, or New York Heart Association (NYHA) class III-IV heart diseaseXx_NEWLINE_xXAny of the following comorbid conditions:\r\n* New York Heart Association classification III or IV cardiovascular disease\r\n* Recent myocardial infarction (=< 30 days)\r\n* Uncontrolled infectionXx_NEWLINE_xXHistory of cardiac disease: congestive heart failure New York Heart Association (NYHA) class > II, unstable angina (anginal symptoms at rest), new-onset angina (within the past 3 months before study entry), myocardial infarction within the past 3 months before study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers, calcium channel blockers, and digoxin are permitted)Xx_NEWLINE_xXPatients with significant cardiovascular disease including congestive heart failure (New York Heart Association [NYHA] class III or IV), active angina pectoris or myocardial infarction within 6 monthsXx_NEWLINE_xXClinically-significant cardiac disease including:\r\n* Recent myocardial infarction (=< 6 months prior to first dose of mirvetuximab soravtansine)\r\n* Unstable angina pectoris\r\n* Uncontrolled congestive heart failure (New York Heart Association > class II)\r\n* Uncontrolled hypertension (>= Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03 grade 3), prior history of hypertensive crisis or hypertensive encephalopathy\r\n* Uncontrolled cardiac arrhythmias\r\n* Clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm)\r\n* Severe aortic stenosis\r\n* Clinically significant peripheral vascular disease\r\n* Cardiac toxicity >= grade 3 following prior chemotherapy\r\n* Corrected QT (QTc) > 470 for females and > 450 for malesXx_NEWLINE_xXHave a serious cardiac condition, such as congestive heart failure; New York Heart Association Class III/IV heart disease; unstable angina pectoris; myocardial infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that are symptomatic or require treatment (not including participants with rate-controlled atrial fibrillation).Xx_NEWLINE_xXNew York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmiaXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease, uncontrolled hypertension, unstable angina, history of myocardial infarction, cardiac failure class II-IVXx_NEWLINE_xXClinically significant cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication within 1 year prior to Day -1 (Visit 1); Grade II or greater peripheral vascular disease at study entryXx_NEWLINE_xXMyocardial infarction, unstable angina within the past 6 months, or congestive heart failure New York Heart Association Class II or greaterXx_NEWLINE_xXPatient has in the opinion of the investigator any intercurrent conditions that could preclude their participation in the study, pose an undue medical hazard, or that could interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (NYHA Class III or IV; refer to Appendix III), unstable angina, cardiac arrhythmia requiring treatment, recent (within the prior 6 months) myocardial infarction, acute coronary syndrome or stroke, severe obstructive pulmonary disease, hypertension requiring more than2 medications for adequate control, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 12 months.Xx_NEWLINE_xXCardiac risk factors including: \r\n* Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent\r\n* Patients with a New York Heart Association classification of III or IVXx_NEWLINE_xXCongestive heart failure (New York Heart Association Class III or IV), myocardial infarction within 12 months before starting study treatment, or unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris.Xx_NEWLINE_xXPatients with clinically significant cardiovascular or cerebrovascular disease:\r\n* History of cerebrovascular accident or transient ischemic attack within past 6 months from registration\r\n* Myocardial infarction, coronary artery bypass grafting (CABG) or unstable angina within the past 6 months from registration\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 from registration\r\n* Clinically significant peripheral vascular disease within past 6 months from registrationXx_NEWLINE_xXPresence of cardiac impairment defined as:\r\n* Prior history of cardiovascular disease including heart failure that meets New York Health Association (NYHA) class III and IV definitions; OR \r\n* History of myocardial infarction/active ischemic heart disease within one year of study entry; OR \r\n* Uncontrolled dysrhythmias; OR \r\n* Poorly controlled anginaXx_NEWLINE_xXSubject with uncontrolled cardiac disease including congestive heart failure class III or IV by the NYHA, unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or unstable cardiac arrhythmia requiring medicationXx_NEWLINE_xXMyocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of study Day 1Xx_NEWLINE_xXUnstable cardiovascular function:\r\n* Electrocardiogram (ECG) abnormalities requiring treatment, or\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3\r\n* Myocardial infarction (MI) within 3 months\r\n* Symptomatic ischemia or anginaXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failure (CHF); myocardial infarction or unstable angina within 6 monthsXx_NEWLINE_xXHistory of cardiac disease including congestive heart failure New York Heart Association (NYHA) Class >/=III, unstable angina (anginal symptoms at rest) or new-onset angina (within the last 6 months) or myocardial infarction within the past 6 months or cardiac arrhythmias requiring anti-arrhythmic therapy except for beta-blockers and digoxin; evidence for uncontrolled coronary artery disease (e.g. major regional wall motion abnormalities on baseline echocardiography or a left ventricular ejection fraction (LVEF) <45%)Xx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association [NYHA) class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXHistory of the following within 6 months prior to first administration of investigational product: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder.Xx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia; myocardial infarction within 6 months prior to randomizationXx_NEWLINE_xXCongestive heart failure > Class II New York Heart Association Functional Classification, current pericarditis, myocardial infarction within 6 months, or symptomatic coronary artery disease.Xx_NEWLINE_xXCurrently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to first dose with study drugXx_NEWLINE_xXClinically 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 II-IV heart disease or known cardiac ejection fraction measurement of < 50 % at baselineXx_NEWLINE_xXSignificant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)Xx_NEWLINE_xXClinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from day 1 of study drug administration, New York Heart Association class III or IV congestive heart failure, or symptomatic arrhythmias requiring therapyXx_NEWLINE_xXRecent history (within 6 months of start of screening) of unstable angina pectoris pattern, myocardial infarction (including non-Q wave MI), or NYHA (New York Heart Association) Class III and IV Congestive Heart Failure (CHF)Xx_NEWLINE_xXAny of the following within 6 months prior to study entry: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attackXx_NEWLINE_xXDocumented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association class III-IV within 6 months prior to their first dose of brentuximab vedotinXx_NEWLINE_xXAny severe concurrent disease or condition (including severe graft-versus-host disease, requirement for dialysis, symptomatic congestive heart failure [New York Heart Association Class III or IV], unstable angina pectoris, cardiac arrhythmia) which, in the judgment of the Investigator, would make the patient inappropriate for study participation.Xx_NEWLINE_xXClinically significant cardiovascular disease (eg, uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).Xx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXA history or evidence of cardiovascular risk including any of the following: A QT interval corrected for heart rate using the Fridericia's formula (QTcF) >=480 millisecond (msec); A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for >30 days prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3); History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3); A history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic>140 millimeters of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy; Patients with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases.Xx_NEWLINE_xXHistory of significant cardiac disease. Includes second/third degree heart block; significant ischemic heart disease; mean QTc interval > 480 msec prior to study start; poorly controlled hypertension; congestive heart failure of NYHA Class II or worseXx_NEWLINE_xXCongestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to prior to C1D1 for Phase 1b or prior to randomization for Phase 2Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Left ventricular ejection fraction (LVEF) < LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula QTcB >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Patients with intra-cardiac defibrillators\r\n* Known cardiac metastasesXx_NEWLINE_xXHistory of cardiac disease including congestive heart failure > New York Heart Association (NYHA) Class II, unstable angina (anginal symptoms at rest) or new-onset angina (within the last 6 months) or myocardial infarction within the past 6 months and cardiac arrhythmias requiring anti-arrhythmic therapy except for beta-blockers and digoxin; evidence for uncontrolled coronary artery disease (e.g. angina pectoris, myocardial infarction within 6 months prior to study entry, major regional wall motion abnormalities upon baseline echocardiography)Xx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 45 % at baseline, if doneXx_NEWLINE_xXThe subject has a history of congestive heart failure, unstable angina, myocardial infarction, cardiac conduction abnormalities including Fridericia corrected QT interval (QTcF) prolongation of > 480 milliseconds (ms) or a pacemaker, clinically relevant impaired cardiovascular function (New York Heart Association (NYHA) class III/IV) or stroke within 3 months prior to enrollment.Xx_NEWLINE_xXNew York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.Xx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention; myocardial infarction within 6 monthsXx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXClinically significant cardiac disease, especially history of myocardial infarction =< 6 months, or congestive heart failure (New York Heart Association [NYHA] classification III or IV) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmiasXx_NEWLINE_xXThe following cardiac abnormalities: Corrected QT (QTc) interval >=480 millisecond. History of acute coronary syndromes (including unstable angina) within the past 24 weeks Coronary angioplasty or stenting within the past 24 weeks. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system. Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (subjects with Grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). History of known arrhythmias (except sinus arrhythmia and atrial fibrillation that is controlled) within the past 24 weeks.Xx_NEWLINE_xXClinically 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 class III-IV heart disease or cardiac ejection fraction measurement of < 50% at baselineXx_NEWLINE_xXHistory or symptoms of cardiovascular disease (New York Heart Association [NYHA] class 2, 3, or 4) within the last 6 months, particularly coronary artery disease, arrhythmias, or conduction defects with risk of cardiovascular instability, uncontrolled hypertension, clinically significant pericardial effusion, or congestive heart failureXx_NEWLINE_xXUncontrolled hypertension, heart disease including history of congestive heart failure, history of myocardial infarction, angina pectoris requiring medication, clinically significant valvular heart disease, high risk arrhythmias, or disease corresponding to New York Heart Association class III or IV.Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities (except asymptomatic patients with a pacemaker with electrocardiogram (ECG) changes reflecting conduction abnormalities secondary to the pacemaker); prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXPatients with serious medical illness, including but not limited to: history of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of grade > 2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.02), thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion restrictive cardiomyopathy) within 6 months prior to first dose of study drug, or New York Heart Association class III or IV heart failure; chronic stable atrial fibrillation on stable anticoagulant therapy is allowedXx_NEWLINE_xXPatients must not have cardiac disease defined as: New York Heart Association (NYHA) > class II; patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.Xx_NEWLINE_xXUnstable angina or myocardial infarction within 4 months prior to randomization, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXMyocardial infarction within 6 months of anti-MIF antibody administration, congestive heart failure (New York Heart Association Class III or Class IV), unstable angina, unstable cardiac arrhythmia requiring medication, or risk factors for polymorphic ventricular tachycardiaXx_NEWLINE_xXHistory of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months prior to study entry; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as greater than or equal to Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring more than 6 months prior to study entry is permitted)Xx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXAny of the following conditions:\r\n* Myocardial infarction =< 6 months prior to registration or has New York Heart Association (NYHA) class III or IV heart failure \r\n* Uncontrolled angina\r\n* Severe uncontrolled ventricular arrhythmias\r\n* Electrocardiographic evidence of acute ischemia\r\n* Active conduction system abnormalities; NOTE: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXHistory of cardiac dysfunction including any of the following:\r\n* Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function\r\n* History of documented congestive heart failure (New York Heart Association functional classification III-IV)\r\n* Documented cardiomyopathyXx_NEWLINE_xXActive angina or Class III or IV Congestive Heart Failure (CHF) (New York Heart Association CHF Functional Classification System) or clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, congestive heart failure, uncontrolled hypertension, or arrhythmias not controlled by outpatient medication.Xx_NEWLINE_xXNew York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECGXx_NEWLINE_xXCongestive heart failure (CHF) (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six monthsXx_NEWLINE_xXThe patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association [NYHA] Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).Xx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following: Clinically significant electrocardiogram abnormalities including second degree (Type II) or third degree atrioventricular block; history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within the past 6 months prior to enrolment, Class III or IV heart failure as defined by the New York Heart Association functional classification system, LVEF below 50%; known cardiac metastasesXx_NEWLINE_xXNormal cardiac function:\r\n* No active coronary artery disease\r\n* No New York Heart Association class II, III, or IV disease\r\n* No arrhythmia requiring treatmentXx_NEWLINE_xXA history or evidence of cardiovascular risk including: a QT interval corrected for heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of current clinically significant uncontrolled arrhythmias (clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible); a history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; a history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators; abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. Subjects with prosthetic valves can be considered eligible provided they meet the criteria as stated above; Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or above 95th age-specific percentile listed in protocol), which cannot be controlled by anti-hypertensive therapy.Xx_NEWLINE_xXActive or clinically significant cardiac disease including:\r\n* Congestive heart failure – New York Heart Association > class II\r\n* Active coronary artery disease\r\n* Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin\r\n* Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before registration, or myocardial infarction within 6 months before registrationXx_NEWLINE_xXClinically significant heart disease as evidenced by myocardial infarction or arterial thrombotic event within the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baselineXx_NEWLINE_xXCardiac disease:\r\n* Congestive heart failure > class II New York Heart Association (NYHA), or\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* Congenital long QT syndrome or taking drugs known to prolong the QT interval\r\n* Subjects taking any drugs with a known risk of causing torsades de pointesXx_NEWLINE_xXClinically significant cardiac dysfunction (including NYHA Class II/III/IV heart failure, left ventricular ejection fraction [LVEF] <50%, active ventricular arrhythmia requiring medication, history of myocardial infarction within 6 months of treatment initiation, clinically significant electrocardiogram [ECG] abnormalities).Xx_NEWLINE_xXPatients with clinically significant cardiovascular disease (eg, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina < 6 months to enrollment, New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade II or greater peripheral vascular disease, and history of cerebrovascular accident (CVA) within 6 months).Xx_NEWLINE_xXHistory of congestive heart failure defined as class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); clinically significant bradycardia (< 50 beats per minute [bpm]) or other uncontrolled, cardiac arrhythmia defined as >= grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension (as determined by the investigator); myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring > 6 months prior to study entry is permitted)Xx_NEWLINE_xXSignificant cardiovascular impairment: congestive heart failure > class II according to the New York Heart Association (NYHA), unstable angina or myocardial infarction within 6 months of enrollment, or serious cardiac arrhythmia (> grade 2)Xx_NEWLINE_xXSerious uncontrolled medical disorder or active systemic infection or current unstable or decompensated medical condition, which makes it undesirable or unsafe for the patient to participate in the study including: New York Heart Association (NYHA) Class 3 or 4, myocardial infarction within 3 months, uncontrolled angina within 3 months, history of clinically significant ventricular arrhythmia, diabetes mellitus with ketoacidosis, or chronic obstructive pulmonary disease (COPD) requiring hospitalization in 6 months prior to the start of treatment with PRI-724.Xx_NEWLINE_xXParticipants with history of cardiovascular disease manifested as:\r\n* History of myocardial infarction\r\n* Unstable angina\r\n* Currently taking medication for treatment of angina\r\n* History of coronary artery bypass surgery\r\n* New York Heart Association class 3 or 4 heart failureXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to randomization.Xx_NEWLINE_xXClinically 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 II-IV heart disease or cardiac ejection fraction measurement of < 50 % at baselineXx_NEWLINE_xXHistory of significant cardiovascular disease (i.e. NYHA class 3 congestive heart failure; myocardial infarction with the past 6 months; unstable angina; coronary angioplasty with the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias)Xx_NEWLINE_xXMyocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication, or uncontrolled hypertension in the opinion of the investigatorXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarct within 6 months before enrollment, New York Heart Association Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalitiesXx_NEWLINE_xXAny of the following concurrent severe and/or uncontrolled medical conditions that could compromise participation in the study: \r\n* ST depression or elevation of >= 1.5 mm in 2 or more leads\r\n* Congenital long QT syndrome\r\n* History or presence of sustained ventricular arrhythmias or atrial fibrillation\r\n* Clinically significant resting bradycardia (< 50 beats per minutes)\r\n* Corrected QT interval (QTc) > 480 msec on screening electrocardiogram (ECG)\r\n* Complete left bundle branch block\r\n* Right bundle branch block + left anterior hemiblock (bifascicular block)\r\n* Unstable angina pectoris =< 6 months prior to starting study drug\r\n* Acute myocardial infarction =< 6 months prior to starting study drug\r\n* Other clinically significant heart disease such as congestive heart failure requiring treatment (New York Heart Association [NYHA] class III or IV) or uncontrolled hypertension (please refer to World Health Organization [WHO]-International Society of Hypertension [ISH] guidelines)Xx_NEWLINE_xXHave a history of New York Heart Association class ?3, unstable angina, myocardial infarction 6 months prior to study drugXx_NEWLINE_xXHave a history of congestive heart failure with a New York Heart Association class greater than 2, unstable angina, recent myocardial infarction (within 6 months of study enrollment), transient ischemic attacks, stroke, or arterial or venous vascular diseaseXx_NEWLINE_xXCongestive heart failure > class II New York Heart Association (NYHA); unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXUnstable angina, myocardial infarction, cerebrovascular accident, >= Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure within 6 months before enrollment.Xx_NEWLINE_xXMyocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication, or uncontrolled hypertensionXx_NEWLINE_xXPatients with a history of syncope, family history of idiopathic sudden death, a history of sustained or clinically significant cardiac arrhythmias, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris, sustained ventricular tachycardia, ventricular fibrillation, advanced heart block, or a history of acute myocardial infarction within the six months preceding enrollmentXx_NEWLINE_xXCompromised cardiovascular function defined as any of the following:\r\n* Electrocardiogram (EKG) evidence of acute ischemia\r\n* EKG evidence of medically significant conduction system abnormalities\r\n* History of myocardial infarction within the last 6 months\r\n* Unstable angina pectoris or cardiac arrhythmia\r\n* History of class 3 or class 4 New York Heart Association congestive heart failure\r\n* Left ventricular ejection fraction (LVEF) < 55% by either echocardiography or radionuclide-based multiple gated acquisition (Echo or MUGA)Xx_NEWLINE_xXClinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome [SVC], New York Heart Association [NYHA] classification of heart disease >= 2 within 3 months before entry); or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmiaXx_NEWLINE_xXCardiac disease: Congestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXClinically significant cardiovascular disease (e.g., hypertension [blood pressure [BP] > 150/100], myocardial infarction or stroke within 6 months, unstable angina), New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXMyocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemakerXx_NEWLINE_xXCardiac disease: Congestive heart failure > class II New York Heart Association (NYHA): unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months, or uncontrolled arrhythmiaXx_NEWLINE_xXHistory of cardiac disease congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or Digoxin are permitted).Xx_NEWLINE_xXCongestive heart failure > class II New York Heart Association (NYHA); patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 monthsXx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV heart failure, arrhythmias or unstable angina, electrocardiograph (ECG) evidence of active ischemia or active conduction system abnormalities, or myocardial infarction within the last 6 months (prior to study entry, ECG abnormalities at screening must be documented by the investigator as not medically relevant)Xx_NEWLINE_xXPatients with clinically significant cardiovascular disease: history of cerebrovascular accident (CVA) within 6 months, myocardial infarction or unstable angina within 6 months, unstable angina pectoris, New York Heart Association class CHF score IIXx_NEWLINE_xXThose with New York Heart Association functional classification II, III or IV; active cardiac conditions including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesiaXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction =< 6 months prior to registration, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXHistory of clinically significant cardiovascular disease including, but not limited to: \r\n* Myocardial infarction or unstable angina =< 6 months prior to treatment initiation \r\n* Clinically significant cardiac arrhythmia \r\n* Deep vein thrombosis, pulmonary embolism, stroke =< 6 months prior to treatment initiation \r\n* Congestive heart failure (New York Heart Association class III-IV) \r\n* Pericarditis/clinically significant pericardial effusion \r\n* Myocarditis \r\n* EndocarditisXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association functional classificationXx_NEWLINE_xXPatients with uncontrolled hypertension (> 160/95), unstable coronary disease evidenced by uncontrolled arrhythmias, unstable angina, decompensated congestive heart failure (CHF) (> New York Heart Association [NYHA] class II), or myocardial infarction within 6 months of study will be excludedXx_NEWLINE_xXPatients may not have any clinically significant cardiovascular disease including the following:\r\n* Myocardial infarction or ventricular tachyarrhythmia within 6 months\r\n* Prolonged QTc > 480 msec at baseline\r\n* Symptomatic congestive heart failure (CHF) of New York Heart Association (NYHA) functional class >= 3\r\n* Major conduction abnormality (unless a cardiac pacemaker is present)Xx_NEWLINE_xXPatients meeting the following criteria are not eligible: history of unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke, peripheral arterial occlusive disease, venous thromboembolism or pulmonary embolism; any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes); prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and Bazett’s correction; symptomatic congestive heart failure within 3 months prior to first dose of ponatinib (New York Heart Association [NYHA] class III or IV)Xx_NEWLINE_xXUncontrolled or severe cardiovascular disease, including myocardial infarct or unstable angina within 6 months prior to study treatment, New York Heart Association (NYHA) class II or greater congestive heart failure, serious arrhythmias requiring medication for treatment, clinically significant pericardial disease or cardiac amyloidosisXx_NEWLINE_xXUnstable cardiovascular function:\r\n* Electrocardiography (ECG) abnormalities requiring treatment, or\r\n* Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3\r\n* Myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXSignificant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, (third-degree atrioventricular [AV] block, ventricular tachycardia, atrial fibrillation with rapid ventricular rate [heart rate (HR) > 100 beats per minute (bpm)]),congestive heart failure, or myocardial infarction within 2 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXHistory of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting; myocardial infarction; unstable angina; coronary artery bypass graft surgery; symptomatic peripheral vascular disease; class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXMyocardial infarction or unstable angina within 6 months prior to enrollment or has New York Hospital Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities\r\n* Fridericia corrected QT interval (QTcF) > 470 msec on the screening of electrocardiogram (ECG) (as mean of triplicate ECGs)Xx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXHistory of clinically significant cardiovascular condition with the past 6 months (e.g. angioplasty or stenting, myocardial infarction, unstable angina, bypass surgery, symptomatic peripheral arterial disease [PAD], class III or IV congestive heart failure)Xx_NEWLINE_xXA history or evidence of cardiovascular risk including any of the following:\r\n* A corrected QT (QTc) interval >= 500 ms at screening\r\n* A history or evidence of current clinically significant uncontrolled arrhythmias\r\n** Exception: Subjects with atrial fibrillation controlled for > 30 days prior to randomization are eligible\r\n* A history (within 6 months prior to randomization) of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty\r\n* A history or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines\r\n* Treatment refractory hypertension defined as a blood pressure of systolic > 150 mmHg and/or diastolic > 100 mm Hg which cannot be controlled by antihypertensive therapy\r\n* Patients with intra-cardiac defibrillators or permanent pacemakersXx_NEWLINE_xXPatient has any of the following cardiac abnormalities:\r\n* Symptomatic congestive heart failure\r\n** History of documented congestive heart failure (New York Heart Association functional classification III-IV), documented cardiomyopathy\r\n** Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)\r\n* Myocardial infarction =< 6 months prior to enrollment\r\n* Unstable angina pectoris\r\n* Serious uncontrolled cardiac arrhythmia\r\n* Symptomatic pericarditis\r\n* Corrected QT interval using Fridericia's formula (QTcF) > 480 msec on the screening electrocardiogram (ECG) (using the QTcF formula)\r\n* Currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drugXx_NEWLINE_xXAny condition precluding exercise, including: New York Heart Association (NYHA) class II, III, or IV congestive heart failure, uncontrolled angina, myocardial infarction in the prior 12 months, orthopedic surgery in the previous 6 months or plans for orthopedic surgery during the study period, chronic pulmonary conditions such as uncontrolled asthma (symptoms > 2 days/week) or dyspnea requiring oxygen, symptomatic peripheral vascular disease, symptomatic anemia, uncontrolled psychiatric conditions such as schizophrenia, or any other comorbidity that would interfere with the ability to complete and comply with the study protocol in the opinion of the investigatorXx_NEWLINE_xXClinically 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)Xx_NEWLINE_xXPatients who have had a myocardial infarction within 6 months of enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXUnstable cardiovascular function:\r\n* Symptomatic ischemia\r\n* Congestive heart failure New York Heart Association (NYHA) class > 3\r\n* Myocardial infarction (MI) within 3 monthsXx_NEWLINE_xXUncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, severe malnutrition or psychiatric illness/social situations that would limit compliance with study requirementsXx_NEWLINE_xXAny of the following cardiovascular conditions or values within 6 months before the first dose of study drug:\r\n* A left-ventricular ejection fraction < 50%\r\n* Myocardial infarction within 2 years of randomization\r\n* New York Heart Association (NYHA) class III or IV heart failureXx_NEWLINE_xXSignificant cardiovascular impairment: history of (a) congestive heart failure greater than New York Heart Association (NYHA) Class II; (b) unstable angina; (c) myocardial infarction; (d) stroke; or (e) cardiac arrhythmia associated with hemodynamic instability within 6 months of the first dose of study drugsXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXClinically 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 therapyXx_NEWLINE_xXClinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXSignificant cardiovascular disease such as New York Heart Association (NYHA) class II or greater, myocardial infarction within the previous 3 months of first study treatment, unstable arrhythmias, unstable angina; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriateXx_NEWLINE_xXUnderlying unstable cardiac or pulmonary disease or symptomatic cardiac disease (New York Heart Association functional class III or IV)Xx_NEWLINE_xXPatient has uncontrolled angina, congestive heart failure (New York Heart Association > class II or known ejection fraction < 40%), uncontrolled cardiac arrhythmia or hypertension, or acute myocardial infarction within 3 monthsXx_NEWLINE_xXPatient has uncontrolled angina, congestive heart failure (New York Heart Association > class II or known ejection fraction < 40%), uncontrolled cardiac arrhythmia or hypertension, or acute myocardial infarction within 3 monthsXx_NEWLINE_xXActive or symptomatic cardiopulmonary disease (myocardial infarction < 1 month, heart failure >= New York Heart Association [NYHA] II, atrial fibrillation with poor rate control, high grade atrioventricular [AV] block, obstructive valvular disease, chronic obstructive pulmonary disease [COPD])Xx_NEWLINE_xXActive or clinically significant cardiac disease including: a. congestive heart failure-New York Heart Association (NYHA) > class II; b. active coronary artery disease; c. cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin; d. unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomizationXx_NEWLINE_xXUnderlying unstable cardiac or pulmonary disease or symptomatic cardiac disease (New York Heart Association functional class III or IV)Xx_NEWLINE_xXPatients with clinically significant cardiac disease (e.g. congestive heart failure New York Heart Association class III or IV, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication), or myocardial infarction within the previous six monthsXx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to Day 1, unstable arrhythmias, or unstable anginaXx_NEWLINE_xXClinically significant cardiovascular disease including:\r\n* Myocardial infarction within six months prior to screening\r\n* Uncontrolled angina within three months prior to screening\r\n* Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated 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 placeXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollmentXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXHas a serious concurrent medical condition, such as: congestive heart failure New York Heart Association (NYHA) class III or IV or uncontrolled hypertension at screening, 12-Lead electrocardiogram (ECG) abnormalities considered by the investigator to be clinically significant including myocardial infarction, angioplasty, or cardiac stent placement within the last 6 months, HIV infection, known Hepatitis B or C infection. Subjects at high risk for Hepatitis B or C infection should have serology testing to rule out infection, a medical condition requiring the therapeutic use of anticoagulants.Xx_NEWLINE_xXUnstable cardiovascular function: symptomatic ischemia (chest pain of cardiac origin), or uncontrolled clinically significant conduction abnormalities (e.g. ventricular tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or myocardial infarction (MI) within 3 months of consent dateXx_NEWLINE_xXEvidence of significant, uncontrolled concomitant diseases, which could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm)Xx_NEWLINE_xXNo myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXPatient had myocardial infarction within 6 months prior to enrollment, New York Hospital Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXActive cardiovascular disease including any of the following:\r\n* New York Heart Association (NYHA) grade II or greater congestive heart failure\r\n* History of myocardial infarction or unstable angina within 6 months prior to day 1\r\n* History of stroke or transient ischemic attack within 6 months prior to day 1Xx_NEWLINE_xXClinically 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 class III-IV heart disease or cardiac ejection fraction measurement of < 50%Xx_NEWLINE_xXPatients 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 registrationXx_NEWLINE_xXPatients with any of the following cardiac conditions:\r\n* Symptomatic restrictive cardiomyopathy\r\n* Dilated cardiomyopathy\r\n* Unstable angina within 4 months prior to enrollment\r\n* New York Heart Association functional class III-IV heart failure on active treatment\r\n* Symptomatic pericardial effusionXx_NEWLINE_xXEXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiography (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXSymptomatic or uncontrolled cardiovascular disease, myocardial infarction or severe/unstable angina within the past 6 months, or New York Heart Association class III or IV congestive heart failureXx_NEWLINE_xXAny major cardiovascular event within 6 months of study initiation, including but not limited to myocardial infarction, unstable angina, cerebrovascular accident, pulmonary embolism, heart failure uncontrolled by medications or New York Heart Association class III or IV heart failureXx_NEWLINE_xXChronic ischemic heart disease with unstable angina, chronic heart failure at class III or IV, and myocardial infarction in the last 6 monthsXx_NEWLINE_xXPatients with history of serious cardiac events defined as: \r\n* Patients with a history of New York Heart Association class 3 or 4 heart failure, or history of myocardial infarction, unstable angina or cerebrovascular accident (CVA) within 6 months of protocol registration \r\n* Patients who have history of PR prolongation (grade 2 or higher) or atrioventricular (AV) blockXx_NEWLINE_xXEvidence of cardiovascular risk including any of the following: QT interval corrected>=470 millisecond, evidence of current clinically significant uncontrolled arrhythmias, history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening, Class III or IV heart failure as defined by the New York Heart Association functional classification system, uncontrolled hypertension, subjects with intra-cardiac defibrillators or permanent pacemakers, abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Left ventricular ejection fraction (LVEF) < LLN\r\n* A QT interval corrected for heart rate using the Bazett’s formula corrected QT (QTcB) >= 480 msec\r\n* History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to registration are eligible)\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to registration\r\n* History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy\r\n* Known cardiac metastasesXx_NEWLINE_xXCardiac dysfunction defined as: Myocardial infarction within six months of study entry, NYHA (New York Heart Association) Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmiasXx_NEWLINE_xXSignificant cardiovascular disease such New York Heart Association (NYHA) class III or greater, myocardial infarction within the previous 3 months, unstable arrhythmias, unstable angina, need for cardiac angioplasty or stenting, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease; subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriateXx_NEWLINE_xXHistory of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseaseXx_NEWLINE_xXClinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome [SVC], New York Heart Association [NYHA] classification of heart disease >= 2 within 3 months before entry; or presence of cardiac disease that, in the opinion of the investigator, increases the risk of ventricular arrhythmiaXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiography (ECG) abnormality at screening must be documented by the investigator as not medically relevantXx_NEWLINE_xXMyocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.Xx_NEWLINE_xXSevere cardiac insufficiency (New York Heart Association class [NYHA] III or IV), with uncontrolled and/or unstable cardiac or coronary artery diseaseXx_NEWLINE_xXMedical illness unrelated to the tumor which in the opinion of the attending physician and principal investigator will preclude administration of the tracer\r\n* This includes patients with uncontrolled infection, chronic renal insufficiency, myocardial infarction within the past 6 months, unstable angina, cardiac arrhythmias other than chronic atrial fibrillation and chronic active or persistent hepatitis, or New York Heart Association Classification III or IV heart diseaseXx_NEWLINE_xXSubject has any one of the following:\r\n* Clinically significant abnormal electrocardiography (ECG) finding at screening\r\n* Congestive heart failure (New York Heart Association class III or IV)\r\n* Myocardial infarction within 12 months prior to starting study treatment\r\n* Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectorisXx_NEWLINE_xXPatients who are clinically unstable, patients who are seriously or terminally ill with a life expectancy of less than 1 month, and patients whose clinical course are unpredictable; for example:\r\n* Patients on life support or in a critical care unit\r\n* Patients with unstable occlusive disease (e.g., crescendo angina)\r\n* Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia\r\n* Patients with uncontrolled congestive heart failure (New York Heart Association [NYHA] class IV)\r\n* Patients with recent cerebral hemorrhage\r\n* Patients who have undergone surgery within 24 hours prior to the study sonographic examinationXx_NEWLINE_xXPATIENT: Patients who are medically unstable, patients who are seriously or terminally ill, and patients whose clinical course is unpredictable; for example:\r\n* Patients on life support or in a critical care unit\r\n* Patients with unstable occlusive disease (e.g., crescendo angina)\r\n* Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia\r\n* Patients with uncontrolled congestive heart failure (New York Heart Association [NYHA] class IV)\r\n* Patients with recent cerebral hemorrhage\r\n* Patients who have undergone surgery within 24 hours prior to the study sonographic examinationXx_NEWLINE_xXClinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by an electrocardiogram (ECG)Xx_NEWLINE_xXMedical illness unrelated to the tumor which in the opinion of the attending physician and principal investigator will preclude administration of the agent; this includes patients with uncontrolled infection, chronic renal insufficiency, myocardial infarction within the past 6 months, unstable angina, cardiac arrhythmias other than chronic atrial fibrillation and chronic active or persistent hepatitis, or New York Heart Association classification III or IV heart diseaseXx_NEWLINE_xXHistory or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, myocardial infarction within 6 months prior to study entryXx_NEWLINE_xXMedical illness unrelated to the tumor which in the opinion of the attending physician and principal investigator will preclude administration of the tracer; this includes patients with uncontrolled infection, chronic renal insufficiency, myocardial infarction within the past 6 months, unstable angina, cardiac arrhythmias other than chronic atrial fibrillation and chronic active or persistent hepatitis, or New York Heart Association Classification III or IV heart diseaseXx_NEWLINE_xXPatients must not have history of any one or more of the following cardiovascular conditions within the past 6 months:\r\n* Cardiac angioplasty or stenting\r\n* Myocardial infarction\r\n* Unstable angina\r\n* Coronary artery bypass graft surgery\r\n* Symptomatic peripheral vascular disease\r\n* Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXClinically 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 baselineXx_NEWLINE_xXAny 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 enrollmentXx_NEWLINE_xXHistory 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) criteriaXx_NEWLINE_xXSubjects must not have an uncontrolled intercurrent illness, including an ongoing or active infection, current pneumonitis, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina, uncontrolled hypertension, cardiac arrhythmia, interstitial lung disease, active coagulopathy, or uncontrolled diabetes.Xx_NEWLINE_xXSignificant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina; patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriateXx_NEWLINE_xXClinically significant cardiopulmonary disease including uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure, uncontrolled angina, uncontrolled hypertension, uncontrolled arrhythmia, myocardial infarction or stroke within 6 months of first protocol treatment, or corrected QT (QTc) > 480 msXx_NEWLINE_xXPatients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:\r\n* Coronary artery bypass graft\r\n* Angioplasty\r\n* Vascular stent\r\n* Myocardial infarction\r\n* Angina pectoris\r\n* Congestive heart failure New York Heart Association grade >= 2 (ventricular arrhythmias requiring continuous therapy)\r\n* Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled\r\n* Hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding\r\n* History of drug abuse or alcohol abuse, as judged by the investigatorXx_NEWLINE_xXCurrently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 2 or higher congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomizationXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXNew York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months; ejection fraction (EF) by multi-gated acquisition (MUGA) or echo should not be less than the institutional lower limit of normalXx_NEWLINE_xXClinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medicationXx_NEWLINE_xXCardiac criteria such as unstable angina, myocardial infarction within 6 months of screening, NY Heart Association Class 1 or 2 heart failure, QTc greater than 470 msec, congenital long Qt syndrome, symptomatic orthostatic hypotension within 6 months of screening, uncontrolled hypertension, or clinically important abnormalities in heart rhythm, conduction, morphology of resting ECGXx_NEWLINE_xXSubject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 1 month prior to study entry results in a left ventricular ejection fraction that is ? 45%.Xx_NEWLINE_xXPatients who are medically unstable, patients who are seriously or terminally ill, and patients whose clinical course is unpredictable; for example:\r\n* Patients on life support or in a critical care unit\r\n* Patients with unstable occlusive disease (eg, crescendo angina)\r\n* Patients with clinically unstable cardiac arrhythmias, such as recurrent ventricular tachycardia\r\n* Patients with uncontrolled congestive heart failure (New York Heart Association [NYHA] class IV)Xx_NEWLINE_xXPotentially 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)Xx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medicationXx_NEWLINE_xXClinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by an electrocardiogram (ECG)Xx_NEWLINE_xXClinically significant heart disease (e.g., congestive heart failure of New York Heart Association class III or IV, angina not well controlled by medication, or myocardial infarction within 6 months)Xx_NEWLINE_xXMyocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemia or active conduction system abnormalitiesXx_NEWLINE_xXClinically 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 metastasesXx_NEWLINE_xXMyocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medicationXx_NEWLINE_xXHave the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension.Xx_NEWLINE_xXHistory or evidence of cardiovascular risk including any of the following:\r\n* Corrected QT (QTc) interval >= 480 msecs\r\n* Clinically significant uncontrolled arrhythmias; exception: subjects with controlled atrial fibrillation for > 30 days prior to day 1 of treatment with GSK1120212 are eligible\r\n* History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 24 weeks\r\n* >= class II heart failure as defined by the New York Heart Association (NYHA) functional classification systemXx_NEWLINE_xXUnderlying unstable cardiac or pulmonary disease or symptomatic cardiac disease (New York Heart Association functional class III or IV) (PCS study)Xx_NEWLINE_xXClinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by an electrocardiogram (ECG)Xx_NEWLINE_xXThe patient has New York Heart Association (NYHA) class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure.Xx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within the protocol-specified period prior to enrollmentXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within the protocol-specified period prior to enrollmentXx_NEWLINE_xXSignificant active cardiac disease within 6 months prior to enrollment, including but not limited to New York Heart Association class 4 cardiac heart failure, unstable angina, myocardial infarctionXx_NEWLINE_xXDocumented history of a cerebral vascular, unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to their first dose of study drug.Xx_NEWLINE_xXHas a history of Class II-IV congestive heart failure or myocardial infarction within 6 months of randomization.Xx_NEWLINE_xXHistory of cardiac disease, including congestive heart failure of New York Heart Association (NYHA) class >II, unstable angina (anginal symptoms at rest) or new-onset angina (within 6 months prior to study entry), myocardial infarction within 6 months prior to study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy except for beta-blockers and digoxin; evidence for uncontrolled coronary artery disease (e.g. angina pectoris, myocardial infarction within 6 months prior to study entry, major regional wall motion abnormalities upon baseline echocardiography or multiple-gated acquisition [MUGA] scan). Patients with a pacemaker are also excludedXx_NEWLINE_xXSignificant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebral vascular accident within 6 months of the first dose of study drug, or cardiac arrhythmia associated with hemodynamic instability.Xx_NEWLINE_xXSignificant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure >115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, myocardial infarction within 6 months prior to Screening, or uncontrolled atrial or ventricular cardiac arrhythmias.Xx_NEWLINE_xX