Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (left ventricular ejection fraction [LVEF] < 50%, as measured by MUGA scan or echocardiogram); prior to study entry, any electrocardiography (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
Patients 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.
Patients who have congestive heart failure (New York Heart Association [NYHA] class III or IV), sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block within the six months preceding enrollment
Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:\r\n* Any history of myocardial infarction\r\n* Any history of clinically significant (as determined by the treating physician) atrial arrhythmia\r\n* Any history of ventricular arrhythmia\r\n* Any history of cerebrovascular accident or transient ischemic attack (TIA)\r\n* Any history of peripheral arterial occlusive disease requiring revascularization\r\n* Unstable angina within 6 months prior to enrollment\r\n* Congestive heart failure within 6 months prior to enrollment\r\n* Venous thromboembolism including deep venous thrombosis or pulmonary embolism within 6 months prior to enrollment\r\n* Unacceptable screening baseline cardiovascular assessment:\r\n** Baseline multi gated acquisition scan (MUGA) (to be done within 30 days of registration) or echocardiogram demonstrating left ventricular ejection fraction (LVEF) < 50 %\r\n** Corrected QT (QTc) >= 480 msec on screening electrocardiogram (ECG) (using the QTc Fridericia [QTcF] formula)
Patients 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 Association
EXCLUSION - PROCUREMENT: Cardiac criteria: prolonged QT syndrome; atrial fibrillation/flutter; myocardial infarction within the last 12 months; cardiac echocardiography with left ventricular systolic function (LVSF) ? 30% or left ventricular ejection fraction (LVEF) ? 50%; cardiac dysfunction New York Heart Association (NYHA) III or IV; cardiac echocardiography with clinically significant pericardial effusion
Any 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 infarction
History 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 syndrome
Congestive 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).
Severe, active co-morbidity, defined as follows:\r\n* Cardiac symptoms; any of the following should be considered for exclusion:\r\n** Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within (6 months)\r\n** Diagnosed congenital long QT syndrome\r\n** Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)\r\n** Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 450 msec)
Uncontrolled angina, congestive heart failure, myocardial infarction (MI) (within last 6 months), congenital long QT syndrome, history of clinically significant ventricular arrhythmia, prolonged QTcF interval on pre-entry electrocardiogram (EKG) (greater than normal range)
Since IL-2 is administered following cell infusion:\r\n* Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence of ischemia on a cardiac stress test (stress thallium, stress multigated acquisition [MUGA], dobutamine echocardiogram or other stress test)\r\n* Similarly, patients with a baseline left ventricular ejection fraction (LVEF) < 45 percent (%) will be excluded\r\n* Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate > 120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia or 3rd degree heart block will be excluded from the study unless cleared by a cardiologist\r\n* Patients with pulmonary function test abnormalities as evidenced by a forced expiratory volume in 1 (FEV1) / forced vital capacity (FVC) < 70% of predicted for normality will be excluded
Patients with the following cardiovascular abnormalities:\r\n* Corrected QT interval (QTc) > 500 msec within 7 days prior to registration for protocol therapy; NOTE: if QTc is > 450 and ? 500 msec, subject to local cardiology review and approval, the patient may be enrolled if the QTc elevation is deemed clinically insignificant\r\n* Acute cardiovascular events within 6 months prior to C1D1: stroke (transient ischemic attack permitted), acute coronary syndrome, peripheral arterial obstruction, clinically significant arrhythmias (e.g., such as paroxysmal atrial fibrillation/atrial flutter, sick sinus syndrome, second or third degree atrio-ventricular blockade); a cardiology consultation may be obtained to clarify clinical significance\r\n* Clinical cardiac heart failure of New York Heart Association class III or IV or left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram at screening
Participants 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 therapy
Significant 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 ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation)\r\n* Cardiac arrhythmia requiring anti-arrhythmic medication(s); note that beta-blockers, calcium channel blockers, and digoxin administered for the purpose rate control of supraventricular tachycardia, including atrial fibrillation and atrial flutter, are not classified as anti-arrhythmic medications for purposes of trial eligibility
Known cardiopulmonary disease defined as:\r\n* Unstable angina pectoris\r\n* Congestive heart failure (New York Heart Association [NYHA] class III or IV)\r\n* Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization more than 6 months prior to enrollment and who are without cardiac symptoms may enroll)\r\n* Cardiomyopathy\r\n* Clinically significant cardiac arrhythmia\r\n** History of polymorphic ventricular fibrillation or Torsade de Pointes\r\n** Permanent atrial fibrillation (a fib), defined as continuous a fib for ? 6 months\r\n** Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening\r\n** Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker) or ablation\r\n** Patients with Paroxysmal a fib or < grade 3 a fib for a period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen\r\n* Implantable cardioverter defibrillator\r\n* Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)\r\n* Pulmonary hypertension
Patients with uncontrolled or significant cardiovascular disease including, but not limited to, any of the following are ineligible:\r\n* Myocardial infarction or stroke/transient ischemic attack (TIA) within the 6 months prior to consent\r\n* Uncontrolled angina within the 3 months prior to consent\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 cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, myocarditis and pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc.)\r\n* Cardiovascular disease-related requirement for daily supplemental oxygen
Not 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 OR
Clinically 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).
Has a history of significant cardiac disease, including:\r\n* History of a recent myocardial infarction (within one year), a past myocardial infarction (more than one year ago) along with current coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by multigated acquisition [MUGA] or echocardiogram [ECHO])\r\n* Current history of angina/coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO)\r\n* Clinical evidence of congestive heart failure requiring medical management (irrespective of ECHO results)
Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: any history of myocardial infarction (MI), stroke, or revascularization; unstable angina or transient ischemic attack prior to enrollment; congestive heart failure prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment; diagnosed or suspected congenital long QT syndrome; any history of clinically significant atrial or ventricular arrhythmias (such as artrial fibrillation, ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes) as determined by the treating physician; prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) unless corrected after electrolyte replacement.
Since IL-2 is administered following cell infusion:\r\n* Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence of ischemia on a cardiac stress test (stress thallium, stress multigated acquisition [MUGA], dobutamine echocardiogram or other stress test)\r\n* Similarly, patients with a baseline left ventricular ejection fraction (LVEF) < 45% will be excluded.\r\n* Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate >120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia or 3rd degree heart block will be excluded from the study unless cleared by a cardiologist\r\n* Patients with pulmonary function test abnormalities as evidenced by a (forced expiratory volume 1 [FEV1]/forced vital capacity [FVC ] < 70% of predicted for normality will be excluded
Uncontrolled intercurrent illness including, but not limited to:\r\n* Malabsorption syndrome significantly affecting gastrointestinal function\r\n* Ongoing or active infection requiring parenteral antibiotics\r\n* Impairment of lung function (chronic obstructive pulmonary disease [COPD] > grade 2, lung conditions requiring oxygen therapy)\r\n* Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)\r\n* Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months\r\n* Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse Events, version 4.03, grade 3])\r\n* Fridericia's correction formula (QTcF) >= 480 msec on screening electrocardiography (EKG)\r\n* Known history of clinically significant QT/corrected QT (QTc) prolongation or torsades de pointes (TdP)\r\n* ST depression or elevation of >= 1.5 mm in 2 or more leads\r\n* Diarrhea of any cause >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2\r\n* Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary\r\n* Symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment and be off steroids)\r\n* Known history of chronic liver or chronic renal failure\r\n* Poor wound healing capacity
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)
Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: Any history of myocardial infarction (MI), stroke, or revascularization; Unstable angina or transient ischemic attack prior to enrollment; Congestive heart failure prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment; Diagnosed or suspected congenital long QT syndrome; Any history of clinically significant atrial or ventricular arrhythmias (such as atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) as determined by the treating physician; Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) unless corrected after electrolyte replacement. Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism; Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 140 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
Any one of the following currently or in the previous 6 months:\r\n* Myocardial infarction\r\n* Congenital long QT syndrome\r\n* Torsade’s de points\r\n* Arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), and left anterior hemiblock (bifascicular block)\r\n* Unstable angina, coronary/peripheral artery bypass graft\r\n* Symptomatic congestive heart failure (congestive heart failure [CHF] New York Heart Association class III or IV)\r\n* Cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism or other clinical significant episode of thrombo-embolic disease (Cases must be discussed in detail with study chair to judge eligibility; anticoagulation (heparin only, no vitamin-K antagonists or factor Xa inhibitors) will be allowed if indicated)\r\n* Ongoing cardiac dysrhythmias of NCI CTCAE grade >= 2, atrial fibrillation of any grade, or QT correction using Fridericia's correction formula (QTcF) interval > 470 msec at screening (except in case of right bundle branch block, these cases must be discussed with sponsor’s medical monitor)
Cardiac: Uncontrolled clinically significant arrhythmias; clinical evidence of significant congestive heart failure (CHF) (NYHA Class III or IV); left ventricular ejection fraction (LVEF) < 50% by echocardiogram
Evidence of significant cardiovascular disease including history of recent (< 6 months prior) myocardial infarction, congestive heart failure, primary cardiac arrhythmias (not due to electrolyte disorder or drug toxicity, for example) beyond occasional premature ventricular contractions (PVC's), angina, positive low-level stress test, or cerebrovascular accident; all patients should have baseline pulmonary function tests; adequate pulmonary function should be documented (forced expiratory volume-one second [FEV1] > 2 liters or >= 75% of predicted for height and age) prior to initiating therapy
Cardiac 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)
Significant cardiovascular disease, including:\r\n* Symptomatic left ventricular dysfunction or baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of =< lower limit of institutional normal (LVEF < 50%)\r\n* Patients with marked baseline prolongation of QT/QTc interval (QTc interval > 450 msec for males or > 470 msec for females)\r\n* Uncontrolled hypertension: systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 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 serious ventricular arrhythmia (ie, 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 Association
Patients 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 failure
Significant 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%
Since IL-2 is administered following cell infusion:\r\n* Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress thallium, stress multi gated acquisition scan [MUGA], dobutamine echocardiogram, or other stress test)\r\n* Similarly, patients who are >= 50 years old with a baseline LVEF < 45% will be excluded\r\n* Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT interval [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate > 120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia, third (3rd) degree heart block will be excluded from the study unless cleared by a cardiologist\r\n* Patients with pulmonary function test abnormalities as evidenced by a forced expiration volume in one second (FEV1)/forced vital capacity (FVC) < 70% of predicted for normality will be excluded
Cardiac:\r\n* History of clinically significant cardiac dysfunction, including the following:\r\n** Current unstable angina\r\n** Current symptomatic congestive heart failure of New York Heart Association (NYHA) class 2 or higher\r\n** History of congenital long QT syndrome or mean corrected QT Fridericia’s formula (QTcF) > 450 msec at baseline or uncorrectable electrolyte abnormalities\r\n** Uncontrolled hypertension >= grade 3 (patients with a history of hypertension controlled with anti-hypertensives to =< grade 1 and patients with hypertension grade 2 that have treating physician approval of safety, are eligible)\r\n** Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 40%, whichever is lower\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 months \r\nNote: Optional tumor biopsies (punch, fine-needle aspiration [FNA], core or excisional) at pre-treatment, week 1, and at progression will be presented to subjects considering this study; additional optional tumor biopsies may also be offered if deemed appropriate by principal investigator; additional subjects at the MTD/RP2D expansion cohort are required to have correlative studies (blood collection and tumor biopsies at the defined time points)
Patient 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)
Clinically 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%;
Significant 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.
Cardiac conditions as follows: \r\n• Uncontrolled hypertension (BP ? 150/95 mmHg, despite medical therapy) \r\n• Left ventricular ejection fraction (LVEF) < 55%, measured by echocardiography \r\n• Atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest \r\n• Symptomatic heart failure (NYHA grade II-IV) \r\n• Prior or current cardiomyopathy \r\n• Severe valvular heart disease \r\n• Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy) \r\n• Acute coronary syndrome within 6 months prior to starting treatment
Have 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)
Patients 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 administration
Since IL-2 is administered following cell infusion:\r\n* Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress thallium, stress multigated acquisition scan [MUGA], dobutamine echocardiogram, or other stress test) \r\n* Similarly, patients who are 50 years old with a baseline LVEF < 45% will be excluded\r\n* Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT interval [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate [HR] > 120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia, third (3rd) degree heart block will be excluded from the study unless cleared by a cardiologist\r\n* Patients with pulmonary function test abnormalities as evidenced by a forced ejection volume in 1 second (FEV1)/forced vital capacity (FVC) < 70% of predicted for normality will be excluded
Concurrent medical condition which may increase the risk of toxicity, including:\r\n* Pleural or pericardial effusion of any grade at the time of screening for study\r\n* Cardiac symptoms; any of the following should be considered for exclusion:\r\n** Uncontrolled angina, congestive heart failure or myocardial infarction (MI) (within 6 months)\r\n** Diagnosed congenital long QT syndrome\r\n** Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)\r\n** Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 450 msec)
Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: \r\n* Any history of myocardial infarction (MI), stroke, or revascularization\r\n* Unstable angina or transient ischemic attack prior to enrollment \r\n* Congestive heart failure prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment \r\n* Diagnosed or suspected congenital long QT syndrome \r\n* Any history of clinically significant atrial or ventricular arrhythmias (such as atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes) as determined by the treating physician\r\n* Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 470 msec) unless corrected after electrolyte replacement\r\n* Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism\r\n* Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 140 mmHg); patients with hypertension should be under treatment on study entry to effect blood pressure control
History 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 entry
Known cardiopulmonary disease defined as:\r\n* Unstable angina\r\n* Congestive heart failure (New York Heart Association class III or IV)\r\n* Myocardial infarction (MI) within 6 months prior to first dose of pevonedistat (patients who had ischemic heart disease resulting in MI and/or revascularization greater than 6 months before treatment and who are without cardiac symptoms may enroll)\r\n* Cardiomyopathy\r\n* Left ventricular ejection fraction < 50% as assessed by echocardiogram or radionuclide angiography\r\n* Clinically significant arrhythmia:\r\n** History of polymorphic ventricular fibrillation or torsade de pointes\r\n** Permanent atrial fibrillation [a fib], defined as continuous a fib for >= 6 months\r\n** Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening\r\n** Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation and \r\n** Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen\r\n* Implantable cardioverter defibrillator\r\n* Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)\r\n* Pulmonary hypertension
Clinically 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 pacemakers
Any 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)
Any 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).
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* 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)
Any other clinically significant heart disease, including angina pectoris, resting bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial fibrillation, acute myocardial infarction, or heart disease requiring cardiac pacemaker or implantable cardioverter/defibrillator
Patients will be ineligible for treatment on this protocol if (prior to protocol entry):\r\n* There is a history of a recent (within one year) myocardial infarction\r\n* There is a current or prior history of angina/coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO)\r\n* There is clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA or ECHO results)
Participant 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 syndrome
Patients 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)
Patients with a history of cardiac disease are excluded: myocardial infarction or arterial thromboembolic events within 6 months prior to baseline, severe or unstable angina, New York Heart Association Class III or IV disease, QTCB (corrected according to Bazett's formula) interval > 470 msec, serious uncontrolled hypertension (systolic > 150 and/or diastolic > 100 mm Hg); baseline electrocardiography, echocardiography and assessment of serum troponin (I) are included in the screening exams; subjects in whom these assays are abnormal (electrocardiogram [EKG] excluding 1st degree branch block, sinus brachycardia, sinus tachycardia or non-specific T wave changes, serum troponin >= grade 2) are ineligible
Patients 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 enrollment
Patients 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 registration
Significant 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 medications
History of any of the following cardiovascular events or conditions within the past 6\n             months prior to enrolment: myocardial infarction, unstable angina, cerebrovascular\n             accident or transient ischemic attack, New York Heart Association Class ? II chronic\n             heart failure, hypokalemia, significant arrhythmia*; QTc interval >430 msec or use of\n             drugs that prolong the QT interval at screening; family history of long QT\n             syndrome.(* Significant arrhythmias are defined as symptoms of syncope or severe\n             palpitations (palpitations requiring referral to cardiac monitoring), or ECG findings\n             of supraventricular tachycardia (including ventricular fibrillation) or ventricular\n             ectopy (ventricular premature depolarization).
Cardiovascular criteria will exclude a patient from participation in the study will include:\r\n* Screening electrocardiogram (ECG) with a QTc > 450 msec;\r\n* Patients with congenital long QT syndrome; \r\n* History or presence of sustained ventricular tachycardia;\r\n* Any history of ventricular fibrillation or torsades de pointes;\r\n* Bradycardia defined as heart rate (HR) < 50 bpm;\r\n* Right bundle branch block + left anterior hemiblock (bifascicular block);\r\n* Patients with myocardial infarction or unstable angina < 6 months prior to starting study drug;\r\n* Congestive heart failure (CHF) New York (NY) Heart Association class III or IV;\r\n* Patients with an ejection fraction =< 45% assessed by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) scan within 14 days of day 1\r\n* Poorly controlled hypertension
Patients with clinically significant cardiovascular disease; this includes:\r\n* Uncontrolled hypertension, defined as systolic greater than 150 mmHg or diastolic greater than 90 mmHg\r\n* Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry\r\n* Congenital long QT syndrome or baseline QTc greater than 480 milliseconds\r\n* Myocardial infarction or unstable angina within 6 months prior to registration\r\n* New York Heart Association (NYHA) class III or greater congestive heart failure\r\n* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate\r\n* Patients who have received prior treatment with an anthracycline (including doxorubicin, excluding liposomal doxorubicin) must have an echocardiogram or multigated acquisition scan (MUGA) assessment and are excluded if they have an ejection fraction less than 50%\r\n* CTCAE v.4.0 grade 2 or greater peripheral vascular disease (at least brief less than 24 hours [hrs]) episodes of ischemia managed non-surgically and without permanent deficit\r\n* History of cardiac angioplasty or stenting within 6 months prior to registration; history of coronary artery bypass graft surgery within 6 months prior to registration\r\n* Arterial thrombosis within 6 months prior to registration
Subject has history (within previous 5 years) of clinically significant pulmonary hypertension, uncontrolled systemic hypertension, hypertensive crisis, congestive heart failure, myocardial infarction, aneurysm or aneurysm repair or the left ventricular ejection fraction (LVEF) less than or equal to 50%.
Patients who have a history of: congestive heart failure, unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, acute MI less than one year prior to study entry, or clinically significant impairment in cardiovascular function.
Since IL-2 is administered following cell infusion:\r\n* Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress thallium, stress multi gated acquisition [MUGA] scan, dobutamine echocardiogram, or other stress test)\r\n* Similarly, patients who are 50 years old with a baseline LVEF < 45% will be excluded\r\n* Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT interval [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate > 120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia, 3rd degree heart block will be excluded from the study unless cleared by a cardiologist\r\n* Patients with pulmonary function test abnormalities as evidenced by a forced expiratory volume of the lung in 1 second (FEV1)/forced vital capacity (FVC) < 70% of predicted for normality will be excluded
Impaired cardiac function:\r\n* Corrected QT interval (QTc) > 480 on screening electrocardiogram (ECG)\r\n* Previous history of angina pectoris or acute myocardial infarction (MI) within 6 months\r\n* Congestive heart failure (New York Heart Association functional classification III-IV) or baseline multigated acquisition scan (MUGA)/echocardiogram (ECHO) shows estimated left ventricular ejection fraction (LVEF) < 45%\r\n* Any history of torsade de pointes, ventricular fibrillation, uncontrolled ventricular tachycardia, or uncontrolled atrial fibrillation
Since interleukin (IL)-2 is administered following cell infusion: \r\n* Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress thallium, stress multigated acquisition [MUGA], dobutamine echocardiogram, or other stress test) \r\n* Similarly, patients who are 50 years old with a baseline LVEF < 45% will be excluded\r\n* Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT interval [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate [HR] > 120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia, 3rd degree heart block will be excluded from the study unless cleared by a cardiologist\r\n* Patients with pulmonary function test abnormalities as evidenced by a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 70% of predicted for normality will be excluded
Have 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 cardiomyopathy
Patients 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 investigator
Patients who have any serious or uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy are not eligible; these include, but are not limited to: \r\n* Active infection that is not well controlled\r\n* Known pleural or pericardial effusion at baseline \r\n* Clinically significant gastrointestinal disease or digestive dysfunction compromising absorption of dasatinib\r\n* Pulmonary arterial hypertension \r\n* Uncontrolled or significant cardiovascular disease, including:\r\n** Myocardial infarction within 6 months of enrollment date\r\n** Uncontrolled angina or congestive heart failure within 3 months of enrollment date\r\n** Left ventricular ejection fraction (LVEF) < 40%\r\n** Significant cardiac conduction abnormality, including: \r\n*** History of clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)\r\n*** History of second or third degree heart block (except for second degree type 1)\r\n*** Corrected QT (QTc) interval > 500 msec, unless a cardiac pacemaker is present\r\n* Prior malignancy active within the previous 3 years, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast\r\n* Subjects with active, known or suspected autoimmune disease; (Note: Subjects with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll)\r\n* Psychiatric illness/social situations that would limit compliance with study requirements\r\n* Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient’s safety or study endpoints
Patients who currently have or have a history of the following within 6 months preceding study entry are not eligible: unstable angina (UA) or myocardial infarction (MI), clinically significant atrial or ventricular arrhythmias (e.g., atrial fibrillation [AF], atrial flutter, ventricular tachycardia, ventricular fibrillation, or torsades de pointes), New York Heart Association (NYHA) class III or IV heart failure
Significant 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 medications
Patients with clinically significant cardiovascular disease; this includes: \r\n* Uncontrolled hypertension, defined as systolic greater than or equal to 160 mm Hg or diastolic greater than or equal to 100 mm Hg despite antihypertensive medications \r\n* Myocardial infarction or unstable angina within 6 months prior to the first date of study treatment\r\n* New York Heart Association (NYHA) class II or greater congestive heart failure\r\n* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication; this does not include asymptomatic atrial fibrillation with controlled ventricular rate\r\n* Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms; \r\n** Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (ECGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is less than or equal to 500 ms, the subject meets eligibility in this regard
Clinically 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 place
Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:\r\n* Any history of myocardial infarction, stroke, or revascularization\r\n* Unstable angina or transient ischemic attack within 6 months prior to registration\r\n* Congestive heart failure within 6 months prior to registration, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards within 6 months prior to registration\r\n* History of clinically significant (as determined by the treating physician) atrial arrhythmia\r\n* Any history of ventricular arrhythmia\r\n* Active venous thromboembolism including deep venous thrombosis or pulmonary embolism that is not amenable to treatment with anticoagulants\r\n* Patients with congenital prolonged QT syndromes and abnormal baseline prolonged corrected QT (QTc) (> 450 ms in men and > 470 ms in women)\r\n* Patients with an ejection fraction =< 50% as assessed by a baseline echocardiogram
Patients 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 bleeding
Patients who have any severe and/or uncontrolled medical conditions or other\r\nconditions that could affect their participation in the study such as:\r\n* Known cardiopulmonary disease defined as:\r\n** Unstable angina\r\n** Congestive heart failure (New York Hear Association [NYHA] class III or IV\r\n** Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as acute chest syndrome [ACS], MI and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll)\r\n** Cardiomyopathy\r\n** Clinically significant arrhythmia:\r\n*** Polymorphic ventricular fibrillation or torsade de pointes\r\n*** Permanent atrial fibrillation [a fib], defined as continuous a fib >= 6 months\r\n*** Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening\r\n*** Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker), or ablation\r\n*** Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen\r\n*** Implantable cardioverter defibrillator\r\n** Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)\r\n** Symptomatic pulmonary hypertension\r\n* Active infection requiring IV antibiotic, antiviral, or anti-fungal medications within 2 weeks of starting study drug\r\n* Known history of human immunodeficiency virus (HIV) seropositivity
Significant 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%)
Patients 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 tachycardia
Significant heart disease defined as:\r\n* Significant coronary arterial disease\r\n** Myocardial infarction in the last 6 months, angina in the previous 3 months,\r\n** Troponin elevation at level of myocardial infarction as defined by the manufacturer\r\n** Ischemic changes on electrocardiogram (ECG)\r\n* Atrio-ventricular block greater than 1st degree, in absence of pacemaker\r\n* Corrected QT interval (QTc) greater than 480 ms (CTCAE 4.0 grade 1 abnormality is acceptable)\r\n* History of ventricular arrhythmia\r\n* Left ventricular ejection fraction below the institutional limit of normal
Patients 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 enrollment
Patients with any of the following:\r\n* History of myocardial infarction within six months\r\n* Patients with corrected QT (QTc) prolongation > 500 msec or other significant electrocardiogram (ECG) abnormality noted within 14 days of treatment\r\n** For patients enrolled in the Phase 1-T portion of the protocol, the QTc should not exceed 470 msec\r\n* New York Heart Association (NYHA) classification of III or IV\r\n* If cardiac function assessment is clinically indicated or performed: left ventricular ejection fraction (LVEF) less than normal per institutional guidelines, or < 55%, if threshold for normal not otherwise specified by institutional guidelines\r\n* Condition requiring concurrent use of drugs or biologics with pro-arrhythmic potential
Uncontrolled or significant cardiovascular disease, including:\r\n* A myocardial infarction within 12 months of registration\r\n* Uncontrolled angina within 6 months of registration\r\n* Congestive heart failure within 6 months of registration\r\n* Diagnosed or suspected congenital long QT syndrome\r\n* Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)\r\n* Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 470 msec)\r\n* Any history of second or third degree heart block (may be eligible if currently have a pacemaker)\r\n* Heart rate < 50/minute on pre-entry electrocardiogram\r\n* Uncontrolled hypertension
History 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 months
Evidence of active heart disease within the 3 months prior to study entry; symptomatic coronary insufficiency or heart block; congestive heart failure; moderate or severe pulmonary dysfunction, torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia, heart block, or congenital long QT syndrome
Patients 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 tachycardia
Abnormal ECGs which are clinically significant such as QT prolongation (QTc > 480 msec), clinically significant cardiac enlargement or hypertrophy, new bundle branch block, or signs of active ischemia. Patients with evidence of prior infarction who are New York Heart Association (NYHA) functional classes II, III, or IV are excluded, as are patients with marked arrhythmias such as Wolff Parkinson White pattern or complete atrioventricular (AV) dissociation.
Clinically 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).
Patients 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 enrollment
Compromised 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)
Patients 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)
Patients 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)
Significant 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 Classification
Significant cardiovascular disease, including:\r\n* Symptomatic left ventricular dysfunction or known baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of < lower limit of institutional normal (LLN); \symptomatic\ is defined as New York Heart Association (NYHA) class II or greater; Note: MUGA and ECHO do not need to be measured to establish eligibility for this study\r\n* Uncontrolled hypertension (in the opinion of the treating provider)\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) within 12 months of first dose of study drug\r\n* Uncontrolled cardiac arrhythmias\r\n* Coronary or peripheral artery bypass graft within 6 months of first dose of study drug\r\n* History of cerebrovascular accident (CVA), transient ischemic attack (TIA), or rest claudication within 6 months of first dose of study drug
Clinically significant cardiovascular disease including:\r\n* Myocardial infarction within six months prior to screening\r\n* Uncontrolled angina within three months prior to screening\r\n* Congestive heart failure New York Heart Association (NYHA) class 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 place
Patients 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 examination
In addition, subjects with any contraindications to exercise testing according to American Heart Association guidelines will not be enrolled; nonetheless, the cardiovascular magnetic resonance (CMR) cardiologist supervising the research portion of the exam will also evaluate each subject for evidence of any contra-indications; the absolute contra-indications include acute myocardial infarction, high-risk unstable angina, uncontrolled cardiac arrhythmias, active endocarditis, symptomatic severe aortic stenosis, decompensated symptomatic heart failure, acute pulmonary embolus or pulmonary infarction, acute non-cardiac disorder that may be aggravated by exercise, acute myocarditis or pericarditis, physical disability that would preclude safe and adequate test performance, and inability to provide consent; the relative contra-indications include left main coronary stenosis, moderate stenotic valvular heart disease, electrolyte abnormalities, tachyarrhythmias or bradyarrhythmias, atrial fibrillation with uncontrolled ventricular rate, hypertrophic cardiomyopathy, and high-degree atrioventricular node block; subjects with uncontrolled hypertension and resting blood pressure exceeding 140/80 mmHg will be excluded
PATIENT: 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 examination
Patients 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 investigator
Any one of the following currently or in the previous 3 months: myocardial infarction, congenital long QT syndrome, torsades de pointes, uncontrolled arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior fascicular hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (congestive heart failure [CHF] New York [NY] Heart Association classification III or IV) , cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism not adequate medically managed with anticoagulants, ongoing cardiac dysrhythmias of CTCAE grade >= 2, symptomatic atrial fibrillation of any grade, corrected QT (QTc) interval >= 481 msec at screening
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 (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)
Patients may not have New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50%; patients with a corrected QT (QTc) > 470 ms, a family history of long QT syndrome, and those on medications known to cause Torsades de Pointes will be excluded from the study