New York Heart Association > Grade 2 congestive heart failure within 6 months prior to study entry, unless asymptomatic and well controlled with medicationXx_NEWLINE_xXSTEP I: Patients should not have New York Heart Association classification III or IV heart failure or myocardial infarction within the previous 6 monthsXx_NEWLINE_xXNo history of congenital prolonged corrected QT (QTc) syndrome, New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)Xx_NEWLINE_xXCongestive heart failure Class III/IV according to the New York Heart Association (NYHA) Functional Classification.Xx_NEWLINE_xXCurrent 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 relevantXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV heart failure, uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunctionXx_NEWLINE_xXSymptomatic congestive heart failure (NYHA class ? II);Xx_NEWLINE_xXNew York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)Xx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXCongestive heart failure (CHF) New York (NY) Heart Association class III or IVXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failure.Xx_NEWLINE_xXCongestive heart failure (NYHA Class III or IV).Xx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressureXx_NEWLINE_xXNew York Heart Association Class II-IV congestive heart failureXx_NEWLINE_xXHistory of or current Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (Appendix B).Xx_NEWLINE_xXMyocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of first dose of AMG 757Xx_NEWLINE_xXPatients with chronic kidney disease (glomerular filtration rate [GFR] < 60), uncontrolled hypertension, congestive heart failure, pre-existing bone marrow dysfunction, or cytopenias\r\n* Congestive heart failure (CHF): New York Heart Association (NYHA) class II-IV at the time of screeningXx_NEWLINE_xXPatients with any class of New York Heart Association (NYHA) congestive heart failure (CHF) or heart failure with preserved ejection fraction (HFPEF)Xx_NEWLINE_xXPatient with symptomatic, or history of documented congestive heart failure (NY Heart Association functional classification III-IV);Xx_NEWLINE_xXNew York Heart Association Classification II, III, or IVXx_NEWLINE_xXSymptomatic congestive heart failure (CHF), New York Heart Association (NYHA) Class III or IV heart failure or other clinical signs of severe cardiac dysfunctionXx_NEWLINE_xXDocumented NYHA Class III or IV congestive heart failure,Xx_NEWLINE_xXPatients 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 enrollmentXx_NEWLINE_xXPatients with QTc interval > 450 msecs or other factors that increase the risk of QTc prolongation or arrhythmic events (ex. heart failure, clinically significant hypokalemia, clinically significant hypomagnesemia, family history of long QT syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excludedXx_NEWLINE_xXCurrent congestive heart failure (New York Heart Association Class II, III or IV)Xx_NEWLINE_xXHeart failure of New York Heart Association Classification III or IV ?6 months prior to Day 1Xx_NEWLINE_xXNew York Heart Association (NYHA) Class II or higher congestive heart failure.Xx_NEWLINE_xXNew York Heart Association heart failure class >= 3Xx_NEWLINE_xXParticipants with a history of congestive heart failure (New York Heart Association [NYHA] class II, III or IV) are excludedXx_NEWLINE_xXAcute heart failure (class III or IV of the NYHA classification)Xx_NEWLINE_xXPatient with cardiac failure class III or IV of the NYHA classificationXx_NEWLINE_xXSymptomatic congestive heart failure of New York heart Association Class III or IVXx_NEWLINE_xXActive angina pectoris or NY Heart Association Class III-IVXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV congestive heart failure.Xx_NEWLINE_xXNew York Heart Association (NYHA) status of less than or equal to (</=)1Xx_NEWLINE_xXNew York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias not adequately controlled, or other significant co-morbidities [e.g. active infection requiring systemic therapy, history of human immunodeficiency virus (HIV) infection, or active Hepatitis B or Hepatitis C].Xx_NEWLINE_xXHistory of documented congestive heart failure (New York Heart Association functional classification III-IV);Xx_NEWLINE_xXNew York Heart Association class III or IV heart failureXx_NEWLINE_xXNew York Heart Association classification III or IV heart failureXx_NEWLINE_xXNew York Heart Association classification III or IV heart failureXx_NEWLINE_xXDiagnosis of symptomatic congestive heart failure (New York Heart Association [NYHA] II-IV) or symptomatic or poorly controlled cardiac arrhythmiaXx_NEWLINE_xXPatients with QTc interval > 450 msecs or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excludedXx_NEWLINE_xXNew York Heart Association Class II, III, or IV congestive heart failureXx_NEWLINE_xXNew York Heart Association Class III or IV heart failureXx_NEWLINE_xXAny condition associated with increased risk of metformin-associated lactic acidosis (e.g. congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)Xx_NEWLINE_xXParticipants with a history of congestive heart failure or New York Heart Association (NYHA) class III or IV functional status are excludedXx_NEWLINE_xXTREATMENT EXCLUSION: Symptomatic cardiac disease (New York Heart Association [NYHA] class III or IV disease)Xx_NEWLINE_xXHistory of documented congestive heart failure (New York Heart Association functional classification III-IV) within 6 months prior to initiation of screeningXx_NEWLINE_xXAdequate cardiac function (?New York Heart Association [NYHA] Class II).Xx_NEWLINE_xXNew York Heart Association (NYHA) functional classification I-IIXx_NEWLINE_xXCongestive heart failure of New York Heart Association (NYHA) Grade >2,Xx_NEWLINE_xXKnown cardiac disorder, including:\r\n* Known inherited coronary disease\r\n* Symptomatic heart failure (New York Heart Association [NYHA] class II-IV prior or current cardiomyopathy, or severe valvular heart disease)\r\n* Current cardiomyopathy\r\n* Severe valvular heart disease\r\n* Atrial fibrillation\r\n* Ejection fraction (ECHO) < 53%\r\n* QTcF > 450 msecXx_NEWLINE_xXCongestive heart failure of New York Heart Association class III/IV,Xx_NEWLINE_xXPatients classified according to the New York Heart Association classification as having class III or IV heart disease.Xx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV heart failureXx_NEWLINE_xXCongestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 40% by multigated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI)Xx_NEWLINE_xXNew York Heart Association class III or IV heart failureXx_NEWLINE_xXCardiovascular disability status of New York Heart Association Class greater than or equal to 3.Xx_NEWLINE_xXPre-existing cardiovascular disease (including congestive heart failure, New York Heart Association [NYHA] grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a corrected QT interval (QTc) > 450 msecXx_NEWLINE_xXcongestive heart failure > class II NYHA,Xx_NEWLINE_xXUncontrolled coronary disease or New York Heart Association (NYHA) class III-IV heart diseaseXx_NEWLINE_xXHeart failure, class IV by New York Heart Association criteriaXx_NEWLINE_xXAny other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including but not limited to:\r\n* Uncontrolled infection\r\n* New York Heart Association (NYHA) III or IV heart failure\r\n* Crohn’s disease or those with ulcerative colitis who have not undergone a colectomy\r\n* Known active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis CXx_NEWLINE_xXSubjects with New York Heart Association (NYHA) class III or IV heart failure.Xx_NEWLINE_xXActive grade III-V cardiac failure as defined by the New York Heart Association criteriaXx_NEWLINE_xXCurrent or history of congestive heart failure New York Heart Association (NHYA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 50%, as measured by MUGA scan or echocardiogram)Xx_NEWLINE_xXSubjects with a history of heart disease, such as congestive heart failure (class II, III, or IV defined by the New York Heart Association functional classification), history of unstable or poorly controlled angina, or history (< 1 year prior to enrollment) of ventricular arrhythmiaXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXUncontrolled illness including but not limited to: symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV heart failure), unstable angina pectoris, uncontrolled cardiac arrhythmia, and psychiatric illness that would limit compliance with study requirementsXx_NEWLINE_xXClass II to IV heart failure as defined by the New York Heart Association functional classification systemXx_NEWLINE_xXThe patients must not be candidates for chemotherapy due to at least one of the following reasons:\r\n* Performance status of 2\r\n* Creatinine clearance =< 60 ml/min as calculated by the Cockcroft-Gault formula\r\n* Cardiac disease such as New York Heart Association (NYHA) class III or IV heart failure or cardiac ischemia within the last 12 months, grade 2 or greater neuropathy, or other comorbidities based on which patient is not considered a candidate for chemotherapyXx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic condition.Xx_NEWLINE_xXA cardiovascular disability status of New York Heart Association class >= 2Xx_NEWLINE_xXHas a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or a serious cardiac arrhythmia requiring treatment Has a corrected QT by Fridericia's formula (QTcF), of >470 ms based on a triplicate 12-lead ECGXx_NEWLINE_xXMyocardial infarction and/or symptomatic congestive heart failure (New York Heart Association > class II) within 12 months of enrollment.Xx_NEWLINE_xXClass II, III or IV heart failure as defined by the NYHA functional class systemXx_NEWLINE_xXPatients with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) that meets New York Heart Association (NYHA) class II or aboveXx_NEWLINE_xXConcurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association (NYHA) class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B, C or HIV, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation.Xx_NEWLINE_xXPatients must have a left ventricular ejection fraction >= 30%, no uncontrolled arrhythmias or New York Heart Association class III-IV heart failureXx_NEWLINE_xXSubjects with unstable angina or New York Heart Association grade II or greater congestive heart failure.Xx_NEWLINE_xXNew York Heart Association stage 3 or 4 cardiac disease.Xx_NEWLINE_xXNew York Heart Association class III or IV heart failureXx_NEWLINE_xXCardiac failure New York Heart Association (NYHA) III or IV Crohn’s disease or ulcerative colitisXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association class >= 2) within the 6 months prior to study drug administrationXx_NEWLINE_xXLeft ventricular ejection fraction (LVEF) that is greater than 40%, or the absence of New York Heart Association (NYHA) classification of greater than stage II congestive heart failureXx_NEWLINE_xXNew York Heart Association class II or greater congestive heart failureXx_NEWLINE_xXInadequate cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than or equal to 40%, or the presence of New York Heart Association (NYHA) classification of greater than stage II congestive heart failureXx_NEWLINE_xXActive grade III-V cardiac failure as defined by the New York Heart Association criteria.Xx_NEWLINE_xXNew York Heart Association Class III to IV heart failure.Xx_NEWLINE_xXHas symptomatic congestive heart failure (New York Heart Association [NYHA] Classes II-IV), unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment.Xx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV heart failure and/or ejection fraction of < 35% as measured by echocardiogram at screening.Xx_NEWLINE_xXIn patients with symptoms of congestive heart failure, New York Heart Association (NYHA) classification of grade III or IVXx_NEWLINE_xXCurrent symptomatic congestive heart failure or history of symptomatic congestive heart failure in the preceding 3 months, defined as New York (NY) Heart Association classification 2- 4Xx_NEWLINE_xXhave any other severe, uncontrolled medical condition, including unstable congestive heart failure (Stage III-IV of the New York Heart Association Functional Classification (Appendix III))Xx_NEWLINE_xXAbsence of New York Heart Association (NYHA) class II, III, or IV congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV heart diseaseXx_NEWLINE_xXActive grade III-V cardiac failure as defined by the New York Heart Association criteria.Xx_NEWLINE_xXNew York Heart Association (NYHA) functional class =< 2Xx_NEWLINE_xXOther clinically significant heart disease (New York Heart Association [NYHA] class 3 heart failure, uncontrolled hypertension)Xx_NEWLINE_xXPatients with a previous history of adriamycin treatment and are at risk of cardiac failure (New York Heart Association [NYHA] class II or above)Xx_NEWLINE_xXAny condition associated with increased risk of metformin-associated lactic acidosis (e.g., congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status; history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)Xx_NEWLINE_xXParticipant has cardiovascular disability status of New York Heart Association Class >Xx_NEWLINE_xXNew York Heart Association stage 3 or 4 cardiac disease.Xx_NEWLINE_xXCardiac conditions as follows: patient has a history of congestive heart failure (CHF) class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment; patient has a cardiac ejection fraction < 50% by either echocardiogram or multi-gated acquisition (MUGA) scanXx_NEWLINE_xXNew York Heart Association (NYHA) classification IIIB or IV heart failureXx_NEWLINE_xXCongestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screeningXx_NEWLINE_xXNew York Heart Association Class III or IV heart failure.Xx_NEWLINE_xXUncontrolled cardiac angina or symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV)Xx_NEWLINE_xXA cardiovascular disability status of New York Heart Association class >= 2Xx_NEWLINE_xXHas been classified according to the New York Heart Association classification as having class III or IV heart diseaseXx_NEWLINE_xXMajor cardiovascular or pulmonary comorbidity that precludes use of general anesthesia (NYHA [New York Heart Association] class III and IV)Xx_NEWLINE_xXCongestive cardiac failure of > grade 2 severity according to the New York Heart Association (NYHA) defined as symptomatic at less than ordinary levels of activityXx_NEWLINE_xXNYHA Class III or IV heart failure, or reduced LVEF <50%Xx_NEWLINE_xXIneligible to receive cisplatin-based neoadjuvant chemotherapy based upon at least one of the following criteria:\r\n* Creatinine clearance < 60 ml/min \r\n* Eastern Cooperative Oncology Group (ECOG) performance status = 2\r\n* Grade ? 2 hearing loss \r\n* Grade ? 2 neuropathy\r\n* New York Heart Association class III heart failureXx_NEWLINE_xXHistory of congestive heart failure New York Heart Association (NYHA) class III or IV or uncontrolled hypertension at screening.Xx_NEWLINE_xXNew York Heart Association (NYHA) class IV heart failureXx_NEWLINE_xXClass 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXClass II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.Xx_NEWLINE_xXCongestive heart failure requiring treatment (New York Heart Association [NYHA] grade >= 2)Xx_NEWLINE_xXNew York Heart Association (NYHA) cardiac class 3-4 heart diseaseXx_NEWLINE_xXSerious intercurrent chronic or acute illness, such as cardiac disease (New York Heart Association [NYHA] class III or IV), hepatic disease, or other illness considered by the principal investigator as unwarranted high risk for investigational drug treatmentXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association classification Il-IV)Xx_NEWLINE_xXCurrent evidence of active and uncontrolled infection, New York Heart Association (NYHA) class III-IV congestive heart failure (CHF), documented Child’s class B-C cirrhosis, active pancreatitis or uncontrolled medical disease which in the opinion of the investigator could compromise assessment of efficacyXx_NEWLINE_xXclass II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system;Xx_NEWLINE_xXCongestive heart failure requiring treatment (New York Heart Association [NYHA] grade >= 2)Xx_NEWLINE_xXNYHA Class III or IV heart failureXx_NEWLINE_xXClass III/IV cardiovascular disability according to the New York Heart Association ClassificationXx_NEWLINE_xXCongestive heart failure > New York Heart Association (NYHA) class 2Xx_NEWLINE_xXCongestive heart failure > New York Heart Association (NYHA) class 2Xx_NEWLINE_xXClass III/IV cardiovascular disability according to the New York Heart Association classificationXx_NEWLINE_xXClass III/IV cardiovascular disability according to the New York Heart Association ClassificationXx_NEWLINE_xXNew York Heart Association functional class III-IV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease, congestive heart failure, clinically significant hypotension, or history of an ejection fraction of =< 30 % (echocardiogram or multi gated acquisition scan [MUGA])Xx_NEWLINE_xXNew York Heart Association > Class II congestive heart failure that is not controlled on standard therapy within 6 months prior to initiation of treatment with Toca 511.Xx_NEWLINE_xXSymptomatic heart failure NYHA Class ? 3Xx_NEWLINE_xXcongestive heart failure (New York Heart Association class III to IV)Xx_NEWLINE_xXCongestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 40% by MUGA scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI)Xx_NEWLINE_xXNew York Heart Association (NYHA) class II or higher congestive heart failureXx_NEWLINE_xXSymptoms of congestive heart failure as defined by the New York Heart Association (NYHA): Functional Classification class III or IV, or medically uncontrolled cardiac rhythm disturbanceXx_NEWLINE_xXCongestive heart failure (CHF) NYHA Class ? 3, orXx_NEWLINE_xXSubject has severe cardiovascular disease, i.e. arrhythmias, requiring chronic treatment, congestive heart failure (New York Heart Association [NYHA] class III or IV) or symptomatic ischemic heart diseaseXx_NEWLINE_xXPatients with moderate to severe heart failure, New York Heart Association (NYHA) class III or IV, liver dysfunction with total bilirubin > 2.5 upper limit of normal, or serum creatinine > 2.5 mg/dL or any form of dialysis; within 30 days prior to enrollmentXx_NEWLINE_xXDocumented New York Heart Association (NYHA) class I, II and IIIXx_NEWLINE_xXNYHA class IV heart failureXx_NEWLINE_xXCongestive heart failure New York Heart Association (NYHA) class III or worse (marked limitation of physical activity; comfortable at rest; less than ordinary activity causes fatigue, palpitation, or dyspnea)Xx_NEWLINE_xXCardiovascular disease resulting in New York Heart Association function status of ? 3.Xx_NEWLINE_xXGrade 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional interventionXx_NEWLINE_xXClinically significant heart disease, defined as New York Heart Association (NYH) class III or IVXx_NEWLINE_xXClass II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification systemXx_NEWLINE_xXClinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) guidelines (Appendix D).Xx_NEWLINE_xXNew York Heart Association class III or greater congestive heart failure within last 6 months or uncontrolled hyperlipidemia (cholesterol > 300 mg/dl; triglyceride 2.5 X upper limit of normal [ULN] despite lipid lowering agent) within last 3 monthsXx_NEWLINE_xXPatients with a New York Heart Association classification of III or IVXx_NEWLINE_xXUncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4) (Appendix B).Xx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXNYHA class III or IV functional classification for heart failure.Xx_NEWLINE_xXPatients with >= New York Heart Association (NYHA) grade 3 heart disease as assessed by history and/or physical examinationXx_NEWLINE_xXNYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressureXx_NEWLINE_xXHave clinical symptomatic congestive heart failure defined at >= Class II of the New York Heart Association functional classification system or LVEF < 50% at baseline.Xx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXPatients with serious intercurrent chronic or acute illness, such as cardiac disease (New York Heart Association [NYHA] class III or IV), hepatic disease, or other illness considered by the principal investigator as unwarranted high risk for investigational drug treatmentXx_NEWLINE_xXCongestive heart failure (New York Heart Association class III or IV)Xx_NEWLINE_xXSignificant cardiovascular abnormalities as defined by any one of the following: New York Heart Association (NYHA) class III or IV congestive heart failure, clinically significant hypotension, uncontrolled symptomatic coronary artery disease, or a documented ejection fraction of < 35%Xx_NEWLINE_xXNew York Heart Association class III/IV heart failureXx_NEWLINE_xXNew York Heart Association class 3-4 heart failureXx_NEWLINE_xXPatients with clinically significant heart disease (NYHA Class III or IV).Xx_NEWLINE_xXConditions which would increase risk of lactic acidosis including:\r\n* Known alcoholism or ingestion of more than 3 alcoholic beverages per day\r\n* History of congestive heart failure defined as New York Heart Association (NYHA) class III or IV\r\n* History of metabolic acidosis\r\n* Ongoing or active infection concerning for sepsis or systemic inflammatory response syndrome (SIRS)Xx_NEWLINE_xXPatients that have been designated Class III or IV by the New York Heart Association Functional Classification.Xx_NEWLINE_xXClass 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXClass III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXNew York Heart Association class III or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) cardiac class 3-4 heart diseaseXx_NEWLINE_xXPatients with New York Heart Association (NYHA) class III or IV heart failure will be excludedXx_NEWLINE_xXActive grade III-V cardiac failure as defined by the New York Heart Association criteriaXx_NEWLINE_xXCongestive heart failure New York Heart Association (NYHA) class 3 or 4Xx_NEWLINE_xXSymptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia; symptomatic heart failure (New York Heart Association [NYHA] class II-IV)Xx_NEWLINE_xXSubjects must not have conditions associated with increased risk of metformin-associated lactic acidosis, including New York Heart Association class III or IV congestive heart failure, history of acidosis of any type, alcoholic liver disease, or habitual intake of 3 or more alcoholic beverages per dayXx_NEWLINE_xXEXCLUSION CRITERIA FOR REGISTRATION: subjects must not have conditions associated with increased risk of metformin-associated lactic acidosis, including New York Heart Association class III or IV congestive heart failure, history of acidosis of any type, alcoholic liver disease, or habitual intake of 3 or more alcoholic beverages per dayXx_NEWLINE_xXPatient with active heart disease (New York Heart Association [NYHA] class >= 3 as assessed by history and physical examination)Xx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXUncontrolled coronary disease or New York Heart Association (NYHA) class III-IV heart diseaseXx_NEWLINE_xXNew York Heart Association classification III or IV heart diseaseXx_NEWLINE_xXCongestive heart failure (New York Heart Association [NYHA] II, III, IV)Xx_NEWLINE_xXCongestive heart failure (CHF) NYHA (New York Heart Association) > Class 2Xx_NEWLINE_xXHeart failure > New York Heart Association (NYHA) class IIXx_NEWLINE_xXConcurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, New York Heart Association (NYHA) class III or IV congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis B, hepatitis C or HIV, or other significant co-morbid conditions that, in the opinion of the Investigator, would impair study participation or cooperation.Xx_NEWLINE_xXHistory of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except atrial fibrillation, paroxysmal supraventricular tachycardia).Xx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV heart failure, uncontrollable supraventricular arrhythmias, any history of a ventricular arrhythmia, or other clinical signs of severe cardiac dysfunctionXx_NEWLINE_xXDocumented NYHA Class III or IV congestive heart failureXx_NEWLINE_xXClinically stable in New York heart association (NYHA) class 2 or 3 for the 3 months preceding screening Inclusion Criteria for Group 2Xx_NEWLINE_xXCongestive heart failure (CHF), grade III or IV per New York Heart Association (NYHA) classificationXx_NEWLINE_xXHas a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or serious cardiac arrhythmia requiring treatmentXx_NEWLINE_xXCongestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA class III or IV, unless an echocardiogram or multigated acquisition scan performed within 3 months before day 1 reveals a left ventricular ejection fraction ? 45%;Xx_NEWLINE_xXPatients with congestive heart failure, Class III or IV, by New York Heart Association (NYHA) criteria.Xx_NEWLINE_xXNew York Heart Association class II/III/IV congestive heart failure with a history of dyspnea, orthopnea, or edema that requires current treatment with angiotensin convering enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, or diureticsXx_NEWLINE_xXSubjects who were diagnosed with New York Heart Association (NYHA) Class II congestive heart failure or have clinically significant arrhythmia not controlled by medication prior to study entry.Xx_NEWLINE_xXNew York Heart Association Functional Classification of Heart Failure: Class III or IV (Appendix 1).Xx_NEWLINE_xXCongestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitionsXx_NEWLINE_xXPatients with NYHA (New York Heart Association) class III or IV heart failure or history of a prior myocardial infarction (MI) within the last five years prior to enrollment in the studyXx_NEWLINE_xXPart 2: history of have severe cardiac disease (New York Heart Association functional class III or IV)Xx_NEWLINE_xXNew York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias not adequately controlled.Xx_NEWLINE_xXHistory or evidence of current >= class II congestive heart failure as defined by New York Heart Association (NYHA)Xx_NEWLINE_xXDocumented New York Heart Association (NYHA) class I, II and IIIXx_NEWLINE_xXSignificant cardiovascular abnormalities as defined by any one of the following: \r\n* Congestive heart failure New York Heart Association (NYHA) classes II-IV; patients with asymptomatic class I congestive heart failure (CHF) may participate in conjunction with a cardiology consultation\r\n* Clinically significant hypotension\r\n* Symptoms of coronary artery disease\r\n* Presence of arrhythmias in electrocardiography (EKG) requiring drug therapyXx_NEWLINE_xXEvidence of New York Heart Association (NYHA) functional class III or IV heart diseaseXx_NEWLINE_xXHistory of symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV).Xx_NEWLINE_xXNew York Heart Association classification III or IVXx_NEWLINE_xXCongestive heart failure > New York Heart Association (NYHA) class IIXx_NEWLINE_xXNew York Heart Association (NYHA) class 3 or 4 congestive heart failure (CHF) symptomsXx_NEWLINE_xXNew York Heart Association (NYHA) congestive heart failure (CHF) class II or betterXx_NEWLINE_xXNew York Heart Association Grade II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association classification III or IVXx_NEWLINE_xXNew York Heart Association classification III or IVXx_NEWLINE_xXParticipants classified according to the New York Heart Association classification as having class III or IV heart diseaseXx_NEWLINE_xXNew York Heart Association classification III or IVXx_NEWLINE_xXCongestive heart failure of any severity (New York Heart Association [NYHA] class I-IV)Xx_NEWLINE_xXAdequate cardiac functions assessed by 2 dimensional (D) echocardiography (ECHO).\r\n* (New York Heart Association [NYHA] cardiac III-IV excluded).Xx_NEWLINE_xXClass II or greater congestive heart failure as described in the New York Heart Association Functional Classification criteria or serious arrhythmias likely to increase the risk of cardiac complications of cytokine therapy (e.g. ventricular tachycardia, frequent ventricular ectopy, or supraventricular tachyarrhythmias requiring chronic therapy)Xx_NEWLINE_xXCongestive heart failure (New York Heart Association [NYHA] class III/IV) or left ventricular ejection fraction (LVEF) < 50% at baselineXx_NEWLINE_xXHeart failure >= New York Heart Association (NYHA) grade 3Xx_NEWLINE_xXPatients must not have ejection fraction decrease > 10% from baseline (as determined by ECHO) or other ejection fraction decrease accompanied by other clinical signs/symptoms of New York Heart Association (NYHA) class III or IV heart failure, measured within 28 days prior to registration; if any question exists regarding individual patient eligibility in this situation, contact the study chair for determinationXx_NEWLINE_xXHeart failure that meets New York Heart Association (NYHA) class III and IV definitionsXx_NEWLINE_xXSymptomatic congestive heart failure of New York Heart Association Class III or IV.Xx_NEWLINE_xXNew York Heart Classification III or IV heart disease (see Appendix G).  Other severe\n             cardiovascular or cardiopulmonary disease, including COPDXx_NEWLINE_xXNew York Heart Association (NYHA) class II or higher congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXSubject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ? 45%.Xx_NEWLINE_xXGrade III/IV congestive heart failure, as defined by New York Heart Association (NYHA) criteria, or myocardial infarction within 6 monthsXx_NEWLINE_xXPatients should not have New York Heart Association classification III or IV heart failureXx_NEWLINE_xXSubject with Class III or IV Congestive Heart Failure as defined by the New York Heart Association (NYHA) functional classification system within the previous 6 months.Xx_NEWLINE_xXSubjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.Xx_NEWLINE_xXCurrent congestive heart failure (New York Heart Association class II-IV).Xx_NEWLINE_xXFor Cohort A: Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or uncontrolled hypertensionXx_NEWLINE_xXFor Cohort B:Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)Xx_NEWLINE_xXPatients with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within approximately 28 days of C1D1Xx_NEWLINE_xXPatient must have no New York Heart Association (NYHA) class II or greater congestive heart failureXx_NEWLINE_xXSubject has unstable angina, a significant cardiac arrhythmia, or New York Heart Association Class 3 or 4 congestive heart failure.Xx_NEWLINE_xXHistory of class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart FailureXx_NEWLINE_xXCongestive cardiac failure of >= Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as subjects with marked limitation of activity and who are comfortable only at rest.Xx_NEWLINE_xXNew York Heart Association (NYHA) class II or higher congestive heart failureXx_NEWLINE_xXEvidence of New York Heart Association (NYHA) functional class III or IV heart diseaseXx_NEWLINE_xXCongestive heart failure (New York Heart Association class III to IV)Xx_NEWLINE_xXAny condition associated with increased risk of metformin-associated lactic acidosis; (e.g. congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)Xx_NEWLINE_xXNew York Heart Association (NYHA) Grade II or greater congestive cardiac failure.Xx_NEWLINE_xXClass III or IV congestive heart failure per New York Heart AssociationXx_NEWLINE_xXNew York Heart Association (NYHA) Class III or IV congestive heart failure;Xx_NEWLINE_xXMyocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II)Xx_NEWLINE_xXPatients are excluded if they have New York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXdocumented New York Heart Association (NYHA) Class III or IV congestive heart failure;Xx_NEWLINE_xXNo New York Heart Association Class > II congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV congestive heart failureXx_NEWLINE_xXNew York Heart Association Grade ? II congestive heart failure.Xx_NEWLINE_xXNew York Heart Association Classification II, III, or IV (see APPENDIX D)Xx_NEWLINE_xXNew York Heart Association (NYHA) class IV congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV congestive heart failureXx_NEWLINE_xXCurrent or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 50%, as measured by MUGA scan or echocardiogram)Xx_NEWLINE_xXknown autoimmune disease, known bleeding diathesis, history of congestive heart failure New York Heart Association (NYHA) class III or IV;Xx_NEWLINE_xXhave congestive heart failure or poorly controlled cardiac arrhythmia per New York Heart Association Class II-IV heart diseaseXx_NEWLINE_xXNew York Heart Association Class III or IV heart failure;Xx_NEWLINE_xXHistory of documented congestive heart failure (New York Heart Association functional classification III-IV)Xx_NEWLINE_xXCongestive heart failure - New York Heart Association (NYHA) > Class II.Xx_NEWLINE_xXCongestive heart failure greater than NYHA Class IIXx_NEWLINE_xXUnstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) congestive heart failure (CHF) class II or betterXx_NEWLINE_xXHave symptomatic congestive heart failure (New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.Xx_NEWLINE_xXNew York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registrationXx_NEWLINE_xXClass III/IV cardiovascular disability according to the New York Heart Association ClassificationXx_NEWLINE_xXNew York Heart Association (NYHA) Class II or greater congestive heart failure.Xx_NEWLINE_xXCongestive heart failure (New York Heart Association [NYHA classification])Xx_NEWLINE_xXHistory or evidence of current ?Class II congestive heart failure as defined by New York Heart Association.Xx_NEWLINE_xXPatients with class III or class IV heart failure by New York Heart Association, those with unstable angina, and those with uncontrolled arrhythmia are not eligibleXx_NEWLINE_xXClinically significant cardiac disease (New York Heart Association, class III or IV)Xx_NEWLINE_xXPatients with New York Heart Association Class II or greater congestive heart failure (Class II is defined as symptoms of fatigue, dyspnea or other symptoms with ordinary physical activity)Xx_NEWLINE_xXEvidence of New York Heart Association (NYHA) functional class III or IV heart diseaseXx_NEWLINE_xXCongestive heart failure (New York Heart Association {NYHXx_NEWLINE_xXSubject has congestive heart failure classified as New York Heart Association Class IV.Xx_NEWLINE_xXSubjects with clinically significant heart disease, such as congestive heart failure (class II, III, or IV defined by the New York Heart Association functional classification), history of unstable or poorly controlled angina, or history (< 1 year) of ventricular arrhythmiaXx_NEWLINE_xX2. Class III or IV heart failure as defined by the New York Heart Association functional classification system up to 6 months before Cycle 1, Day 1.Xx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXSubjects who have a history or current evidence of uncontrolled cardiovascular disease i.e. NYHA (New York Heart Association) Class III or IV.Xx_NEWLINE_xXCongestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA Class III or IV in the past, unless a Screening echocardiogram or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a left ventricular ejection fraction that is ? 45%.Xx_NEWLINE_xXHas any other severe, uncontrolled medical condition, including unstable congestive heart failure (Stage III-IV of the New York Heart Association Functional Classification) or has a known or suspected allergy to the study drug or any study drug component.Xx_NEWLINE_xXThe participant has symptomatic congestive heart failure (New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.Xx_NEWLINE_xXNew York Heart Association classification III or IV heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) Class II or higher congestive heart failure.Xx_NEWLINE_xXCongestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screeningXx_NEWLINE_xXNew York Heart Association (NYHA) >= grade II or greaterXx_NEWLINE_xXNew York Heart Association functional class III-IV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease (CAD), congestive heart failure, clinically significant hypotension or history of an ejection fraction of =< 30% (echocardiogram or multi-gated acquisition scan [MUGA])Xx_NEWLINE_xXCongestive heart failure > New York Heart Association (NYHA) class 2Xx_NEWLINE_xXAny known unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failureXx_NEWLINE_xXCongestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 45% by echocardiogram, or cardiac magnetic resonance imaging (MRI)Xx_NEWLINE_xXCongestive heart failure, defined as New York Heart Association (NYHA) Class II, within 3 months before C1D1 (see Appendix 1).Xx_NEWLINE_xXParticipant has a cardiovascular disability status of New York Heart Association Class greater than 2.Xx_NEWLINE_xXAny condition associated with increased risk of metformin-associated lactic acidosis (e.g., congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status, history of acidosis of any type, intake of 3 or more alcoholic beverages per day on average over the past 6 months)Xx_NEWLINE_xXGrade 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXCongestive heart failure (New York Heart Association ? Grade 2)Xx_NEWLINE_xXCongestive heart failure > class II New York Heart Association (NYHA) or unstable anginaXx_NEWLINE_xXNew York Heart Association (NYHA) congestive heart failure (CHF) class II or betterXx_NEWLINE_xXSubjects with unstable angina or New York Heart Association grade II or greater congestive heart failureXx_NEWLINE_xXPatients must have a left ventricular ejection fraction > 30%, no uncontrolled arrhythmias or New York Heart Association class III-IV heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association >/= Grade 3 congestive heart failure within 6 months prior to study entryXx_NEWLINE_xXHistory of Class III or IV congestive heart failure, as defined by the New York Heart Association Classification of Congestive Heart FailureXx_NEWLINE_xXNew York Heart Association class III or IV cardiovascular diseaseXx_NEWLINE_xXHistory of documented congestive heart failure (New York Heart Association functional classification III-IV)Xx_NEWLINE_xXPrior anthracycline treatment and at risk of cardiac failure (New York Heart Association Class 2)Xx_NEWLINE_xXSubject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ? 45%.Xx_NEWLINE_xXNew York Heart Association Class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition, or hypertensive or metabolic conditionXx_NEWLINE_xXNo symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registrationXx_NEWLINE_xXSevere cardiovascular disease including symptomatic angina pectoris, symptomatic cardiac arrhythmia, or symptomatic congestive heart failure (New York Heart Association class II-IV); subjects carrying a diagnosis of congestive heart failure which is asymptomatic are eligible so long as a baseline and follow-up echocardiogram are performed as per the study calendarXx_NEWLINE_xXSignificant cardiovascular disease including congestive heart failure (New York Heart Association class II or higher) or active angina pectorisXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), or unstable angina pectorisXx_NEWLINE_xXCurrent New York Heart Association (NYHA) class II, III, or IV congestive heart failure or symptomatic heart failure within 60 days prior to the start of study drugsXx_NEWLINE_xXHistory of congestive heart failure of any New York Heart Association (NYHA) criteriaXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), or unstable angina pectorisXx_NEWLINE_xXPatients with class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system\r\n* Abnormal cardiac valve morphology (subjects with minimal abnormalities, can be entered on study with approval)Xx_NEWLINE_xXNew York Heart Association (NYHA) Grade II or greater congestive heart failure.Xx_NEWLINE_xXPatients with myocardial impairment of any cause (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)Xx_NEWLINE_xXNew York Heart Association grade II or greater congestive heart failureXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] class II-IV)Xx_NEWLINE_xXPatient has any condition associated with increased risk of metformin-associated lactic acidosis (e.g. congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)Xx_NEWLINE_xXPatients must not have unstable angina or New York Heart Association (NYHA) classification of congestive heart failure of grade >= 2Xx_NEWLINE_xXThe following groups of patients are eligible provided they have New York Heart Association class II (NYHA) cardiac function on baseline echocardiogram (ECHO)/multi gated acquisition scan (MUGA):\r\n* Those with a history of class II heart failure who are asymptomatic on treatment\r\n* Those with prior anthracycline exposure\r\n* Those who have received central thoracic radiation that included the heart in the radiotherapy portXx_NEWLINE_xXClass III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXEvidence of New York Heart Association (NYHA) functional class III or IV heart diseaseXx_NEWLINE_xXModerate or severe heart disease based on New York Heart Association (NYHA) criteriaXx_NEWLINE_xXUncontrolled congestive heart failure (NYHA II, III, IV).Xx_NEWLINE_xXUnstable angina or New York Heart Association (NYHA) grade II or greater congestive heart failure; multiple comorbidity that preclude a major abdominal surgeryXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), unstable angina pectoris or congenital long QT syndromeXx_NEWLINE_xXNew York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)Xx_NEWLINE_xXClass III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXEvidence of current Class II, III, or IV heart failure as defined by the New York Heart Association [NYHA, 1994] functional classification system at the time of transition to this study.Xx_NEWLINE_xXPatients must not have a history of cardiac disease, defined as New York Heart Association class II or greater or clinical evidence of congestive heart failureXx_NEWLINE_xXPatients must not have a history of cardiac disease, defined as New York Heart Association class II or greater or clinical evidence of congestive heart failure; all patients must have a MUGA scan or 2-dimensional (D) echocardiogram indicating an ejection fraction of >= 45% within 42 days prior to registration; the method used at baseline must be used for later monitoringXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXHistory of uncontrolled congestive heart failure defined as New York Heart Association (NYHA) class III or greaterXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or higher congestive heart failureXx_NEWLINE_xXNew York Heart Association Class III or IV heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) Grade III or greater congestive heart failureXx_NEWLINE_xXClass II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXCongestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction < 50% by multi-gated acquisition (MUGA) scan or by transthoracic echocardiogramXx_NEWLINE_xXActive congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional interventionXx_NEWLINE_xXPatients with congestive heart failure, class III or IV, by the New York Heart Association (NYHA) criteriaXx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, the following:\r\n* Active infection\r\n* Congestive heart-failure (New York Heart Association [NYHA] grade III or IV)Xx_NEWLINE_xXOther clinically significant heart disease (e.g. congestive heart failure [CHF] New York [NY] Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)Xx_NEWLINE_xXClass II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system at the time of transition to this studyXx_NEWLINE_xXPatients with New York Heart Association class 3 or 4 diseaseXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) Grade II or greater congestive heart failureXx_NEWLINE_xXUncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York Heart Association (NYHA) functional classificationXx_NEWLINE_xXNew York Heart Association Class III or IV cardiac disease, including preexisting clinically significant ventricular arrhythmia, congestive heart failure, or cardiomyopathyXx_NEWLINE_xXMajor cardiac dysfunction, such as uncontrolled angina, congestive heart failure with New York Heart Association (NYHA) class III or higher, known left ventricular ejection fraction less than 40%Xx_NEWLINE_xXUncontrolled malignant arrhythmias or clinical evidence of congestive heart failure (New York class IV)Xx_NEWLINE_xXSubject currently has Class 3 or 4 New York Heart Association congestive heart failure.Xx_NEWLINE_xXClinical evidence of significant congestive heart failure (CHF) (New York Heart Association [NYHA] Class III or IV)Xx_NEWLINE_xXHas decompensated congestive heart failure as defined by New York Heart Association (NYHA) functional classification III or IVXx_NEWLINE_xXClinically significant cardiac disease (New York [NY] Heart Association class III or IV) or pulmonary diseaseXx_NEWLINE_xXPatients with any class of New York Heart Association (NYHA) CHF or heart failure with preserved ejection fraction (HFPEF)Xx_NEWLINE_xXSubject currently has Class III or IV New York Heart Association congestive heart failure.Xx_NEWLINE_xXPatients with New York Heart Association (NYHA) heart failure class > 2Xx_NEWLINE_xX-  Subject currently has Class 3 or 4 New York Heart Association congestive heart failure.Xx_NEWLINE_xXNo prior history of:\r\n* Congestive heart failure (New York Heart Association [NYHA] class I to IV)\r\n* Known dihydropyrimidine dehydrogenase (DPD) deficiencyXx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV heart diseaseXx_NEWLINE_xXHistory of congestive heart failure New York Heart Association (NYHA) class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within three months results in a left ventricular ejection fraction that is ? 45%;Xx_NEWLINE_xXUnstable angina, myocardial infarction or New York Heart Association (NYHA) class III/IV congestive heart failure within 30 days preceding study enrollmentXx_NEWLINE_xXSevere cardiovascular disease; New York Heart Association (NYHA) functional classification >= 2Xx_NEWLINE_xXHistory of documented congestive heart failure (CHF), New York Heart Association class II/III/IV, with a history of dyspnea, orthopnea or edema that requires current treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics; NOTE: use of these medications for the treatment of hypertension is allowedXx_NEWLINE_xXAny of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association ([NYHA] Appendix G) ? Class 2Xx_NEWLINE_xXNew York Heart Association Grade II or greater congestive heart failureXx_NEWLINE_xXAbnormal cardiac function as manifested by NYHA (New York Heart Association) class III or IV heart failure or history of a prior myocardial infarction (MI) within the last five years prior to enrollment in the studyXx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV)Xx_NEWLINE_xXPatient with active heart disease (New York Heart Association [NYHA] class greater than or equal to 2 as assessed by history and physical examination)Xx_NEWLINE_xXAny of the following cardiovascular conditions or values within 6 months before the first dose of study drug: myocardial infarction and the New York Heart Association (NYHA) class III or IV heart failureXx_NEWLINE_xXClass II-IV congestive heart failure, as defined by the New York Heart AssociationXx_NEWLINE_xXNew York Heart Association functional class III-IV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease, congestive heart failure, clinically significant hypotension, or an ejection fraction of =< 40 % (echocardiogram or MUGA)Xx_NEWLINE_xXAny uncontrolled congestive heart failure New York Heart Association class III or IVXx_NEWLINE_xXUncontrolled hypertension or congestive heart failure Class III/IV per the New York Heart Association's Heart Failure GuidelinesXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXPatients with New York Heart Association (NYHA) class 3 or 4 congestive heart failureXx_NEWLINE_xXClass II-IV New York Heart Association (NYHA) congestive heart failureXx_NEWLINE_xXNew York Heart Association class II or greater congestive heart failureXx_NEWLINE_xXClass III or IV congestive heart failure by New York Heart AssociationXx_NEWLINE_xXcongestive heart failure greater than New York Heart Association (NYHA) Class II according to the NYHA Functional Classification.Xx_NEWLINE_xXCongestive heart failure ? Class 3 based on New York Heart Association Functional ClassificationXx_NEWLINE_xXOther clinically significant heart disease (e.g., congestive heart failure (CHF) New York (NY) Heart Association class II or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)Xx_NEWLINE_xXGrade 3 or 4 cardiac disease as defined by the New York Heart Association Functional ClassificationXx_NEWLINE_xXNew York Heart Association Classification III or IVXx_NEWLINE_xXHistory of, or current, documented congestive heart failure (New York Heart Association functional classification III - IV), documented cardiomyopathy.Xx_NEWLINE_xXHave congestive heart failure (CHF) New York Heart Association class ?3 or symptomatic or poorly controlled cardiac arrhythmia.Xx_NEWLINE_xXSubject has current symptomatic heart failure or a history of congestive heart failure New York Heart Association (NYHA) class 3 or 4Xx_NEWLINE_xXNew York Heart Association classification III or IV congestive heart failureXx_NEWLINE_xXHistory of any clinically significant cardiovascular disorder (i.e., symptoms above Class II per New York Heart Association [NYHA] Functional Classification);Xx_NEWLINE_xXHas heart failure of Class III or IV.Xx_NEWLINE_xXNew York Heart Association Classification III or IVXx_NEWLINE_xXNew York Heart Association (NYHA) Grade II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association Classification II, III, or IVXx_NEWLINE_xXUnstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class III or IV congestive heart failureXx_NEWLINE_xXCondition associated with increased risk of metformin-associated lactic acidosis:\r\n* New York Heart Association class III or IV heart failure\r\n* Intake of 3 or more alcoholic beverages per day\r\n* Known history of lactic acidosisXx_NEWLINE_xXNew York Heart Association (NYHA) congestive heart failure (CHF) class II or betterXx_NEWLINE_xXCurrent congestive heart failure (New York Heart Association Class II-IV).Xx_NEWLINE_xXSubjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1Xx_NEWLINE_xXHas heart failure of Class III or IVXx_NEWLINE_xXPatients with history of and/or current evidence of myocardial impairment (e.g. cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)Xx_NEWLINE_xXCongestive heart failure or prior history of New York Heart Association (NYHA) class III/ IV cardiac disease;Xx_NEWLINE_xXCongestive heart failure New York Heart Association Class III or IV, or Class II with a recent decompensation requiring hospitalization within 4 weeks before screening.Xx_NEWLINE_xXA history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelinesXx_NEWLINE_xXNew York Heart Association Classification III or IV (see Appendix F)Xx_NEWLINE_xXClinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) guidelines.Xx_NEWLINE_xXDONOR: History of severe cardiovascular disease, defined as New York Heart Association class III or IVXx_NEWLINE_xXClinically evident congestive heart failure > class II of the NYHA guidelines.Xx_NEWLINE_xXSubject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ? 45%Xx_NEWLINE_xXA New York Heart Association (NYHA) classification of IV.Xx_NEWLINE_xXClass II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification systemXx_NEWLINE_xXHistory of class III or IV congestive heart failure, as defined by the New York Heart AssociationXx_NEWLINE_xXNew York Heart Association Classification III or IV (see Appendix E)Xx_NEWLINE_xXNew York Heart Association (NYHA) class III or IV; NOTE: patients classified as NYHA class II controlled with treatment may participate, with increased monitoringXx_NEWLINE_xXSymptomatic heart failure – New York Heart Association (NYHA) class >= II symptomsXx_NEWLINE_xXCongestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or known ejection fraction < 40% by multi gated acquisition scan (MUGA) or < 50% by echocardiogram and/or magnetic resonance imaging (MRI)Xx_NEWLINE_xXHistory of cardiac disease including congestive heart failure > New York Heart Association (NYHA) Class IIXx_NEWLINE_xXHistory of cardiac heart failure of New York Heart Association Class II or greater or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and paroxysmal supraventricular tachycardia)Xx_NEWLINE_xXClass III or IV cardiovascular disease according to the New York Heart Association's (NYHA) Functional Criteria.Xx_NEWLINE_xXNo New York Heart Association (NYHA) class III or IV heart diseaseXx_NEWLINE_xXHistory of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] classes II?IV)Xx_NEWLINE_xXSymptomatic congestive heart failure of New York Heart Association Class III or IVXx_NEWLINE_xXNew York Heart Association classification III or IVXx_NEWLINE_xXNew York Heart Association (NYHA) classification III or IV heart failure (see Appendix G) despite medical managementXx_NEWLINE_xXCongestive heart failure of New York Heart Association (NYHA) class III or higher severity at study entryXx_NEWLINE_xXA history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA)Xx_NEWLINE_xXClass III or IV cardiovascular disease according to the New York Heart Association's (NYHA) Functional Criteria.Xx_NEWLINE_xXNew York Heart Association class III or IV heart failureXx_NEWLINE_xXHeart failure ?3 (New York Heart Association(NYHA))Xx_NEWLINE_xXClass II or greater congestive heart failure as described in the New York Heart Association Functional Classification criteriaXx_NEWLINE_xXPatients with a history of congestive heart failure of any New York Heart Association classXx_NEWLINE_xXCongestive 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%Xx_NEWLINE_xXThe following groups of patients are eligible after consultation with a cardiologist and at the coordinating center PI’s discretion, provided they have New York Heart Association class II (NYHA) cardiac function on baseline echocardiogram (ECHO)/multigated acquisition scan (MUGA):\r\n* Those with a history of class II heart failure who are asymptomatic on treatment\r\n* Those with prior anthracycline exposure greater than a cumulative dose of 350 mg/m^2\r\n* Those who have received central thoracic radiation that included the heart in the radiotherapy portXx_NEWLINE_xXCardiac function:\r\n* Known inherited coronary disease\r\n* Symptomatic heart failure (New York Heart Association [NYHA] class II-IV prior or current cardiomyopathy, or severe valvular heart disease)\r\n* Prior or current cardiomyopathy\r\n* Severe valvular heart disease\r\n* History of atrial fibrillationXx_NEWLINE_xXNew York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to registrationXx_NEWLINE_xXPatients with New York Heart Association (NYHA) class II-IV heart failureXx_NEWLINE_xXNYHA Grade II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association grade 2 or greater congestive failureXx_NEWLINE_xXNew York Heart Association (NYHA) classification III or IV congestive heart failureXx_NEWLINE_xXHistory of documented congestive heart failure (CHF), New York Heart Association class II/III/IV, with a history of dyspnea, orthopnea or edema that requires current treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics; NOTE: use of these medications for the treatment of hypertension is allowedXx_NEWLINE_xXNew York Heart Association ? Class II congestive heart failure; Clinically significant abnormality on ECGXx_NEWLINE_xXUncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV), or unstable angina pectorisXx_NEWLINE_xXCardiac failure, New York Heart Association (NYHA) Class II according to the NYHA Functional Classification,Xx_NEWLINE_xXThe participant has current clinically-relevant coronary artery disease (New York Heart Association III or IV) or uncontrolled congestive heart failure.Xx_NEWLINE_xXHistory of cardiac heart failure of any New York Heart Association criteria or serious cardiac arrhythmia requiring treatmentXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXClass II, III, or IV heart failure as defined by the New York Heart Association functional classification system.Xx_NEWLINE_xXNew York Heart Association (NYHA) Class II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) classification III or IV heart diseaseXx_NEWLINE_xXHas Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.Xx_NEWLINE_xXPatients with history of and/or current evidence of myocardial impairment (e.g. cardiomyopathy,ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV staging)Xx_NEWLINE_xXClinically significant heart disease (New York Heart Association [NYHA] class III or IV) within six monthsXx_NEWLINE_xXNew York Heart Association functional classification for congestive heart failure (NYHA CHF) < 3Xx_NEWLINE_xXClass II to IV heart failure as defined by the New York Heart Association functional classification system; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction (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 appropriate, to be eligibleXx_NEWLINE_xXSubject currently has Class 3 or 4 New York Heart Association congestive heart failure.Xx_NEWLINE_xXNew York Heart Association (NYHA) classification I or IIXx_NEWLINE_xXHistory of symptomatic congestive heart failure of any New York Heart Association class or serious cardiac arrhythmia requiring treatmentXx_NEWLINE_xXNew York Heart Association Classification III or IV heartXx_NEWLINE_xXHistory of congestive heart failure (CHF) New York Heart Association (NYHA) class 3 or 4;Xx_NEWLINE_xXNo current New York Heart Association classification II, III, or IV congestive heart failureXx_NEWLINE_xXUncontrolled heart failure as defined by New York Heart Association (NYHA) class 3 or 4Xx_NEWLINE_xXHave New York Heart Association class II or greater congestive heart failureXx_NEWLINE_xXClinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 or Class 4.Xx_NEWLINE_xXCurrent or history of New York Heart Association Class III or IV heart failure.Xx_NEWLINE_xXPatients with diagnosed New York Heart Association (NYHA) class III-IV failure or documented ejection fraction (EF) < 30%Xx_NEWLINE_xXSevere cardiac disease (New York Heart Association functional class III or IV) or coronary artery diseaseXx_NEWLINE_xXNew York Heart Association class III or IV heart failureXx_NEWLINE_xXNew York Heart Association (NYHA) grade II or greater congestive heart failureXx_NEWLINE_xXNew York Heart Association classification III or IV heart failureXx_NEWLINE_xXHistory of New York Heart Association Class 3 or 4 heart failure;Xx_NEWLINE_xXSymptomatic congestive heart failure (New York Heart Association II-IV), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.Xx_NEWLINE_xXUncontrolled cardiac angina or symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV)Xx_NEWLINE_xXHave with history of severe cardiac disease (New York Heart Association functional class III or IV)Xx_NEWLINE_xXPatients with any condition associated with increased risk of metformin-associated lactic acidosis (e.g., congestive heart failure defined as New York Heart Association class III or IV functional status, history of acidosis of any type)Xx_NEWLINE_xXSubjects with classification of 3 or higher heart failure as classified by the New York Heart Association (NYHA)Xx_NEWLINE_xXPatients with pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association [NYHA] grade III-IV), or arrhythmia known to increase the risk or thromboembolic events (e.g., atrial fibrillation)Xx_NEWLINE_xXNYHA stage 3 or 4 congestive heart failureXx_NEWLINE_xXCongestive Heart Failure NY Heart Association class III or IVXx_NEWLINE_xXSevere cardiac disease (New York Heart Association class III or greater)Xx_NEWLINE_xXPatient has congestive heart failure Class III/IV according to the New York Heart Association (NYHA) Functional ClassificationXx_NEWLINE_xXPatients with a documented history of congestive heart failure (CHF) greater than New York Heart Association (NYHA) grade IIXx_NEWLINE_xXClass II to IV heart failure as defined by the New York Heart Association functional classification systemXx_NEWLINE_xXNew York Heart Association (NYHA) class IV congestive heart failure;Xx_NEWLINE_xXNo condition associated with increased risk of metformin-associated lactic acidosis (e.g. congestive heart failure defined as New York Heart Association [NYHA] class III or IV functional status, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)Xx_NEWLINE_xXSymptomatic congestive heart failure of New York heart Association Class III or IVXx_NEWLINE_xXNew York Heart Association Stage 3 or 4 cardiac diseaseXx_NEWLINE_xXNew York Heart Association (NYHA) class III and IV congestive heart failureXx_NEWLINE_xXPatients with class II heart failure or worse, per New York Heart Association (NYHA) classificationXx_NEWLINE_xXCongestive heart failure or New York Heart Association (NYHA) status >= 2Xx_NEWLINE_xXCongestive heart failure or New York Heart Association (NYHA) status >= 2Xx_NEWLINE_xXCongestive heart failure or New York Heart Association (NYHA) status >= 2Xx_NEWLINE_xXCongestive heart failure (New York Heart Association [NYHA] class III or IV)Xx_NEWLINE_xXNew York Heart Association (NYHA) class III and IV congestive heart failureXx_NEWLINE_xXCongestive heart failure (New York Heart Association functional classification III-IV)Xx_NEWLINE_xXHas symptomatic congestive heart failure[New York Heart Association (NYHA) Classes III-IV], unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatmentXx_NEWLINE_xXCongestive heart failure of New York Heart Association Class ? 3 or known left ventricular ejection fraction < 40%, orXx_NEWLINE_xXPatients with uncontrolled congestive heart failure (New York Heart Association [NYHA] Class IV)Xx_NEWLINE_xXCongestive heart failure or New York Heart Association (NYHA) status >= 2Xx_NEWLINE_xXPatient with known Class III/IV congestive heart failure according to the New York Heart Association classificationXx_NEWLINE_xXNew York Heart Association class III/IV cardiac diseaseXx_NEWLINE_xXNormal left ventricular ejection fraction at baseline and no evidence of New York Heart Association class II to IV heart failureXx_NEWLINE_xXPatients 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 studyXx_NEWLINE_xXActive congestive heart failure (NYHA Class III-IV) ischemia, conduction abnormalitiesXx_NEWLINE_xXCurrent or history of New York Heart Association Class III or IV heart failureXx_NEWLINE_xXCongestive heart failure (New York Heart Class III or IV).Xx_NEWLINE_xXHistory of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment.Xx_NEWLINE_xXHistory of documented congestive heart failure (New York Heart Association functional classification III-IV).Xx_NEWLINE_xX