A history of any of the following: sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, cardiac arrest, Mobitz II second degree heart block or third degree heart block; known presence of dilated, hypertrophic, or restrictive cardiomyopathy
Have documented major electrocardiogram (ECG) abnormalities which are clinically significant at the investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, bundle-branch blocks, ventricular hypertrophy, or recent myocardial infarction).
Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia, or corrected QT interval (Fridericia’s correction; QTcF) > 470 msec
History or family history of Long QT Syndrome or Torsade de Pointes. Myocardial infarction, CABG, coronary or cerebral artery stenting and /or angioplasty, stroke, cardiac surgery, or hospitalization for congestive heart failure within 3 months or greater than Class 2 Angina Pectoris or NYHA Heart Failure Class >2. QTcF > 470 msec, PR > 280 msec, Mobitz II 2nd degree AV Block, 2:1 AV Block, High Grade AV Block, or Complete Heart Block, unless the patient has an implanted pacemaker or implantable cardiac defibrillator (ICD) with backup pacing capabilities.
For Part G: Have a baseline electrocardiogram (obtained from Day -14 to Day -1) with any of the following abnormal findings: ventricular arrhythmia, evidence of acute myocardial ischemia, heart block (of any degree), or QTc prolongation (defined as QTcB ?450 milliseconds).
Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
QTc prolongation (defined as a QTc > 450 msecs) or other significant ECG abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats per minute [bpm]). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation.
No evidence of PR prolongation or atrioventricular (AV) block on baseline electrocardiogram (ECG)
Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
CRITERIA SPECIFIC FOR COHORT #2 (MCL): Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac pacemaker who have a QTc interval of >= 470msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation
Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation/flutter, left bundle branch block, 2nd-degree atrioventricular (AV) block type II, 3rd degree AV block, Grade ?2 bradycardia, or corrected QT (QTc) >450 msec (for men) or >470 msec (for women).
Subjects with a history of significant cardiac disease including: congestive heart failure requiring therapy; history of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment; clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block); left ventricular ejection fraction (LVEF) < 50% evaluated by echocardiogram (ECHO) or multigated acquisition scan (MUGA); increased Fridericia's correction formula (QTcF) (> 450 for men and > 470 for women).
Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and third-degree AV block).
Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation
Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation
Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation/flutter, left bundle-branch block, 2nd-degree atrioventricular (AV) block type II, 3rd degree AV block, Grade ?2 bradycardia, or QT corrected for heart rate (QTc) >450 msec (for men) or >470 msec (for women).
Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) >= 470 msec; subjects with a cardiac pacemaker who have a QTc interval of >= 470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation
Patients with a history of PR prolongation or atrioventricular (AV) block
Other significant electrocardiogram (EKG) abnormalities including second (2nd) degree atrio-ventricular (AV) block type II, third (3rd) degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (corrected QT [QTc] > 500 millisecond [msec]), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with persistent and uncontrolled atrial fibrillation will be excluded; the protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist
History of significant cardiac disease defined as:\r\n* Symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] classes III-IV)\r\n* High-risk uncontrolled arrhythmias; i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia or higher-grade atrioventricular (AV) block (second degree AV-block type 2 [mobitz 2] or third degree AV-block)\r\n* Prolongation of QT interval > 480 msecs\r\n* History of myocardial infarction within last 12 months\r\n* Clinically significant valvular heart disease\r\n* Angina pectoris requiring anti-angina treatment\r\n* Current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg); initiation or adjustment of anti-hypertensive medication is permitted prior to study entry
Relapsed/refractory MCL: Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, bradycardia (< 50 beats per minute [bpm]), or corrected QT (QTc) > 500 msec
Newly diagnosed MCL: Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, bradycardia (< 50 bpm), or QTc > 500 msec
Patient with evidence of clinically significant bradycardia (heart rate [HR] < 50), or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree atrioventricular (AV) block (Mobitz type 2), patient with uncontrolled hypertension (>= 140/90 mmHg). Patients who are controlled on antihypertensive medication will be allowed to enter the study
History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
High-grade (second degree or above) atrioventricular (AV) block or persistent sinus bradycardia of less than 50 beats per minute (BPM)
Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular block (AV block) type II, 3rd degree block, bradycardia (< 50 beats per minute [bpm]), or corrected QT (QTc) > 500 msec.
Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade atrioventricular (AV) block
Subject with clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes, second degree or third degree atrioventricular heart block without a permanent pacemaker in place)
Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ? II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ?2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
QTcF prolongation defined as a QTcF interval >470 msec or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min).
History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Patients with a history of atrial arrhythmias should be discussed with the Medical Monitor.
History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be discussed with the medical monitor
Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block
Wolff-Parkinson White syndrome or first/second/third degree atrioventricular (AV) block or sinus node dysfunction or the presence of an intra-cardiac defibrillator
have documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments) at the investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrio ventricular block, complete bundle branch block, ventricular hypertrophy, or recent myocardial infarction).
Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block
History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to second (2nd) degree atrioventricular (AV) block type II, third (3rd) degree block, QT prolongation (corrected QT [QTc] > 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with active atrial fibrillation will be excluded; the protocol excludes patients who have within the past year had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin equivalent vitamin K antagonist
Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block
Any history of second- or third-degree heart block. (Patients with pacemakers may be eligible.)
Inability to determine the QTcF interval Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
Patients with New York Heart Association (NYHA) class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to atrial fibrillation, 2nd degree atrioventricular (AV) block type II, 3rd degree block, torsades de pointes, QT prolongation (corrected QT [QTc] > 450 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute [bpm]), hypotension, light headedness and syncope; patients with atrial fibrillation will be excluded even if they are rate-controlled; if there are any active cardiac issues, cardiology consultation will be obtained for clearance
Significant screening ECG abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, and QTc > 480 msec.
Significant screening ECG abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, and QTc ? 480 ms.
Adequate cardiac conduction by ECG without evidence of second- or third-degree atrioventricular block and meeting all of the following ECG criteria:
No evidence of second- or third-degree atrioventricular block
First degree atrioventricular (AV) block on ECG in which PR interval lengthened > 200 milliseconds; second degree; or third degree
Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block.
Severe sinus bradycardia; heart block, second or third degree or sick sinus syndrome (if no artificial pacemaker present)
Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class IIIB or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities (not including 1st degree atrioventricular (AV)-block, Wenckebach type 2nd degree heart block, or left bundle branch block; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be evaluted by the investigator or an authorized physician sub-investigator); note: there is no lower limit of left ventricular ejection fraction below which patients are excluded from participation
Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) >= 470 msec
Patients with any clinically significant cardiovascular disease including the following:\r\n* Myocardial infarction or ventricular tachyarrhythmia within 6 months\r\n* Prolonged QTc > 480 msec by the Fridericia correction\r\n* Major conduction abnormality, such as 2nd or 3rd degree heart block or symptomatic bundle branch block, unless a cardiac pacemaker is present
First degree atrioventricular (AV) block
Second degree AV block Type 1 (Mobitz Type 1/ Wenckebach type)
History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place.
Clinically relevant findings in the ECG such as a second-degree or third-degree atrioventricular (AV) block (subjects with AV block and pacemaker in place for >1 year and checked by a cardiologist within ?6 months before the first dose of study drug will not be excluded), prolongation of the QRS complex over 120 msec or of the QTc interval (Fridericia, QTcF) over 470 msec (subjects with a pacemaker and QRS interval over 120 msec or QTc inverval over 470 msec may be enrolled on a case-by-case basis, following a discussion between the investigator and the sponsor).
Patients with second (2nd) or third (3rd) degree atrioventricular (AV) block
AV block (other than 1o AV Block with PR > 200 msec)
History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (<60 bpm), heart block (excluding 1st degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG
Other significant electrocardiogram (EKG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
Grade 2 or 3 atrioventricular (AV) block (Mobitz type I is permitted) or sick sinus syndrome, unless subject has a pacemaker
History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
Any history of second or third degree heart block;
Patients with sick-sinus syndrome, sino-atrial block, third degree heart block, atrial fibrillation, and those with permanent pacemakers
Patients must not have history of or presence of Mobitz type II 2nd degree or 3rd degree atrioventricular block or sick sinus syndrome, unless patient has a pacemaker
Sustained or symptomatic ventricular dysrhythmias uncontrolled with drug therapy or implantable device; significant conduction defects (i.e.: second or third degree atrio-ventricular block or sick sinus syndrome)
Allergies or inability to tolerate beta blockers previously due to bradycardia, hypotension, or atrioventricular (AV) block
History of second (Mobitz II) or third degree heart block (subjects with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias while using the pacemaker);
Second (2nd) or third (3rd) degree heart block as assessed by preoperative electrocardiogram (EKG)
Significant conduction defects (i.e. second or third degree atrio-ventricular block or sick sinus syndrome)
Second- or third-degree atrioventricular (AV) block
Have documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments) at the investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, complete bundle branch block, ventricular hypertrophy, or recent myocardial infarction).