Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia
Phase: PHASE1
Conditions: Ventricular Tachycardia, Cardiomyopathy, Premature Ventricular Contractions
Sponsor: Washington University School of Medicine

Version 09/26/2018 
 
page 1 of 41 
 
 
Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation (ENCORE) for Treatment of 
Ventricular Tachycardia 
 
Protocol #: 5.0 
Version Date: 09/26/2018 
 
Principal Investigators 
 
 
Phillip Cuculich, MD  
 
 
 
 
 
 
Phone: (314) 454-7698 
 
 
 
 
 
 
Email: pcuculic@DOM.wustl.edu 
 
 
 
 
 
 
Department of Medicine 
Division of Cardiovascular Diseases  
4921 Parkview Place, Suite 8A 
 
 
 
 
 
 
St. Louis, MO 63110 
 
Clifford Robinson, MD 
 
 
 
 
 
 
 
Phone: (314) 362-8567 
 
 
 
 
 
 
Email: crobinson@radonc.wustl.edu 
 
 
 
 
 
 
Department of Radiation Oncology 
4921 Parkview Place, Box 8224 
 
 
 
 
 
 
St. Louis, MO 63110 
 
 
 
 
 
 
 
Sub-Investigators 
 
 
 
Modality 
Sasa Mutic, PhD 
 
 
 
Radiation Oncology – Physics 
Jeffrey Bradley, MD 
 
 
 
Radiation Oncology – Clinical 
Michael Roach, MD   
 
 
Radiation Oncology – Clinical 
Pamela Samson, MD, MPHS  
 
Radiation Oncology – Biostatistics 
 
Data Safety Monitoring Board 
 
 
 
Marye Gleva, MD 
 
 
 
Medicine—Clinical Cardiac Electrophysiology 
 
Richard Bach, MD 
 
 
 
Medicine—Cardiovascular Diseases 
 
Ed Geltman, MD 
 
 
 
Medicine—Heart Failure/Transplant 
Jiayi (Jay) Huang, MD   
 
 
Radiation Oncology – Clinical  
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure. Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them 
 
 
 

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Table of Contents 
PROTOCOL REVISION HISTORY ....................................................................................................... 4 
1.0 
BACKGROUND AND RATIONALE .......................................................................................... 5 
1.1 
Ventricular tachycardia (VT) and sudden cardiac arrest (SCA) ........................................ 5 
1.2 
Current management of VT.............................................................................................. 5 
1.3 
Stereotactic body radiotherapy (SBRT) ............................................................................ 6 
1.4 
SBRT for arrhythmia ......................................................................................................... 8 
1.5 
Electrocardiographic Imaging (ECGI): Noninvasive Electrical Mapping ......................... 11 
1.6 
ENCORE for VT at Washington University ...................................................................... 11 
1.7 
Study Rationale .............................................................................................................. 18 
2.0 
OBJECTIVES ........................................................................................................................ 18 
2.1 
Primary Objectives ......................................................................................................... 18 
2.2 
Secondary Objectives ..................................................................................................... 18 
2.3 
Exploratory Objectives ................................................................................................... 19 
3.0 
PATIENT SELECTION ........................................................................................................... 20 
3.1 
Inclusion Criteria ............................................................................................................ 20 
3.2 
Exclusion Criteria ............................................................................................................ 20 
4.0 
TREATMENT PLAN .............................................................................................................. 21 
4.1 
Noninvasive Imaging for Scar/Fibrosis, Edema, Inflammation ...................................... 21 
4.2 
Noninvasive Electrical Imaging ....................................................................................... 24 
4.3 
Targeting the Area for Noninvasive Ablation ................................................................. 25 
4.4 
Radiation Therapy Guidelines ........................................................................................ 25 
4.5 
Evaluability Guidelines ................................................................................................... 28 
4.6 
General Concomitant Medication and Supportive Care Guidelines .............................. 28 
4.7 
Women of Childbearing Potential .................................................................................. 28 
4.8 
Duration of Therapy ....................................................................................................... 29 
4.9 
Duration of Follow up .................................................................................................... 29 
4.10 
Management of ICD Programming and Antiarrhythmic Medications During Follow up
 
29 
5.0 
REGULATORY AND REPORTING REQUIREMENTS .............................................................. 30 
5.1 
Adverse Events (AEs) ...................................................................................................... 30 
5.2 
Serious Adverse Events (SAEs) ....................................................................................... 31 
5.3 
Unanticipated Problems ................................................................................................. 31 

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5.4 
Noncompliance .............................................................................................................. 31 
5.5 
Serious Noncompliance .................................................................................................. 31 
5.6 
Protocol Exceptions ........................................................................................................ 31 
5.7 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
32 
5.8 
Timeframe for Reporting Required Events .................................................................... 32 
6.0 
CORRELATIVE STUDIES ....................................................................................................... 32 
7.0       STUDY CALENDAR .............................................................................................................. 33 
8.0 
DATA SUBMISSION SCHEDULE ........................................................................................... 34 
Toxicity Form ............................................................................................................................. 34 
9.0 
MEASUREMENT OF EFFECT ............................................................................................... 34 
10.0 DATA AND SAFETY MONITORING ...................................................................................... 35 
11.0 STATISTICAL CONSIDERATIONS ......................................................................................... 35 
11.1 
Early Stopping Criteria ................................................................................................ 35 
11.2 
Sample Size Justification ............................................................................................. 35 
11.3 
Analytic Plan for Primary Objectives .......................................................................... 36 
11.4 
Analytic Plan for Secondary and Exploratory Objectives ........................................... 36 
12.0 REFERENCES ....................................................................................................................... 38 
 
 

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PROTOCOL REVISION HISTORY 
 
Description  
 
 
Version Date  
 
IRB Submission Date 
Initial Approval Version 
 
06/23/2016 
 
 
06/23/2016 
 
Amendment 1 
 
 
01/16/2018 
 
 
01/16/2018 
Summary of Changes 
Protocol Version Date 06/23/2016 
Protocol Version Date 01/16/2018 
Page 1 
Sub-Investigators           Modality 
Original: 
Rojano Kashani, PhD          Radiation Oncology-Physics 
Page 1 
Sub-Investigators           Modality 
Removal of Sub-Investigator: 
Rojano Kashani, PhD          Radiation Oncology-Physics 
Page 32 
6.0 Correlative Studies 
Original: 
Not previously included. 
Page 32 
6.0 Correlative Studies 
Addition: 
In patients who die or undergo a heart transplant, clinical reports will be reviewed 
and abstracted of any pathologic, histologic, or autopsy analysis.  Additionally, 
clinically processed tissue submitted to the Department of Pathology may be 
requested for additional analysis for research purposes, including, but not limited 
to, assessment of the location and degree of baseline injury outside the 
radiotherapy target and evidence of on and off-target injury from radiotherapy. 
 
Amendment 2 
 
 
09/26/2018 
 
 
09/26/2018 
Summary of Changes 
Protocol Version Date 01/16/2018 
Protocol Version Date 09/26/2018 
Page 1 
Sub-Investigators           Modality 
Original: 
Todd Dewees, PhD          Radiation Oncology-Biostatistics 
Page 1 
Sub-Investigators                            Modality 
Removal of Sub-Investigator: 
Todd Dewees, PhD                          Radiation Oncology-- Biostatistics 
Addition of Sub-Investigator: 
Pamela Samson, MD, MPHS          Radiation Oncology - Biostatistics 
Page 4 
Protocol Revision History 
Original: 
Not previously included. 
Page 4 
Protocol Revision History 
Addition: 
Addition of protocol amendments, version dates, and summary of changes for all 
protocol amendments. 
Page 31 
5.2 Serious Adverse Events (SAEs) 
Original: 
Not previously included. 
Page 31 
5.2 Serious Adverse Events (SAEs) 
Addition: 
Definition:  An adverse event that is any undesirable experience associated with 
the use of a medical product in a patient that results in death, hospitalization (new 
or prolonged), disability or permanent damage, or is life-threatening. 
 
Specific to this protocol, SAEs are defined as AEs with CTCAE v4.0 grade 3 or higher 
resulting in hospitalization or grade 4-5 AE. Treatment-related SAEs were SAEs that 
are possibly, probably, or definitely related to protocol treatment. 
Page 32 
5.8 Timeframe for Reporting Required Events 
Original: 
Not previously included. 
Page 32 
5.8 Timeframe for Reporting Required Events 
Clarification:  
Adverse events captured in the CRFs will be tracked for 12 months following SBRT. 
For the purposes of this protocol, reportable adverse events are grade 3, 4, or 5 
toxicities that did not predate SBRT and are possibly, probably or definitely 
attributable to treatment. Patients will be assessed using the CTCAE v4.0. 
Page 33 
7.0 Study Calendar 
Original: 
Included up to 12 months of follow up. 
Page 33 
7.0 Study Calendar 
Administrative Change: 
The calendar was updated to match the previously approved Informed Consent 
Document.  Extended follow up time point added to collect medical history, device 
interrogations, and adverse event assessment.  The extended follow up time frame 
will last up to 5 years post-completion of study treatment. 
Page 34 
8.0 Data Submission Schedule 
Original: 
Follow-Form included up to 12 months post-SBRT for 
the submission schedule. 
Page 34 
8.0 Data Submission Schedule 
Addition: 
Addition of 2 years post-SBRT, 3 years post-SBRT, 4 years post-SBRT, and 5 years 
post-SBRT for the submission schedule for the follow-up form. 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Ventricular tachycardia (VT) and sudden cardiac arrest (SCA) 
 
Sudden cardiac arrest (SCA) is the single largest cause of death in the developed world. In 
the United States, over 325,000 deaths are due to SCA; more than lung cancer, breast 
cancer and AIDS combined [1]. A majority of SCA is due to cardiac arrhythmias, namely 
ventricular tachycardia (VT). Underlying cardiomyopathies and scarring most often cause 
ventricular arrhythmias. The scar from the cardiomyopathy (i.e., previous heart attack) 
forms the substrate for abnormal electrical circuits within the heart, which causes VT. 
Survival from an out-of-hospital SCA is only 10%.  Patients who survive SCA have an 
estimated 40-60% chance of developing another ventricular arrhythmia in the 
subsequent year. [2, 3] 
 
1.2 
Current management of VT 
 
For patients who have survived SCA from VT, the current clinical management strategy 
consists of two goals: 1) prevent the arrhythmia from happening again and 2) protect the 
patient from dying if the arrhythmia does happen again.   
 
The second goal (protection) consists of installation of an implantable cardiac defibrillator 
(ICD) into the body.  This device is used to deliver a burst of energy (shock) to restore 
regular rhythm if VT were to recur.  While life-saving, shocks from an ICD are painful to 
patients and repeated shocks lead to a poor quality of life, largely driven by anxiety and 
depression [4-6].  Some evidence has also linked ICD shocks to increased risk of death [7].  
 
To prevent VT and subsequent ICD therapies, patients can opt to take oral antiarrhythmic 
medications. Long-term medication use usually consists of administration of amiodarone, 
which has a significant cumulative adverse effect profile, including toxicities to hepatic, 
pulmonary, thyroid, skin, ophthalmologic and neurologic systems. An invasive catheter 
ablation procedure is often viewed as second-line, adjunctive therapy for the 
management of VT after failure of medication. This procedure generally takes 4-8 hours, 
often uses general anesthesia, and requires access to the inside of the heart through the 
veins or arteries of the leg or access to the outside of the heart through the skin 
underneath the breastbone. Long flexible catheters are inserted and maneuvered to 
identify critical components of the abnormal electrical circuit that causes VT. Once 
identified, radiofrequency energy is applied to the tip of the catheter (usually 3.5mm tip) 
to heat up the critical tissue to the point of cellular destruction (ablation), thus rendering 
it electrically inert. These critical components of the circuit are often located within 
abnormal cardiac tissue, most commonly from previous myocardial infarctions.  
 
Despite important advances in invasive cardiac mapping and catheter ablation 
technologies, the success rates of catheter ablation to prevent VT in patients with 

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structural heart disease remain modest. Five randomized clinical trials of VT ablation 
procedures have been performed [8-12] and are summarized in a recent meta-analysis  
[13]. Other large multi-center studies have been published which did not randomize 
catheter ablation against medical therapy but are nonetheless important when assessing 
the overall success rates of this therapy [14-17]. In the meta-analysis that included 457 
participants with largely ischemic cardiomyopathy and mean left ventricular ejection 
fraction of 30-35%, the recurrence rate of VT was 35% (range 12-50%) with catheter 
ablation (n=266) during a follow up of 6-22 months.  This compared favorably to a 
recurrence rate of 55% (range 33-75%) in the medical-only control group (n=191). In other 
large prospective observational studies, risk of VT recurrence at one year after extensive 
catheter ablation approaches 50% [14-17].  
 
VT ablation procedures can “fail” for many reasons. Commonly cited limitations include: 
1) inability to map hemodynamically unstable VT; 2) difficult mapping due to multiple 
different VT circuits; 3) inability to create necessary radiofrequency ablation due to depth 
of myocardial scar; 4) inability to reach the critical component of the VT circuit with a 
catheter; 5) protective structures (i.e., epicardial fat) around the critical component of the 
VT circuit; and 6) late development of new abnormal circuits through myocardial scar 
after the original ablation. Methods to improve the success of VT ablation procedures 
need to address these key limitations. Examples of alternative methods in development 
for enhanced tissue destruction include: 1) injection of alcohol into smaller blood vessels 
to induce larger myocardial infarction; 2) development of catheters with extendable 
needles to impale ventricular myocardium to allow deeper radiofrequency ablation; and 
3) using two ablation catheters to encircle the critical component of the scar in hopes of 
deeper penetration of thermal energy.  
 
Because of its invasive nature, there are risks to a catheter ablation procedure. Risks of 
serious complications include death (3%), stroke/transient ischemic attack (1-2%), cardiac 
perforation (1-2%), third-degree heart block (1.6%), pericardial effusion/tamponade (1%), 
worsening heart failure and cardiogenic shock (1-2%), uncontrollable VT (1%), and sepsis 
(<1%). Anecdotally, several centers report higher rates of adverse events in patients with 
more advanced and global cardiomyopathies. Future improvements in VT ablation 
technologies will need to address these significant adverse event rates, particularly 
among the sickest patients, and for those who have already failed traditional catheter 
ablation. A noninvasive approach to cardiac ablation has the potential to significantly 
improve safety and provide a viable option for VT refractory to ablation and medication. 
An attractive alternative to thermal ablation with radiofrequency energy may be 
noninvasive stereotactic radiotherapy.            
 
1.3 
Stereotactic body radiotherapy (SBRT) 
 
Stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy 
(SABR) or stereotactic radiosurgery (SRS), is a culmination of several decades worth of 
progress in radiation oncology, allowing for the precise delivery of high doses of radiation 

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to targets in the body over few (typically, < 5) fractions with minimal exposure of normal 
adjacent tissue.  [18] 
 
Such treatments have been successfully used to treat malignant and benign tumors in all 
body sites, most commonly in the brain, lung, liver, and spine.  Advances in image 
guidance (orthogonal kV:kV imaging, conebeam CT (CBCT), etc.) and motion management 
(4D-CT, internal and external fiducials, etc.) have been central to the success of SBRT, 
particularly for tumors that are mobile.  For example, it is now well established by multiple 
prospective clinical trials that SBRT delivered over 3-5 fractions results in local control 
rates > 90% for inoperable early stage lung cancer, with remarkably low rates of toxicity 
(<5-10% risk of grade 2+ pneumonitis, 15% risk of grade 1+ chest wall pain).[19, 20])  An 
example of a typical lung cancer SBRT plan and follow-up is provided in Figure 1. 
 
Figure 1.  (A) SBRT treatment plan.  (B) Pre-treatment, planning volume, and post-
treatment images. 
 
(A) 
 
 
 

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(B) 
 
 
All manufacturers of modern radiotherapy delivery systems have SBRT options or 
capabilities, with a variety of different methods for delivery.  None of these delivery 
methods has been shown to be any more successful at delivering SBRT treatments than 
another when performed in the context of a carefully commissioned machine and 
workflow including standardization of immobilization, imaging, planning techniques and 
tissue constraints, and plan and machine QA.  To this end, SBRT has now become a 
commonly used and mainstream method for tumor treatments with rapidly expanding 
indications. 
 
1.4 
SBRT for arrhythmia  
 
Preclinical dose finding studies in porcine models have demonstrated that large (25 to 35 
Gy), single fraction doses of SBRT can be accurately delivered to discrete targets in the 
heart, resulting in fibrosis that correlates to electrical isolation, similar to that found in 
catheter ablation.  [21-26] In the earliest of these publications, Maguire et al reported on 
single fraction Cyber Knife radiosurgery (25 Gy (N=1), 35 Gy (N=1)) delivery to the right 
superior and left superior pulmonary veins in two Hanford mini-swine. [21] Animals were 
followed for six months and underwent electrophysiology (EP) testing, transesophageal 
echocardiography, and subsequently pathologic analysis.  At the last time point, the EP 
study documented intended pulmonary vein isolation (electrical block) using a decapolar 
Lasso catheter, and echocardiographic monitoring of atrial and ventricular function six 
months post radiosurgery demonstrated normal cardiac function.  Histologic analysis 
showed transmural fibrosis and contiguity of the ablation scar within the target.  No 
adverse events were noted. 
 
In a follow-up study from the same group, Sharma et al reported results from a dose (25 
to 50 Gy) and location response experiment using single fraction Cyber Knife radiosurgery 
in 16 Hanford-Sinclair mini swine. [23] Targets included the cavotricuspid isthmus, AV 
node, pulmonary vein–left atrial junction, or left atrial appendage.  Ranging from 25 to 
196 days after treatment, animals were investigated with repeat electroanatomic voltage 
mapping and transesophageal echocardiography, when possible. The animals then were 
sacrificed and pathology specimens taken.  Dose finding suggested that 25 Gy was the 

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minimum dose needed to produce an electrophysiologic effect, and this was consistently 
observed by 90 days.  The method was deemed feasible for producing bidirectional 
cavotricuspid isthmus block and AV nodal conduction block.  In addition, the pulmonary 
vein–left atrial junction and left atrial appendage showed marked voltage reduction to 
less than 0.05 mV.  Histologic analysis demonstrated effects consistent with radiotherapy 
effect confined to the targeted areas with no evidence of damage outside the heart. 
 
In a more recent publication from Blanck et al, a dose response experiment was 
performed on 9 mini-pigs (0 Gy and 17.5-35 Gy in 2.5-Gy steps) delivered to the right 
superior pulmonary vein. [7] Baseline MRI and electrophysiology were performed at 
baseline and 6 months after treatment. In contrast to the CyberHeart group, transmural 
scarring of cardiac muscle tissue was noted with doses ≥ 32.5 Gy.   Likewise, 
complete 
circumferential scarring of the RSPV was not achieved at any dose level.  Heart function 
was not affected, as verified by MRI and electrocardiogram evaluation.  Adjacent critical 
structures were not damaged, as verified by pathology. 
 
While the reasons for discrepancy in the required single fraction dose for effect are 
somewhat unclear, part of the difference may stem purely from subtleties in differences 
in dose planning and delivery for a given prescription dose.  In the studies from the 
CyberHeart group, for a prescription dose of 25 Gy, maximum doses in the target volume 
may have exceeded 120-130% of prescription dose (Max doses > 30-39 Gy).  In contrast, 
in the study from Blanck et al, for a suggested dose of 32.5 Gy, the maximum dose to the 
target with their delivery system would generally not exceed 107% of prescription dose 
by convention (Max dose 35 Gy).  As such, both studies may in fact be suggesting the same 
dose range for effect, despite the differences in prescription dose. 
 
The published literature on the use of SBRT for treatment of arrhythmia in humans is 
limited and appears restricted to only 5 patients to date (November 2015).  The first-in-
man report was presented in poster form at the Heart Rhythm On Demand meeting in 
2013 [27] and has since been published [28].  In this first reported experience by Loo et 
al, a case of a 71 year old male with medically refractory VT was presented. [28] The 
patient had known coronary artery disease treated with bypass in 2000, a baseline 
ejection fraction of 24%, and placement of an ICD in 2009 when VT began.  The patient 
also had a history of atrial fibrillation and COPD.  He became refractory to escalating doses 
of sotalol and mexiletine. Catheter ablation was deemed medically contraindicated, and 
he was therefore treated with single fraction CyberKnife radiosurgery to 25 Gy prescribed 
to the 70% isodose line (Max dose 33 Gy) delivered in a single fraction to an area of the 
left ventricular scar as defined by pre-treatment PET and 12-lead ECG, encompassing the 
infero-septal, inferior, and infero-lateral walls from base to apex.  A temporary pacing 
wire (Oscor, Inc., Miami Lakes, FL) was fluoroscopically placed in the RV apex as an 
imaging fiducial marker that could be dynamically tracked to compensate for respiratory 
motion.  Total beam-on time was 90 minutes.  All dose constraints to nearby organs at 
risk were met.   
 

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There were no immediate complications following treatment.  Follow-up ICD 
interrogations revealed a decrease in total VT episodes from an average of 562 episodes 
per month in the 2 months pre-SBRT to an average of 52 episodes per month in months 
2 to 9 post-STAR. At 3 months post-STAR, frequent nonsustained and pace-terminated VT 
occurred, associated with reduction of the sotalol dose to 40 mg bid and mexiletine dose 
to 150 mg bid. Intracardiac electrograms from the patient’s ICD during VT were similar to 
those from pretreatment VT; however, the cycle length of the VT slowed from 380–411ms 
to 470 ms pre versus post STAR. Titration of mexiletine and sotalol dosing back to 150 mg 
tid and 80 mg bid, respectively, resulted in no further episodes of VT. Repeat PET/CT at 
2.5 months post SBRT demonstrated mild extension of the inferior scar, with a more 
complete perfusion defect within the inferior scar.  Nine months after treatment, the 
patient was admitted with COPD exacerbation and recurrent VT, and expired from 
respiratory failure. 
 
In 2014, Cvek et al reported their experience in a 72 year old female with VT refractory to 
medication and both endocardial and epicardial catheter ablations.  [29]  The patient had 
been treated for more than a decade for cardiomyopathy, had a baseline ejection fraction 
of 25%, and grade III/IV mitral regurgitation.  ICD was placed in 2013 following an episode 
of syncope.  The patient was maximally treated with beta-blockers as amiodarone was 
contraindicated due to prolonged QT-interval.  Because of repetitive arrhythmic storms, 
other treatment options were evaluated. She was not a candidate for cardiac surgery due 
to severe comorbidity, including systemic hypertension, paroxysmal atrial fibrillation, 
diabetes mellitus, chronic pulmonary obstruction disease, and chronic renal dysfunction. 
As all standard treatment options were exhausted, she became a candidate for 
stereotactic radiosurgery.  A total dose of 25 Gy was prescribed to the 82% isodose line 
(Max dose 30.5 Gy) to the base of the lateral wall of the left ventricle based on CARTO 
mapping and prior EP studies.  The LV electrode of the stimulation system in the lateral 
branch of coronary sinus was used as fiducial marker for respiratory tracking.  Ten days 
after the radiosurgery session, the number of PVCs decreased from 9-10% to 1-3%, and 
non-sustained ventricle tachycardias (nsVT) diminished as documented in ECG monitoring 
during hospitalization and during repetitive ambulatory ECG Holter monitoring.  Ten days 
post-treatment, only minimal elevation of troponin T serum level was detected (0.024-
0.033). After six weeks, no complications or side effects were found. There were no signs 
of radiation pneumonitis nor pericardial effusion. 
 
Lastly, in a recently reported abstract at EHRA Europace – Cardiostim 2015, Zei et al with 
the CyberHeart group reported on 4 patients (3 refractory VT, 1 refractory atrial 
fibrillation) treated with cardiac SBRT, one of which was already reported in the first-in-
man report above. [30] A total dose of 25 Gy was delivered in a single fraction for all 
patients (2- inferior wall of left ventricle; 1 - ventricular septum; 1- atrial myocardium).  
Average ablation volume was 2.1 cc.  There were no post treatment ICD firings.  Reduction 
in arrhythmia burden was seen in all patients.  Quality of life was stable or improved. 
 
As such, there is now solid preclinical porcine data suggesting feasibility and safety of 

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delivering single fraction SBRT to discrete areas in the heart for purposes of creating scar 
and reducing arrhythmia burden.  Similarly, though the literature base is quite small and 
median follow-up short, there are now at least 5 documented cases in the literature of 
successfully delivering SBRT to 25 Gy in a single fraction for refractory arrhythmia (4 VT, 
1 atrial fibrillation).  Thus, the early safety and promising efficacy results, particularly in 
the at risk VT population who often have limited options (continued medical 
management, heart transplant, or hospice, etc.), justifies exploring this noninvasive 
strategy further. 
 
1.5 
Electrocardiographic Imaging (ECGI): Noninvasive Electrical Mapping 
 
The scattered previous reports of noninvasive cardiac ablation have been performed in 
the absence of detailed electrical mapping. Washington University has been at the 
forefront 
of 
developing 
a 
noninvasive 
cardiac 
mapping 
system, 
called 
Electrocardiographic Imaging (ECGI), which is an important development toward 
improving four-dimensional precision of imaging cardiac electrophysiology. This is a 
noninvasive imaging approach, similar to CT or MRI, except that it is designed to image 
cardiac electrical function.  In brief, ECGI measures body surface electrical potentials at 
over 200 sites on the torso. It incorporates the patient-specific anatomy of the heart with 
the recording leads on the body surface to noninvasively reconstruct the electrical activity 
on a three-dimensional model of the patient’s heart surface.  
 
This modality has been validated extensively in animal and tank-torso models. It has been 
used to image cardiac electrophysiology in a number of normal and disease states in 
humans as well. [32-41] 
 
ECGI represents an important link in the development of an entirely noninvasive mapping 
& ablation system, as it adds noninvasive electrophysiologic mapping to the other 
noninvasive myocardial scar imaging (from standard modalities such as echo, SPECT, MRI) 
to provide the most accurate plan for noninvasive ablation.   
 
1.6 
ENCORE for VT at Washington University 
 
Combining the noninvasive electrical map (ECGI) with noninvasive anatomic/scar images 
allows for greatest precision to target noninvasive stereotactic beam radiation for cardiac 
arrhythmias.  We call this process EP-guided Noninvasive Cardiac Radioablation 
(ENCORE).  In April 2015, the first patient was treated with ENCORE at Washington 
University for refractory VT.  As of May 2016, we have treated a total of 5 patients with 
refractory VT. Three of the patients had one or more prior catheter ablations with 
subsequent progression of VT.  One patient had recent mitral valve replacement, and 
catheter ablation was contraindicated.  The most recent patient treated was 83 years old, 
with multiple medical comorbidities, previous intolerance to anesthesia necessitating ICU 
admission, and subsequently declined catheter ablation.  Table 1 summarizes our 
experience to date. 

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Table 1.  Summary of Wash U ENCORE clinical experience to date. 
Pt 
Age 
(years) 
Sex 
Prior catheter 
ablations 
Target 
Target 
volume 
(ITV, cc’s) 
Dose 
(Gy) in 
1 fx 
Follow-up as of 
5/23/2016 
Delivery 
Number of 
VT 
episodes in 
3 months 
before 
ENCORE 
Number of VT 
episodes after 
ENCORE 
1 
61 
M 
1 
Anteroseptal to 
anterolateral  LV 
base 
51.3 
25 
13 mo 
2 arc VMAT 
>30 
1 at 12 months, 
now  off meds 
2 
60 
M 
0  
(contraindicated due 
to recent heart 
surgery) 
Focal anterolateral 
LV base 
17.3 
25 
10 mo 
Non-coplanar 
IMRT 
>17 
3 in first week,  
now off meds 
3 
65 
M 
2 
Inferior LV 
44.5 
25 
10 mo 
2 arc VMAT 
5 
1 at 6 months,  
now off meds 
4 
62 
M 
6 
Septal RVOT, LV 
summit, LV basal 
septum 
53.0 
25 
7 mo 
2 arc VMAT 
>1000 
Invasively mapped 
4 weeks post 
treatment. 
 
0 since, off meds 
5 
83 
F 
0  
(contraindicated due 
to severe 
comorbidities) 
Mid inferior, 
inferolateral LV 
81.1 
25 
2 weeks (censored) 
3 arc VMAT 
>1000 
233 VT episodes 
over 13 days after 
treatment 

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Of the first 3 patients, all had a dramatic reduction in the number and frequency of VT 
episodes after ENCORE, and all eventually had termination of VT.  The 2 most recent 
patients had substantially more VT (both over 1000 episodes in the month before), and 
one of the two patients was demonstrating a reduction in VT pattern as of censored follow 
up. Only one of the five patients who received ENCORE protocol did not have an 
improvement in VT burden. At 3 weeks post-ENCORE treatment, a repeat catheter 
ablation was performed. Analysis of the invasive study will help answer questions 
regarding efficacy.  While there have not been any acute toxicities to date with ENCORE 
protocol, and all patients who received ENCORE protocol were discharged from the 
hospital, Patient #5 did suffer from an embolic stroke 13 days after ENCORE protocol.  She 
was known to have dilated cardiomyopathy with an EF of 18%, had a history of atrial 
fibrillation. She was deemed to be a poor candidate for oral anticoagulation. As such, she 
was at risk of such a complication independent of therapy. However, given the temporal 
nature of treatment to the stroke, we are assuming that this is possibly related to therapy.  
 
The overall pattern of efficacy for all five patients in the ENCORE-VT Pilot study is shown 
below in Figure 2A, 2B, 2C. Importantly, all patients who underwent ENCORE had a 
reduction in ICD therapies and VT burden. This effect is seen in the absence of 
antiarrhythmic medications, which were aggressively weaned off in the first 6 weeks after 
treatment. The longitudinal heart function, as measured by cardiac echocardiography, is 
shown in figure 2D. None of the 5 patients had a reduction in LVEF after treatment (mean 
+5% in LVEF, range 0 to +15%).  Serial CT scans were also performed, showing mild peri-
ablation lung fibrosis at 3 months that largely resolved by 12 months (Figure 2E).  
 
 
 
 
 
 
 

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In all of the clinical cases reported in the literature to date, treatment was delivered using 
the CyberKnife, a robot linac with orthogonal kV:kV image guidance.  Such a delivery 
system allows for diverse treatment to all sites of the body, but does require placement 
of a fiducial for x-ray image guidance, and due to the nature of the step-and-shoot 
delivery of the robot linac, treatment times average 1.5 hours. 
 
At Washington University, all treatments delivered to date have been on an image-guided 
radiotherapy (IGRT)-equipped linear accelerator per our typical lung SBRT workflow.  
These units are equipped with an onboard cone beam CT (CBCT) which allows for 
acquisition of high fidelity volumetric images of the thorax which can be directly 
registered to the planning CT, allowing for accurate, near real time alignment of the heart 
and target volume.  This precludes the need for invasive placement of a fiducial marker.  
In comparison, VMAT treatment times for our patients have averaged approximately 10 

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minutes.  Figure 3 is an example of a ENCORE treatment plan for patient #1. In all cases, 
overall treatment time is substantially faster than the previously reported cases in the 
literature, which results in improved patient comfort and may also improve overall 
delivery accuracy, as increased time on the treatment machine has been correlated with 
“drift” away from the isocenter over time. [31] 
 
Unlike other centers, treatments at Washington University have been delivered to regions 
that combine anatomic and electrical abnormalities. Anatomic abnormalities are defined 
as regions of ventricular scar, determined from clinical cardiac imaging modalities such as 
delayed-enhancing cardiac MRI (DE cMRI), nuclear computed tomography (SPECT) and/or 
previous intracardiac mapping. Electrical abnormalities are identified by 12-lead ECG 
during a clinical VT or 12-lead ECG during an induced VT from a noninvasive programmed 
stimulation procedure (NIPS). Figure 3 is an example of a ENCORE treatment plan 
developed for patient #1, targeting an area of anatomic scar that was identified with DE 
cMRI which overlapped with the area of electrical abnormalities based on 12-lead ECGs 
of VT obtained during NIPS. The results for each patient are depicted in the bar graph. 
 
 

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Figure 3.  ENCORE procedure. TOP LEFT—Cardiac MRI demonstrating the extensive mid-
myocardial scar (yellow arrows); TOP MIDDLE—Noninvasive electrical mapping (ECGI) 
performed during VT; TOP RIGHT—Noninvasive ablation treatment plan (light green is 
target volume) combining electrical and anatomic information; BOTTOM—Stereotactic 
radiotherapy delivered with 2 VMAT noncoplanar arcs to 25 Gy/single fraction.  
 
 
 
 
As such, the delivery methods within this protocol are novel inasmuch as they are 1) 
rapid; 2) entirely non-invasive; 3) guided by noninvasive imaging of the electrical and 
structural abnormalities. 
 
 

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1.7 
Study Rationale 
 
Patients with VT either refractory to catheter ablation or deemed medically too frail or 
challenging to treat with catheter ablation have limited options, with one-year survival 
below 20%.  Preclinical data described above demonstrate that single fraction SBRT to 
discrete portions of the heart is feasible and may result in a reduction or elimination of 
VT.  Overall safety and early efficacy of SBRT have not been rigorously studied in a 
prospective trial to date. The ENCORE therapy described herein provides for a potentially 
rapid and totally non-invasive method for delivering such therapy. 
 
The purpose of this phase I/II study is to demonstrate the short-term safety and 
preliminary efficacy of ENCORE for patients with VT refractory to standard treatments. 
 
 
2.0 
OBJECTIVES  
 
2.1 
Primary Objectives 
 
1. Phase I - Demonstrate acute (≤ 90 days) safety of noninvasive stereotactic cardiac 
ablation radiotherapy (ENCORE). The primary safety endpoint is defined by a ≤ 20% 
rate of serious adverse events (SAEs) using CTCAE v4.0 criteria that are 
possibly/probably/definitely related to study treatment, based on previously 
published data for expected invasive catheter-based VT-ablation procedures.   
  
2. Phase II - Demonstrate preliminary efficacy of ENCORE. The primary efficacy endpoint 
is defined by the number of subjects with a reduction in ICD therapies (ATP and ICD 
shocks) comparing the period six months before ENCORE treatment to the six months 
after ENCORE treatment as adjudicated by continuous ICD monitoring.  There will be 
a six-week “blanking period” after therapy to allow for ablation effect.  For patients 
with PVC-induced cardiomyopathy, the primary efficacy will be any reduction in PVC 
burden based on ambulatory heart monitors.  
 
2.2 
Secondary Objectives 
 
1. Determine six-month and twelve-month survival (overall mortality endpoint) after 
treatment with ENCORE. 
 
2. Determine late toxicity endpoint (>90 days to 12 months), as tracked prospectively 
after treatment using CTCAE v4.0 criteria. 
 
3. Determine patient-reported health related quality of life endpoint (HRQOL) as 
measured by changes between pre-treatment and 6-week, 6-month, and 12-month 
post treatment scores on the standardized SF-36 questionnaire. 

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4. Evaluate stricter efficacy endpoint of ENCORE treatment, as defined by number of 
patients who have had 50% reduction in any VT therapies (ATP or ICD shocks) after 
ENCORE treatment (6 months before vs. 6 months after treatment, with a 6 week 
blanking period immediately after treatment). For patients with PVC-induced 
cardiomyopathy, the stricter efficacy will be >50% reduction in PVC burden based on 
ambulatory heart monitors. 
 
5. Evaluate strictest efficacy endpoint of ENCORE treatment, as defined by number of 
patients who have had 95% reduction in any VT (ATP or ICD shocks) after ENCORE 
treatment (6 months before vs. 6 months after treatment, with a 6 week blanking 
period immediately after treatment). For patients with PVC-induced cardiomyopathy, 
the strictest efficacy will be abolition of PVC burden (<1%) based on ambulatory heart 
monitors. 
 
6. Evaluate the most clinically useful efficacy endpoint of ENCORE treatment, namely, 
number of patients with reduction specifically in ICD shocks (6 months before vs. 6 
months after treatment, with a 6 week blanking period immediately after treatment). 
For patients with PVC-induced cardiomyopathy, the most clinically useful efficacy will 
be improvement in cardiac function in the setting of any improvement in PVC burden. 
 
7. Evaluate longer-term durability endpoint of ENCORE treatment, as defined by 
number of patients with reduction in VT therapies (ATP or ICD shock and ICD shock 
alone) during the early phase (treatment to 6 months, with 6 week blanking period) 
vs. the late phase (6 months to 1 year). For patients with PVC-induced 
cardiomyopathy, the longer-term durability efficacy will be persistence of any 
reduction in PVC burden based on ambulatory heart monitors during early phase vs. 
late phase. 
 
 
2.3 
Exploratory Objectives 
 
1. To better understand the mechanisms and timing of radiotherapy injury, we will 
obtain serum blood markers of myocardial injury (troponin), endothelial injury (E-
selectin), fibrosis (galectin-3) and prothrombotic markers (von Willibrand factor) at 
baseline, 3 days and 3 months after ENCORE treatment. 
 
2. Evolution of electrical remodeling as obtained with noninvasive ECGI from baseline 
to 3 months and 12 months after ENCORE treatment 
 
3. To better understand the effect of radiotherapy on edema, fibrosis, cardiac 
inflammation, cardiac metabolism and localized cardiac function, we plan to use 
serial cardiac imaging (DE-cMRI when possible, FDG-PET in all) at baseline, 3 days and 
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3.0 
PATIENT SELECTION  
 
3.1 
Inclusion Criteria 
 
1. DOCUMENTED VT:  
a. Patient must have documented sustained monomorphic ventricular 
tachycardia as documented on either a 12-lead ECG or intracardiac ICD 
interrogation 
— OR—  
b. Monomorphic PVCs documented on a 12-lead ECG.  
 
2. ANTIARRHYTHMIC MEDICATION: Patient must have failed or become intolerant to at 
least one antiarrhythmic medication (amiodarone, sotalol, or mexiletine).   
–AND— 
3. CATHETER ABLATION: Patient must have failed at least one invasive catheter ablation 
procedure, or have a contraindication to a catheter ablation procedure (e.g., LV 
thrombus, severe pulmonary disease), or have VT thought to arise from a protected 
location (e.g., epicardial VT with history of previous cardiac surgery).  
 
4. MINIMUM VT BURDEN: Patient must have either: 
a. At least 3 VT episodes (sustained VT, ICD ATP or ICD shock) over previous 6 
months prior to enrollment 
 –OR— 
b. >20% PVC burden with a cardiomyopathy (LVEF<50%) 
 
5. Patient must be deemed medically fit for stereotactic body radiation therapy by the 
treating physician. 
 
6. Patient must be > 18 years old. 
 
7. Patient must be able to understand and be willing to sign an IRB approved written 
informed consent document.   
 
3.2 
Exclusion Criteria 
 
1. 
Patient must not have past history of radiotherapy within the projected 
treatment field. 
 
2. 
Advanced symptomatic heart failure as defined as NYHA Class IV heart failure 
(inotrope dependent and/or current left-ventricular assist device (LVAD)) 
 
3. 
Polymorphic VT or ventricular fibrillation (VF) as a clinical heart rhythm (as 
determined by 12-lead ECG and/or ICD interrogation).  

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4. 
More than 3 distinct clinical VT morphologies observed (ECG or ICD 
interrogation or invasive EP study) OR more than 5 distinct induced VT 
morphologies during ECGI testing. 
 
5. 
Advanced myocardial scar substrate that would require stereotactic delivery to 
a target volume deemed unsafe by the treating physician.   
 
6. 
Unlikely to live 12 months, in the absence of VT, as best based on clinical 
judgment by the treating and enrolling physicians.   
 
7. 
Patient must not be pregnant and/or breastfeeding and must have a negative 
pregnancy test within 14 days of study entry. 
 
 
4.0 
TREATMENT PLAN 
 
4.1 
Noninvasive Imaging for Scar/Fibrosis, Edema, Inflammation 
 
To maximize the potential benefit and minimize the risks of noninvasive 
radioablation, we will perform extensive imaging of cardiac ventricular scar or 
inflammation harboring the VT circuit using clinically available imaging tests, 
including magnetic resonance imaging (MRI), positron emission testing (PET), and 
myocardial perfusion imaging (MPI/SPECT) when available. If these studies have 
been performed previously within one year, additional testing is not needed. Refer 
to Section 7.0 Study Calendar for anticipated timing of clinical cardiac imaging 
modalities. The role of each test and potential risk to each is described briefly 
below. 
 
4.1.1 Magnetic Resonance Imaging (MRI) 
 
When coupled with administration of IV contrast agent (gadolinium), cardiac MRI 
is the gold-standard imaging study for detailed evaluation of the distribution of 
fibrosis and scar. In this study, MRI will be performed prior to the procedure 
(baseline study) to help determine the target volume for radioablation using the 
best-practices to safely acquire the data and the latest sequences for artifact-
reduction, called Wideband sequences (55, 56).  
 
Immediately after treatment (day 3), MRI will be used to evaluate for the presence 
of local edema at the treated site (T2-weighted imaging) and to screen for acute 
injury, such as pericardial effusion.  
 
MRI will be performed again 3 months after the treatment to evaluate for any 
changes in cardiac fibrosis and scar from the baseline study. It will also screen for 

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potential toxicities, including changes in myocardial function, valvular 
performance or pericardial effusion.  
 
This type of serial MRI has never been performed after administration of cardiac 
radiotherapy, and the results are expected to provide important insight into the 
mechanisms and timing of the radiobiological effect of this treatment. We 
perceive this knowledge to be of utmost importance in determining the projected 
time course of the safety and clinical effect for future patients receiving this type 
of therapy.  
 
We anticipate that most or all of the patients who are enrolled into this study will 
have cardiac defibrillators (ICDs) to treat ventricular arrhythmias. Historically, the 
presence of an ICD has been a contraindication to performing MRI for various 
theoretical and observed concerns. Over the course of the past decade, great 
strides have been made to safely allow patients with ICDs to undergo MRI scans. 
These are reviewed in several recent publications (42-53).  The most prominent of 
these is the completion of a large registry to characterize the risks of undergoing 
MRI with a cardiac device (MAGNASAFE.org). This registry and other publications 
(50) have defined the substantial safety margin of MRI use in patients with cardiac 
devices, and these studies form the basis for an upcoming professional guideline 
statement regarding the expanded and safe use of MRI in patients with cardiac 
devices (anticipated 2016 release). In short, the MAGNASAFE registry was a 
multicenter trial of 1,500 patients with cardiac devices who underwent MRI 
scanning on a 1.5 T scanner. Of the 1500 MRI scans, only 1 patient developed a 
clinical event (generator failure due to inappropriate sensing) which was deemed 
to be caused by inappropriate ICD programming. The overall positive results of the 
MAGNASAFE study have resulted in the national CMS National Coverage 
Determination (NCD) allowing for coverage of MRIs in patients with cardiac 
devices if they are performed in a research study that meets CED (coverage with 
evidence development) criteria.” (Medicare website: CAG-00399R2). Since the 
release of MAGNASAFE, a number of trials including patients who are specific to 
our population (patients with VT, with implanted ICD, undergoing cardiac MRI) 
have been published (42-53). In these studies, there were no adverse effects of 
cardiac MRI with appropriate pre-scan ICD programming, further supporting the 
overall safety of this scan in the appropriately selected patients.  
 
A second major advance is the development of MRI-conditional cardiac devices, 
which are now commercially available from several manufacturers (Medtronic, 
Biotronik). Whenever possible, we plan to use these devices for new implants at 
our hospital. However, we expect most patients who enroll into this study will 
have older legacy devices, which do not have specific MRI-conditional labeling.  
 
In this study, we recognize the potential risks involved with MRI in patients with 
ICDs, and these risks will be shared with patients in full disclosure, using language 

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and images from a recently published “Cardiology Patient Page” article (54). MRI 
remains the gold standard for assessment of fibrosis and edema, and we believe 
the large benefits of precision guidance of radiotherapy outweigh the small 
potential risks of ICD system changes.  Patients who are unwilling to accept these 
risks, or patients in whom we believe the risks to be excessive will not undergo 
MRI. We will then use clinically available imaging, such as nuclear MPI/SPECT, 
which is less specific and sensitive than MRI.  
 
Patients in whom we will NOT offer an MRI include: 
a) Newly implanted ICD system (any component added < 6 weeks) 
b) Dependence on ICD system for pacing (complete heart block or severe 
sinus node dysfunction without ventricular escape)  
c) Presence of abandoned, fractured or epicardial cardiac leads 
d) Active noncardiac implanted device (other than cardiac device) 
e) Abdominal position of cardiac device 
f) Battery voltage of ICD at elective replacement interval 
g) Increased risk to administration of IV gadolinium such as renal 
impairment (estimated glomerular filtration rate (eGFR) < 40) or 
previous adverse reaction to IV gadolinium. 
h) Patient preference 
 
For patients who undergo MRI, several safeguards have been developed as “best 
practices” and will be used for this study. These include: 
a) Supervision of appropriately trained personnel for the duration of the 
MRI scan 
b) Pre-treatment and post-treatment ICD device checks 
c) Pre-treatment ICD programming per standardized protocol 
(MAGNASAFE registry) to minimize chances of untoward ICD effects, 
including asynchronous or inhibited pacing mode (VOO/DOO or 
VVI/DDI setting), disabling magnet response, disabling episode 
memory, and disabling therapies for tachyarrhythmia. A full risk-
mitigation protocol has been developed and is available as a 
supplement to this protocol.  
 
4.1.2  Positron Emissions Testing (PET) 
 
PET uses a special camera to measure specific signal in heart cells emitted from 
injected radioisotopes (called tracers). The amount of radiation received from PET 
is small, and the risk of procedural complication is exceedingly low. In this study, 
the radioisotope will be Fludeoxyglucose (FDG). This isotope tests for areas of 
inflammation and ischemia, which may be particularly important in patients with 
nonischemic reasons for cardiomyopathy. The FDG-PET imaging will be done in all 
patients, unless contraindicated due to previous adverse reaction. The 

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information gained from FDG-PET cardiac metabolism will be combined with the 
scar imaging from MRI to help guide radioablation.  
 
 
4.2 
Noninvasive Electrical Imaging  
 
The method of electrocardiographic imaging (ECGI) is described in Section 1.5 
above.  Graphically, it is illustrated below: 
 
 
 
In brief, the patient undergoes a CT scan while wearing a “vest” of electrodes that 
record heart beats. The electrical information from the surface of the body can 
then be computed onto the patient-specific heart model to noninvasively display 
the characteristics of the imaged heartbeat. Useful information includes: where 
the beat begins, how it depolarizes the heart, which parts of the heart have 
abnormal signals from previous heart attacks or scar. Fitting the vest of electrodes 
on the patient, obtaining electrical signals, and performing the CT scan is generally 
completed in under 30 minutes.  
 
In this study, prior to treatment, patients will undergo ECGI during a noninvasive-
programmed stimulation (called NIPS) procedure. A NIPS procedure is a 
commonly performed procedure in the cardiac electrophysiology lab. The patient 
receives light IV sedation for the procedure, and vital signs are monitored closely. 
Communication with the patient’s ICD is established, and the ICD is used to 
intentionally induce ventricular tachycardia through basic pacing maneuvers. 
Once the VT is induced, a 12-lead ECG and 256-lead ECGI are obtained (less than 
10 seconds). The ICD is then again used to pace-terminate the VT (less than 10 
seconds).  
 
In this study, the NIPS will be performed in a standardized fashion. In the fasting 
state, single, double, and then triple extrastimuli will be delivered to refractoriness 
at drive trains of 600 and 400 ms, via the right ventricular ICD lead. Results from 

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the NIPS will yield electrical information (ECG and ECGI) that guides targeting of 
the noninvasive ablation to the areas of origin of the ventricular arrhythmias.  
 
Despite the perceived risk of intentionally inducing a potentially life-threatening 
arrhythmia, NIPS is considered a rather low-risk procedure in the EP lab. Common 
risks include: 
 Hypotension or adverse reaction to IV sedation (usually propofol); 
 Induction of an arrhythmia that cannot be terminated by pacing, requiring 
external cardioversion/defibrillation or use of the ICD is necessary to 
restore regular rhythm 
 
Contraindications for NIPS include: 
 Because of the possibility for cardioversion/defibrillation, the most 
common contraindication for NIPS is the presence of atrial fibrillation in a 
patient that cannot receive anticoagulation 
 Hemodynamic or medical instability prior to procedure 
 ICD at elective replacement interval (ERI) or end of service (EOS) 
 
During follow-up after treatment, ECGI will be performed as a standalone 
procedure, without the need to perform NIPS. 
 
 
4.3 
Targeting the Area for Noninvasive Ablation 
 
The clinical cardiac electrophysiologist will determine the region of the heart to 
be targeted for noninvasive ablation on an individual patient basis. The decision 
combines: A) scar architecture from cardiac MRI; B) inflammation location from 
PET; C) 12-lead ECG interpretation; D) 3-dimensional ECGI interpretation, using 
previously published criteria for origin of VT; E) anatomic considerations from CT 
scan; F) reduced cardiac motion or myocardial thinning, suggestive of previous 
cardiac injury or scar.  As a general rule, efforts will be made to target all areas of 
VT origin and adjacent scar or inflammatory regions that harbor related circuits. 
In almost all cases, the targeted area will avoid areas of healthy tissue and focus 
on areas that demonstrate severely reduced cardiac motion.    
 
  
4.4 
Radiation Therapy Guidelines 
 
4.4.1 Dose, Fractionation 
 
Radiotherapy will consist of stereotactic body therapy to be given over one 
fraction. Patients will be planned for a dose of 25 Gy in a single fraction to the PTV.   
  
4.4.2 Simulation Procedures/Patient Positioning 

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Patients will be immobilized using a system (such as BodyFIX) that is known to 
keep immobilization setup uncertainty to ≤ 3 mm. All patients will undergo free 
breathing CT simulation using thin (≤ 3 mm) slice thickness CT.  An additional 
respiratory correlated 4D-CT will be acquired and co-registered to the planning CT 
for purposes of assessing respiratory motion. IV contrast will be used to facilitate 
definition of cardiac structures when not otherwise contraindicated.  Esophageal 
contrast will be used to facilitate definition of the esophagus and upper stomach 
when not otherwise contraindicated.  Additional clinical images may be co-
registered to the planning CT based on availability and at the discretion of the 
clinician. 
 
4.4.3 Target Volumes 
 
The treatment target will be defined using radiation oncology principles of target 
definition.  The gross target volume (GTV) will be segmented through 
corroboration of all previously acquired imaging (MRI, CT, SPECT, etc.) and EP data 
(12-lead EKG, prior catheter mapping, ECGI, etc.).  An internal target volume (ITV) 
will be created based on the 4D-CT to account for any impact on the summative 
effect of respiratory and averaged-out cardiac motion.  No clinical target volume 
(CTV) expansions will be utilized.  The PTV will be generated at the discretion of 
the treating physician based on immobilization, machine uncertainties, and setup 
uncertainty, but should generally range between 0.3 cm and 0.7 cm.  
 
4.4.4 Treatment Planning 
 
All patients will be planned to a target dose of 25 Gy in a single fraction to the PTV, 
subject to organ at risk (OAR) dose constraints.  Coverage goal of the PTV will be 
for > 95% of the PTV to be covered by > 95% of the prescription dose, although in 
situations where a critical OAR structure is violated, coverage of PTV will be 
compromised in order to meet dose constraints. 
 
Dose limits are being employed as means to minimize the likelihood of toxicity, 
but true tolerance to OARs are not well described for single fraction schemes to 
the central thorax, and therefore prioritization will be employed for planning 
purposes taking into account the balance between PTV coverage and relative 
consequences of toxicity to specific OARs. 
 
Priority Definition 
1 
Obey spinal cord constraints.  No deviations allowed. 
2 
Respect PTV coverage requirements. 
3 
Respect OAR constraints.  If the PTV is next to or involving an OAR 
(not the spinal cord), then likely the guideline constraints cannot be 
met.  In such cases, dose to OAR should not exceed 105% of 

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prescription dose and effort should be made to avoid treating the 
entire circumference of the structure (particularly trachea, 
bronchus, esophagus). 
 
4.4.5 OAR Contouring 
 
In order to verify dose limits to OARs, OARs must be contoured such that 
appropriate volume histograms can be generated. Instructions for the contouring 
of these organs are as listed in the table below.  An OAR may be omitted from 
contouring and subsequent evaluation in the DVH if it is > 10 cm from the PTV, or 
at the discretion of the treating radiation oncologist if it is determined that no 
clinically meaningful dose will be received by the OAR. 
 
Serial Tissue 
Contouring 
Volume 
Volume Max 
(Gy) 
Max Point 
Dose (Gy)** 
Spinal Cord and 
medulla 
Entire bony canal 
<0.35 cc 
<1.2 cc 
10 Gy 
8 Gy 
14 Gy 
Spinal Cord 
Subvolume 
(5-6 mm above and 
below level treated 
per Ryu) 
 
<10% of 
subvolume 
10 Gy 
14 Gy 
Esophagus* 
Include the mucosal, submucosa, 
and all muscular layers out to the 
fatty adventitia  
<5 cc 
11.9 Gy 
15.4 Gy 
Heart/Pericardium 
Contoured along with the 
pericardial sac. The superior aspect 
(or base) for purposes of 
contouring will begin at the level of 
the inferior aspect of the aortic 
arch (aorto-pulmonary window) 
and extend inferiorly to the apex of 
the heart. 
<15 cc 
16 Gy 
22 Gy 
Great vessels 
The wall and lumen of the named 
vessel 
<10 cc 
31 Gy 
37 Gy 
Trachea and Large 
Bronchus* 
Contour the trachea and cartilage 
rings starting 10 cm superior to the 
PTV extending inferiorly to the 
bronchi ending at the first 
bifurcation of the named lobar 
bronchus. 
<4 cc 
17.4 Gy 
20.2 Gy 
Rib 
 
<5 cc 
28 Gy 
33 Gy 
Skin 
The outer 0.5 cm of the body 
surface anywhere within the whole 
body contour. 
<10 cc 
25.5 Gy 
27.5 Gy 

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Stomach 
The entire stomach wall and the 
gastric contents included from the 
GE junction to the proximal 
duodenum at the pyloris. 
<5 cc 
17.4 Gy 
22 Gy 
Parallel Tissue 
 
Critical 
Volume 
(cc) 
Critical 
Volume 
Dose Max 
(Gy) 
 
Lung (Right & Left) 
Contour right and left lung as one 
structure including all parenchymal 
lung tissue but exluding the GTV 
and major airways (trachea and 
main/lobar bronchi) 
1500 cc 
7 Gy 
 
Lung (Right & Left) 
 
1000 cc 
7.6 Gy 
V-8Gy <37% 
Liver 
Contour right and left lobes as one 
structure including all parenchymal 
liver tissue but excluding the GTV 
and major draining ducts, 
extrahepatic portal vein, and gall 
bladder. 
700 cc 
11 Gy 
 
 
4.5 
Evaluability Guidelines 
 
Patients who complete the full intended dose of single fraction SBRT are evaluable for 
both the primary and secondary objectives. 
 
4.6 
General Concomitant Medication and Supportive Care Guidelines 
 
In the rare event that a patient is taking an anti-neoplastic therapy (chemotherapy, 
targeted therapy) for any reason (immune disease, malignancy), said medication must be 
withheld at least 7 days prior to and 7 days after delivery of SBRT.   
 
All other standard concomitant medications deemed necessary for management of the 
patient’s arrhythmia and overall health should be continued, and need not be altered for 
purposes of SBRT delivery. 
 
Though not yet seen in our preliminary experience, given the proximity of the esophagus 
and stomach to the heart, it is possible that patients may develop esophagitis or gastritis.  
Treatment of esophagitis/gastritis varies with the severity of the patient’s symptoms; for 
example, diet adjustment and narcotic management may be sufficient for grade 2 
complications. Nutritional support via gastric tube or jejunostomy tube may be initiated 
upon development of grade 3-4 complications, per mutual preference of the treating 
physician and patient. 
 
4.7 
Women of Childbearing Potential 

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Women of childbearing potential (women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required 
to have a negative pregnancy test within 14 days prior to the start of SBRT.  
 
If a patient is suspected to be pregnant, SBRT should not be administered. In addition a 
positive urine test must be confirmed by a serum pregnancy test. If it is confirmed that 
the patient is not pregnant, the patient may resume therapy.  
 
4.8 
Duration of Therapy 
 
Because this study involves administration of a single fraction of SBRT over the course of 
approximately 10 minutes, there is no option for discontinuation of treatment once 
initiated. 
 
4.9 
Duration of Follow up 
 
Patients will be followed per protocol for 12 months following the completion of SBRT or 
until death, whichever occurs first. Follow-up is per the treatment calendar (see Section 
8.0) and consists of routine clinical visits, 12-lead EKG and implanted device interrogations 
to evaluate toxicity and treatment response, and evaluation of QOL. Patients will be 
followed by office visits, phone calls, and review of medical record.  Any additional follow-
up and imaging will be obtained off-study as per routine clinical policies of the treating 
physician.  After 12 months, patients will be followed at the discretion of the treating 
physicians. Patients will be tracked for clinical outcomes up to 5 years after completion of 
radiation via review of the medical record. 
 
4.10 
Management of ICD Programming and Antiarrhythmic Medications During 
Follow up 
 
ICD programming parameters and antiarrhythmic medication dosing should be patient-
specific decisions, left to the treating physician taking into account risks and benefits of 
the various strategies. Ideal settings are suggested below: 
 ICD programming should include a zone for detection at least 20ms slower than 
the slowest clinical or induced VT. ICD therapy may or may not be programmed to 
deliver therapy in this zone, subject to decisions about patient symptoms and 
tolerances during VT.  
 Antiarrhythmic medications should be maintained at pre-treatment doses for at 
least the first 6 weeks, barring any development of adverse medication effect. 
 With each subsequent visit after the first 6 weeks, doses of at least one 
antiarrhythmic medication should be reduced if no VT has been observed on ICD 
device check.  

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 If not contraindicated, oral anticoagulation is preferred during the first month 
after treatment (warfarin, dabigatran, rivaroxaban, apixaban or edoxaban) to 
minimize risks of stroke.   
 
 
5.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
5.1 
Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease.  
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity 
reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website.  
 
Advancing heart failure symptoms will be monitored closely, and represent a difficult 
endpoint to assess objectively. It is acknowledged that heart failure progression is an 
expected natural history irrespective of cardiac ablation. Inotrope or mechanical support 
may become necessary, and if used, specific scoring criteria will be used to adjudicate 
treatment-related HF progression vs. natural history of HF. For the purposes of this study, 
which studies the short-term toxicities of the therapy, treatment-related adverse heart 
failure event will be defined as either:  
1) 
Acute worsening of heart failure symptoms requiring initiation of new 
IV vasoactive medications (inotropes or vasopressors) within the first six 
weeks of treatment;   
2) 
Acute reduction in left ventricular ejection fraction (>10% reduction) 
within the first six weeks of treatment 
 
We recognize that because of the relatively slow-acting nature of radiotherapy, potential 
treatment-related heart failure progression fall outside the six-week window defined 
above. Long-term clinical care and observation will be important, but are outside the 
scope of this project. For best patient care, decisions regarding heart transplant status 
and candidacy for inotrope or mechanical support will not be affected by enrollment in 
this study.  
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP). A copy of this guidance can be 
found on OHRP’s website:  
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
 
 

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5.2 
Serious Adverse Events (SAEs) 
 
Definition:  An adverse event that is any undesirable experience associated with the use 
of a medical product in a patient that results in death, hospitalization (new or 
prolonged), disability or permanent damage, or is life-threatening. 
 
Specific to this protocol, SAEs are defined as AEs with CTCAE v4.0 grade 3 or higher 
resulting in hospitalization or grade 4-5 AE. Treatment-related SAEs were SAEs that are 
possibly, probably, or definitely related to protocol treatment. 
 
5.3 
Unanticipated Problems 
 
Definition: 
  
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and  
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
 
5.4 
Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human subjects research or failure to follow the determinations of the IRB. 
Noncompliance may occur due to lack of knowledge or due to deliberate choice to ignore 
regulations, institutional policies, or determinations of the IRB 
 
5.5 
Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial harm 
 
5.6 
Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control.  Exceptions apply only to a single participant or a singular situation.  
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 

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5.7 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events:  
 
• 
Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct 
of the study.  
• 
Noncompliance with federal regulations or the requirements or determinations 
of the IRB.  
• 
Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study.  
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event. The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event 
 
5.8 
Timeframe for Reporting Required Events 
 
Adverse events captured in the CRFs will be tracked for 12 months following SBRT. For 
the purposes of this protocol, reportable adverse events are grade 3, 4, or 5 toxicities that 
did not predate SBRT and are possibly, probably or definitely attributable to treatment. 
Patients will be assessed using the CTCAE v4.0. 
 
 
6.0 
CORRELATIVE STUDIES 
 
Quality of life (QOL) will be measured at baseline, 6 weeks, 6 months, and 12 months post 
completion of ENCORE, using the SF-36 questionnaire.  Changes between baseline and each time 
point, as well as changes between time points, will be measured. 
 
ECGI will be obtained at baseline, 3 and 12 months after ENCORE treatment.  Comparisons will 
be made of the putative purely ECGI-derived target volume vs. clinically-derived target volume 
on protocol, as well as comparison of post-ENCORE month ECGI with baseline ECGI with 
correlation of changes on ECGI with ENCORE dose distribution 
 
Delayed contrast enhanced cardiac MRI (DE cMRI) will be obtained at baseline, 1-3 days and 3 
months after ENCORE treatment. While initial MRI will help identify anatomic scar to target 
therapy, follow up DE cMRI will be used to identify tissue edema and myocardial ablation, as well 
as assess for cardiac and extracardiac complications. 
 
Blood work will be drawn at baseline, 3 days and 3 months after ENCORE treatment. Specific 
markers will be used to assess for biochemical evidence of myocyte injury (troponin), endothelial 

Version 09/26/2018 
 
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injury/activation (E-selectin), fibrosis (galectin-3), and prothrombotic effects (von Willibrand 
factor).   
 
In patients who die or undergo a heart transplant, clinical reports will be reviewed and abstracted 
of any pathologic, histologic, or autopsy analysis.  Additionally, clinically processed tissue 
submitted to the Department of Pathology may be requested for additional analysis for research 
purposes, including, but not limited to, assessment of the location and degree of baseline injury 
outside the radiotherapy target and evidence of on and off-target injury from radiotherapy. 
 
7.0 
STUDY CALENDAR  
* For patients with PVC-induced cardiomyopathy-indications only 
** Patients will be followed as per routine clinical practice, with data being collected from the 
medical record on outcomes for up to 5 years post-completion of study treatment. Device 
interrogation, 24 hour heart monitors, and imaging will be performed as clinically indicated 
but are not mandated by the protocol. Capture of AEs will be performed as described in 
Section 5.1. 
 
 
Screening Baseline ENCORE 
tx 
Day 
3 
2 
wk 
4 
wk 
6 
wk 
3 
mo 
6 
mo 
12 
mo 
Extended 
F/U** 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
Device 
interrogation 
(Standard of 
care) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24 Hour heart 
monitor* 
(Standard of 
care) 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 QoL 
 
X 
 
 
 
 
X 
 
X 
X 
 
12-lead EKG 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
NIPS 
 
X 
 
 
 
 
 
 
 
 
 
Cardiac CT + 
ECGI 
 
X 
 
 
 
 
 
X 
 
X 
 
Cardiac MRI + 
PET 
 
X 
 
X 
 
 
 
X 
 
 
 
Adverse events 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood work 
 
X 
 
X 
 
 
X 
X 
 
 
 

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8.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
ENCORE Form 
Completion of last fraction of SBRT 
Toxicity Form 
6 weeks post-SBRT 
3 months post-SBRT 
6 months post-SBRT 
QOL Form 
Baseline  
6 weeks post-SBRT 
6 months post-SBRT 
12 months post-SBRT 
Follow-Up Form 
6 weeks post-SBRT 
3 months post-SBRT 
6 months post-SBRT 
12 months post-SBRT 
2 years post-SBRT 
3 years post-SBRT 
4 years post-SBRT 
5 years post-SBRT 
 
 
9.0 
MEASUREMENT OF EFFECT 
 
1. Acute (≤ 90 days) safety of ENCORE will be defined as a ≤ 20% rate of protocol-
specific serious of serious adverse events (SAEs) using CTCAE v4.0 criteria that are 
possibly/probably/definitely related to study treatment, based on previously 
published data for expected invasive catheter-based VT-ablation procedures.  Early 
stopping rules have been created such that if 5 or more patients develop ENCORE 
related SAEs out of the first 10 patients, this would be deemed significantly greater 
than 20% (alpha < 0.05), and the trial will be halted. 
 
2. Preliminary efficacy of ENCORE will defined by the number of subjects with a 
reduction in ICD therapies (six month period before ENCORE treatment compared to 
six month period after ENCORE treatment) as adjudicated by continuous ICD 
monitoring.     
 

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10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Data and Safety Monitoring Committee (DSMC) will meet to review data semi-annually beginning 
six months after accrual has begun. The report will be prepared by the study statistician with 
assistance from the study team and will be reviewed by the DSMC, which will consist at minimum 
of a radiation oncologist, a cardiologist, and a statistician.  The report will include:  
 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician.  
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, study status, and phase of study.  
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason.  
• 
Study-wide target accrual and study-wide actual accrual.  
• 
Protocol activation date.  
• 
Average rate of accrual observed in year 1, year 2, and subsequent years  
• 
Expected accrual end date 
• 
Objectives of protocol with supporting data and list the number of participants who have 
met each objective.  
• 
Measures of efficacy.  
• 
Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules.  
• 
Summary of toxicities 
• 
Abstract submissions/publications  
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO according to 
institutional guidelines. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Early Stopping Criteria 
 
Through a one sample test for proportions, assuming a maximal clinically acceptable SAE 
rate of 20%, 5 or more SAEs out of the first 10 patients would be significantly greater than 
20% (alpha < 0.05).  As such, the protocol will be halted if 5 or more of the first 10 patients 
develop a SAE. 
 
11.2 
Sample Size Justification 

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A total of 19 patients will be enrolled, which provides an optimal balance between 
assuring a high likelihood of safety (Phase I) with a preliminary assessment of efficacy 
(Phase II). 
 
For the phase I component, the baseline rate of SAEs for catheter ablation is assumed to 
be 10-15%.  Given the population being studied and a reasonable expectation that 
patients may be at a higher than typical risk of toxicity from any salvage therapy, we 
assume that SAE rates up to 20% would be clinically acceptable.  Having said that, given 
that this is a totally noninvasive technique, it may well be that rates of toxicity are lower 
than that expected with catheter ablation.  After exploring patient ranges from 15-25 
patients, it was determined that 19 patients would provide a 75.4% power to detect an 
SAE rate about 20% (range, 5%-20%, alpha = 0.0829).   
 
For the phase II component, while some single institution series report much higher 
success rates, the baseline efficacy rate of catheter ablation in prospective trials ranges 
from 50-65%.  As this is a salvage therapy in a high risk population, we assume that 
efficacy rates as low as 40% would be clinically acceptable.  Using the 19 patient sample 
determined above, it was determined that 19 patients would provide 81.5% power to 
determine that ENCORE is not worse than 40% effective for the treatment of VT (range, 
40-65%, alpha = 0.0885). 
 
11.3 
Analytic Plan for Primary Objectives 
 
SAEs defined by CTCAE v4.0 criteria within 90 days of ENCORE that are 
possibly/probably/definitely related to study treatment will be recorded.  ENCORE 
therapy will be deemed safe if the rate of SAEs is ≤ 20%.  An additional early stopping rule 
dictates that if 5 or more out of the first 10 patients develop ENCORE related SAEs, the 
trial will be halted. 
 
The number of ICD therapies delivered in the 6 month periods preceding and following 
ENCORE therapy will be recorded for each patient by interrogation of the ICD.  ENCORE 
therapy will be deemed efficacious if there is a reduction in ICD therapies before and after 
treatment.  The proportion of patients with efficacious ENCORE therapy will be 
calculated, with the intent of demonstrating at least 40% efficacy.  
 
11.4 
Analytic Plan for Secondary and Exploratory Objectives 
 
Adverse events will be tabulated by type and grade. 
 
Descriptive statistics will be used to describe efficacy and strict efficacy, changes in SF-36 
scores, changes in ECGI, differences in purely ECGI derived vs. clinically-derived target 
volumes. 
 

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Dose-volume parameters to the ENCORE target as defined by ECGI and the clinical target 
volume will be correlated with the reduction in VT through descriptive statistics and Cox 
regression. 
 
 
 

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