Stereotactic Ablative Radiotherapy (SABR) for Refractory Ventricular Tachycardia - a Phase I/II Study
Phase: NA
Conditions: Refractory Ventricular Tachycardia
Sponsor: University of California, Los Angeles

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Stereotactic Ablative Radiotherapy of Refractory Ventricular Tachycardia – a Phase I/II 
Study 
 
Principal Investigator: 
 
Robert K Chin, M.D., Ph.D. 
Assistant Professor, UCLA Radiation Oncology 
 
 
NCT03349892 
 
Protocol Date/Version 21JUN2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Stereotactic Ablative Radiotherapy of Refractory Ventricular Tachycardia – a Phase I/II 
Study 
 
Principal Investigator: 
 
Robert K Chin, M.D., Ph.D. 
Assistant Professor, UCLA Radiation Oncology 
 
Co-Investigators: 
 
Nzhde Agazaryan, Ph.D. 
Professor, UCLA Radiation Oncology, Chief of Clinical Medical Physics 
 
Noel G. Boyle, M.D. Ph.D. 
Professor, UCLA Medicine (Cardiology), Director of Cardiac Electrophysiology at UCLA-
Santa Monica and DGSOM 
 
Jason Bradfield, M.D. 
Assistant Professor, UCLA Medicine (Cardiology), Director of Cardiac Electrophysiology 
at UCLA-Olive View. 
 
Minsong Cao, Ph.D. 
Assistant Professor, UCLA Radiation Oncology, Medical Physics 
 
Paul Finn, M.D. 
Professor, UCLA Diagnostic Radiology, Chair of Diagnostic Cardiovascular Imaging 
 
Peng Hu, Ph.D. 
Assistant Professor, UCLA Diagnostic Radiology 
 
Patrick Kupelian, M.D. 
Professor and Vice Chair, UCLA Radiation Oncology 
 
Percy Lee, M.D. 
Associate Professor, UCLA Radiation Oncology 
 

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Daniel Low, Ph.D. 
Professor, UCLA Radiation Oncology, Chief of Medical Physics 
 
Ann Raldow, M.D. 
Assistant Professor, UCLA Radiation Oncology 
 
Kalyanam Shivkumar, M.D. Ph.D. 
Professor, UCLA Medicine and Radiology, Director UCLA Cardiac Arrhythmia Center 
 
Michael Steinberg, M.D. 
Professor and Chair, UCLA Radiation Oncology 
Amar Kishan, M.D. 
Assistant Professor, UCLA Radiation Oncology 
 
Albert J. Chang, M.D, Ph.D 
Assistant Professor, UCLA Radiation Oncology 
 
Study Coordinator 
Victoria A. Ramirez, CCRC 
 
Study Center: 
 
UCLA Jonsson Comprehensive Cancer Center 
Department of Radiation Oncology 
200 UCLA Medical Plaza, Suite B265 
Los Angeles, California 90095 
 
UCLA Cardiac Arrhythmia Center 
100 UCLA Medical Plaza, Suite 690 
Los Angeles, California 90095 
 
 
 
 
 

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INDEX 
 
PROTOCOL SYNOPOSIS 
 
SCHEMA 
 
1. OBJECTIVES 
2. BACKGROUND 
3. PATIENT SELECTION 
4. REGISTRATION PROCESS 
5. TREATMENT PLAN 
6. PHARMACEUTICAL INFORMATION 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
8. STUDY CALENDAR 
9. DATA REPORTING/REGULATORY CONSIDERATIONS 
10. STATISTICAL CONSIDERATIONS 
11. REFERENCES 
 
 

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PROTOCOL SYNOPOSIS: 
 
CONCEPT/RATIONALE: 
Sudden cardiac death accounts for more than 326,000 deaths per year in the US alone, and a 
significant portion of these are attributable to ventricular arrhythmia subsequent to ischemic (ICM) 
or non-ischemic cardiomyopathy (NICM). Even with current gold-standard therapies, a large 
number of patients have uncontrolled arrhythmia leading to either death or poor quality of life due 
to recurrent implantable cardioverter defibrillator (ICD therapies) shock rescue.  
 
Stereotactic ablative radiotherapy (SABR) is routinely used in radiation oncology to accurately 
ablate small moving targets in single session treatments with minimal toxicity. There is preliminary 
data in both animal studies and clinical case reports of control of VT in otherwise refractory 
patients following a 30-min single session stereotactic ablative radiotherapy.  
 
This protocol will offer compassionate use/palliative therapy for patients that have failed all other 
available therapies.  During this initial study, data will be gathered on efficacy and toxicity to guide 
future multi-institutional studies. This is a highly collaborative effort between radiation oncology, 
radiology and cardiology/cardiac electrophysiology. If successful, this non-invasive approach to 
treat ventricular arrhythmias has the potential to significantly impact the quality of life and mortality 
risk of a large group of patients who at this time have few viable treatment options. 
 
PRIMARY OBJECTIVE (S): 
 
(1) Phase Ib portion: To determine maximal tolerated dose (MTD) for stereotactic ablative 
radiotherapy of targets in the cardiac myocardium 
(2) Phase IIa portion: To make a preliminary assessment of the efficacy of stereotactic 
ablative radiotherapy technique for the control of ventricular arrhythmia 
 
SECONDARY OBJECTIVE (S): 
 
(1) To determine impact on overall cardiac function (ejection fraction) 
(2) To determine impact on quality of life 
(3) To determine impact on overall survival 
(4) To assess treatment-related toxicity by serum markers, imaging, and histology 
 
PRIMARY ENDPOINT (S): 
(1) Phase Ib portion: Achievement of maximal tolerated dose of SABR 
(2) Phase IIa portion: To estimate the ICD shock free survival rate at the MTD of SABR 
 
SECONDARY ENDPOINT (S): 
(1) Salvage definitive anti-arrhythmia therapy (cardiac transplant) 
(2) Return of ventricular tachycardia requiring defibrillation, intravenous drug therapy or 
readmission to hospital.  
(3) Ventricular tachycardia burden as measured by number of ICD shocks in the periods of 
3,6 and 12 months pre and post the SABR procedure 
(4) Decline of LV ejection fraction by more than 5% on two consecutive echocardiograms 
(5) Persistent increase in baseline supplemental oxygen requirement by 1L for a duration of 
>3 months 
(6) Use of steroids for radiotherapy related indications 

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(7) Overall survival 
(8) QOL Questionnaire (SF-36) 
 
STUDY DESIGN: 
Single arm, phase Ib/2a dose escalation study with an expansion cohort to determine the maximal 
tolerated dose (MTD) for stereotactic ablative radiotherapy of targets in the cardiac myocardium 
and to make a preliminary assessment of the efficacy of the treatment. The dose escalation will 
be guided by Time-to-Event Continual Reassessment Method (TITE-CRM) to ensure more 
patients will be spared dose limiting toxicities and more patients will be entered on the dose level 
that will be chosen as minimal dose of maximal effect. This design also allows for continual accrual 
of patients when delayed adverse events may be observed. 
 
NUMBER OF PATIENTS: 
30 
 
ELIGIBILITY CRITERIA: 
- 
Documented sustained ventricular arrhythmias refractory to or not a suitable candidate for 
catheter based RFA ablative therapy 
- 
Documented sustained ventricular arrhythmias refractory to or not a suitable candidate for 
cardiac sympathetic denervation therapy 
- 
Documented ventricular arrhythmias refractory to or not a suitable candidate for cardiac 
transplantation 
- 
Documented sustained ventricular arrhythmias refractory to or not a suitable candidate for 
additional medical management 
- 
ICD in place with documented episodes recurrent VT despite best clinical management 
previous refusal of ICD with recurrent sustained ventricular arrhythmias 
- 
If ischemic cardiomyopathy, myocardial infarction occurred more than one month prior to 
enrollment 
- 
No history of prior radiotherapy to the chest 
- 
Prescribed dose must be deliverable using SABR technique 
- 
Age ≥ 18 years  
- 
Karnofsky Performance Status (KPS) > 70 
- 
If a woman is of childbearing potential, a negative serum pregnancy test must be 
documented. Women of childbearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; or abstinence) for at least 4 weeks after study 
treatment. 
- 
Ability to understand and willingness to sign a written informed consent 
 
INTERVENTION AND MODE OF DELIVERY: 
Intervention will be delivered on a clinical device radiotherapy system capable of stereotactic 
radiotherapy to the chest, with on-board image guided radiotherapy capabilities, respiratory 
motion management, and Intensity Modulated Radiotherapy Treatment (IMRT) planning.  
 
DURATION OF INTERVENTION AND EVALUATION: 
Study treatment will be single fraction stereotactic ablative radiotherapy (SABR) with routine 
clinical follow up for five years or until heart transplant or death. 
 
 
 
 
 
 

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STATISTICAL METHODS: 
 
SAMPLE SIZE JUSTIFICATION: 
Phase Ib portion: Dose escalation will be based on Time-to-Event Continual Reassessment 
Method (TITE-CRM). A sample size of 22 patients will be used. Monte Carlo simulations show 
that the proposed sample size has acceptable probability of correctly selecting a dose with 
acceptable toxicity and enough patients treated about the target dose for characterization of the 
efficacy endpoints, while being feasible for completion within 25 months. 
 
Phase IIa portion: Approximately 8 additional patients will be enrolled at the MTD.  Based on the 
simulation results for Phase 1b, a total of 16-20 patients (8-12 patients in the dose escalation 
cohort and 8 in the expansion cohort) will be used to assess efficacy. Literatures suggest 6-month 
ICD shock free survival rate is about 50%. Assuming the proposed SABR treatment will yield 6-
month ICD shock free survival rate of 80%, a sample size of 16 patients achieves 80% power to 
detect a 30% difference in 6-month ICD shock free survival, using a one-sided one-sample exact 
Binomial test, at a 0.10 significance level. 
 
FUNDING, REGULATORY, AND FEASIBILITY ISSUES: 
UCLA Department of Radiation Oncology has the capability, equipment, and expertise to perform 
highly accurate stereotactic radiotherapy. Diagnostic cardiac MRI with and without contrast will 
be used for evaluation and treatment planning purposes. Electrophysiologic study data may be 
incorporated into treatment planning. Clinical and radiographic follow-up will be performed per 
standard of care with blood samples and questionnaires (SF-36) issued per study protocol.  Study 
associated costs outside of standard of care will be covered by the Department of Radiation 
Oncology. 
 
PATIENT ACCEPTABILITY/ETHICS AND CONSENT ISSUES: 
Only patients able to give informed consent will be eligible for the study 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-MI ventricular tachycardia (VT) refractory 
to standard and salvage therapies 
Patient enrollment after confirming eligibility 
Diagnostic cardiac MRI study and CT treatment 
simulation study to define target lesion. 
Continued clinical follow-up 
Stereotactic ablative radiotherapy (SABR)      
Dose escalation 15Gy, 20Gy, 25Gy, 30Gy, 35Gy 

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1.0 OBJECTIVES 
1.1 Primary objectives 
1.1.1 To determine the maximal tolerated dose of SABR to cardiac targets and whether SABR to 
the region of origin of the clinical ventricular arrhythmia decreases the risk of recurrent ICD 
therapies or sustained ventricular arrhythmias in otherwise refractory patients. 
 
1.2 Secondary objectives 
1.2.1 To determine impact on overall cardiac fitness 
1.2.2 To determine impact on quality of life 
1.2.3 To determine impact on overall survival 
1.2.4 To assess treatment-related toxicity by serum markers, imaging, and histology 
 
2.0 BACKGROUND 
Sudden cardiac death (SCD) is a significant public health hazard, accounting for more than 
326,000 deaths per year in the US alone[1]. This is a larger toll than deaths from lung, colon, 
breast and prostate cancers combined. In part, this bleak statistic is due to resuscitation being 
successful in only some 10% of cases [2]. Even the routine use of implantable cardioverter-
defibrillators (ICDs) to rescue patients from these arrhythmias in the context of either primary or 
secondary prevention have been less than ideal, as elderly patients may actually exhibit 
increased mortality even when these devices function appropriately[3]. Thus, attention has been 
focused mainly on preventing the malignant arrhythmias that contribute to SCD. Estimates vary, 
but some 22% of SCD patient initially present with VT, and in select populations, up to 83% of 
SCDs can be attributed to ventricular arrhythmia [4, 5]. In the majority of cases, the life-
threatening arrhythmias arise from slowly conducting scar related circuits that result from 
devitalized cardiac tissues following a myocardial infarction or other insult. Conventional 
therapies for ventricular arrhythmia have significant drawbacks with respect to impact on quality 
of life, invasiveness, and efficacy. For example, gold standard front-line therapy for those who 
fail anti-arrhythmic drug therapy consists of endocardial catheter ablation. However, in large 
multi-center trials the efficacy of catheter based ablation is around 50% at 12 months [6, 7]. In 
part, this is explained by substrate mapping issues, including complex arrhythmias with multiple 
potential reentry circuits, unstable VTs due to hemodynamic intolerance, and reentry paths deep 
to the endocardium which limit the efficacy of ablation. When endocardial ablation fails, pre-
existing limited cardiovascular fitness of these patients and procedural expertise limited to 
relatively few specialized centers make the more complex subxiphoid percutaneous epicardial 
approaches available only to a minority of patients.  
 
Should these procedures fail to control recurrent VT’s, salvage procedures are available but 
again with significant limitations. For example, cardiac transplantation has traditionally been the 
salvage therapy of choice. However, the both the functional demands this treatment places on 
patients and the limited number of available donor organs have made this a relatively 
uncommon salvage treatment. More recently, surgical resection of the bilateral stellate ganglion 
pioneered at UCLA has shown improved success, with control of some 50% of patients 
refractory to medical and ablation therapies [8, 9]. Despite its promise, the technical demands of 
this technique have limited its applications to a few number of academic centers, and has thus 
limited its impact to-date. Given the prevalence of VT in patients with structural heart disease 
and the modest at best success of current interventional therapies, a large number of patients 

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are left without effective therapy. These patients are usually maintained on defibrillators that are 
life-saving, but with unpredictable electrical shocks which significantly detract from their quality 
of life, and in some populations’ length of life [3]. 
 
Within the field of radiation oncology, there is a large body of experience and techniques for 
very accurate delivery of radiation to very small targets – stereotactic ablative radiotherapy 
(SABR). Within the cranium, for example, targets that are millimeters in diameter are verifiably 
treated with high doses of radiation with sub-millimeter accuracy. This has been routine practice 
now for many decades. Outside of the cranium, the periodic motions of respiration and cardiac 
contractions have made this targeting more challenging. Even then, motion management 
systems developed recently are able to reduce the error of delivery of high dose radiation 
delivery to below 5-millimeters. These consist of either fixed abdominal compression to 
minimize diaphragm travel, or algorithms to track and predict target location based on the 
periodicity of the respiratory cycle. Both these techniques are now in routine clinical use to allow 
extra-cranial stereotactic ablative radiotherapy (SABR). Within the chest, this is most commonly 
directed against early stage lung malignancies as well as oligometastatic lesions. Ablation of 
targets with SABR techniques have the advantage that targets are treated under direct 
visualization, the treatment is non-invasive, can be completed in a single session, and patients 
return home immediately after. The ability to non-invasively and accurately ablate small targets 
within the body offers a multitude of therapeutic opportunities outside of oncology. This project 
will pioneer SABR techniques specifically for anti-arrhythmic indications. 
 
Early large animal studies have shown that a sufficiently high dose of radiation can be delivered 
safely to a targeted area of the ventricular myocardium, and that this treatment causes a 
homogenous scarring that suppresses local action potentials [10-12]. Long-term clinical and 
histopathological follow-up in these animal studies showed no significant toxicity outside the 
target region. In humans, there is a significant experience of the left ventricle receiving these 
high radiation doses incidentally, in the form inevitable dose spillage from SABR treatments for 
centrally located early stage lung cancers [13]. Regions of the heart exposed to a single dose of 
radiation >20 Gy begin to show metabolic changes on follow up PET scans at 6 months, but this 
does not correlate with any compromise of the cardiac function[14]. Indeed, the toxicity profile of 
SABR specifically directed against post-MI and non-ischemic lesions that are most likely 
substrates for slow conduction and VT is likely to be even superior to this, as these sections of 
the myocardium are already scarred from previous insult. With regard to efficacy, there are thus 
far only two independent case reports of first-in-man studies using the existing clinical linear 
accelerators systems on a compassionate use basis showing decreased VTs after targeted 
radiotherapy, and absence of treatment associated toxicity [15, 16]. In contrast animal studies, 
where electrophysiologic changes were seen months later, control of VTs in these two patients 
were noted starting some 48hrs from completion of treatment [15, 16].  
 
 
 
 
 
 

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3.0 PATIENT SELECTION 
3.1 Conditions for patient eligibility 
3.1.1 Documented ventricular arrhythmias refractory to or not a suitable candidate for catheter 
based RFA ablative therapy 
3.1.2 Documented ventricular arrhythmias refractory to or not a suitable candidate for cardiac 
sympathetic denervation  
3.1.3 Documented ventricular arrhythmias refractory to or not a suitable candidate for cardiac 
transplantation 
3.1.4 Documented ventricular arrhythmias refractory to or not a suitable candidate for additional 
medical management 
5. 
ICD in place with documented episodes recurrent VT despite best clinical management or 
prior refusal of ICD and recurrent sustained VT 
6. 
If ischemic cardiomyopathy, myocardial infarction occurred more than one month prior to 
enrollment 
7. 
No history of prior radiotherapy to the chest 
3.1.7 Must be safely treatable with SRS 
3.1.8 Age ≥ 18 years 
3.1.9 Karnofsky Performance Status ≥70 
3.1.10 if a woman is of childbearing potential, a negative serum pregnancy test must be 
documented. Women of childbearing potential must agree to use adequate contraception 
(hormonal or barrier method of birth control; or abstinence) for at least 4 weeks following 
the study treatment. 
3.1.11 Ability to understand and willingness to sign a written informed consent 
 
3.2 Conditions for patient ineligibility  
3.2.1 Patients who have previously received therapeutic radiation therapy to the chest 
3.2.2 Patients who are eligible for standard of care salvage therapies 
3.2.3 Patients with genetic conditions or co-morbidities making them ineligible for radiotherapy 
3.2.4 Patients with concurrent arrhythmias outside the left ventricle 
3.2.5 Pregnant women, or women of childbearing potential who are sexually active and not 
willing/able to use medically acceptable forms of contraception for the entire study period and for 
up to 4 weeks after the study treatment. 
3.2.6 Refusal to sign the informed consent 
3.2.7 Patients who are participating in a concurrent clinical trial  
 
4.0 REGISTRATION PROCEDURES 
4.1 General guidelines 
Patients seen at UCLA as new or follow up patient with VT refractory to standard frontline and 
salvage therapies will be informed of this clinical trial if eligible. The decision to participate will be 
voluntary. Eligible patients who decides not to participate will continue to be offered standard 
therapies. 
 
4.2 Registration Process 
Informed consent form will be given to the patient for review. Consent will be obtained after a 
clear and thorough discussion between the patient and the study investigator in clinic. To register 
a patient, the research coordinator will obtain or complete: (1) Documentation of refractory 
ventricular tachycardia (VT;); (2) baseline LV ejection fraction within last 30 days; (3) List of 
previously failed procedures; (4) List of previously failed medications; (5) signed informed consent 
form; (6) signed HIPAA authorization form. 
 

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Upon confirmation of eligibility and enrollment in the study, the following will be obtained: (1) 
diagnostic cardiac MRI for radiation therapy planning, (2) CT-simulation, (3) routine cardiac panel 
blood samples (if not done within the previous 14 days) and research blood samples (50 ml), (4) 
Cardiac quality of life questionnaire (SF-36). 
 
5.0 TREATMENT PLAN 
5.1 Radiation Simulation and Planning 
Enrolled patients, after confirmation of eligibility, will undergo radiation simulation and treatment 
planning. A thoracic alpha cradle will be used. This will be fused with diagnostic cardiac MRI with 
delayed enhancement sequences to identify the regions of scar potentially contributing to the 
clinical VT. This will also be fused with electro-anatomical mapping of previous electrophysiology 
3-D mapping data if available. 
 
The responsible study investigator(s), will delineate the regions of delayed enhancement visible 
on MRI as gross tumor volume (GTV). Areas outside the MRI scar identified by electrophysiology 
as harboring additional potential areas of critical to the clinical VT will be included in this volume. 
No expansion for clinical treatment volume will be used. Without respiratory gating, an internal 
target volume (ITV) expansion will be used. Planning target volume (PTV) expansion will consist 
of 6mm superior-inferior, with 6mm circumferential. Dose will be prescribed to the 70-80% isodose 
line to meet tolerance.  PTV prescription dose will begin at 15Gy x 1, and increase in stepwise 3 
by 3 fashion to 20Gy, 25Gy, 30Gy, and 35Gy per protocol safety parameters. 
 
Delineation of normal structures including spinal cord, esophagus, heart, great vessels, trachea 
and large bronchus, rib, skin, stomach, and bilateral lungs will be performed. The radiation 
physicist will optimize the radiation therapy treatment plan and the responsible study 
investigator(s) will review it prior to approval for treatment. Dose volume histograms (DVH), and 
normal tissue constraint parameters specified below will be used to judge the quality of the plan 
and optimize doses to the GTV/PTV as well as maximally sparing of organs at risk (OARs). The 
dose and volume of the heart will be recorded. 
 
Treatment will be delivered in a single session treatment lasting 30-45 minutes in the Department 
of Radiation Oncology.  Patient will be accompanied by an electrophysiology attending to ensure 
patient safety.  The treatment area will have prearranged ACLS supplies in place prior to patient 
arrival. 
 
5.2 Objects at Risk (OAR) Dose Constraints 
The dose constraints below for OARs will be used to assess the dosimetry for the plan. Doses 
that exceed the constraints below can be delivered if study investigators agree that the deviation 
is acceptable and unlikely to cause excessive morbidity.  
 
Serial Tissue 
Volume (cc) 
Volume Max 
(Gy) 
Max Point Dose 
(Gy) 
Endpoint 
(≥Grade 3) 
Spinal Cord 
<0.35 cc 
<1.2 cc 
10 Gy 
7 Gy 
14Gy 
myelitis 
Esophagus 
<5 cc 
11.9 Gy 
15.4 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
14 Gy 
17.5 Gy 
neuropathy 
Great Vessels 
<10 cc 
31 Gy 
37 Gy 
aneurysm 

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Trachea and 
Large Bronchus 
<4 cc 
10.5 Gy 
20.2 Gy 
stenosis/fistula 
Rib 
<1 cc 
22 Gy 
30 Gy 
pain or fracture 
Skin 
<10 cc 
23 Gy 
26 Gy 
ulceration 
Stomach 
<10 cc 
11.2 Gy 
12.4 Gy 
Ulceration/fistula 
Parallel Tissue 
Critical Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint 
(≥Grade 3) 
Lung (Right & 
Left) 
1500 cc 
7 Gy 
 
Basic Lung 
Function 
Lung (Right & 
Left) 
1000 cc 
7.4 Gy 
 
Pneumonitis 
 
5.3 Patient follow-up after treatment 
Patients will be followed clinically after treatment, including routine evaluation of recordings of VT 
on the calendar day post-treatment, 1 week (+/- 7 days), 1 month (+/- 7 days), 3 months, 6 months, 
9 months, 12 months, 15 months, 18 months and 21 months post treatment (+/- 2 weeks) and 
every six months thereafter (+/- 2 weeks) until 60 months post-treatment or until death or until 
heart transplant.  
 
Routine cardiac panel blood samples and research blood samples (50 ml) will be collected on the 
calendar day following treatment and 1 week after treatment (+/- 7 days), 1 month post treatment 
(+/- 7 days), and at 3 months post-treatment (+/- 2 weeks) and 12 months post-treatment (+/- 2 
weeks).  
 
Patients will fill out questionnaire (SF-36) at each follow up visit.  
 
Patients will continue any other routine follow up visits and monitoring with their 
electrophysiologist as is routine for patients with ICDs and VT. 
 
5.4 Criteria for removal from study 
5.4.1 The patient withdraws. 
5.4.2 The investigator may withdraw a patient from the study for one or more of the following 
reasons: failure of the patient to follow instructions of the protocol study staff, the investigator 
decides that continuing participation could be harmful to the patient, the patient is not tolerating 
treatment times/patient discomfort, the patient needs treatment not allowed in the study, the 
study is cancelled, other administrative reasons or unanticipated circumstances.  
 
6.0 PHARMACEUTICAL INFORMATION 
6.1 Investigational Agent or Device 
Device 
 
6.2 Availability 
Not applicable. 
 
 

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6.3 Agent Ordering 
Not applicable. 
 
6.4 Agent Accountability 
Not applicable. 
 
7.0 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Toxicity assessment will be performed using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) Version 4.0 for early (≤ 3 months), and late (> 3 months) 
radiation toxicity.  
 
7.1 Treatment Toxicities 
7.1.1 Constitutional symptoms  
Constitutional symptoms that may be attributed to radiation therapy may include loss of appetite, 
nausea, and vomiting. Patients will be seen while they are receiving radiation therapy per 
standard of care. Counseling and medications may be prescribed to alleviate these symptoms 
while the patient is on treatment. It is expected that symptoms will improve and resolve 2-4 days 
after completion of therapy. 
 
7.1.2 Radiation esophagitis 
Radiation esophagitis is due to radiation-induced inflammation of the esophagus, and may appear 
starting several days after treatment. Patient will be seen on a weekly basis while they are 
receiving radiation therapy per standard of care. Counseling and medications may be prescribed 
to alleviate these symptoms while the patient is on treatment. It is expected that that symptoms 
will improve and resolve 2-4 days after completion of therapy.  
 
7.1.3 Radiation pneumonitis 
Presenting symptoms of radiation pneumonitis are very similar to acute bacterial pneumonia. 
Patients present with fatigue, fever, shortness of breath, nonproductive cough, and pulmonary 
infiltrate on chest-x-ray or CT scan. On imaging, radiation-induced infiltrate are geometric in shape 
and conform to the high-dose regions that have been irradiated. The expected time-frame for 
radiation pneumonitis is 4 weeks to 12 weeks after completing radiation therapy to the thorax. 
Subjects will be informed of this risk, and counseled to call the principal investigator immediately. 
Management of radiation pneumonitis is very different from bacterial pneumonia, and may require 
a long slow-taper of high dose steroid therapy.  
 
7.1.4 Skin reaction 
Unintended skin reaction due to radiation therapy to the chest is now an uncommon side effect. 
However, if the target is close to the anterior chest wall, skin reaction may occur several days 
after the end of radiation therapy. Appropriate skin care and topical medications will be given to 
the patient when there are signs of skin reaction. It is expected to be self-limiting, and improve 1 
week after the end of therapy. 
 
7.1.5 Radiation pericarditis and fibrosis 
Radiation therapy close to the pericardium may cause inflammation of the lining of the heart, and 
radiation-induced pericarditis. Fluid-accumulation in the pericardium may be a consequence. 
Symptoms can be similar to radiation pneumonitis: shortness of breath, fever, and dry cough. 
Signs on CT scan and clinical exam are keys to its expedient diagnosis. Since this toxicity occurs 
generally after radiation therapy between 4 weeks to 12 weeks, close follow-up after treatment is 
essential. Subjects will be informed of the risk, and counseled to call the principal investigator 

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immediately. Management includes watchful waiting, medication, as well as surgical option 
depending on timing and severity of the complication. 
 
7.1.6 Radiation pulmonary fibrosis 
Radiation pulmonary fibrosis is a potential late-side effect of radiation therapy to the thorax. Its 
severity may or may not correlate with symptoms relating to pneumonitis, which occurs faster 
than radiation-induced lung fibrosis. Radiation pulmonary fibrosis can occur 3 months to 1 year 
after radiation therapy. Treatments include exercise, medications used for patients with COPD, 
and oxygen.  
 
7.1.7 Fistula formation 
Radiation fistula formation between the trachea/bronchus and esophagus is a potential late-side 
effect of radiation therapy to the thorax. It is primarily due to injury of these hollow structures that 
is unable to be repaired by normal tissue repair mechanisms. It is a rare complication in the 
modern era of therapeutic radiation therapy. General time course for radiation-induced fistula 
formation is 6 months to 2 years after treatment. Main treatment option is surgical intervention 
and repair.  
 
 

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8.0 STUDY CALENDAR 
 
Pre-
study 
Pre-
RT 
RT 
Follow-up (in time post- RT) 
 
1 
Day 
1 Wk 
(+/- 7 
days) 
1 Mo 
(+/- 7 
days) 
3 Mo 
(+/- 2 
wks) 
6 Mo 
(+/- 2 
wks) 
9 Mo 
(+/- 2 
wks) 
12 Mo 
(+/- 2 
wks) 
15 
Mo 
(+/- 
2 
wks) 
18 
Mo 
(+/- 
2 
wks) 
21 
Mo 
(+/- 
2 
wks) 
SABR* 
 
 
x  
 
 
 
 
 
 
 
 
 
Informed 
Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Initial 
consultation 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Electrophysiology 
Confirmed 
Refractory VT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Planning:  
CT and MRI 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Imaging: Cardiac 
MRI to Visualize 
Target 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Blood Samples  
 
x 
 
x 
x 
x 
x 
 
 
x 
 
 
 
Follow-up visit 
 
 
 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
QOL 
Questionnaire 
(SF-36) 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
*SABR: Stereotactic Ablative Radiotherapy 
 

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9.0 DATA REPORTING/REGULATORY CONSIDERATIONS 
9.1 Monitoring Plan 
Any potential adverse events will be discussed at the monthly internal study team meeting, led 
by the principal investigator.  
 
9.2 Data Management 
The principal investigator and research coordinator will be responsible for the database records 
of patient data. The data will be kept on the research coordinator’s computer under password 
protection. A chart with all the relevant research patient information will be maintained for each 
patient by the research coordinator. 
 
9.3 Confidentiality 
Study data will be maintained in password protected computer files. Only research personnel 
will have access to this information. When possible, identifiers will be removed. Only research 
personnel and investigators will keep the study data along with identifiers together in the same 
database under password protection accessible.  
 
10. STATISTICAL CONSIDERATIONS 
 
10.1 Study Design and Objectives 
 
This is a single arm, phase Ib/2a dose escalation study with an expansion cohort with the primary 
objectives of determining the maximal tolerated dose (MTD) for stereotactic ablative radiotherapy 
of targets in the cardiac myocardium and assessing the preliminary efficacy of the treatment for 
the control of ventricular arrhythmia. The secondary objectives are to determine the treatment 
impact on overall cardiac function (ejection fraction), on quality of life, on overall survival and to 
assess treatment-related toxicity by serum markers, imaging, and histology. 
 
The dose escalation will be guided by Time-to-Event Continual Reassessment Method (TITE-
CRM) [17] to ensure more patients will be spared dose limiting toxicities and more patients will be 
entered on the dose level that will be chosen as minimal dose of maximal effect. This design also 
allows for continual accrual of patients when delayed adverse events may be observed. 
 
10.2 Sample Size and Power Considerations 
 
10.2.1. Phase Ib dose-escalation portion: 
A dose escalation design based on TITE-CRM will be used for this phase. A sample size of 22 
patients will be used. We will investigate five different dose levels (15Gy x 1, 20Gy x 1, 25Gy x 
1, 30Gy x 1, 35Gy x 1). The main advantage of TITE-CRM is that one can update the best 
guess regarding the optimal dose by using all the information accrued during the study. This 
method also incorporates the time to toxicity for each patient to avoid prolonged trial suspension 
while patients are being observed for late-onset toxicities.  
We will start at a low initial dose 15Gy to ensure a maximum number of patients treated in a 
wide range of the dose-probability curve. We will only allow one-step escalation at a time and 
one patient at each step.  Specifically, suppose that our targeted MTD of SABR is the dose level 
associated with a 20% probability of dose-limiting toxicity (DLT). Each of the five dose levels will 

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be assigned with prior guesses of DLT probabilities (0.02, 0.05, 0.10, 0.15 and 0.20, 
respectively) according to the investigator’s experience and results from previous studies [13, 
15, 16]. A one-parameter logistic model with fixed scale parameter equals to 3 will be chosen to 
fit the does-toxicity curve. The logarithm of the model parameter is assumed to follow a normal 
distribution with mean of 0 and standard deviation of 0.3. Starting with patient treated at the 
lowest dose (15Gy X 1), the posterior DLT probability of each dose level based on the logistic 
model will be re-estimated after each new patient inclusion. We will choose the dose level with 
the updated posterior success probability closest to our target DLT rate (20%) to administrate to 
the next patient. The process will continue until the exhaustion of the proposed sample size, and 
the dose with the posterior DLT probability closest to 20% will be selected as the MTD. 
Meanwhile, we will closely monitor adverse events and other safety endpoints. 
Monte Carlo simulations were used to assess the operating characteristics of this design. 1000 
trials were simulated using 3 different assumptions about the true probabilities of DLT at each 
dose: A) same as the prior probabilities; B) somewhat more toxic than the prior probabilities; C) 
more toxic than the prior probabilities with significant increase in toxicity between doses 30Gy 
and 35Gy. Among the operating characteristics considered in the sample size were the 
expected number of DLTs, the probability of selecting the correct dose (that associated with a 
20% probability of DLT) as the target dose at the end of the trial, the time required to complete 
the trial, and the number of patients treated at or near the target dose. Sample sizes from 20 to 
30 were evaluated, as were different rates of patient accrual. A sample size of 22 patients was 
determined to have acceptable probability of correctly selecting a dose with acceptable toxicity 
and enough patients treated about the target dose for characterization of the efficacy endpoints, 
while being feasible for completion within 25 months. The simulation results based on n=22 
patients are shown in Table 1: 
Table 1: Operative Characteristics of TITE-CRM Design 
Dose-toxicity curve (logistic model):  
Pr(DLT at dose Xi)=exp[3+exp(beta)Xi]/[1+ exp[3+exp(beta)Xi],  
where beta~ Normal(0,0.3) 
 
Scenario A 
proposed doses 
15Gy 
20Gy 
25Gy 
30Gy 
35Gy 
true probability of toxicity 
0.02 
0.05 
0.1 
0.15 
0.2 
prior probability (guess) of toxicity 
0.02 
0.05 
0.1 
0.15 
0.2 
probability of a dose being selected as the MTD 
0.001 
0.01 
0.11 
0.22 
0.66 
average number of patients treated at this dose 
level 
1.0 
1.6 
3.3 
4.3 
11.8 
average number of DLTs at this dose level 
0.0 
0.1 
0.3 
0.7 
2.3 
  
Scenario B 
proposed doses 
15Gy 
20Gy 
25Gy 
30Gy 
35Gy 
true probability of toxicity 
0.04 
0.1 
0.2 
0.3 
0.4 

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prior probability (guess) of toxicity 
0.02 
0.05 
0.1 
0.15 
0.2 
probability of a dose being selected as the MTD 
0.01 
0.18 
0.45 
0.26 
0.10 
average number of patients treated at this dose 
level 
1.3 
4.3 
7.3 
4.7 
4.4 
average number of DLTs at this dose level 
0.1 
0.4 
1.5 
1.4 
1.7 
  
Scenario C 
proposed doses 
15Gy 
20Gy 
25Gy 
30Gy 
35Gy 
true probability of toxicity 
0.08 
0.2 
0.35 
0.5 
0.7 
prior probability (guess) of toxicity 
0.02 
0.05 
0.1 
0.15 
0.2 
probability of a dose being selected as the MTD 
0.14 
0.62 
0.23 
0.01 
0.001 
average number of patients treated at this dose 
level 
3.5 
9.6 
6.0 
1.9 
1.1 
average number of DLTs at this dose level 
0.3 
1.9 
2.1 
1.0 
0.7 
 
Note: The dose-toxicity curve is assumed to follow a logistic model as stated in the table.  The true 
probabilities of DLT vary in three different scenarios, while the prior probabilities are the same.  The 
target probability for DLT is 0.2. For each scenario, 1000 trials are simulated. In each trial, a total of 22 
subjects are used.  The trial starts at the lowest dose and only allows one dosage escalation at a time. 
The design assumes an accrual rate of one patient per month and a 3-month observed window for DLT. 
The study duration is estimated to be 25 months. 
 
10.2.2. Phase IIa expansion portion: 
The primary objective of the expansion phase is to assess the preliminary efficacy of the 
treatment by evaluating the ICD shock free survival rate at 6 months.  Approximately 8 
additional patients will be enrolled at the MTD. Based on the simulation results in Table 1, a 
total of 16-20 patients (8-12 patients in the dose escalation cohort and 8 in the expansion 
cohort) will be used to further assess toxicity, ICD shock free survival rate, overall survival, 
quality of life and overall cardiac function. Literature suggest 6-month ICD shock free survival 
rate is about 50%[6, 8, 9]. Assuming the proposed SABR treatment will yield 6-month ICD shock 
free survival rate of 80%, a sample size of 16 patients achieves 80% power to detect a 30% 
difference in 6-month ICD shock free survival, using a one-sided one-sample exact Binomial 
test, at a 0.10 significance level. 
 
10.3 Planned Methods of Analysis 
10.3.1  Analysis of Primary Endpoints 
10.3.1.1  Analysis of Dose-Limiting Toxicities 
The primary endpoint in Phase Ib portion is to either reach the MTD or a total dose of 35Gy. 
Toxicity will be graded using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v. 
4.0. A dose-limiting toxicity (DLT) is any treatment-related grade 3, 4, or 5 toxicities in the 
following categories: gastrointestinal, cardiovascular, pulmonary, neurologic, or constitutional 
symptoms OR any other grade 4 or 5 toxicity attributed to the therapy. All reported DLTs will be 

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verified by the principal investigator, DSMB as independent review before final determination 
that a DLT has occurred. The study will close when either of the following events occurs: 1) the 
MTD is reached, or 2) the highest protocol dose level is treated and tolerated (a prescribed dose 
of 35Gy) 
 
10.3.1.1 Analysis of Preliminary Efficacy 
 
The primary endpoint in Phase IIa portion is ICD shock free survival rate at 6 months.  For patients 
treated at MTD, we will calculate the ICD shock free rate and the corresponding 95% confidence 
interval.  
 
10.3.2  Analysis of Secondary Endpoints 
1) Incidence of salvage definitive anti-arrhythmia therapy (cardiac transplant) will be 
calculated and tabulated; 
2) Incidence of return of ventricular tachycardia requiring defibrillation, intravenous drug 
therapy or readmission to hospital will be calculated and tabulated; 
3) Incidence of ICD shocks in the periods of 3,6 and 12 months pre and post the SABR 
procedure will be calculated and tabulated; 
4) Incidence of decline of LV ejection fraction by more than 5% on two consecutive 
echocardiograms will be calculated and tabulated; 
5) Incidence of persistent increase in baseline supplemental oxygen requirement by 1L 
for a duration of >3 months will be calculated and tabulated; 
6) Incidence of Use of steroids for radiotherapy related indications 
7) Overall survival will be estimated by Kaplan-Meier method. Summaries of the number 
and percentage of patients who have died, are still in survival follow-up, are lost to 
follow-up and have withdrawn consent will be provided along with median overall 
survival. 
8) The score of quality of life questionnaire will be summarized at each time point and 
comparison of pre- and post-treatment scores will be carried out by non-parametric 
Wilcoxon sign-rank test. 
10.3.3 Safety Analysis 
Overall exposure to study agent, the numbers of patients completing the study, and the dose 
intensity will be summarized using descriptive statistics. Serum markers, imaging, and histology 
will be assessed throughout the study period for toxicity. AEs and SAEs will be reported using a 
CTCAE v4.0 terminology and severity. 
 
10.4 Interim Analysis 
Interim reports will be prepared every six months until the results of the study are published. In 
general, the interim reports will contain information about patient accrual rate with projected 
completion dates, status of QA review and compliance rate of treatment per protocol, and the 
frequencies and severity of toxicity.  
 

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Yung, D., et al., Survival after implantable cardioverter-defibrillator implantation in the elderly. 
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Bayes de Luna, A., P. Coumel, and J.F. Leclercq, Ambulatory sudden cardiac death: mechanisms 
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Tanner, H., et al., Catheter ablation of recurrent scar-related ventricular tachycardia using 
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Ajijola, O.A., et al., Bilateral cardiac sympathetic denervation: why, who and when? Expert Rev 
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Sharma, A., et al., Noninvasive stereotactic radiosurgery (CyberHeart) for creation of ablation 
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Videtic, G.M., et al., 30 Gy or 34 Gy? Comparing 2 single-fraction SBRT dose schedules for stage I 
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