A Pilot and Feasibility Trial to Determine the Rate of the Brain Relapse in Small Cell Lung Cancer (SCLC) Patients With Brain Metastases Treated With Stereotactic Radiosurgery (SRS) Followed by Tumor Treating Fields (TTF)
Phase: NA
Conditions: Brain Metastases, Small Cell Lung Cancer
Sponsor: Drexell Hunter Boggs

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 1 of 36 
Amendment # 6 
RAD 1704/UAB 1793: A Pilot and Feasibility Trial to Determine the Rate of Brain 
Relapse in Small Cell Lung Cancer (SCLC) Patients with Brain Metastases Treated 
with Stereotactic Radiosurgery (SRS) Followed by Tumor Treating Fields (TTF) 
 
TABLE OF CONTENTS 
 
1.0 
OBJECTIVES 
2.0 
BACKGROUND AND RATIONALE 
3.0 
SCHEMA 
4.0 
PATIENT SELECTION CRITERIA 
5.0 
DEVICE INFORMATION 
6.0 
TREATMENT PLAN 
7.0 
THERAPY MODIFICATIONS 
8.0 
STUDY PARAMETERS 
9.0 
EVALAUTION CRITERIA 
10.0 PATIENT REGISTRATION 
11.0 STATISTICAL CONSIDERATIONS 
12.0 REFERENCES 
 
APPENDICES 
Appendix A: Graded Prognostic Assessment (GPA) 
Appendix B: Karnofsky Performance Status (KPS) 
 
 
 
Principal Investigator: 
D. Hunter Boggs, M.D. 
University of Alabama at Birmingham 
Hazelrig-Salter Radiation Oncology Center 
1700 6th Avenue South, 176F, Suite 2232 
Birmingham, AL  35233 
Phone:  205-934-5581 
 
Co-Investigators: 
Francisco Robert, MD 
Aparna Hegde MD 
Sam Marcrom MD 
Markus Bredel, MD, PhD 
Chris Willey, MD, PhD 
Kristen Riley, MD 
Barton Guthrie, MD 
James Markert, MD 
John Fiveash, MD 
Houman Sotoudeh, MD 
Richard Popple, PhD 
Kristen Triebel Gerstenecker, PsyD, ABPP 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 2 of 36 
Amendment # 6 
 
 
Biostatistician: 
Peng Li, PhD 
 
Research Nurse Coordinators: 
Katherine Wood Reeves, RN, MPH 
Diana Hablitz, RN, MSN, CPNP, CCRA 
 
Data Coordinator: 
Melissa Deakle 
 
Regulatory: 
Kristin Webb, CCRP 
 
 
Document History Table: 
 
Version/Update Date 
Amendment # 6 
January 10, 2020 
Amendment # 5 
August 14, 2019 
Amendment # 4 
March 7, 2019 
Amendment # 3 
November 4, 2018 
Amendment # 2 
March 20, 2018 
Amendment # 1 
March 13, 2018 
Protocol Update 
11/5/2017 
Protocol Update 
6/21/2017 
Original Version 
6/19/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 3 of 36 
Amendment # 6 
 
 
1.0 
OBJECTIVES 
1.1 Primary:  
1.1.1 To determine the rate of distant brain metastases at 6 months in 
patients with SCLC brain metastases receiving SRS followed by 
Novo TTF-200A. 
1.2 Secondary:  
1.2.1 Determine the feasibility of SRS in patients SCLC brain metastases 
followed by Novo TTF-200A.  
1.2.2 Determine the rate of distant brain metastases (outside the 100% 
isodose volume) at 1 year in patients with SCLC brain metastases 
receiving SRS followed by Novo TTF-200A.  
• 
Determine the rates of toxicity from SRS for patients with 
brain metastases followed by Novo TTF-200A. 
• 
Determine the rate of CTCAE physician reported toxicity. 
• 
Determine the rate of neurocognitive toxicity using 
neurocognitive tests. 
1.2.3 Characterize quality of life using standardized metrics 
1.2.4 Determine the rate of local control of targeted lesions.  
1.2.5 Determine the rate of overall survival  
 
2.0 
BACKGROUND AND RATIONALE 
2.1 Small Cell Lung Cancer Brain Metastases Overview 
SCLC, representing 10-15% of all lung cancers, grows rapidly and spreads to 
distant organs early in the disease course. SCLC spreads to the brain in 
approximately 40% of all patients. Without treatment, the median survival for 
a patient with brain metastases is less than 3 months [1-5]. Historically, whole 
brain radiation therapy (WBRT) has been used to treat brain metastases with 
a median survival on the order of 6 months [2-5]. For patients with a limited 
number of brain metastases, focal treatment with surgery or SRS is 
associated with an increase in survival [6]. Multiple studies have shown that 
the addition of WBRT to SRS for brain metastases does not improve survival 
[7]. However the rate of distant brain failures with omission of WBRT is 
approximately 50%. To reduce this intracranial relapse risk while sparing the 
patient the toxic effects of whole brain radiotherapy, the METIS trial is 
investigating the addition of NovoTTF-100M to SRS in non-small cell lung 
cancer patients [8].  Due to the perceived high intracranial relapse rate for 
small cell lung cancer patients, most physicians advocate WBRT for any 
amount of measurable brain metastases. 
 
 
2.2 Neurocognitive Sequelae of Whole Brain Radiation 
WBRT includes a large volume of normal tissue that may not need to be 
irradiated to therapeutic doses. Investigators from Memorial Sloan-Kettering 
Cancer Center have described dementia in 11% of long-term survivors after 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
whole brain radiation. Lower grade neurocognitive complications are even 
more common [9,10]. In an effort to avoid this long-term toxicity, there has 
been increased interest in avoiding WBRT in patients with brain metastases.  
More recently, Chang et al reported a randomized trial at MD Anderson 
including 58 patients randomized to SRS alone or SRS plus WBRT in 
NSCLC patients [11]. In this study detailed neuro-cognitive and quality of life 
(QOL) assessments were performed including the Functional Assessment of 
Cancer Therapy- Brain (FACT-BR) and Hopkins Verbal Learning Test-
revised (HVLT-R). Accrual to the study was stopped early when an interim 
analysis revealed a difference in total recall at 4 months, the primary endpoint 
of the trial, in favor of the group that was treated with SRS alone. This 
outcome was observed despite the use of an adjuvant WBRT dose that was 
relatively modest at 30 Gy in 12 fractions of 2.5 Gy. The mean probability of 
decline was 52% with combination therapy vs. 24% with SRS alone. Delayed 
recall and delayed recognition also favored the SRS alone arm. Within the 
limitations of a small study, QOL as measured by FACT-BR did not differ 
between the two groups. Local control of the treated tumors strongly favored 
the group that received combined therapy (100% vs. 67%), and there was a 
lower risk of developing tumors elsewhere in the brain. Paradoxically, 
preventing recurrences in the brain did not lead to an improvement in overall 
survival. In fact, overall survival favored the group that received SRS alone.   
This confounding observation brings into question whether other differences 
between the groups might be contributing not only to survival but also to the 
neuro-cognitive outcomes. 
 
2.3 Role of Radiosurgery Without Whole Brain Radiation for SCLC Brain 
Metastases 
No prospective trials have been conducted to evaluate local control, patterns 
of relapse, and toxicity with SRS for SCLC brain metastases specifically. 
Many physicians continue to give WBRT for SCLC brain metastases with the 
assumption that rates of relapse within the brain are higher than in other 
malignancies. However, limited retrospective studies of salvage SRS after 
WBRT show 6 and 12 month relapse rates of 25% and 47%, respectively 
[12]. In comparison, relapse rates after upfront SRS alone in other 
malignancies are 35% at 6 months and 49.5% at 12 months [13]. Patients 
managed initially with SRS alone do have a higher incidence of developing 
subsequent brain metastases, but retrospective and prospective studies 
suggest no decrement to neurologic outcome in these patients, mostly due to 
successful salvage with WBRT [14]. 
 
2.4 Rationale for the Use of Tumor Treating Fields (TTFields) 
TTFields are a non-invasive, regional antimitotic treatment modality with 
minimal toxicity which have been approved for the treatment of recurrent and 
newly diagnosed glioblastoma (GBM) by the Food and Drug Administration 
(FDA) in the United States and have obtained a CE mark in Europe for the 
same indications. TTFields act by delivering low intensity (1-3 V/cm), 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
intermediate frequency (100-300 kHz), alternating electric fields to the tumor 
using non-invasive transducer arrays placed on the skin around the region of 
the body containing the tumor. TTFields act predominantly during two phases 
of mitosis: 1) during metaphase, by disrupting the formation of the mitotic 
spindle, and 2) during cytokinesis, by dielectrophoretic dislocation of 
intracellular constituents resulting in apoptosis [15,16]. The efficacy of 
TTFields is frequency dependent on specific cell types. The anti-mitotic effect 
of TTFields has been shown in multiple cell lines when the appropriate 
frequency was utilized. This includes primary brain tumor cell lines and cell 
lines from other tumors which commonly metastasize to the brain 
(glioblastoma at 200 kHz [17], NSCLC at 150kHz [18]; breast carcinoma at 
120kHZ [19]; melanoma at 100kHz [15]).  
 
The effect of TTFields is directional, i.e., TTFields are most effective when 
applied in the direction of the division axis of the dividing cell [15,17]. In order 
to increase the efficacy of TTFields, two sequential field directions can be 
applied to tumors by using two perpendicular pairs of transducer arrays. 
Using two directional TTFields in pilot clinical testing demonstrated TTFields 
to be biologically active in human tumors. In a pilot trial [21], TTFields were 
shown to decrease the size of skin metastases from breast cancer and from 
malignant melanoma. In addition, in a phase I/II trial in 42 pretreated 
advanced NSCLC patients TTFields were applied to the chest and upper 
abdomen together with systemic pemetrexed [22]. This trial demonstrated 
that TTFields therapy were well tolerated by NSCLC patients without any 
detectable increase in systemic toxicity due to pemetrexed. Interestingly, 
patients in this trial showed promising local disease control in the lungs and 
median survival time when compared to historical data in advanced NSCLC 
with pemetrexed alone. In addition, a phase III trial of TTFields as 
monotherapy compared to active chemotherapy in recurrent glioblastoma 
patients [23] showed Optune™ to be equivalent to active chemotherapy in 
extending survival, associated with minimal toxicity, good quality of life, and 
activity within the brain (14% response rate). Finally, a phase III trial of 
Optune™ combined with maintenance temozolomide compared to 
maintenance temozolomide alone has shown that that combined therapy led 
to a significant improvement in both PFS and OS in patients with newly 
diagnosed GBM [24], without the addition of high grade toxicity and without 
decline in quality of life. 
 
2.5 Preclinical Results with TTFields 
Human squamous cell carcinoma (HTB 182), human adenocarcinoma 
(H1299, A549, HCC827) murine squamous cell carcinoma (KLN 205) and 
murine Lewis lung carcinoma (LLC1) cells have been subjected to low 
intensity TTFields in preclinical studies. These experiments showed that 
TTFields significantly inhibit culture proliferation. A frequency dependency 
was clearly demonstrated, with an optimal inhibitory frequency of 150 kHz for 
these cultures. A reduction of 31-57% in the number of viable cancer cells, 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
compared to control cultures, was seen following 72 hours of continuous 
TTFields treatment in these cell lines (p<0.05). TTFields were found to 
significantly impair the colony-forming ability of all tested cell lines in culture 
[17,18].  
 
In addition, two animal models were used to test the in vivo application of 
continuous TTFields for the treatment of NSCLC. In an autologous model of 
C57BL/6 mice, LLC1 tumors were implanted in the left lung of the mice 11 
days prior to treatment initiation. Bi-directional, 150 kHz TTFields were 
applied for 6 days by means of two pairs of insulated transducer arrays 
placed on the animal’s chest skin overlaying the lung area, so that two 
perpendicular field directions were delivered sequentially to the lungs. 
TTFields were applied for at least 90% of the duration of the experimental 
treatment. Following treatment, mice were sacrificed and tumors excised. 
TTFields reduced tumor volume by 36%±38% compared to control mice 
tumors (p<0.05) [25,26].  
 
In addition, KLN-205-T1 cells were used to establish an orthotopic, syngeneic 
animal model for testing the effects of TTFields in lung squamous cell 
carcinoma. The cells were injected into the left lung lobe of DBA/2 mice. 
Seven days after tumor inoculation, mice were treated with TTFields. Tumor 
volume and weight were determined post mortem. KLN-205-T1 tumors 
demonstrated a 47±17% reduction in tumor volume as compared to control 
animals, after treatment with TTFields (P=0.04). Similarly, the weight of the 
left lung lobe carrying the KLN-205-T1 tumors was reduced after treatment 
with TTFields to 72±6% of controls (P=0.01) [25,26]. 
 
A meta-analysis of cancer cell lines found that DMS 114 (biopsied tumor from 
a patient with small cell lung cancer) responded optimally to TTFields at a 
frequency of 200mHz, which will be used for our study [32]. 
 
2.6 Metastasis Prevention Using TTFields 
In addition to the impact on the primary tumor, TTFields have been tested for 
their potential to inhibit metastatic spread of solid tumors to the lungs in two 
animal models [27]: (1) Mice injected with malignant melanoma cells 
(B16F10) into the tail vein, (2) New Zealand white rabbits implanted with VX- 
2 tumors within the kidney capsule. The mice and rabbits were treated using 
two-directional TTFields at 100–200 kHz. Animals were either monitored for 
survival, or sacrificed for pathological and histological analysis of the lungs. 
The total number of lung surface metastases and the absolute weight of the 
lungs were both significantly lower in TTFields treated mice than in sham 
control mice (P<0.05). TTFields treated rabbits survived significantly longer 
than sham control animals. This extension in survival was found to be due to 
an inhibition of metastatic spread, seeding or growth in the lungs of TTFields 
treated rabbits compared to controls. Histologically, extensive peri- and intra-

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
tumoral immune cell infiltration were seen in TTFields treated rabbits only 
(Figure 1). 
 
 
2.6.1 Delivery TTFields to the Infratentorial Region 
Computational simulations on a phantom model were conducted in order to 
examine the distribution of TTFields in the infratentorial region. The same 
treatment parameters were assumed for these simulations as the NovoTTF-
100M delivers to patients treated on the EF-25 study. These simulations were 
performed using the Sim4Life 1.2 Software package (ZMT, Zurich, 
Switzerland) on several models. The permittivity and conductivity were 
assigned to the tissues of the phantom based on the Gabriel Model [37]. 
Electric field distributions were calculated using the Sim4Life quasi-static low 
frequency finite element solver. The simulations performed demonstrated for 
the first time that by placing a pair of arrays on the lateral aspects of the 
occipital plane of the scalp, or placing a pair of arrays on the vertex of the 
scalp and on the posterior-inferior aspect of the neck, respectively, a 
therapeutic distribution of TTFields is obtained throughout the cerebellum and 
brain stem. Importantly, at the same time, these layouts also still provide 
therapeutic TTFields levels in the supratentorial region, demonstrating the 
feasibility of treating both supra- and infratentorial regions in cases where 
metastases affect both regions of the brain. 
 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 8 of 36 
Amendment # 6 
 
 
2.6.2 Combined Infra- & Supratentorial Array Layout 
*Left Up Right Behind Ear 
 
 
 
*Right Up Left Behind Ear 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 9 of 36 
Amendment # 6 
 
 
*Left Up Right Down 
 
 
 
*Right Up Left Down 
 
 
 
2.7 Clinical Results with TTFields in Glioblastoma 
Based on promising pilot data in both recurrent and newly diagnosed 
glioblastoma, a phase III trial was conducted in the United States and Europe 
to test the safety and efficacy of 200 kHz TTFields alone versus active 
chemotherapy in patients with recurrent glioblastoma [16]. The primary 
endpoint was overall survival. Patients (median age 54 years (range 23-80), 
Karnofsky performance status 80% (range 50-100)) were randomized to 200 
kHz TTFields alone (n=120) or active chemotherapy control (n=117). Active 
chemotherapy control arm included “physician choice” chemotherapy that 
predominantly included bevacizumab based regimens, irinotecan or 
nitrosurea. The median number of prior treatments was 2 (range 1-6). Median 
overall survival was 6.6 vs. 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; 
p=0.27), 1-year survival rate was 20% and 20% and progression-free survival 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 10 of 36 
Amendment # 6 
rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTFields 
versus chemotherapy treated patients. Responses were more frequent in the 
TTFields arm (14% vs. 9.6%, p=0.19). The most common TTFields-related 
adverse event was mild (14%) to moderate (2%) skin irritation beneath the 
transducer arrays, which was again expected with use of the transducer 
arrays. These adverse events were effectively treated with topical 
hydrocortisone. Patients receiving chemotherapy had significantly more 
gastrointestinal, hematological and infectious complications. Quality of life 
analyses favored TTFields in most domains. Specifically, cognitive and 
emotional function were reported to be much better in the TTFields treated 
patients than with chemotherapy.  
 
The results of this phase III trial demonstrated comparable efficacy with this 
chemotherapy-free treatment (200 kHz TTFields) to chemotherapy (including 
bevacizumab) in recurrent glioblastoma with a more favorable safety profile 
and quality of life and supported FDA approval of TTFields in recurrent 
glioblastoma in 2011 and a CE mark in Europe.  
 
Registry data from 457 recurrent GBM patients who started Optune™ 
prescribed by the treating physician in the US between October 2011 and 
November 2013 showed an even higher median overall survival of 9.6 
months, with baseline characteristics similar to those of patients treated 
under the pivotal clinical trial [28,29]. The 2-year survival rate in this 
population was 30% (compared to 9% in Optune™-treated patients on the 
clinical trial). Compliance was a clear predictor of survival on Optune™, and 
patients treated with the device for at least 18 hours per day had significantly 
longer survival time. No new safety signals have been detected in this 
registry dataset and the only common adverse event related to Optune™ was 
skin reaction.  
 
Based on this clinical data in recurrent GBM and a pilot trial in newly 
diagnosed GBM with Optune™ in combination with temozolomide that 
demonstrated favorable safety profile and promising efficacy, an international 
phase III trial in newly diagnosed GBM, evaluating the role of Optune™ in 
combination with temozolomide maintenance after surgery and 
chemoradiation versus temozolomide alone was conducted. In the final 
analysis (n=695), progression-free survival was 7.1 months for 
Optune™/temozolomide vs. 4.2 months for temozolomide alone (hazard ratio 
(HR) 0.694 (95% CI: 0.558- 0.863), log rank p = 0.0010) and overall survival 
was 19.4 months for Optune™/temozolomide vs. 16.6 months for 
temozolomide alone (HR 0.754 (95% CI: 0.595-0.955), p = 0.0229). This 
translates into 2-year survival rates of 43% (95% CI: 36-50%) vs. 29% (95% 
CI: 21-38%). No significant added toxicity was seen in the temozolomide 
/Optune™ arm. Quality of life and gross cognitive function were also 
comparable in the 2 arms.  
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 11 of 36 
Amendment # 6 
Based on the data submitted to FDA from this newly diagnosed GBM study, 
FDA approved Optune™ in combination with temozolomide for the treatment 
of adult patients with newly diagnosed GBM on October 5, 2015. In the US, 
Optune™ with temozolomide is indicated for the treatment of adult patients 
with newly diagnosed, supratentorial glioblastoma following maximal 
debulking surgery and completion of radiation therapy together with 
concomitant standard of care chemotherapy. 
 
2.8 Clinical Results with TTFields in Brain Metastasis from Non-Small Cell 
Lung Cancer (NSCLC) 
A prospective, randomized controlled phase II study is currently being 
conducted in Europe to study the efficacy of 150 kHz TTFields in brain 
metastasis from NSCLC. Sixty (60) NSCLC patients (randomized at a 1:1 
ratio) with 1-5 brain metastases who underwent optimal standard local 
treatment (Stereotactic Radio Surgery (SRS) / Neurosurgery / combination of 
both) are to be included in this trial. The treatment group receives TTFields 
therapy using the NovoTTF-100M System and the control group receives 
supportive care alone. Patients also receive the best standard of care 
treatment for their systemic disease. The primary endpoint is time to local 
and distant progression in the brain. Sixteen (16) patients have been enrolled 
in the study to date. There have been no device-related serious adverse 
events (SAE) reported nor has there been any unanticipated serious adverse 
device effects (USADE). Expected contact dermatitis was reported in around 
25% of the patients to date. The study is ongoing and enrollment continues. 
Another prospective, randomized trial is also currently being conducted 
internationally to directly compare observation and NovoTTF-100M after SRS 
for NSCLC brain metastases. This study is ongoing and enrollment 
continues. 
 
2.9 Rationale for Conducting the Clinical Investigation 
TTFields are a novel, non-invasive regional anti-mitotic treatment modality. 
Pre-clinical studies and clinical data in Glioblastoma Multiforme have 
demonstrated a favorable safety profile and clinical superiority when treating 
the brain with TTFields. In addition, durable responses have been 
demonstrated with 200 kHz TTFields monotherapy for supratentorial tumors 
of the brain.  
 
The development of brain metastases is devastating for SCLC patients and 
their families. Treatment options in this setting are limited to SRS or WBRT or 
a combination thereof. Few clinicians treat SCLC brain metastases with SRS 
alone because intracranial recurrence is high due to the fact that the entire 
brain is not treated. WBRT treats the entire brain and improves intracranial 
control, but at the risk of neurocognitive complications. Thus, new therapeutic 
options are needed, particularly ones that allow for greater intracranial control 
while minimizing the risk of neurocognitive adverse events. As such, TTFields 
following SRS may allow for sufficient regional treatment of the brain to 

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Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 13 of 36 
Amendment # 6 
4.0 
PATIENT SELECTION CRITERIA 
4.1 Inclusion Criteria 
4.1.1 All subjects must have history of histologically confirmed small cell 
lung cancer.  Brain biopsy is not required unless diagnosis is 
judged to be in doubt by the treating physician. 
4.1.2  Brain metastases must be amenable to SRS. 
• Longest diameter < 4 cm  
4.1.3 Prior prophylactic cranial irradiation (PCI) or whole brain 
radiotherapy (WBRT) is allowed.  
4.1.4 Prior Metastatic lesions in the brain are allowed. Patients must 
have new or progressing lesions after prior brain directed therapy. 
4.1.5 Prior systemic therapy is allowed after diagnosis of brain 
metastases provided that restaging MRI shows measurable 
intracranial disease. 
4.1.6 Karnofsky performance status (KPS) of greater than or equal to 70 
(Appendix B) 
4.1.7 Age greater than or equal to 18 years. 
4.1.8 Life expectancy greater than 3 months. 
4.1.9 Must receive optimal therapy for extracranial disease and may 
continue on systemic therapy during TTF administration. 
4.1.10 Ability to operate the NovoTTF-200A device independently or with 
caregiver aid. 
4.1.11 Previous clinical trial enrollment is allowed. 
4.1.12 Subjects given written informed consent. 
 
4.2 Exclusion Criteria 
4.2.1 Patients with significant edema leading to risk of brain herniation. 
4.2.2 Diffuse Leptomeningeal metastases with radiographic involvement 
in the brain and/or spinal cord. This does not include local 
leptomeningeal involvement which is defined as leptomeningeal 
enhancement within direct contact of targetable metastases. 
4.2.3 Implantable electronic device in the brain. 
4.2.4 Implanted pacemaker, programmable shunts, defibrillator, deep 
brain stimulator, other implanted electronic devices in the brain, or 
documented clinically significant arrhythmias.  
4.2.5 Evidence of increased intracranial pressure (midline shift > 5mm, 
clinically significant papilledema, vomiting and nausea, or reduced 
level of consciousness).  
4.2.6 Known allergies to medical adhesives or hydrogel. 
4.2.7 Currently pregnant or breastfeeding. 
4.2.8 Insufficient recovery from all active toxicities of prior therapies. 
4.2.9 Women of childbearing potential who are not using an effective 
method of contraception are excluded.   
 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
5.0 
DEVICE INFORMATION 
5.1 Description of the Investigational Device and its Intended Purpose 
The NovoTTF-200A System is an investigational medical device for the 
treatment of brain metastases from small cell lung cancer (SCLC). It is 
intended to be used exclusively by patients in a clinical trial. The device is a 
portable battery or power supply operated system which produces alternating 
electrical fields, called tumor treating fields (TTFields) within the human body. 
TTFields are applied to the patient by electrically-insulated surface 
transducer arrays.  NovoTTF-200A disrupts the rapid cell division exhibited 
by cancer cells.  
 
5.2 Details Concerning the Manufacturer of the Investigational Device 
The NovoTTF-200A System is manufactured by Novocure Ltd., Topaz 
Building, MATAM center, Haifa 31905, Israel. Novocure Ltd. is an EN ISO 
13485 approved and 21CFR820 compliant medical device company 
developing electric field based therapy for cancer patients. Novocure's 
headquarters are located in Israel. Novocure GmbH is the EN ISO 13485 
approved and 21CFR820 compliant Novocure Ltd global distribution center. 
Novocure GmbH is based in Switzerland. 
 
5.3 System Parts and their Identification 
The NovoTTF-200A System is composed of several parts, which are shown 
in the picture below. 1) NovoTTF-200A Electric Field Generator (the device), 
2) Portable Batteries, 3) Charger for Portable Batteries, 4) Plug In Power 
Supply, 5) Connection Cable and Box (CAD), 6) Transducer Arrays, 7) Power 
Cords, 8) Shoulder Bag and Strap, and 9) Portable Battery Case. 
 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
5.4 Traceability 
All parts of the NovoTTF-200A System are identified by a unique and 
personal serial number. Transducer arrays are identified by lot number. 
Novocure maintains traceability of all parts through paper documentation and 
SAP ERP: 
 
Steps 
Traceability ensured by 
Manufacturing 
EN ISO 13485 Vendor Quality System 
Receiving 
SOP-USOC-002 Incoming Inspection 
and SAP ERP 
Storage 
SOP-USOC-004 Stockroom and SAP 
ERP 
Shipping 
SOP-USOC-003 Shipping-Final 
release SAP ERP 
Use 
SAP ERP 
 
5.5 Intended Purpose of the Investigational Device in the Proposed 
Clinical Investigation 
The NovoTTF-200A System is intended for the treatment of patients 18 years 
of age or older with recently diagnosed brain metastases from small cell lung 
cancer (SCLC) following treatment of the metastases using stereotactic 
radiosurgery (SRS). 
 
5.6 The Populations and Indications for which the Investigational Device 
is Intended 
Patients with histology or cytology based diagnosis of SCLC, above 18 years 
of age, with brain metastases amenable to SRS. 
 
5.7 Materials that will be in Contact with Tissues 
The transducer arrays are adhesive bandages that hold insulated ceramic 
discs that are needed to deliver treatment. The transducer arrays should be 
used with NovoTTF-200A only. Four transducer arrays are used at one time. 
There are two different color transducer arrays, one type has a white 
connection end and one has a black connection end. The patient will need 
two transducer arrays with white connection ends, and two transducer arrays 
with black connection ends every time they change their arrays. Put the 
transducer arrays on a clean, shaven scalp. The patient will put them on their 
scalp in the place where the study doctor and/or Device Support Specialist 
(DSS) instructed them, based on their tumor location. The transducer arrays 
are disposable. They will be changed at least two times per week (every 4 
days at most).  
 
5.8 Training and Specific Medical or Surgical Procedures Involved in the 
Use of the Investigational Device 
The NovoTTF-200A System is easy to use and a simple training by the 
Device Support Specialist (DSS) is sufficient for patients and the study team 
to apply the investigational device according to its intended use. No specific 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Amendment # 6 
medical/surgical procedures are needed for the use of the investigational 
device. 
 
5.9 Risks and Benefits of the Investigational Device 
The risks associated with use of the NovoTTF-200A are the same as those 
associated with use of the approved Optune System. Principally, the risks are 
electrical or mechanical failure leading to electrical shock, electromagnetic 
interference, etc., as well as the risk that the treatment will not be effective in 
delaying tumor progression or causing regression. Additional risks include 
skin irritation, and skin breakdown or infection at electrode sites. Technical 
failure is extremely unlikely due to stringent compliance with all standard 
design and manufacturing safety protocols. In addition, appropriate measures 
have been taken to minimize the risk to study subjects, including preclinical in 
vitro and in vivo testing to ensure safe operation of the device. Furthermore, 
there have been no device-related serious adverse events or unanticipated 
serious adverse device effects reported in the 16 patients who have been 
enrolled in the ongoing pilot study to date. 
 
 
 
6.0 
TREATMENT PLAN 
6.1 Stereotactic Radiosurgery Timing 
6.1.1 SRS must be delivered within 21 days of enrollment and ideally 
after discussion at a multi-disciplinary radiosurgery tumor 
board/conference. 
 
6.2 Localization and Immobilization 
6.2.1 A frameless radiosurgery approach will be utilized. A thermoplastic 
mask will be used to immobilize the head during treatment. 
6.2.2 All patients will have a brain MRI (3T) with and without contrast 
suitable for SRS planning. T1-weighted, T2 and/or FLAIR MRI of 
the brain (maximum slice thickness 5mm). FLAIR imaging is 
preferred.  
6.2.3 A treatment planning MRI, ideally within 10 days of radiosurgery, 
may be obtained in addition to the screening MRI. 
 
6.3 Stereotactic Radiosurgery Dose Specifications 
6.3.1 For all tumors, the dose will be prescribed to the minimum isodose 
volume that covers the gross target volume (GTV), typically 40-85% 
line. 
6.3.2 Tumors with volume < 4 mL will be prescribed 18-22 Gy at the 
lesion periphery. Tumors 4-10 mL will be prescribed 15-20 Gy at 
the periphery. Additional increase or decrease in dose by up to 2 
Gy is allowed. 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Amendment # 6 
6.3.3 Tumors over 2cm may be treated with a 5 fraction approach at the 
discretion of the physician. Typical doses per fraction are 5-6Gy per 
fraction for a total of 25 or 30Gy. 
6.3.4 The goal of treatment planning will be to obtain conformity such that 
the conformity index (CI, ratio of planning isodose volume to target 
volume) does not exceed 2:1. 
 
 
6.4 SRS Target Volume Delineations 
6.4.1 Target volume delineation will be based on a three-dimensional 
spoiled gradient (3D-SPGR) multi-plane MRI scan (or similar 
sequences suitable for target delineation) fused with the treatment 
planning CT scan. The CT should not be exclusively used for target 
volume delineation. 
6.4.2 Definition of the GTV: The GTV includes the contrast-enhancing 
tumor, but not surrounding edema. 
6.4.3 Definition of the PTV: The PTV equals the GTV. 
6.4.4 No margin for microscopic spread or setup error is allowed. 
 
6.5 Critical Structures 
6.5.1 The maximum allowed doses to brainstem, optic nerves, and optic 
chiasm for single fraction treatments are as follows: 
Table 6.5.1: Critical Structure Dose Constraints 
Structure 
Maximum Point Dose (Gy) 
Brainstem 
14 
Optic Nerves 
10 
Optic Chiasm 
10 
6.5.2 The dose to a small volume of the target may be reduced below the 
prescription to meet these constraints at the discretion of the 
treating radiation oncologist. 
 
6.6 Technical Factors 
6.6.1 SRS will be delivered using FDA-approved stereotactic localization 
and linear accelerators. 
 
6.7 Tumor Treating Fields (TTFields) 
6.7.1 Treatment planning: Transducer array layout will be determined by 
the investigator or Novocure using the NovoTALTM software 
supplied by Novocure. NovoTAL can be used for multiple tumors as 
is often the case with GBM (the approved indication for the Optune 
System). There is no difference in the field mapping algorithm 
based on histology of the tumor or frequency of the TTFields. 
6.7.2 Patient training: Patients will be trained in the use of the device by 
the Device Support Specialist (DSS) trained by Novocure or can be 
done by the investigator and/or a designated health care provider 
(e.g. nurse). . 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
6.7.3 Treatment initiation: NovoTTF-200A may be initiated by the Device 
Support Specialist (DSS) or the investigator within 7 days of SRS. 
All patients will be required to shave their heads to initiate array 
placement and TTFields. Array placement will be performed based 
on the Transducer Array Layout map calculated during treatment 
planning, avoiding areas of skin damage as a result of SRS. 
6.7.4 Treatment duration: Treatment with the device will be continuous 
with breaks allowed for personal needs (e.g. showering, array 
exchange). Patients must use the device for at least 18 hours a day 
on average. Treatment will be continued until first cerebral 
progression in the brain (as defined in the protocol), death, or 
unacceptable side effects to patient. Patients must use the device 
for a minimum of 4 weeks from treatment initiation. A treatment 
break of 3 days in NovoTTF-200A every month is allowed. 
However, the patient should use the device for at least 18 hours a 
day on average as stated above.  
6.7.5 The NovoTTF-200A System will be programmed by Novocure to 
deliver 200kHz TTFields. There will be no adjustments made to the 
device by investigators or patients/caregivers. 
6.7.6 Transducer Array replacement: Patients will replace the Transducer 
Arrays twice to three times per week with the help of a caregiver. At 
each array replacement the patient’s scalp will be reshaved and 
skin treated according to the guidelines set out below. 
6.7.7 Compliance assessment: The device will be inspected either by the 
investigator or by a Novocure representative on a monthly basis to 
assess patient compliance with therapy.  
 
6.7.8 The following skin care guidelines should be closely adhered 
to: 
• If the skin beneath the Transducer Arrays is inflamed, a high 
potency topical steroid (e.g. clobetasol) should be prescribed to 
the patient. The patient or caregiver should apply the ointment 
after removing the arrays and cleaning the scalp with baby oil 
and medical alcohol. The ointment should be left on the scalp 
for at least 30 minutes prior to washing the skin with a mild 
shampoo and applying a new set of arrays.  
• At each array replacement, the new set of arrays should be 
shifted by approximately 2 cm compared to the previous layout 
so that the array discs are placed between the areas of skin 
irritation. At the next array replacement the arrays should be 
shifted back to their original location. 
• If the dermis is breached (skin erosions, ulcers, open sores, 
punctate lesions, etc.) an antibiotic ointment (e.g. mupiricin) 
should be prescribed and used in place of the steroid ointment. 
Any evidence of infection should result in bacterial cultures 
being taken. 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
• 
There will be no “dose” adjustments to the device for 
adverse events. Reasons for breaks in treatment for 
longer than 24 hours will be documented in the CRFs. 
The maximum duration of treatment break allowed for 
adverse events related to TTFields is 3 weeks. 
 
 
6.8 Systemic and Supportive Therapy 
6.8.1 Optimal systemic therapy for existing extracranial disease should 
be given to all patients on the study according to physician 
discretion. Systemic therapy may continue throughout NovoTTF- 
200A treatment. Understanding that most of these patients will 
receive chemotherapy and immunotherapy as part of their standard 
regimen, it is not possible to completely control for the effect of 
systemic therapy on brain metastases. To attempt to account for 
this in the reporting of our data, chemotherapy, including dosing 
and regimen changes, will be prospectively recorded in the study 
CRFs. 
 
6.8.2 Patients should also receive the best supportive care available at 
each site including steroids for brain edema. Steroid dosing 
throughout the trial will be documented. Patients should not receive 
any intrathecal chemotherapy while on study (outside of protocol 
treatment). In addition, supportive care will include standard of care 
treatments for the treatment of each patient’s symptoms as 
determined by the treating physician. For example: anti-epileptic 
drugs, anticoagulants, pain control medications, and nausea control 
medications. The supportive care prescribed by the physician to 
each patient will be recorded in the study CRFs. 
 
6.8.3 Previous clinical trial enrollment pertaining to the patient’s small cell 
lung cancer will be documented in the CRFs, including description 
of trial and intervention received.  
 
6.9 Salvage Therapy 
6.9.1 If distant cerebral progression (not within 100% isodose volume) is 
noted at time of follow-up, salvage therapy may be undertaken as 
follows: 
• If the patient develops new metastases and no previous PCI, 
whole brain RT may be offered if reasonable life expectancy 
and discontinuation of TTF. 
• If previous whole brain radiotherapy or declining performance 
status, consider supportive care versus repeat whole brain RT 
with discontinuation of TTF. 
• Discontinue NovoTTF-200A after sign of 1st progression.  

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
• If an enlarging lesion is found on follow-up MRI that was not 
initially treated with SRS due to small size or uncertainty on the 
pretreatment MRI, this will not constitute an intracranial failure. 
Such lesions may receive SRS and the patient can stay on trial.  
 
 
7.0 
THERAPY MODIFICATIONS 
7.1 Non-Study Treatment 
7.1.1 All medications and other treatments taken by the subject during 
the study, including those treatments initiated prior to the start of 
the study, must be recorded on the medical record. 
7.1.2 The use of corticosteroids to manage symptoms of disease or 
treatment is allowed at the discretion of the treating physician. 
 
7.2 Concomitant Medication 
7.2.1 All medications since protocol enrollment will be recorded in the 
medical record. 
7.2.2 Non-cytotoxic systemic therapies such as hormonal agents or 
bisphosphonates may be administered during the study evaluation 
period. 
 
7.3 Adverse Events (AE’s), Adverse Device Effects, Serious Adverse 
Events (SAE’s), and Device Deficiencies  
7.3.1 Definition of AE: Any untoward medical occurrence, which does 
not necessarily have a causal relationship with the study treatment.  
This includes any physical or clinical change experienced by the 
subject, whether or not considered related to the study treatment.  
An AE can therefore be any unfavorable or unintended sign 
(including an abnormal laboratory finding, for example), symptom or 
disease (including the onset of new illness and the exacerbation of 
pre-existing conditions) temporally associated with the study 
treatment. Progressive disease is not considered to be an AE.   All 
AE’s will be recorded in the medical record. 
 
An adverse event (AE) is any untoward medical occurrence, 
unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in subjects, users or 
other persons whether or not related to the investigational medical 
device. This includes events related to the investigational device or 
the comparator, events related to the procedures involved (any 
procedures in the clinical investigation plan).  
 
• Possible Adverse Events (AEs) 
a. Stereotactic Radiosurgery (SRS). The following are 
possible side effects of SRS: 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
-Bleeding from the points where an immobilization frame 
was attached to the skull.  
-Tingling or itching where the frame was attached.  
-Skin Irritation 
-Pain 
-Nausea and vomiting 
-Headache 
-Dizziness 
-Hair Loss (rare) 
-Fatigue 
-Radiation necrosis 
-Brain Edema 
-Seizure 
-Claustrophobia 
 
b. Novo TTF-220A System (200 kHz TTFields) 
In the phase III trial in patients with recurrent GBM 
device-related adverse events (grades 1 and 2) included: 
medical device site reaction (skin reaction) 16%, 
headache 3%, malaise 2%, muscle twitching 1%, fall 1%, 
and skin ulcer 1%. There were no serious adverse 
events attributed to the device. Treatment with the 
NovoTTF-200A is not expected to cause any serious 
side effects. However, it is possible that investigational 
treatment may cause any of the following:  
-Local heat and tingling “electric” sensation beneath the 
transducer array 
-Allergic reaction to the adhesive or to the gel 
-Skin irritation or skin breakdown 
-Infection at the sites of transducer array contact with the 
skin 
-Open sores, ulceration or blisters underneath transducer 
arrays 
-Headache 
-Fatigue 
-Seizures 
-Falls 
-Muscle twitching 
 
7.3.2 Definition of SAE: Any event occurring during the study evaluation 
period that results in any of the following outcomes: 
• Death (i.e. any grade 5 AE) 
• Inpatient hospitalization 
All SAE’s must be recorded in the medical record.  The onset and 
end dates, severity, duration, effect on study treatment 
administration (e.g., discontinuation/cancellation), relationship to 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
study treatment, and administration of any drug(s) to treat this 
event will be recorded for each SAE. 
 
A planned hospitalization for pre-existing condition, or a procedure 
required by the clinical investigation plan, without a serious 
deterioration in health, is not considered to be a serious adverse 
event. All SAE’s must be recorded in the patient’s medical record. 
The onset and end dates, severity, duration, effect on study 
treatment administration (e.g., discontinuation/cancellation), 
relationship to study treatment, and administration of any drug(s) to 
treat this event will be recorded for each SAE.  
 
7.3.3 Serious Adverse Device Effect (SADE): A SADE is any adverse 
device effect that has resulted in any of the consequences 
characteristic of a serious adverse events.  
 
7.3.4 Unanticipated Serious Adverse Device Effect (USADE): A USADE 
is any serious adverse device effect whose nature, incidence, 
severity or outcome has not been identified in the current version of 
the risk analysis report. Anticipated SADEs are effects whose 
nature, incidence, severity or outcome has been previously 
identified in the risk analysis report. Any potential USADEs will be 
reported to the Principal Investigator (Dr. Hunter Boggs) or their 
designee by calling (205) 975-5581. A written report should be 
submitted to the local IRB and UAB Clinical Trials Monitoring 
Committee per institutional policy, within 10 days of the investigator 
learning of the event. The PI will investigate the events are 
USADEs and, if so, report them to the Company (Novocure), as 
soon as possible but no later than the next business day after 
learning of the event. Expedited report for FDA submission to follow 
within 10 working days after first learning of the event by the PI, in 
accordance with 21 CFR Part 812.   
 
7.3.5 Device Deficiency: A device deficiency is defined as the 
inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance, such as malfunction, 
misuse, or use error and inadequate labeling.  
 
 
7.4 Guidelines for Adverse Event Evaluations and Reporting 
7.4.1 Grading of an AEs and SAEs: The descriptions and grading scales 
found in the revised NCI Common Toxicity Criteria (CTC) version 
4.0 will be utilized for assessing severity of adverse events. If the 
toxicity is not characterized adequately by the NCI toxicity scale, 
the investigator will use the adjectives MILD, MODERATE, 
SEVERE to describe the maximum intensity of the adverse event. 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
For purposes of consistency, these intensity grades are defined as 
follows: 
MILD 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observation only; intervention not indicated.  
MODERATE 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living 
(ADL) 
SEVERE 
Grade 3 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limited self-care ADL 
POTENTIALLY 
LIFE-
THREATENING 
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
DEATH 
Grade 5 
Death related to AE.  
 
 
 
 
Modified Grade for NovoTTF-200A Related Skin Adverse Events:  
Grade 1- Asymptomatic or mild symptoms AND 
1. No intervention required OR only topical treatment intervention indicated 
2. Treatment interruption of less than 3 days may be required.  
Grade 2 – Moderate symptoms AND Systemic Therapy required OR event is requiring 
interruption of NovoTTF-200A for more than 3 days.  
Grade 3 – Severe or medically significant but not immediately life threatening AND 
hospitalization OR prolongation of existing hospitalization indicated 
Grade 4- Life threatening consequences AND urgent intervention indicated 
 
 
7.4.2 Determination of Causality of Adverse Events: The investigator 
must assess the relationship of any AE or SAE to the use of study 
treatment using the following guidelines noted in Table 7.4.2. 
 
Table 7.4.2: ATTRIBUTION OF ADVERSE EVENTS 
Code 
Descriptor 
Definition 
5 
Definite 
The adverse event is clearly related to the investigational 
treatment(s) 
4 
Probable 
The adverse event is likely related to the investigational 
treatment(s) 
3 
Possible 
The adverse event may be related to the investigational 
treatment(s) 
2 
Unlikely 
The adverse event is doubtfully related to the investigational 
treatment(s) 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
1 
Unrelated 
The adverse event is clearly not related to the investigational 
treatment(s) 
 
 
7.5 Monitoring of Adverse Events 
7.5.1 Subjects having AE’s or SAE’s will be monitored with relevant 
clinical assessments and laboratory tests as determined by the 
subject’s treating physicians.  ALL adverse events must be followed 
to satisfactory resolution or stabilization of the event(s). 
7.5.2 Any actions taken and follow-up results must be recorded in the 
subject’s medical record. 
7.5.3 For all AE’s or SAE’s which require the subject to be discontinued 
from the study, relevant clinical assessments and laboratory tests 
will be repeated as clinically indicated, until final resolution or 
stabilization of the event(s). 
 
7.6 Adverse Event Reporting and Other Reportable Events 
7.6.1 For the purpose of this guidance and based on the definitions 
above, the following events are considered reportable events: 
• Any SAE,  
• Any investigational device deficiency that might have left to a 
SAE if: a) suitable action had not been taken, or b) 
intervention had not been made, or c) if circumstances had 
been less fortunate,  
• New findings/updated relation to already report events,  
• USADEs.  
 
The PI will notify the company (Novocure), by the next business 
day, after becoming aware of any of the above reportable events. 
Notification will be sent to Novocure, by email, to 
support@novocure.com.  
 
The company (Novocure) will promptly advise Dr. Boggs of adverse 
reactions or side effects related to NovoTTF-200A which may 
become known to them during the course of the study.  
 
7.6.2 Notification of all events must be reported to Principal Investigator 
(Dr. Hunter Boggs) or their designee by calling (205) 975-5581.  A 
written report should be submitted to the appropriate Institutional 
Review Board (IRB) and UAB Clinical Trials Monitoring Committee 
per institutional policy. 
 
7.6.3 Adverse events and other reportable events will be reported to the 
UAB Clinical Trials Monitoring Committee. 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
 
7.7 Data Safety Monitoring Plan 
7.7.1 This protocol will follow the UAB Data and Safety Monitoring Plan 
maintained by the UAB Comprehensive Cancer Center. 
7.7.2 Serious adverse events will be reviewed in the UAB Radiosurgery 
Conference and the Department of Radiation Oncology Quality 
Assurance committees. 
 
7.8 Early Termination 
Patients may be discontinued from study prior to completion of study 
requirements for any of the following reasons: 
7.8.1 The patient has a clinically significant adverse event as determined 
by the Principal Investigator. 
7.8.2 The patient requests to be withdrawn from the study. 
7.8.3 The patient fails to comply with the requirements for study 
evaluations/visits. 
7.8.4 The development of circumstances that prevent study 
evaluations/visits. 
7.8.5 Other conditions for which, in the investigator's opinion, it is in the 
patient's best interest to be withdrawn from the study. 
7.8.6 Patient did not meet eligibility requirements. 
 
7.9 Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there 
is sufficient reasonable cause. Written notification, documenting the reason 
for study suspension or termination, will be provided by the suspending or 
terminating party to the investigators, funding agency, and regulatory 
authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform the IRB and will provide the reason(s) for the termination or 
suspension. Circumstances that may warrant termination or suspension 
include, but are not limited to:  
• Determination of unexpected, significant, or unacceptable risk to 
participants. 
• Demonstration of lack of efficacy that would warrant stopping defined 
as rapid (1 month) intracranial failure in > 5 patients. 
• Insufficient compliance to NovoTTF-200A protocol requirements 
defined as > 5 patients unable to meet device compliance of wearing 
NovoTTF-200A at least 12 hours a day on average over the course of 
a month. Noncompliance is also defined as failure to wear this device 
at least 20 out of 30 days.  
• Data that is not sufficiently complete and/or evaluable.  
• Determination of futility. 
 
Study may resume once concerns about safety, protocol compliance, data 
quality are addressed and satisfy the sponsor, IRB and/or FDA. 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
 
8.0 
STUDY PARAMETERS 
8.1 In the absence of symptoms requiring earlier evaluation, the Day 30 MRI 
and physical exam will be used to determine if toxicity has developed.  
Acute and Late Toxicity are defined in Section 11.3. 
8.2 Day 0 is defined as the day of radiosurgery. 
8.3 Baseline evaluations must take place within 3 weeks (21 days) of study 
enrollment. 
8.4 “1 Month” evaluation may be done within 7 days of the specified day. “3 
Month” evaluation may be done within 14 days of the specified day. 
8.5 Six month evaluations (6mo) may take place six months from the day of 
SRS, plus or minus 30 days.  Similarly, the twelve month evaluations 
(12mo) will take place 12 months from the day of SRS, plus or minus 30 
days 
 
 
 
Table 8.1: Required evaluations and therapies 
 
Baseline 
Day of 
SRS 
(D0) 
Day 1-7 
1mo 
(+/- 7 days) 
3mo 
(+/- 14  days) 
6mo 
(+/- 30 days) 
9mo      
(+/- 30 days)
12mo    
(+/- 30 days) 
MRI 
x 
 
 
X 
x 
x 
x 
x 
H & P 
x1 
 
 
x1 
x1 
x1 
x1 
x1 
Neurological 
Exam 
x 
 
 
X 
x 
x 
x 
x 
Toxicity 
 
 
 
X 
x 
x 
x 
x 
GPA* 
x 
 
 
 
 
 
 
 
KPS* 
x 
 
 
X 
x 
x 
x 
x 
βHCG 
X2 
 
 
 
 
 
 
 
Measurement of 
Brain Mets 
(RANO) 
x 
 
 
X 
x 
x 
x 
x 
Placement of 
TTF device 
 
 
x 
 
 
 
 
 
Con Meds 
x 
 
 
X 
x 
x 
x 
x 
Neurocognitive 
Testing 
x 
 
 
X 
x 
x 
x 
x 
Quality of Life 
Questionnaire 
x 
 
 
X 
x 
x 
x 
x 
CBC with diff 
x 
 
 
 
x 
x 
x 
x 
CMP 
x 
 
 
 
x  
x 
x 
x 
PT/PTT 
x 
 
 
 
 
 
 
 
Device 
Compliance 
 
 
 
Monthly 
*See Appendices 
1 record medications 
2If applicable, per Section 4.2.12 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
 
9.0 
EVALUATION CRITERIA 
9.1 Pretreatment Evaluations (Baseline) 
9.1.1 The following will be performed within 21 days: 
• Verify informed consent is signed. 
• Gadolinium enhanced T1-weighted, T2 and/or FLAIR MRI (3T) 
of the brain (maximum slice thickness 5mm). FLAIR imaging is 
preferred.  
9.1.1..1 
Treatment planning MRI may be repeated if 
diagnostic MRI is outside of the 21 day window 
• Measurement of brain metastases per protocol. 
• Medical history. 
• Concomitant medications. 
• Graded prognostic assessment (GPA) score recording. 
• Karnofsky performance status (KPS) score recording. 
• Physical examination and vital signs. 
• Neurological examination. 
• Neurocognitive testing: Hopkins Verbal Learning Test (HVLT-R) 
for free recall, delayed recall, and delayed recognition; 
Controlled Oral Word Association Test (COWAT); and Trail 
Making Tests (TMT) Parts A and B.  
• Quality of Life questionnaire (EORTC QLQ C30 with BN20 
addendum) 
• Pregnancy test (if applicable) within 14 days. 
• Complete blood count including differential. 
• Serum chemistry panel, including: BUN, Creatinine, Sodium, 
Potassium, ALT, AST, Bilirubin, PT, and PTT. 
 
 
9.2 Treatment Phase (Day 0) 
9.2.1 Radiosurgery  
 
 
9.3 Follow-Up 
9.3.1 At the one, three, six, nine, and twelve month evaluations, the 
following will be performed:  
• Medical history, physical examination, and vital signs. 
• Neurological examination. 
• Toxicity and Adverse Events. 
• Karnofsky performance status (KPS) score recording.  
• Concomitant medications. 
• Contrast-enhanced T1-weighted, T2 and/or FLAIR MRI (3T) 
using similar sequences and slice thickness obtained for SRS 
planning (maximum slice thickness 5mm). FLAIR imaging is 
preferred.  

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
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Protocol Version: January 10, 2020 
 
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Amendment # 6 
• Measurement of brain metastases per protocol. 
• Neurocognitive testing: Hopkins Verbal Learning Test (HVLT-R) 
for free recall, delayed recall, and delayed recognition; 
Controlled Oral Word Association Test (COWAT); and Trail 
Making Tests (TMT) Parts A and B.  
• Quality of Life questionnaire (EORTC QLQ C30 with BN20 
addendum). 
 
9.3.2 At the three, six, nine, and twelve month evaluations, the following 
will be performed: 
• Complete blood count including differential. 
• Serum chemistry panel, including: BUN, Creatinine, Sodium, 
Potassium, ALT, AST, and Bilirubin. 
 
9.3.3 Device compliance will be evaluated monthly.  
 
10.0 PATIENT REGISTRATION 
10.1 Patients can be registered by calling 205-975-2879. 
 
11.0 STATISTICAL CONSIDERATIONS 
11.1 Study Endpoints 
11.1.1 Primary endpoint: The primary endpoint is rate of distant CNS 
progression at 6 months. Distant progression is defined as 
development of a new metastases outside of the previously treated 
100% isodose volume. The 6 month time interval will be defined 
from the day of SRS to the time of the 6 month follow-up MRI. We 
estimate no more than 50% of patients will suffer distant brain 
relapses during time period. In Takahashi’s study, the rate of 
development of brain metastases in patients with small cell lung 
cancer who did not have whole brain radiation was 70% [34]. Also 
in this study, the estimated rate of failure in the brain after 
prophylactic cranial irradiation (radiotherapy delivered to the whole 
brain) was approximately 50%. As WBRT is the current standard of 
care for patients with small cell lung cancer, a 50% intracranial 
relapse rate would be similar to the historical control of whole brain 
radiotherapy in Takahashi’s study. This would signal that SRS 
combined with NovoTTF-200A may be as efficacious as whole 
brain RT and warrants further investigation in larger studies. 
 
11.1.2 Secondary endpoints: overall survival, local tumor control, and 
distant CNS progression (outside of the previously treated 100% 
isodose volume) at one year, neurological death, time to first brain 
directed radiation, change in neurocognitive metric, and change in 
quality of life at 6 months and one year. 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 29 of 36 
Amendment # 6 
11.1.3 Selection of Lesions for the Assessment of Cerebral  
Response: 
• When more than one lesion is measurable lesion is present at 
the SRS planning MRI, all lesions up to a maximum of five 
lesions should be identified as target lesions and will be 
recorded and measured at the SRS planning MRI.  
• Target lesions should be selected on the basis of their size 
(longest diameter) and as those that can be measured 
reproducibly.  
 
11.1.4 Assessment of Cerebral Response: 
• A sum of the diameters for all target lesions will be calculated 
and reported as the baseline sum of longest diameters, taken 
from the SRS planning MRI.  
• All other lesions should be identified as non-target lesions and 
should also be recorded at baseline (SRS planning MRI). 
Measurements are not required and these lesions should be 
classified as present, absent, or unequivocal progression, and 
followed up. 
• All target lesions should have their actual measurement 
recorded, even if very small. If the lesion disappears, the value 
should be recorded as 0 mm. However, if the lesion is 
sufficiently small (but still present) to be assigned an exact 
measure; a default value of 5 mm should be recorded on the 
case report form.  
• The definition of clinical deterioration is left to the discretion of 
the treating physician, but it is recommended that patients who 
have a decrease in score on the Karnofsky performances scale 
from 100 or 90 to 70 points or less, a decrease of minimum 20 
points from 80 or less, or a decrease from any baseline to 50 
points or less, for at least 7 days, be considered as having 
neurological deterioration, unless this functional impairment is 
attributable to comorbid events, treatment-related toxicity, or 
changes in corticosteroid dose. 
 
 
11.1.5 Special cases of cerebral response 
• Coalescing lesions: Lesions might coalesce during treatment. 
As lesions coalesce, a plane between them may be maintained 
that would aid in obtaining maximum longest diameter of each 
individual lesion. If the lesions have truly coalesced such that 
they are no longer separable, the vector of the longest diameter 
in this instance should be the maximum longest diameter for the 
coalesced lesion.  
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 30 of 36 
Amendment # 6 
• Radiation necrosis: If radiographical evidence of progression 
exists, but clinical evidence indicates that the radiological 
changes are due to treatment effect and not to progression of 
brain metastases (e.g. radiation necrosis), patients should 
undergo perfusion MRI, magnetic resonance spectroscopy, or 
18FLT or 18FDG PET imaging if available at the treating 
institution to help distinguish between treatment effects and 
recurrent tumor. All additional imaging studies must be shared 
with the central radiology lab. Patients can be continued on 
protocol therapy while true disease progression is being ruled 
out. If subsequent testing shows that progression has occurred 
for a lesion that has previously been suspected as radiation 
necrosis, all previous unidimensional measurements of that 
lesion should be added to the total sum of diameters calculated 
for response assessment from the date of the scan this issue 
was first raised.  
 
• Use of Corticosteroids: In the absence of clinical deterioration 
related to the tumor, an increase in corticosteroid dose alone 
should not be used as a sole determinant of progression. 
Patients with stable imaging results and whose corticosteroid 
dose has increased for reasons other than clinical deterioration 
related to the tumor do not qualify as having stable disease or 
progression. 
 
 
11.1.6 Cerebral Response for Target Lesions: 
• Complete response: Disappearance of all target lesions; with 
no new lesions, no use of corticosteroids, and patient is stable 
or improved clinically.  
• Partial response: At least a 30% decrease in the sum longest 
diameter of target lesions, taking as reference the baseline sum 
longest diameter (from SRS planning MRI); no new lesions; 
stable to decreased corticosteroid dose; stable or improved 
clinically.  
• Progressive disease: At least a 20% increase in the sum 
longest diameter of target lesions, taking as reference the 
smallest sum on study (this includes the SRS planning MRI if 
that is the smallest on study). In addition to the relative increase 
of 20%, at least one lesion must increase by an absolute value 
of 5 mm or more to be considered progression.  
• Stable disease: neither sufficient shrinkage to qualify for partial 
response nor sufficient increase to qualify for progressive 
disease, taking as reference the smallest sum longest diameter 
while on study. 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 31 of 36 
Amendment # 6 
11.1.7 Cerebral Response for Non-Target Lesions: 
• Non-target lesions should be assessed qualitatively at each of 
the time points specified in the protocol.  
• Complete response: Requires all of the following: 
disappearance of all enhancing non-target lesions, no new CNS 
lesions.  
• Non-complete response or non-progressive disease 
Persistence of one or more non-target lesion or lesions.  
• Progressive disease: Any of the following: unequivocal 
progression of existing enhancing non-target lesions, new 
lesion(s) (except while on immunotherapy-based treatment), or 
unequivocal progression of existing tumor related non-
enhancing (T2/FLAIR) lesions. 
• Summary of response criteria adapted from RANO-BM: 
 
 
• Secondary endpoints include acute toxicity, late toxicity, local 
control, neurocognitive change, overall survival, distant brain 
progression, quality of life, and adverse events associated with 
SRS and/or TTFields. 
 
11.2 Sample Size 
11.2.1 We plan to enroll 20 patients up to a 3 year time period. 
11.2.2 Data will be collected according to the following proportions: 
• No. of patients meeting eligibility criteria / No. of patients 
evaluated 
• No. of patients enrolled / No. of patients meeting eligibility 
criteria 
• No. of patients completing 6 months of follow-up/No. of patients 
enrolled 
• No. of patients compliant to Novo-TTF use/No. of patients 
enrolled. 
11.2.3 We estimate that 80% of patients will meet compliance criteria for 
Novo-TTF.   
 
11.3 Toxicity Evaluations 
11.3.1 Acute and late toxicity will be graded according to the CTCAE v 4.0 
criteria [30]. 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 32 of 36 
Amendment # 6 
11.3.2  Definition of acute toxicity: Any possible, probable, or definite 
treatment-related AE or SAE occurring within six months or less 
from the date of SRS. 
11.3.3 Definition of late toxicity: Any possible, probable, or definite 
treatment-related AE or SAE occurring more than six months from 
date of SRS. 
 
11.4 Efficacy Evaluations 
11.4.1 Distant intracranial recurrence will be defined as a measurable 
lesion deemed likely to be a brain metastasis found outside of the 
previously treated 100% isodose volume. 
• 
Exception: An enlarging lesion that was not treated 
on the initial SRS course due to uncertainty of 
imaging characteristics.  
11.4.2 Local Recurrence will be defined as a measurable lesion deemed 
likely to be a brain metastasis found within the previously treated 
100% isodose volume. 
11.4.3 Contrast-enhanced MRI’s obtained at 2-3 month intervals will be 
used to evaluate local control and incidence of intracranial 
recurrence. 
11.4.4 Imaging performed at the discretion of the treating physician (i.e. in 
response to new or progressive symptoms) may be used to 
evaluate for local control or leptomeningeal dissemination.  Such 
studies can substitute for the required 6 and 12 month evaluations 
if either occurs within plus or minus 30 days of the specified date. 
 
11.5 Data Management: Data collection will be coordinated by the research 
nurse and overseen by the Radiation Oncology Research Committee. 
 
 
11.6 Statistical Analysis 
11.6.1 Primary endpoints: the primary endpoint is rate of distant CNS 
progression at 6 months, which will be calculated as the total 
number patients with such events divided by the total number of 
patients. Its 95% confidence interval will also be provided. Distant 
progression is defined as development of a new metastases 
outside of the previously treated 100% isodose volume. The 6 
month time interval will be defined from the day of SRS to the time 
of the 6 month follow-up MRI. 
11.6.2 Secondary endpoints. Overall survival will be measured as time 
from first SRS treatment to date of death, or censored as the last 
follow up. Overall survival rates will be analyzed using the Kaplan-
Meier (KM) method. Time to other events such as local recurrence, 
distant CNS progression, neurological death, or first brain directed 
radiation will be measured as time from first SRS treatment to date 
of such events, or death, whichever occurs first. All the time-to-

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 33 of 36 
Amendment # 6 
events will be analyzed using KM method. Neurocognitive function 
raw scores will be derived for HVLT-R free recall, delayed recall, 
and delayed recognition; COWAT; and TMT Parts A and B at each 
assessment point. The following summary statistics will be 
estimated: mean, median, quartiles, and variance of all 
measurements. The changes over time at different assessment 
points will also be graphically presented through scatter plots, and 
scatterplot matrices. Quality of life will be presented descriptively 
over time for each of the general and symptom scales of EORTC 
QLQ C30 and BN20 addendum according to the EORTC coding 
manual.  
11.6.3 Toxicity and AE. Acute toxicity during NovoTTF-200A treatment 
based on incidence and severity of treatment emergent adverse 
events will be evaluated using the CTCAE version 4.0. Adverse 
events will be presented as overall incidence, incidence by severity 
and incidence by relatedness to therapy. 
 
 
12.0 REFERENCES 
1. Ortuzar, W., et al. Brain metastases as the primary site of relapse in two 
randomized phase III pemetrexed trials in advanced non-small-cell lung cancer. 
Clin Lung Cancer. 13: p. 24-30 
2. Chow, E., et al. Prospective assessment of patient-rated symptoms following 
whole brain radiotherapy for brain metastases. J Pain Symptom Manage, 2005. 
30: p. 18-23. 
3. Mehta, M.P., et al. The American Society for Therapeutic Radiology and 
Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain 
metastases. Int J Radiat Oncol Biol Phys, 2005. 63: p. 37-46. 
4. Tsao, M.N., N.S. Lloyd, and R.K. Wong. Clinical practice guideline on the optimal 
radiotherapeutic management of brain metastases. BMC Cancer, 2005. 5: p. 34. 
5. Tsao, M.N., et al. Radiotherapeutic management of brain metastases: a 
systematic review and meta-analysis. Cancer Treat Rev, 2005. 31: p. 256-73. 
6. Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the 
treatment of single metastases to the brain. N Engl J Med. Vol 322; 1990:494-
500. 
7. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain 
radiation therapy vs stereotactic radiosurgery alone for treatment of brain 
metastases: a randomized controlled trial. JAMA. Vol 295; 2006:2483-2491. 
8. NovoCure. Effects of TTFields (150 kHz) in non-small cell lung cancer (NSCLC) 
patients with 1-10 brain metastases following radiosurgery (METIS). Available 
from: https://clinicaltrials.gov/ct2/show/NCT02831959. NLM identifier: 
NCT02831959. Accessed June 19, 2011. 
9. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients 
cured of brain metastases. Neurology. Vol 39; 1989:789-796. 
10. Corn BW, Moughan J, Knisely JPS, et al. Prospective evaluation of quality of life 
and neurocognitive effects in patients with multiple brain metastases receiving 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
whole-brain radiotherapy with or without thalidomide on Radiation Therapy 
Oncology Group (RTOG) trial 0118. Int J Radiat Oncol Biol Phys. Vol 71; 
2008:71-78. 
11. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain 
metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: 
a randomised controlled trial. The Lancet Oncology. Vol 10; 2009:1037-1044. 
12. Yomo S, Hayashi M. Is stereotactic radiosurgery a rational treatment option for 
brain metastases from small cell lung cancer? A retrospective analysis of 70 
consecutive patients. BMC Cancer. 2015;15:95. 
13. Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs 
Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in 
Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA. 
2016;316(4):401-409. 
14. Sneed PK, Lamborn KR, Forstner JM, et al. Radiosurgery for brain metastases: 
is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys. Vol 43; 
1999:549-558. 
15. Kirson, E.D., et al. Disruption of cancer cell replication by alternating electric 
fields. Cancer Res, 2004. 64(9): p. 3288-95. 
16. Lee, S.X., et al. CB-17. Mitosis Interference of Cancer Cells During Anaphase By 
Electric Field from NovoTTF-100A. in Society for Neuro Oncology Annual 
Meeting. 2011. Orange County, California Neuro Oncol. 
17. Kirson, E.D., et al. Alternating electric fields arrest cell proliferation in animal 
tumor models and human brain tumors. Proc Natl Acad Sci U S A, 2007. 
104(24): p. 10152-7. 
18. Pless, M. and U. Weinberg, Tumor treating fields: concept, evidence and future. 
Expert Opin Investig Drugs,2011. 20(8): p. 1099-106. 
19. Schneiderman, R.S., et al. TTFields alone and in combination with 
chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines 
that over-express ABC transporters. BMC Cancer, 2010. 10: p. 229. 
20. Kirson, E.D., et al. Disruption of cancer cell replication by alternating electric 
fields. Cancer Res, 2004. 64(9): p. 3288-95. 
21. Salzberg, M., et al. A pilot study with very low-intensity, intermediate-frequency 
electric fields in patients with locally advanced and/or metastatic solid tumors. 
Onkologie, 2008. 31(7): p. 362-5. 
22. Pless, M., et al. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in 
combination with pemetrexed for advanced non-small cell lung cancer. Lung 
Cancer, 2013. 81(3): p. 445-50. 
23. Stupp, R., et al. NovoTTF-100A versus physician’s choice chemotherapy in 
recurrent glioblastoma: A randomised phase III trial of a novel treatment 
modality, EJC 2012 September 2012; 48(14) 
24. Stupp R, Taillibert S, Kanner AA, et al. Maintenance Therapy With Tumor-
Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A 
Randomized Clinical Trial. JAMA 2015;314(23):2535-2543. 
25. Novocure data on file 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
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Amendment # 6 
26. Giladi M., et al. Alternating Electric Fields (Tumor Treating Fields Therapy) Can 
Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both 
in vitro and in vivo. Semin Oncol, 2014 
27. Kirson, E.D., et al. Alternating electric fields (TTFields) inhibit metastatic spread 
of solid tumors to the lungs. Clin Exp Metastasis, 2009. 26(7): p. 633-40. 
28. Wong, E.T., et al. NovoTTF-100A alternating electric fields therapy for recurrent 
glioblastoma: an analysis of patient registry data. J Clin Oncol, 2014. (suppl; 
abstr e13033) 
29. Wong, E.T., et al. Abstract C7: Novo- TTF-100A alternating electric fields therapy 
for recurrent glioblastoma: an analysis of patient registry data. Presented at: 16th 
Biennial Canadian Neuro-Oncology Meeting; June 12-14, 2014; Halifax, Canada 
30. National Cancer Institute, National Institutes of Health, U.S. Department of 
Health and Human Services. Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0. [last accessed March 16, 2015];NIH publication # 09-7473. 
Published May 29, 2009; Revised Version 4.03 June 14, 2010. Available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5×7.pdf. 
31. Lin N.U., et al. Response assessment criteria for brain metastases: proposal 
from the RANO group. Lancet Oncol, 2015. 16(6):e270-8. 
32. Giladi M. et al. Meta-analysis fo cancer cell lines based on their response to 
TTFields. J Clin Oncol, 2015. (31, no.15_suppl). Epublished ahead of print.  
33. Gabriel S, et al. The dielectric properties of biological tissues: III. Parametric 
models for the dielectric spectrum of tissues. Phys Med Biol. 1996;41(11):2271-
2293. 
34. Takahashi, T., Yamanaka, T., Seto, T., Harada, H., Nokihara, H., Saka, H., ... & 
Takeda, K. (2017). Prophylactic cranial irradiation versus observation in patients 
with extensive-disease small-cell lung cancer: a multicentre, randomised, open-
label, phase 3 trial. The Lancet Oncology, 18(5), 663-671. 
 
APPENDIX A: Graded Prognostic Assessment (GPA) 
 
Score
 
0
0.5
1 
Age 
>60
50-59
<50 
KPS 
<70
70-80
90-100 
# of CNS metastases 
>3
2-3
1 
Extracranial Metastasis 
Present
-
None 
 
 
 
 
 
 

Department of Radiation Oncology 
University of Alabama at Birmingham 
 
RAD 1704 
Protocol Version: January 10, 2020 
 
Page 36 of 36 
Amendment # 6 
APPENDIX B: Karnofsky Performance Status (KPS) 
 
100  
Normal.  No complaints; No evidence of disease 
90 
 Able to carry on normal activity; minor signs or symptoms of 
disease 
80  
Normal activity with effort; some signs or symptoms of disease 
70  
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most 
personal needs 
50  
Requires considerable assistance and frequent medical care 
40  
Disabled; requires special care and assistance 
30  
Severely disabled; hospital admission is indicated although death is 
not imminent 
20  
Very sick; hospital admission necessary, active supportive 
treatment necessary 
10  
Moribund; fatal processes progressing rapidly 
0  
Dead