A Prospective Phase II Trial of NovoTTF-100A With Bevacizumab (Avastin) in Patients With Recurrent Glioblastoma
Phase: PHASE2
Conditions: Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Sponsor: Case Comprehensive Cancer Center

 
  
 
CLINICAL PROTOCOL  
Title:  
A Prospective Phase II Trial of NovoTTF-100A with 
Bevacizumab (Avastin) in Patients with Recurrent Glioblastoma  
Protocol Number:  
CASE3313  
Protocol EF-  
Principal Investigator:  
Manmeet Ahluwalia, MD.  
Study Sponsor:  
Cleveland Clinic,  
9500 Euclid Ave,   
Cleveland, Ohio 44195  
  
NovoCure Ltd.  
POB 15022  
MATAM Center  
Haifa, 31905, Israel  
Signature & Date:  
  
Signed: ______________________ Dated: _______________  
Version Date:  
 03/31/2020  
  
SYNOPSIS:  
Name of Sponsor/Company: Cleveland Clinic  
                                                  NovoCure Ltd.  
Therapies under investigation: Bevacizumab   
                                                     NovoTTF-100A  
Title of Study: A Prospective Phase II Trial of NovoTTF-100A with Bevacizumab in Patients with 
Recurrent Glioblastoma  
Study Centers: Cleveland Clinic, University of Cincinnati, Boca Raton Regional Hospital  
Principal Investigator: Manmeet Ahluwalia, MD.  

 
  
2 
Studied period (years): 3 years  
Date first patient enrolled: April 2013  
Estimated date endpoint obtained:  December 2017  
Estimated date last patient completed:  December 2017  
Phase of development: 2  
  
Rationale:   
Despite advances in surgery, radiation therapy and chemotherapy, including establishment of 
concurrent radiation and temozolomide followed by temozolomide as standard of care, glioblastoma 
(GBM) remains an incurable disease with a dismal median overall survival of 15-18 months1.   
Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a humanized monoclonal antibody 
that inhibits VEGF and is the first antiangiogenic therapy to be approved for use in patients with 
cancer. The BRAIN study, a phase II randomized trial evaluated the role of bevacizumab (alone or in 
combination with irinotecan) in 167 patients with recurrent GBM2. The progression free survival 
(PFS) at 6 months (PFS-6) was 42.6% and 50.3%, objective response rate (ORR) was 28.2% and 
37.8% and median overall survival (OS) was 9.2 months and 8.7 months in the monotherapy and 
combination arms respectively. In a study done at the National Cancer Institute (NCI), 48 patients 
with recurrent GBM were treated with bevacizumab producing a response rate (RR) of 35%, PFS-6 of 
29% and a median OS of 31 weeks3. Clinical benefit was evident with decreasing cerebral edema, 
tapering steroid doses and improvement in neurological function in nearly half of the patients. 
Addition of irinotecan to patients who progressed following bevacizumab did not provide any 
additional benefit.  
  
The results of these two studies compared favorably to historic controls of PFS-6 of 15% for GBM4 
and the Food and Drug Administration (FDA) approved bevacizumab for patients with recurrent 
GBM in May 2009 as a monotherapy.  However, the duration of effect of bevacizumab appears to be 
limited and there are growing concerns about the long-term efficacy of bevacizumab. To date, clinical 
trials with bevacizumab with recurrent glioblastoma have shown an improvement of PFS without  
 

 
  
3 
substantial improvement in OS.   
  
Emerging patterns of tumor progression distant from the primary site and recurrence after 
bevacizumab therapy suggest that VEGF inhibition alone is insufficient for long-term tumor control 
and may change the natural history of glioma progression. Hence strategies that target invasion may 
be needed to prevent this pattern of resistance.  
  
Bevacizumab has been associated with prolonged OS in phase III trials of metastatic colorectal and 
non-small-cell lung cancers and with prolonged PFS in metastatic breast and renal cancers in 
combination with chemotherapy or biologics. Except GBM, all the approved indications for 
bevacizumab have been in combination with chemotherapy. However based on the results of the 
BRAIN study, bevacizumab was approved as a monotherapy. One hypothesis for the lack of survival 
benefit in GBM with the addition of chemotherapy to bevacizumab is that treatment with 
bevacizumab leads to normalization of the blood brain barrier (BBB) and this may decrease 
peritumoral edema, producing short-term benefit.  
  
Novocure (Haifa, Israel) has developed a novel therapy (NovoTTF-100A) utilizing alternating electric 
fields and has shown that when properly tuned, very low intensity, intermediate frequency electric 
fields (TTFields) inhibit the growth of tumor cells (including glioma).  Given its mechanism of 
action, TTFields are explained in detail with both preclinical and clinical data provided below and in 
the attached appendix, NovoTTF not dependent on the BBB for its efficacy. The inhibitory effect 
with TTFields has been demonstrated in all proliferating cancer cell types tested, whereas, 
nonproliferating cells and normal tissues were unaffected. Promising clinical results have been 
demonstrated in pilot studies of both newly diagnosed GBM in combination with temozolomide as 
well as recurrent GBM when treated with NovoTTF-100A.   In a phase III trial NovoTTF 
monotherapy demonstrated comparable efficacy to chemotherapy with a more favorable safety profile 
and quality of life benefit in the recurrent GBM setting resulting in FDA approval of NovoTTF given 
the single agent activity of NovoTTF and bevacizumab in GBM and the mechanism of action of 
NovoTTF not being limited by normalization of the blood brain barrier by use of bevacizumab, this is 
a rational and promising combination to evaluate further in a clinical trial.  

 
  
4 
Objectives:   
Primary:  
• 
To determine the efficacy of the combination of bevacizumab and NovoTTF-100A in 
bevacizumab-naïve patients with recurrent GBM as measured by 6-month progression-free 
survival (PFS6) Secondary:  
• 
To assess safety and tolerability of the combination of bevacizumab and NovoTTF-100A in 
this population  
• 
To evaluate overall survival in this population  
• 
To determine objective response rate (ORR) by modified RANO criteria in this population  
• 
To assess time-to-progression in this population  
• 
To assess neurocognitive outcome and quality of life in this population  
  
 
Methodology:   
This is an open label single arm phase 2 trial evaluating the efficacy and safety of the combination of 
bevacizumab and NovoTTF-100A in bevacizumab-naïve patients with recurrent GBM.   
Number of Patients:   
Approximately 40 patients with recurrent GBM will be enrolled in this phase II trial. An additional 8 
patients may be enrolled to replace ineligible patients or patients who withdraw consent prior to 
receiving study treatment.    

 
  
5 
Eligibility Criteria:   
Inclusion criteria:  
1. Patients with histologically confirmed glioblastoma or other grade IV malignant glioma (i.e.  
gliosarcoma, small cell glioblastoma, etc.), recurrent after prior external-beam fractionated 
radiotherapy and temozolomide chemotherapy.  
2. Patients with upto two prior recurrences are allowed.  
3. Karnofsky performance status ≥ 70.  
4. Age ≥ 22 years old.     
5. Patients must have the following laboratory values:  
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L  
• 
Platelets ≥ 100 x 109/L  
• 
Hemoglobin (Hgb) > 9 g/dL  
• 
Serum total bilirubin: ≤ 1.5 x ULN  
• 
ALT and AST ≤ 3.0 x ULN  
• 
Serum creatinine ≤ 1.5 x ULN   
• 
Blood coagulation parameters: INR ≤ 1.5  
6. Minimum interval since completion of radiation treatment is 12 weeks  
7. Minimum interval since last drug therapy:  
• 
3 weeks since last non-cytotoxic therapy  
• 
3 weeks must have elapsed since the completion of a non-nitrosourea-containing 
chemotherapy regimen  
• 
6 weeks since the completion of a nitrosourea-containing chemotherapy regimen.  
8. Patients must have signed an approved informed consent and authorization permitting release 
of personal health information.  
 

 
  
6 
9. Patients with the potential for pregnancy or impregnating their partner must agree to follow 
acceptable birth control methods to avoid conception. The effects of bevacizumab on 
developing fetus or nursing infant are not known.  Female patients of child-bearing potential 
must have a negative pregnancy test.  
10. Patients must have no concurrent malignancy except curatively treated basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I 
or II cancer from which the patient is in complete remission. Patients with other prior 
malignancies must be disease-free for ≥ three years.  
11. Patients must be maintained on a stable corticosteroid regimen from the time of their baseline 
scan until the start of treatment and/or for at least 5 days before starting treatment.  
Exclusion criteria:  
1. Patients who have had previous treatment either with bevacizumab, and or NovoTTF 100A 
system  
2. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or 
intrapelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, 
or patients who have had minor procedures, percutaneous biopsies or placement of vascular 
access device ≤ 1 week prior to starting study drug,  or who have not recovered from side 
effects of such procedure or injury  
3. Patients with impaired cardiac function or clinically significant cardiac diseases, including any 
of the following:  
• 
History or presence of serious uncontrolled ventricular arrhythmias  
• 
Any of the following within 6 months prior to starting study drug: myocardial infarction 
(MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart 
Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), 
Pulmonary Embolism (PE)  
• 
Uncontrolled hypertension (defined by a SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg while 
on anti-hypertensive medications)  
4. Patients with cirrhosis, or active viral or nonviral hepatitis.  
5. Implanted pacemaker, shunts, defibrillator or deep brain stimulator, other implanted electronic 
devices in the brain or documented clinically significant arrhythmias.  
6. Infra-tentorial tumor  
7. Evidence of increased intracranial pressure (clinically significant papilledema, vomiting and 
nausea or reduced level of consciousness)  
8. Known sensitivity to conductive hydrogels   
9. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory)    

 
  
7 
10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or 
uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or  

 
  
8 
d 
 
compromise compliance with the protocol  
11. Pregnant or breast-feeding women  
12. Patients unwilling or unable to comply with the protocol  
13. Patients with leptomeningeal disease  
Duration of Treatment:   
Bevacizumab will be given at a dose of 10mg/Kg IV every 2 weeks and NovoTTF-100A will be worn 
continuously. Previously studies have shown that patient who wear NovoTTF-100A system > 18 
hours/ day derive more benefit from the device.    
Patients are eligible for treatment with the combination of bevacizumab and NovoTTF-100A until 
disease progression or unacceptable toxicity.   
 A patient should be withdrawn from study treatment if, in the opinion of the Investigator, it is 
medically necessary, or if it is the wish of the patient.  In addition, patients will be withdrawn from 
treatment in the case of:  
1. Modified RANO criteria defined disease progression. In cases where modified RANO criteria 
cannot be applied, progression should be based on unequivocal evidence of progressive 
disease sufficient to require a change in therapy.  
2. A need for surgery, radiation, or for other anticancer therapy not specified in the protocol.  
3. Lost to follow-up or noncompliant.  
4. Pregnancy.  Pregnant patients should be followed for the duration of the pregnancy and the 
outcome of the pregnancy should be documented.  
  
Parameters to be Assessed:  
Safety:    
Safety assessments will include physical exams, performance status, laboratory results (complete 
blood counts and serum chemistry) and 12-lead ECG’s (in patients who develop arrhythmia), and 
additional studies as clinically indicated.  Data Safety Toxicity Committee will review safety data.  
See Section 10 for data safety monitoring. In addition, recurring teleconferences will be held with the 
principal investigator or other investigators.    
Efficacy:    
Modified RANO criteria will be applied to assess response and progression.   
  Survival will be calculated using the KM methodology  ( time from enrollment to date of death or      
ate of last follow-up)    

 
  
9 
Statistical methods:  
This trial will enroll enough participants to discriminate between a 36% and 56% PFS6 rate. The trial 
will accrue 40 participants. The trial will be declared successful if at least 20 achieve PFS6. This 
design assumes an exact 5% type I error (one-sided) and a maximum 20% type II error.  Primary 
Endpoint:   
• 
Efficacy of the combination of bevacizumab and NovoTTF-100A in bevacizumab-naïve 
patients with recurrent GBM as measured by 6-month progression-free survival (PFS6) by KM 
methodology.  
  
Secondary Endpoints:   
  
• 
Safety and tolerability of combination of bevacizumab and NovoTTF-100A in this population 
by CTCAE version 4.0.  
• 
Median overall survival (OS) by KM methodology.  
• 
Objective response rate (ORR) using modified RANO criteria.  
• 
Time-to-progression in this population by KM methodology.  
• 
Time to reliable change (decline) in neurocognitive function by KM methodology  
  
Funding, Regulatory, and Feasibility Issues:   
Up to 48 patients will be enrolled for a total of 40 evaluable patients in the trial.  Every year 125-150 
patients with recurrent GBM are seen at Cleveland Clinic. Approximately 2-3 patients per month will 
be entered onto the study and accrual will be completed in 6-12 months. All patients will be followed 
until progression.  
Patient Acceptability/Ethics and Consent Issues:   
There are no effective therapies for patients with recurrent GBM that have increased survival and the 
combination of bevacizumab and NovoTTF-100A  is promising as bevacizumab has improved 
progression free survival however without improvement in overall survival and addition of 
NovoTTF-100A  may help prevent invasion that is one of the mechanisms of resistance in GBM 
patients that progress on bevacizumab.  Both NovoTTF and bevacizumab are approved by the FDA 
as single agents in the treatment of recurrent GBM. The efficacy of the combination is not known and 
may offer additional benefits to this patient population.  

 
  
10 
 
 
 
TABLE OF CONTENTS  
SYNOPSIS:..................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 
8  
1. 
OBJECTIVE ......................................................................................................................... 
10  
1.1. 
Study Design ..................................................................................................................... 
10  
2. 
BACKGROUND AND RATIONALE: ................................................................................ 
10  
2.1. 
Glioblastoma and Angiogenesis ....................................................................................... 
10  
2.2. 
Vascular Endothelial Growth Factor and GBM ................................................................ 
11  
2.3. 
Angiogenesis and invasion in glioblastoma ...................................................................... 
11  
2.4. 
Introduction to electric fields ............................................................................................ 
12  
2.5. 
NovoCure’s Tumor treating electric fields (TTFields) ..................................................... 
12  
2.6. 
Mechanisms of action of TTFields ................................................................................... 
13  
2.7. 
In Vivo effects of TTFields ............................................................................................... 
14  
2.8. 
The NovoTTF-100A Device ............................................................................................. 
15  
2.9. 
Effect of NovoTTF-100A on recurrent GBM patients – Pivotal study ............................ 
15  
2.10. 
NovoTTF-100A Treatment ........................................................................................... 
18  
2.11. 
Potential Adverse Events: ............................................................................................. 
19  
3. 
SELECTION AND WITHDRAWL OF PATIENTS ........................................................... 
21  
3.1. 
ELIGIBILITY CRITERIA: .............................................................................................. 
21  
3.2. 
Duration of Treatment and Patient Withdrawal Criteria ................................................... 
23  

 
  
11 
4. 
ENDPOINTS ........................................................................................................................ 
23  
4.1. 
Primary Endpoint: ............................................................................................................. 
23  
4.2. 
Secondary Endpoints: ....................................................................................................... 
23  
5. 
STATISTICAL CONSIDERATIONS.................................................................................. 24  
5.1. 
Sample Size/Accrual Rate ................................................................................................. 
24  
6. 
DRUG THERAPY ................................................................................................................ 
24  
6.1. 
Bevacizumab ..................................................................................................................... 
24  
6.2. 
General: ............................................................................................................................. 
25  
6.3. 
OTHER THERAPY .......................................................................................................... 
27  
7. 
TREATMENT PLAN ........................................................................................................... 
27  
7.1. 
Duration of Therapy & Criteria for Removal from Study Treatment ............................... 
28  
8. 
Assessment of Safety ............................................................................................................ 
30  
8.1. 
Safety Parameters .............................................................................................................. 
30  
8.1.1. 
Laboratory Safety Assessments .................................................................................... 
31  
8.1.1.1. 
Hematology, Serum Chemistry, Coagulation, Pregnancy Test ............................ 
31  
8.1.1.2. 
Urinalysis .............................................................................................................. 
31  
8.1.1.3. 
Physical Examination............................................................................................ 31  
8.1.1.4. 
Vital Signs ............................................................................................................. 
31  
8.1.1.5. 
Performance Status ............................................................................................... 
32  
8.1.1.6. 
ECG....................................................................................................................... 32  
8.1.1.7. 
Neurocognitive Function (NCF) ........................................................................... 
32  
8.1.1.8. 
Quality of Life (QOL) ........................................................................................... 
32  
8.1.2. 
ADVERSE EVENT REPORTING............................................................................... 32  

 
  
12 
8.1.2.1. 
Grading of Adverse Event Severity ...................................................................... 
32  
8.2. 
A congenital anomaly/birth defect .................................................................................... 
33  
8.2.1. 
Routine Adverse Event Reporting ................................................................................ 
34  
8.2.2. 
Unanticipated Adverse Device Effect Event (UADE) Reporting ................................. 
34  
9. 
DATA SAFETY MONITORING PLAN ............................................................................. 
34  
10. MEASUREMENT OF EFFECT....................................................................................... 34 
10.1. Response Assessment ................................................................................................... 
34  
References: .................................................................................................................................... 
38  
Appendix 1:  National cancer institute (NCI) common terminology criteria for adverse events  
(CTCAE) ....................................................................................................................................... 41  

 
  
13 
Appendix 2:  Karnofsky performance scale and ECOG performance scale Error! Bookmark not 
defined.  
 

 
  
14 
   
1. OBJECTIVE  
1.1. Study Design  
This will be an open label Phase II trial in adult (age ≥ 22 years) with recurrent glioblastoma 
(GBM).  
  
 
1.1.1.  
Primary:  
To determine the efficacy of the combination of bevacizumab and NovoTTF100A 
in bevacizumab-naïve patients with recurrent GBM as measured by 6-month progression-
free survival (PFS6)  
  
 
1.1.2.  
Secondary:  
• To assess safety and tolerability of the combination of bevacizumab and 
NovoTTF-100A in this population,  
• To evaluate overall survival in this population,  
• To determine objective response rate (ORR) by modified RANO criteria 
in this population,  
• To assess time-to-progression in this population • To assess 
neurocognitive function (NCF) and quality of life (QOL) in this 
population.  
  
2. BACKGROUND AND RATIONALE:   
2.1.  Glioblastoma and Angiogenesis  
Although the recent addition of temozolomide to radiation therapy for the treatment of 
glioblastoma (GBM) has resulted in improved outcomes, the estimated 2-year survival with 
maximal therapy remains only 27%1. Despite treatment of patients with GBM with maximal 
possible surgical resection, radiation and temozolomide almost all patients recur.  The prognosis 
is especially grim for patients who have recurrent GBM. The median survival for these patients 
remains only 3-9 months. Hence, new therapies for GBM are urgently needed. One promising 
area of therapeutic approach has been targeting the angiogenesis. Angiogenesis, the formation of 
new capillaries and blood vessels, is a tightly controlled, multi-step process that is a component 
of normal physiology. It is also a key development in the formation and proliferation of cancers 
particularly for them to grow beyond 2-3 mm in size5-6. GBM is one of the most vascular of all 
solid tumors with increased vascular density and expression of multiple proangiogenic growth 
factors and their receptors both on the tumor vasculature and on tumor cells themselves7. These 
include members of the vascular endothelial growth factor (VEGF) family, basic fibroblast 
growth factor (bFGF), transforming growth factor beta (TGF), tumor necrosis factor alpha 
(TNF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGF), 
hepatocyte growth factor (HGF), angiogenin, interleukin-8 and placental growth factor  (PlGF) 8-
9. The VEGF pathway is believed to be the main pathway involved in the angiogenesis in GBM, 

 
  
15 
and VEGF-A and its receptor VEGFR-2, in particular, appear to be the key in stimulating 
angiogenesis in GBM7.   
  
2.2.  Vascular Endothelial Growth Factor and GBM  
VEGF-A (hereafter referred to as VEGF) is one of several related cytokines in the VEGF 
family, but is distinct in that it acts as an endothelial cell-specific mitogen and is the most 
commonly expressed of its class10. The biological activity of VEGF is mediated principally by 
two tyrosine kinase receptors, VEGFR-1 and VEGFR-29-10. VEGF is overexpressed in GBM 
both on tumor cells and on the cells in the surrounding stroma11. Increased expression of VEGF 
is associated with increased tumor aggressiveness and decreased survival in GBM. VEGFR-2 is 
the main receptor for VEGF and therefore, the primary mediator of VEGF activity on endothelial 
and tumor cells12. Like VEGF, VEGFR-2 expression is strongly upregulated in tumor 
endothelium10. VEGFR-2 expression has been associated with increased tumor microvessel 
density, advanced disease, increased risk of metastasis and recurrence, and lower relapse-free 
survival in patients with a variety of cancers5. Based on these observations, anti-VEGF 
approaches have been increasingly studied in GBM in clinical trials.   
  
Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a humanized monoclonal 
antibody that inhibits VEGF and is the first antiangiogenic therapy to be approved for use in 
patients with cancer. In combination with chemotherapy or biologics, bevacuzimab was 
associated with prolonged overall survival (OS) in phase III trials of metastatic colorectal13  and 
non–small-cell lung14 cancers and with prolonged PFS in metastatic breast15  and renal16 cancers 
compared with placebo or chemotherapy alone. In a single-institute, phase II trial of patients with 
recurrent glioblastoma, bevacuzimab in combination with irinotecan demonstrated 46% 6-month 
PFS and 57% overall response (OR) rates17. This represented substantial improvement over prior 
trials for recurrent malignant glioma that, in aggregate, have resulted in response rates less of 
than 15% and median PFS of 9 weeks4. Following this a phase II randomized clinical trial was 
performed to evaluate the benefit of the addition of irinotecan to bevacizumab. In this clinical 
trial 167 patients with recurrent GBM received either bevacizumab alone or bevacizumab in 
combination with irinotecan; there was no statistically significant difference in the median 
overall survival (OS) for bevacizumab therapy alone (9.2 months) when compared to the 
combination bevacizumab and irinotecan therapy (8.7 months)2. Another phase II study 
evaluated the approach of bevacizumab monotherapy in patients with recurrent GBM followed 
by irinotecan combined with bevacizumab3. In this study, 17/48 patients (35%) achieved an 
initial radiographic response and the PFS-6 was reported to be 29%. Based on the results of these 
two Phase II trials, FDA approved bevacizumab for patients with recurrent GBM2-3.   However, 
the duration of effect of bevacizumab appears to be limited and there are growing concerns about 
the long-term efficacy of bevacizumab. Emerging patterns of tumor progression distant from the 
primary site and recurrence after bevacizumab therapy suggest that VEGF inhibition alone is 
insufficient for long-term tumor control and may change the natural history of glioma 
progression18. Hence strategies that target invasion may be needed to prevent this pattern of 
resistance.  

 
  
16 
2.3.  Angiogenesis and invasion in glioblastoma   
The two processes, angiogenesis and tumor cell invasion, are closely associated.  In gliomas, 
VEGF promotes both angiogenesis and invasion of tumor cells19.  “Invasion” of endothelial cells 
into the tumor is an important component of the angiogenic process. In most studies, bevacizumab 
was used in combination with traditional cytotoxic agents. In other tumors bevacuzimab has been 
associated with prolonged overall survival (OS) in phase III trials of metastatic colorectal13  and 
non–small-cell lung14 cancers and with prolonged PFS in metastatic breast15  and renal16 cancers 
combination with chemotherapy or biologics. However this has not been the case in GBM as 
treatment with bevacizumab leads to normalization of the blood brain barrier and this decreases 
the amount of chemotherapy or targeted therapy reaching the tumor.  
2.4.  Introduction to electric fields   
 In the laboratory setting and in clinical practice, alternating electric fields show a wide range of 
effects on living tissues. At very low frequencies (under 1 kHz), alternating electric fields stimulate 
excitable tissues through membrane depolarisation20-21. The transmission of such fields by 
radiation is insignificant and therefore they are usually applied directly by contact electrodes 
(transducer arrays), though some applications have also used insulated electrodes (transducer 
arrays). Some well known examples of such effects include nerve, muscle and heart stimulation 
by alternating electric fields20-21. In addition, low frequency pulsed electric fields have been 
claimed to stimulate bone growth and accelerate fracture healing. However, as the frequency of 
the alternating electric field increases above 1 kHz, the stimulatory effect diminishes. Under these 
conditions although a greater fraction of the fields penetrates the cells, due to the parallel resistor-
capacitor nature of all biological membranes, the stimulatory power greatly diminishes as the 
alternating cell membrane hyper–depolarization cycles are integrated such that the net effect is 
nulled.   
 At very high frequencies (i.e., above many MHz), while the integration becomes even more 
effective, a completely different biological effect is observed. At these frequencies tissue heating 
becomes dominant due to dielectric losses. This effect becomes more intense as field intensity or 
tissue dissipation factor increase22. This phenomenon serves as the basis for some commonly used 
medical treatment modalities including diathermy and radio frequency tumor ablation, which can 
be applied through insulated electrodes (transducer arrays)23.  
Intermediate frequency electric fields (i.e., tens of kHz to MHz), alternate too fast to cause nerve-
muscle stimulation and involve only minute dielectric losses (heating). Such fields, of low to 
moderate intensities, are commonly considered to have no biological effect22. However, a number 
of non-thermal effects, of minor biological consequence, have been reported even at low field 
intensities. These include microscopic particle alignment (i.e., the pearl chain effect24) and cell 
rotation25. With pulsed relatively strong electric fields, > 103 V/cm and 100 ms pulse length, 
reversible pore formation appears in the cell membrane, a phenomenon usually called 
electroporation26.  
2.5. NovoCure’s Tumor treating electric fields (TTFields)  
Preclinical studies have shown that when properly tuned, very low intensity, intermediate 
frequency electric fields (TTFields) stunt the growth of tumor cells27. This inhibitory effect was 
demonstrated in all proliferating cancer cell types tested, whereas, non-proliferating cells and 
normal tissues were unaffected. Interestingly, different cell types showed specific intensity and 

 
  
17 
frequency dependencies of TTField inhibition. It has been shown that two main processes occur at 
the cellular level during exposure to TTFields: arrest of proliferation and dividing cell destruction. 
The damage caused by TTFields to these replicating cells was dependent on the orientation of the 
division process in relation to the field vectors, indicating that this effect is non-thermal. Indeed, 
temperature measurements made within culture dishes during treatment and on the skin above 
treated tumors in-vivo, showed no significant elevation in temperature compared to control 
cultures/mice. Also, TTFields caused the dividing cells to orient in the direction of the applied field 
in a manner similar to that described in cultured human corneal epithelial cells exposed to constant 
electric fields28. At the sub-cellular level it was found that TTFields disrupt the normal 
polymerization-depolymerization process of microtubules during mitosis. Indeed, the described 
abnormal mitotic configurations seen after exposure to TTFields are similar to the morphological 
abnormalities seen in cells treated with agents that interfere directly29-30 or indirectly31-33  with 
microtubule polymerization (e.g., paclitaxel).  
2.6.  Mechanisms of action of TTFields  
In order to explain how TTFields cause orientation dependent damage to dividing cells and 
disrupt the proper formation of the mitotic spindle Novocure modeled the forces exerted by 
TTFields on intracellular charges and polar particles using finite element simulations. Two main 
mechanisms by means of which the electric fields may affect dividing cells were recognized. The 
first relates to the field effect on polar macromolecule orientation. Within this framework, during 
the early phases of mitosis, i.e., in pre-telophase, when tubulin polymerization-depolymerization 
drives the proliferation process, the electric field forces any tubulin dimers, positioned further than 
14nm away from the growing end of a microtubule, to orient in the direction of the field. This force 
moment, (10-5 pN) acting on the dimers, is sufficient to interfere with the proper process of 
assembly and disassembly of microtubules that is essential for chromosome alignment and 
separation34. This effect can explain the mitotic arrest of TTField treated cells35.   
The second mechanism, which interferes with cell division, and is most likely to play an 
important role in cell destruction, becomes dominant during cleavage. As seen in simulations, the 
electric field within quiescent cells is homogenous, whereas the field inside mitotic cells, during 
cytokinesis, is not homogenous. An increased field line concentration (indicating increased field 
intensity) is seen at the furrow, a phenomenon that highly resembles the focusing of a light beam 
by a lens. This in-homogeneity in field intensity exerts a unidirectional electric force, on all 
intracellular charged and polar entities (including induced dipoles), pulling them towards the 
furrow (regardless of field polarity). For example, for a cleavage furrow that reached a diameter of 
1µm in an external field of only 1 V/cm, the force exerted on the microtubules is in the order of 
5pN. This magnitude is compatible with the reported forces necessary to stall microtubule 
polymerization which is 4.3 pN36. With regards to other particles, such as cytoplasmic organelles, 
they are polarized by the field within dividing cells. Once polarized, the forces acting on such 
particles may reach values up to an order of 60 pN resulting in their movement towards the furrow 
at velocities that may approach 0.03 m/sec. At such velocity, cytoplasmic organelles would pile up 
at the cleavage furrow within a few minutes, interfering with cytokinesis and possibly leading to 
cell destruction. It has also been found that the electric forces acting on intracellular particles are 
maximal when the axis of division is aligned with the external field. This is consistent with the 
dependence of the destructive effect of TTFields on the angle between division axis and the field, 

 
  
18 
as demonstrated experimentally. In addition, the calculated dependence of the magnitude of this 
force on frequency is consistent with the experimentally determined frequency dependence of the 
inhibitory effect of TTFields on melanoma and glioma cell proliferation (120 kHz vs. 200 kHz, 
respectively).  
  
Figure 1 Tumor Treating Fields Mechanism of Action: (A) Disruption of the formation of 
the mitotic spindle in metaphase and (B) Positive dielectrophoresis during anaphase.  
2.7.  In Vivo effects of TTFields   
Novocure has shown that TTFields can be applied effectively to animals through electrodes 
(transducer arrays) placed on the surface of the body27, 37. Using a special type of electrically 
insulated electrodes (transducer arrays), significant inhibition of the growth of both intradermal 
melanoma (B16F1) in mice and intracranial glioma (F-98) in rats was seen after less then one week 
of treatment. This growth inhibition was accompanied by a decrease in angiogenesis within the 
tumor, due to inhibition of endothelial cell proliferation.   
Extensive safety studies in healthy rabbits and rats exposed to TTFields for protracted periods 
of time have shown no treatment related side effects.  The reasons for the surprisingly low toxicity 
of TTField treatment can be explained in the light of the known passive electric properties of 
normal tissues within the body and the effects of electric fields applied via insulated electrodes 
(transducer arrays). More specifically, two types of toxicities may be expected in an electric field 
based treatment modality. First, the fields could interfere with the normal function of excitable 
tissues within the body causing, in extreme cases, cardiac arrhythmias and seizures. However, this 
is not truly a concern with TTFields since, as frequencies increase above 1 kHz, excitation by 
sinusoidal electric fields decreases dramatically due to the parallel resistorcapacitor nature of the 
cell membrane (with a time constant of about 1ms).  Thus, as expected, in both acute and chronic 
application of TTFields to healthy animals, no evidence of abnormal cardiac rhythms or pathologic 
neurological activity was seen.   
Secondly, the anti-mitotic effect of TTFields might be expected to damage the replication of 
rapidly dividing normal cells within the body (bone marrow, small intestine mucosa). Surprisingly, 
no treatment related toxicities were found in any of the animal safety trials performed by Novocure, 

 
  
19 
even when field intensities 3 fold higher than the effective anti-tumoral dose were used. The lack 
of damage to intestinal mucosa in TTField-treated animals is probably a reflection of the fact that 
the small intestine mucosal cells have a slower replication cycle than neoplastic cells and that the 
intestine itself most likely changes its orientation in relation to the applied field quite often, 
lowering the efficacy of TTField mediated mitotic disruption. Bone marrow, on the other hand, is 
naturally protected from TTFields by the high electric resistance of both bone and bone marrow 
compared to most other tissues in the body. To test the later assumption, the TTField intensity 
within the bone marrow of a long bone was modeled using the finite element mesh (FEM) method. 
It was found that the intensity of TTFields was 100-fold lower within the bone marrow compared 
to the surrounding tissues (including within solid tumors). Thus, hematopoietic cell replication 
should not be affected even when TTField intensities 10-fold higher than necessary to inhibit tumor 
growth are applied.  
2.8. The NovoTTF-100A Device   
The NovoTTF-100A is a portable battery operated device which produces TTFields within the 
human body using surface electrodes (transducer arrays). The TTFields are delivered to the patient 
by means of surface transducer arrays that are electrically insulated, so that resistively coupled 
electric currents are not delivered to the patient. The transducer arrays, which incorporate a layer 
of adhesive hydrogel and a layer of hypoallergenic medical tape, are placed on the patient’s shaved 
head. The transducer arrays must be replaced every three to four days and the scalp re-shaved in 
order to maintain optimal capacitative coupling between the transducer arrays and the patient head. 
All the treatment parameters are pre-set by Novocure so there are no electrical output adjustments 
available to the patient. The patient must learn to apply and change transducer arrays and change 
and recharge depleted device batteries and to connect to an external electrical outlet.  
  
Novocure Device Support Specialists and/or Clinical Science Liaisons will be available at all 
clinical sites participating in the trial to train and support patients, research staff and health care 
professionals with the operation and management of the device. In addition, Novocure provides a 
24/7 support line for patients and the health care team.     
2.9. Effect of NovoTTF-100A on recurrent GBM patients – Pivotal study   
A pilot study was performed enrolling 10 recurrent GBM patients treated with the NovoTTF-
100A device as monotherapy37-38. All patients underwent surgery and radiotherapy for the primary 
tumor. Only 1 patient was chemotherapy naïve, the rest having received either Temozolomide or 
other chemotherapeutic agents, as adjuvant treatment, prior to recurrence.  
   
All patients were treated with multiple four-week treatment courses using continuous, 24hour 
a day, 200 kHz, 0.7 V/cm TTFields. TTFields were applied through two sets of opposing insulated 
transducer arrays and alternated at a 1 second duty cycle between two perpendicular field directions 
through the tumor. Patients completed between 1 and 15 treatment courses leading to maximal 
treatment duration of 14.5 months. Overall, more than 70, 4 week treatment courses were 
completed (> 7 courses per patient on average). The treatment was well tolerated with no treatment 
related serious adverse events seen in any of the patients. Patients received treatment on average 
about three quarters of the scheduled time. Considering the continuous nature of NovoTTF 
treatment (i.e., 24 hours a day for many months) this figure indicates that compliance with 

 
  
20 
treatment, similar to the newly diagnosed pilot study was very high, with patients taking very few 
days off treatment and stopping only for short periods of time during treatment for personal needs. 
Mild to moderate contact dermatitis appeared beneath the transducer gel in 8 of the 10 patients 
during treatment. The skin reaction improved with use of topical corticosteroids and regular 
shifting of the location of the transducer arrays.  
  
The median progression free survival (PFS) of the patients in this study exceeded historical 
controls4 dramatically (26.1 weeks versus 9 weeks, respectively). The PFS at 6 months (PFS6) was 
50% compared to 15% in historical controls4. Until the last report 7 of the 10 patients have died. 
The remaining 3 patients are still alive and 2 of them are progression free. Median overall survival 
was 62 weeks. Response rate was 25% (1 CR + 1 PR) and only two patients had progressive disease 
despite treatment.   
  
Effect of NovoTTF-100A on recurrent GBM patients – Pivotal study NovoTTF: 
Recurrent GBM Phase III Trial (EF‐11) 
 
  
Figure 2: Schema of the EF-11 trial- Effect of NovoTTF-100A in Recurrent Glioblastoma 
Multiforme (GBM)  
  
Based on the promising data from the pilot trial, Novocure conducted a prospective, 
randomized, open label, active parallel control trial to compare the effectiveness and safety 
outcomes of recurrent GBM subjects treated with NovoTTF-100A monotherapy (n=120) to those 
treated with an effective best standard of care chemotherapy (including bevacizumab; n=117).  
Best standard of care chemotherapy was investigator chosen with the most common treatments as 
follows: 31% bevacizumab based regimens, 31% irinotecan and 25% nitrosureas. Patient 
characteristics were well balanced between treatment arms and 90% of patients were at their 
second or beyond recurrence (Figure 2). NovoTTF-100A subjects had comparable overall survival 

 
  
21 
to subjects receiving the best available chemotherapy (OS 6.6 vs. 6.0 months; HR 0.86; p=0.98, 
shown in Figure 3)39.  Similar results showing comparability of NovoTTF-100A to chemotherapy 
were seen in all secondary endpoints (e.g., PFS6 = 21.4% for NovoTTF-100A vs. 15.2% for 
chemotherapy). In addition, objective response rates were seen with NovoTTF-100A monotherapy 
14 vs. 9.6% for chemotherapy (p = 0.19).    
  
  
 
  
Figure 3: Overall survival (Kaplan Meier curves)  
  
NovoTTF-100A subjects experienced fewer adverse events in general, significantly fewer 
treatment related adverse events, and significantly lower gastrointestinal, hematological and 
infectious adverse events compared to chemotherapy controls.  The only device-related adverse 
events seen were a mild to moderate skin irritation beneath the device transducer arrays, which 
was easily treated with topical ointments. Finally, quality of life measures (EORTC – QLQ C30 
symptom and general scales) were better in NovoTTF-100A subjects as a group when compared 
to subjects receiving effective best standard of care chemotherapy.   
  
  Given the clinical interest in bevacizumab in the setting of recurrent GBM two exploratory 
survival analyses were performed in a subset of bevacizumab treated patients: 1) NovoTTF-
100A treatment versus patients that had received bevacizumab-based regimens on the 
chemotherapy arm of the trial and 2) NovoTTF-100A versus chemotherapy in the subset of 
patients that had progressed on prior bevacizumab (~20%).  In the first exploratory analysis, 
median OS was significantly longer for the NovoTTF-100A treated patients than for those 
treated with a bevacizumab based regimen (6.6 vs. 5.0 months; HR 0.65, p = 0.048; CI 0.51 to 
0.90)40  (Figure 3).  In the second exploratory analysis, median OS in patients who had 

 
  
22 
progressed on bevacizumab, was significantly longer when treated with NovoTTF-100A 
compared to chemotherapy (6.3 vs. 3.3 months; HR 0.39; p = 0.01; CI 0.19 to 0.79) (Figure 4).   
  
Treatment options for patients with recurrent GBM progressing on bevacizumab remains 
a significant clinical challenge and an important area of study.  Given the single agent activity of 
NovoTTF, especially in patients who have progressed on bevacizumab, coupled with the fact 
that the mechanism of action of NovoTTF not being limited by normalization of the BBB by use 
of concomitant bevacizumab makes a rational and compelling case for evaluation of the 
combination of Novocure TTF and bevacizumab in patients with recurrent GBM who progress 
on bevacizumab.  In addition, the favorable safety profile of NovoTTF suggests that the 
combination will add little additional toxicity.   
  
In summary, a combination of NovoTTF-100A and bevacizumab is promising:  
1. The mechanism of action of NovoTTF-100A is not limited by normalization of 
the blood brain barrier by use of bevacizumab  
2. Two approaches have non overlapping toxicities.    
3. Both approaches demonstrated efficacy and have been approved by the FDA.  
  
Hence we propose a trial of a combination of NovoTTF-100A and bevacizumab in patients 
with recurrent GBM who are bevacizumab naive.  
2.10. NovoTTF-100A Treatment    
  
1. 
Treatment planning: Transducer array layout will 
be determined based on the location of the patient’s 
tumor(s) on MRI. Patient training: Patients will be trained 
in the use of the device by the investigator, a designated 
health care provider (eg. Nurse) or device technician 
trained by Novocure. Novocure is currently validating the 
software used for external use.  Once validated, the 
investigator using the NovoTAMTM software supplied by 
Novocure will determine the transducer array layout. 
Investigators will be trained in the utilization of this 
software by a Novocure representative. In the meantime, 
investigators will forward MRIs to Novocure for array 
layout planning.  
2. 
Treatment initiation: NovoTTF-100A treatment 
will be initiated by the investigator as per  
protocol.  All patients will be required to shave their 
heads to initiate array placement and TTField therapy.  
Array placement will be performed based on the 
transducer array map calculated during treatment 
planning.  

 
  
23 
3. Treatment duration: Treatment with the device will be continuous with breaks allowed 
for personal needs (eg. showering, array exchange). Patients must use the device for at 
least 18 hours a day on average. Treatment will be continued until disease progression in 
the brain, death, or unacceptable side effects to patient.   
4. The NovoTTF-100A device will be programmed by Novocure to deliver 200kHz 
TTFields in two sequential, perpendicular field directions at a maximal intensity of 
707mA RMS. There will be no adjustments made to the device by investigators or 
patients/caregivers.   
5. 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 
re-
shaved and skin treated 
according to the 
guidelines set out 
below.  
6. Compliance assessment: The device will be interrogated on a monthly basis to assess 
patient compliance with therapy. Novocure is currently validating the software for 
investigator use, using the NovoPCATM . Until this is available Novocure device 
technicians will conduct the monthly compliance assessment.  
7. The following skin care guidelines should be closely adhered to:  
a. If the skin beneath the transducer arrays is inflamed a hydrocortisone ointment 
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.   
b. 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.  
c. If the dermis is breached (ulcers, open sores, punctate lesions, cuts, etc.) an 
antibiotic ointment (e.g. mupiricin) should be prescribed and used in place of the 
hydrocortisone ointment.  
d. 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.  
2.11. Potential Adverse Events:  
  

 
  
24 
NovoTTF-100A  
Treatment with the NovoTTF-100A is not expected to cause any serious side effects.   
However, it is possible that treatment may cause any of the following:  
1. Local warmth and tingling “electric” sensation beneath the transducer array  
2. Allergic reaction to the adhesive or to the gel  
3. Skin irritation or skin breakdown  
4. Infection at the sites of transducer array contact with the skin  
5. Transducer array overheating leading to pain and/or local skin burns  
6. Headache  
7. Fatigue  
In the phase III trial of NovoTTF-100A monotherapy vs. physician’s choice chemotherapy in 
recurrent GBM the following moderate to severe adverse events (regardless of causality) were 
seen:  
 
 
TTF (n=116)  
Active Control (n=91)  
System  
Adverse event term  
%  (% gr. 3+4)  
%  (% gr. 3+4)  
Hematological  
3 (0)  
17 (4)  
 
Leukopenia  
0 (0)  
5 (1)  
 
Neutropenia   
0 (0)  
2 (1)  
 
Thrombocytopenia  
1 (1)†  
7 (2)  
Gastrointestinal disorders  
4 (1)  
17 (3)  
 
Abdominal pain  
0 (0)  
3 (0)  
 
Diarrhea  
0 (0)  
6 (2)  
 
Nausea / Vomiting  
2 (0)  
7 (0)  
General deterioration and malaise  
5 (1)  
6 (1)  
Infections  
4 (0)  
8 (1)  
Skin rash (transducer arrays)  
2 (0)  
0 (0)  
Metabolism and nutrition disorders  
4 (1)  
6 (3)  
Musculoskeletal Disorders  
2 (0)  
5 (0)  

 
  
25 
Nervous system disorders  
30 (7)  
28 (7)  
 
Brain edema  
0 (0)  
2 (0)  
 
Cognitive disorder  
2 (1)  
2 (1)  
 
Convulsion  
7 (2)  
5 (2)  
 
Dysphasia  
2 (0)  
1 (0)  
 
Headache  
8 (1)  
6 (0)  
 
Hemianopsia  
1 (0)  
3 (1)  
 
Hemiparesis  
3 (1)  
2 (1)  
 
Neuropathy peripheral  
2 (0)  
2 (0)  
Psychiatric disorders  
5 (0)  
4 (0)  
Renal and urinary disorders  
3 (1)  
3 (0)  
Respiratory Disorders  
1 (0)  
3 (1)  
Vascular disorders  
3 (1)  
4 (3)  
  
Pulmonary embolism  
1 (1)  
2 (2)  
  
Hypertension  
1 (0)  
1 (1)  
  
Deep vein 
thrombosis  
1 (0)  
1 (0)  
† thrombocytopenia from prior chemotherapy, normalized 
subsequ 
ently.  
  
3. SELECTION AND WITHDRAWL OF PATIENTS  
3.1. ELIGIBILITY CRITERIA:   
Inclusion criteria:  

 
  
26 
1. Patients with histologically confirmed glioblastoma or other grade IV malignant glioma 
(i.e. gliosarcoma, small cell glioblastoma, etc.), recurrent after prior external-beam 
fractionated radiotherapy and temozolomide chemotherapy.  
2. Patients with upto two prior recurrences are allowed.  
3. Karnofsky performance status ≥ 70%.  
4. Age ≥ 22 years old.     
5. Patients must have the following laboratory values:  
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L  
• 
Platelets ≥ 100 x 109/L  
• 
Hemoglobin (Hgb) > 9 g/dL  
• 
Serum total bilirubin: ≤ 1.5 x ULN  
• 
ALT and AST ≤ 3.0 x ULN  
• 
Serum creatinine ≤ 1.5 x ULN   
• 
Blood coagulation parameters: INR ≤ 1.5  
6. Minimum interval since completion of radiation treatment is 12 weeks  
7. Minimum interval since last drug therapy:  
• 
3 weeks since last non-cytotoxic therapy  
• 
3 weeks must have elapsed since the completion of a non-nitrosoureacontaining 
chemotherapy regimen  
• 
6 weeks since the completion of a nitrosourea-containing chemotherapy 
regimen.  
8. Patients must have signed an approved informed consent and authorization permitting 
release of personal health information.  
9. Patients with the potential for pregnancy or impregnating their partner must agree to 
follow acceptable birth control methods to avoid conception. The effects of bevacizumab 
on developing fetus or nursing infant are not known.  Female patients of child-bearing 
potential must have a negative pregnancy test.  
10. Patients must have no concurrent malignancy except curatively treated basal or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated 
stage I or II cancer from which the patient is in complete remission. Patients with other 
prior malignancies must be disease-free for ≥ three years.  
11. Patients must be maintained on a stable corticosteroid regimen from the time of their 
baseline scan until the start of treatment and/or for at least 5 days before starting 
treatment.  

 
  
27 
Exclusion criteria:  
1. Patients who have had previous treatment with either bevacizumab and/ or NovoTTF 
100A system.  
2. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or 
intrapelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study 
drug, or patients who have had minor procedures, percutaneous biopsies or placement of 
vascular access device ≤ 1 week prior to starting study drug,  or who have not recovered 
from side effects of such procedure or injury  
3. Patients with impaired cardiac function or clinically significant cardiac diseases, 
including any of the following:  
• 
History or presence of serious uncontrolled ventricular arrhythmias  
• 
Any of the following within 6 months prior to starting study drug: myocardial 
infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), 
Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient 
Ischemic Attack (TIA), Pulmonary Embolism (PE)  
• 
Uncontrolled hypertension (defined by a SBP ≥ 160 mm Hg or DBP ≥ 100 mm 
Hg while on anti-hypertensive medications)  
4. Patients with cirrhosis, or active viral or nonviral hepatitis.  
5. Implanted pacemaker, shunts, defibrillator or deep brain stimulator, other implanted 
electronic devices in the brain or documented clinically significant arrhythmias.  
6. Infra-tentorial tumor  
7. Evidence of increased intracranial pressure (clinically significant papilledema, vomiting 
and nausea or reduced level of consciousness)  
8. Known sensitivity to conductive hydrogels   
9. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory)    
10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active 
or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety 
risks or compromise compliance with the protocol  
11. Pregnant or breast-feeding women  
12. Patients unwilling or unable to comply with the protocol  
13. Patients with leptomeningeal disease  
3.2.  Duration of Treatment and Patient Withdrawal Criteria  
Patients are eligible for treatment with the combination of bevacizumab and NovoTTF-100A 
until disease progression or unacceptable toxicity.  A patient should be withdrawn from study 

 
  
28 
treatment if, in the opinion of the Investigator, it is medically necessary, or if it is the wish of the 
patient.  If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient.  In any circumstance, every effort should be made to document patient outcome.  
Data to be collected at the end of study visit are described in the Schedule of Assessments 
(Table).  Patients will be followed for at least 28 days after the last dose of bevacizumab and 
removal of NovoTTF-100A for adverse events.  If the patient withdraws consent, no further 
evaluations should be performed, and no attempts should be made to collect additional data. In 
addition, patients will be withdrawn from treatment in the case of:  
• 
Modified RANO criteria defined disease progression. In cases where Modified 
RANO criteria cannot be applied, progression should be based on unequivocal 
evidence of progressive disease sufficient to require a change in therapy.  
• 
A need for surgery, radiation, or for other anticancer therapy not specified in the 
protocol.  
• 
Lost to follow-up or noncompliant.  
• 
Pregnancy.  Pregnant patients should be followed for the duration of the 
pregnancy and the outcome of the pregnancy should be documented.   
4. ENDPOINTS  
4.1.  Primary Endpoint:   
1. Efficacy of combination of bevacizumab and NovoTTF-100A in bevacizumab-naïve 
patients with recurrent GBM as measured by 6-month progression-free survival 
(PFS6)  
4.2.  Secondary Endpoints:    
1. Safety and tolerability of combination of bevacizumab and NovoTTF-100A in this 
population   by CTCAE version 4.0.  
2. Median overall survival (OS) by KM methodology  
3. Objective response rate (ORR) using modified RANO criteria.  
4. To assess time-to-progression in this population  
5. To assess neurocognitive function (NCF) and quality of life (QOL) in this population.  
 
5. STATISTICAL CONSIDERATIONS   
In the randomized Phase II trial of bevacizumab with or without irinotecan in recurrent GBM 
participants in first or second relapse. Participants were treated with bevacizumab 10 mg/kg 
every 2 weeks, alone or in combination with irinotecan2. In the bevacizumab monotherapy arm 
(n=85), the response rate was 28% and PFS6 43%2. In reviewing this trial for purposes of 
approval, the FDA conducted an independent imaging review and determined that the response 
rate was 26% and the PFS6 was 36%41.  

 
  
29 
5.1. Sample Size/Accrual Rate  
This trial will be a single arm multicenter phase II and will accrue 25 participants. We will 
estimate PFS6 in this trial following FDA estimate. The 95% confidence interval around 36% will 
be 18-58% with 25 patients. The trial will be conducted at Cleveland Clinic, Ohio State University 
and University of Cincinnati. Every year 125-150 patients with recurrent GBM are seen at 
Cleveland Clinic. Approximately 2 patients per month will be entered onto the study and accrual 
will be completed in 12 months. All patients will be followed until progression.  
  
5.2 Data Analysis  
  
Since all patients will have the potential for at least six months of follow-up PFS will be 
summarized both as the simple proportion of patients progression-free at 6 months and using the 
method of Kaplan and Meier. Secondary endpoints such as response, toxicity, neurocognitive 
function and QOL (based on the FACT-Br) will be summarized using frequency counts and 
proportions or medians and ranges as appropriate. Changes from baseline at a particular timepoint 
will be assessed using methods such as chi-square tests and the Wilcoxon signed rank test, while 
the overall time to neurocognitive decline and overall survival will be assessed using the Kaplan-
Meier method. Exploratory comparisons of time-to-event data such as overall PFS, overall 
survival, and neurocognitive decline will be conducted using methods such as the logrank test and 
proportional hazards model. Tests of significance of secondary endpoints will generally be two-
sided and no adjustment will be made for multiple comparisons due to the exploratory nature of 
these studies.  
  
6. DRUG THERAPY   
6.1.  Bevacizumab   
Bevacizumab will be administered intravenously on days 1 and 15 of each 28 day cycle. 
Bevacizumab is approved for patients with recurrent GBM and will be from the commercial supply 
and not provided in the study. The dose of bevacizumab will be 10 mg/kg of actual body weight. 
The dose will be determined using body weight determined at the beginning of each treatment 
cycle.    
6.2.  General:   
Prior to each treatment, the patient should be carefully assessed with special attention to blood 
pressure, proteinuria, bleeding and cardiovascular events, as well as symptoms or signs of bowel 
perforation and reversible posterior leukoencephalopathy syndrome (RPLS).  Infusional reactions: 
Routine premedication is not required for the first dose of bevacizumab. If infusional reactions 
occur, acetaminophen, diphenhydramine, steroids or other medications may be given for symptom 
control and for premedication as needed.  Anaphylactic precautions should be observed during 
bevacizumab administration.   
• 
Hypertension: Patients should have blood pressure monitored prior to each 
infusion of bevacizumab.  Hypertensive medication should be initiated or 
increased for optimal blood pressure control according to standard public heath 
guidelines.   

 
  
30 
• 
Surgery and wound complication issues and surgery: The appropriate interval 
from discontinuation of bevacizumab to subsequent elective surgery required to 
reduce the risk of impaired wound healing has not been determined.  Decision on 
such an interval should take into consideration the half-life of bevacizumab.  It is 
generally recommended that bevacizumab should be discontinued at least 4-8 
weeks prior to major elective surgery.  In addition, bevacizumab should not be 
restarted until at least 4 weeks after major surgery provided that the wound has 
adequately healed; in cases of high risk procedures such as liver resection, 
thoracotomy or neurosurgery, it is recommended that bevacizumab be resumed no 
earlier than 8 weeks after surgery.  
  
Bevacizumab Dose Modifications   
The dose of bevacizumab will be 10 mg/kg delivered intravenously. There will be no 
dose reduction for bevacizumab.  Treatment should be interrupted or discontinued for certain 
adverse events, as described below. If bevacizumab is interrupted for ANY reason for > 8 weeks, 
the patient should discontinue bevacizumab therapy on protocol. If the bevacizumab therapy  is 
discontinued and the patient is maintained on the protocol on only NovoTTF 100A system, then 
the laboratory tests pertaining to bevacizumab may be discontinued and the patient need to be 
followed only once every 4 weeks and can discontinue bevacizumab related labs such as urine 
analysis.   
Treatment Modification for Bevacizumab- Related Adverse Events  
  
Event   
CTCAE.v4.0 Grade   
Action To Be Taken   
Allergic reactions or Acute  
Grade 1‐3   
If infusion‐related or allergic reactions occur, premedications should be 
infusional reactions/  
given with the next dose and infusion time may not be reduced for the cytokine release 
syndrome   subsequent infusion. Follow the guidelines in Section 7.3 for  
bevacizumab administration. For patients with grade 3 reactions, 
bevacizumab infusion should be stopped and not restarted on the same 
day. At the physicians’ discretion, bevacizumab may be permanently 
discontinued or re‐instituted with premedications and at a rate of 90+15 
min. If bevacizumab is re‐instituted, the patient should be closely 
monitored for a duration comparable to or longer than the duration of 
the previous reactions.   
 
 
Grade 4   
Discontinue bevacizumab   
Arterial Thrombosis ‐Cardiac 
ischemia/ infraction ‐CNS 
ischemia (TIA, CVA) ‐any 
peripheral or visceral arterial 
ischemia/thrombosis   
Grade 2 ( if new or 
worsened since 
bevacizumab therapy) 
Discontinue bevacizumab   
 
Grade 3‐4   
Discontinue   
Venous Thrombosis   
 
 

 
  
31 
 
Grade 3 OR 
asymptomatic grade 
4   
Hold bevacizumab treatment. If the planned duration of full‐dose 
anticoagulation is < 2 weeks, bevacizumab should be held until the 
fulldose anticoagulation period is over. If the planned duration of 
fulldose anticoagulation is >2 weeks, bevacizumab (or placebo) may be 
resumed during the period of full‐dose anticoagulation IF all of the 
criteria below are met: -The subject must have an in‐range INR (usually 
2‐3) on a stable dose of warfarin or be on a stable dose of heparin prior 
to restarting bevacizumab -The subject must not have pathological 
conditions that carry high risk of bleeding (eg, tumor involving major 
vessels or other conditions) -The subject must not have had 
hemorrhagic events while on study.If thromboemboli worsen/recur 
upon resumption of study therapy, discontinue bevacizumab   
 
Grade 4  
(symptomatic)   
Discontinue bevacizumab   
Hypertension*   
[Treat with 
antihypertensive 
medication as 
needed. The goal 
of BP control 
should be 
consistent with 
general medical 
practice]   
 
 
Grade 1   
Consider increased BP monitoring   
 
Grade 2 
asymptomatic but  
diastolic BP < 100 
mmHg   
Begin anti‐hypertensive therapy and continue bevacizumab   
 
‐Grade 2‐3 
Symptomatic OR 
Diastolic BP > 100 
mmHg   
• Hold bevacizumab until symptoms resolve AND BP < 160/90mmHg*   
 
Grade 4   
Discontinue bevacizumab   
Congestive Heart Failure   
Grade 3   
• Discontinue bevacizumab   
 
Grade 4  
Discontinue Bevacizumab  
 
Grade 4   
Discontinue bevacizumab   
Proteinuria   
[Proteinuria should be monitored by urine analysis for urine protein creatinine (UPC) ratio prior 
to every other dose of bevacizumab   
UPC ratio < 3.5   
Continue bevacizumab   
UPC ratio > 3.5   
Hold bevacizumab (or placebo)until UPC recovers to < 3.5   
Grade 4 or  
Discontinue bevacizumab  
nephrotic syndrome   
Hemorrhage (CNS or 
pulmonary)   
Grade 2‐4   
• Discontinue bevacizumab   
Hemorrhage (non‐CNS; 
nonpulmonary)   
Grade 3   
• Patients receiving full‐dose anticoagulation should discontinue 
bevacizumab • For patients not on full‐dose anticoagulation, hold 
bevacizumabuntil ALL of the following criteria are met: ‐the bleeding has 
resolved and Hb is stable ‐there is no bleeding diathesis that would 
increase the risk of therapy ‐there is no anatomic or pathologic condition 
that could increase the risk of hemorrhage recurrence. • Patients who 
experience recurrence of grade 3 hemorrhage should discontinue study 
therapy   
Grade 4   
Discontinue bevacizumab   

 
  
32 
RPLS (reversible posterior 
leukoencephalopathy syndrome 
or PRES (posterior reversible 
encephalopathy syndrome)   
• Hold bevacizumab  in patients with symptoms/signs suggestive of RPLS; subsequent 
management should include MRI scans and control of HTN • Discontinue bevacizumab   upon 
diagnosis of RPLS   
Wound dehiscence requiring  
medical or surgical 
intervention   
•Discontinue bevacizumab    
GI perforation, GI leak or 
fistula   
Discontinue bevacizumab     
Bowel obstruction   
Grade 2 requiring  • Hold bevacizumab   until complete resolution, with a minimum of 4 
medical  weeks after surgery.  intervention   
 
Grade 3‐4   
• Hold bevacizumab until complete resolution • If surgery is required, 
patient may restart bevacizumab after full recovery from surgery, and at 
investigator’s discretion   
Other unspecified 
bevacizumab‐related AEs 
(except controlled 
nausea/vomiting).   
Grade 3   
Hold bevacizumab until symptoms resolve to < grade 1   
Grade 4   
• Discontinue bevacizumab• Upon consultation with the study chair, 
resumption of bevacizumab may be considered if a patient is benefiting 
from therapy and the grade 4 toxicity is transient, has recovered to < 
grade 1 and unlikely to recur with retreatment   
  
  
6.3. OTHER THERAPY  
Permitted Supportive Therapy  
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication.  
• 
Anticonvulsants: Anticonvulsants may be used as clinically indicated. Doses at 
study entry and at specific time points of the treatment must be recorded.  
• 
Corticosteroids: Corticosteroids may be administered at the treating physician’s 
discretion. Doses at study entry and at specific time points of the treatment must 
be recorded.  
7. TREATMENT PLAN  
Treatment will be administered on an outpatient basis.  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy.   
7.1.  Duration of Therapy & Criteria for Removal from Study Treatment  
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies:  
• Disease progression,  
• Intercurrent illness that prevents further administration of treatment,  
• Unacceptable adverse event(s)   
• Participant demonstrates an inability or unwillingness to comply with protocol  

 
  
33 
• Participant becomes pregnant,  
• Participant decides to withdraw from the treatment phase of the study, or  
• General or specific changes in the participant’s condition render the participant unacceptable 
for further treatment in the opinion of the treating investigator.   
 

 
  
34 
  
 
1.  
Table:    
Schedule of Assessments   
Protocol Activities  
Screening  
*Cycle 1  
*Cycles 2  
*Cycles 
3+  
End 
of  
Study 
[3]  
**Post  
Treatment  
Followup  
Day -28  
Day 1 [1,2]  
Day 
15  
Day 1 
[1]  
Day 
15  
Day  
1  
[1]  
Day 
15  
28 Days  
Baseline Documentation  
   
   
   
   
   
   
   
   
   
Informed Consent [4]  
X  
   
   
   
   
   
   
   
   
Medical and Oncology 
History  
X  
   
   
   
   
   
   
   
   
Physical Examination [5]  
X  
X  
   
X  
   
X  
   
X  
X  
Vital Signs [6]  
X  
X  
X  
X  
X  
X  
X  
X  
   
Laboratory Studies  
   
   
   
   
   
   
   
   
   
Pregnancy Test [7]  
Day -7  
   
   
   
   
   
   
   
   
Hematology [8]  
X  
X  
   
X  
   
X  
  
   
   
Coagulation   
X  
  
  
  
  
  
  
  
  
Blood Chemistry [8]  
X  
X  
   
X  
   
X  
  
   
   
Urinalysis [9]  
X  
X  
   
X  
   
X  
   
   
   
Treatment w/ Drug or 
Device  
   
   
   
   
   
   
   
   
   
Bevacizumab  
   
X   
X  
X   
X  
X   
X  
   
   
NovoTTF-100A  
   
Device***  
   
   
   
   
   
   
   
Tumor Assessments  
   
   
   
   
   
   
   
   
   
CT or MRI Scans [10]  
X  
   
   
   
   
X  
   
X  
   
Other Clinical Assessments  
   
   
   
   
   
   
   
   
   
12-Lead ECG [11]  
X  
   
   
   
   
   
   
   
   
Neurocognitive function  
[12]  
X  
  
  
X  
  
X†  
  
  
X  
Quality of Life [13]  
X  
X  
  
X  
  
X  
  
  
X  
Concomitant   
Medications/Treatments 
[14]  
X  
X  
   
X  
   
X  
   
X  
X  

 
  
35 
Adverse Events [15]  
   
X  
X  
X  
X  
X  
X  
X  
X  
*Each cycle is 28 days in duration. The allowable window for each visit within the cycle is 
+/- 4 days unless otherwise stated.  
**Allowable window Post Treatment Follow-up is ±2 weeks *** 
Allowable window for device placement is  14 days  
† Cognitive function to be assessed every even numbered cycle.  
  

 
  
36 
  
Schedule of Assessments Footnotes  
1  
Days of Treatment: All assessments should be performed prior to dosing unless otherwise indicated.    
Cycle 1 Day 1: Hematology, coagulation, blood chemistry, urinalysis, physical examination, pregnancy test not 
required if acceptable screening assessment is performed within 7 days prior to the start of treatment with 2 
 
Bevacizumab.   
End of Study: Assessments only need to be completed if not completed during the previous 2 weeks on study 
3  
(during the last 8 weeks on study for radiologic tumor assessments).  
Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 4 
 
28-day screening period.  
Physical Examination: Examination of major body systems, karnofsky performance status, and vital signs (heart 
rate, temperature, blood pressure, weight). The physical examination will include evaluation of skin under transducer 5 
 
arrays.   
Vital Signs: Heart rate, temperature, blood pressure, weight (only needed for day 1 of every cycle and weight not 6 
 
required for day 15 of every cycle).  
Pregnancy Test: Testing to be performed locally. All female patients of childbearing potential must have a negative 
7  
serum or urine pregnancy test within 7 days of Cycle 1 Day 1 in order to be enrolled in the trial.  
   
Hematology and Chemistry:  Testing to be performed locally. In addition to the assessments scheduled for the 
clinical trial, patients should undergo assessment as appropriate to ensure safe treatment.   
Hematology: CBC with differential and platelet count  
Coagulation Prothrombin Time (PT) or Internalized Normalized Ration (INR)  
Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline 
phosphatase, total protein, albumin, sodium, potassium, bicarbonate, chloride, calcium, phosphorus, blood urea nitrogen, 
8  
creatinine, and glucose  
9  
Urinalysis: urine analysis for urine protein creatinine (UPC) ratio prior to every other dose of bevacizumab  
CT or MRI Tumor Imaging: MRI will be performed every 8 weeks. Assessments should be performed whenever 
10 disease progression is suspected.  Allowable window for tumor imaging studies is +/- 7 days.   
11 12-Lead ECG: Single tracing 12-lead ECG will be performed at screening.   
Neurocognitive Function (NCF): Testing to be completed by trained study staff within 7 days of day 1, every other 
12 cycle (e.g., every 2 months) after baseline.  
13 Quality of Life (QOL): To be completed within 7 days of day 1 of each cycle.  
Concomitant Medications and Treatments: Concomitant medications and treatments will be recorded from 28 
days prior to the start of study   
14 treatment and up to 28 days following the last dose of study treatment.   
Adverse Events: Baseline Emergent Adverse Events/Adverse Events: Patients must be followed for safety from the 
day of informed consent until  at least 28 days after the last dose of study treatment, or until all serious or  
15 NOVOCURE TTF related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later.   

 
  
37 
8. Assessment of Safety  
8.1. Safety Parameters  
Safety will be characterized in terms of the incidence, timing, severity (graded by the  
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE],  
Version 4.0), seriousness, and relatedness of adverse events and laboratory abnormalities.  In 
addition, physical examination, vital signs, and Karnofsky performance status will be serially 
monitored.  Laboratory safety analyses will be based on the local laboratory data, and will 
include hematology, serum chemistry (including liver and kidney function), urinalysis, serum or 
urine pregnancy testing, and coagulation profile.   
8.1.1. Laboratory Safety Assessments  
Abnormal and clinically significant laboratory tests should be recorded as adverse events.  
To meet the definition of clinically significant, the test result generally requires a change in 
medical management (e.g. new medication, unplanned treatment, additional tests, etc.).  
 
8.1.1.1.  
Hematology, Serum Chemistry, Coagulation, Pregnancy Test   
Assessments will be performed at the time points indicated in the Schedule of  
Assessments (Table) and analyzed at local laboratories.  Investigators may have additional blood 
tests performed for the purpose of planning treatment administration, or for following adverse 
events as clinically indicated.   
• 
Hematology: CBC with differential and platelet count  
• 
Coagulation: Prothrombin Time (PT) or Internalized Normalized Ration (INR) 
will be assessed  
• 
Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate 
transaminase (AST), alkaline phosphatase, total protein, albumin, sodium, 
potassium, bicarbonate, chloride, calcium, phosphorus, blood urea nitrogen, 
creatinine, and glucose  
• 
Pregnancy Test: Serum or urine pregnancy tests will be performed locally on all 
female patients of childbearing potential. Patients must be surgically sterile (i.e.:  
hysterectomy) or be postmenopausal, or must agree to use effective 
contraception during the study and for 3 months following last dose of 
bevacizumab.  The definition of effective contraception will be based on the 
judgment of the Principal Investigator or a designated associate.  
 
8.1.1.2.  
Urinalysis   
8.1.1.3.  
Urine analysis for urine protein creatinine (UPC) ratio 
prior to every other dose of bevacizumab Physical Examination   
A physical examination including, but not limited to, general appearance, head, eyes, 
ears, nose, throat, neck, heart, chest, abdomen, musculoskeletal, extremities, skin, lymph nodes, 
neurological genitourinary (as appropriate), and rectal (as appropriate) will be assessed at time 

 
  
38 
points indicated within the Schedule of Assessments (table). The physical examination will 
include examination of known and suspected sites of disease.    
 
8.1.1.4.  
Vital Signs   
Heart rate, temperature, blood pressure, respiratory rate and weight will be assessed at 
time points indicated within the Schedule of Assessments (table).  
 
8.1.1.5.  
Performance Status   
The Karnofsky performance scale will be used to assess performance status at Screening.   
 
8.1.1.6.  
ECG  
A single 12-lead (with a 10–second rhythm strip) tracing will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate standard intervals automatically. 
ECG will be performed according to the Schedule of Assessments (table).   
 
8.1.1.7.  
Neurocognitive Function (NCF)  
The following NCF tests were selected because they are widely-used standardized 
psychometric instruments that have been shown to be sensitive to the neurotoxic effects of 
cancer treatment in brain tumor clinical trials42.  The tests have published normative data that 
takes into account age, and where appropriate, education and gender.  The tests were also 
selected to minimize the effects of repeated administration.  Data obtained in other studies 
reveals that patients tend to perform normally on tests of attention span, reflecting adequate 
effort is being put forth, and that mood disturbance does not correlate with the results of the 
cognitive portion of the battery.  The memory test has six alternate forms.  The other tests 
measure motor and information processing speed and are relatively resistant to the effects of 
practice.    
  
Cognitive Function  
Test    
  
  
Time to Administer (min)
Memory   
 
Hopkins Verbal Learning Test  
  
5  
Verbal fluency  
  
Controlled Oral Word Association  
  
5  
Visual-motor speed  
Trail Making Test Part A  
  
  
2  
Executive Function  
Trail Making Test Part B  
  
  
5  
Motor dexterity  
  
Grooved Pegboard  
  
  
  
3  
 
8.1.1.8.  
Quality of Life (QOL)  
The assessment of QOL has become accepted as an important endpoint.  There are  
several validated measures, including the Functional Assessment of Cancer Therapy including 
Brain Tumor module (FACT-Br43). It evaluates the self-reported impact of illness on several 
important domains, including self-care, social support/function, emotional state, occupational 
role, and specific symptom impact on daily functions. This measure is completed by the subject 
and takes approximately 5 minutes.      
  

 
  
39 
8.1.2. ADVERSE EVENT REPORTING  
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 for grading of all adverse events.  
 
8.1.2.1.  
Grading of Adverse Event Severity  
To report adverse events on the CRFs, the Investigator will use the severity grading as 
described in NCI CTCAE (Version 4.0).    
Every effort should be made by the Investigator to assess the adverse event according to 
CTCAE criteria. If the Investigator is unable to assess severity because the term is not described 
in NCI (Version 4.0), severity of MILD, MODERATE, SEVERE, LIFE-THREATENING, or 
FATAL may be used to describe the maximum intensity of the adverse event. For purposes of 
consistency, these intensity grades are defined as follows:   
 
2.  
Table: Adverse Event Grading  
Grade  
Non-CTCAE  
Severity  
Definition  
1  
Mild   
Does not interfere with patient’s usual function  
2  
Moderate  
Interferes to some extent with patient’s usual 
function  
3  
Severe  
Interferes significantly with patient’s usual 
function  
4  
Life-Threatening  
Results in immediate risk of patient’s death  
5  
Fatal  
Results in patient’s death  
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with patient’s usual function) but would not be classified as serious unless it met 
one of the criteria for serious events.     
   
Adverse Events (AEs)  
Definition of an AE: Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of unrelated, unlikely, possible, probable, or definite).  
  
Serious Adverse Events (SAEs)  
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes:  
• 
Death  
• 
A life-threatening adverse drug experience  

 
  
40 
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant disability/incapacity  
A medwatch form should be completed for each SAE, Novocure (and Cleveland 
Clinic must be notified (refer to patient as an IST patient).  
8.2. A congenital anomaly/birth defect  
Important adverse events that may not result in death, may not be life-threatening, or do not 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may acutely jeopardize the patient without immediate medical intervention to 
prevent one of the outcomes listed above. Serious may also includes any other event that the 
investigator or company judges to be serious. In addition, serious adverse events will be reported 
to local IRB according to institutional requirements. Death due to disease progression need not 
be reported to the study monitor. These SAEs will be captured in the CRFs as described for 
regular AEs.   
8.2.1. Routine Adverse Event Reporting   
All adverse events must be reported in the source documentation and CRFs with 
appropriate information, including severity and rating of causality to the study drug/treatment. 
Adequate source documentation must be available to characterize the severity, duration and 
causality of each reported adverse event.   
8.2.2. Unanticipated Adverse Device Effect Event (UADE) Reporting   
Any potential unanticipated adverse device effect (UADE) will be reported to the study 
monitor and local IRB/EC within 10 days of the investigator learning of the event. The medical 
monitor will investigate whether the adverse event is a UADE and, if so, report the UADE to 
the Sponsor, as soon as possible but no later than 3 days after first learning of the event. 
Expedited report for FDA submission and reporting to other IRBs/ECs to follow within 10 
working days after first learning of the event by the medical monitor.  The report will contain 
the following:   
• 
The initials of the subject, patient MRN #, protocol # and title   
• 
The date the event occurred   
• 
A description of the UADE   
• 
An explanation of how the UADE was handled   
• 
A description of the subject's condition   
• 
Indication if the subject remains on the study   
• 
Indication if the event is considered related to the NovoTTF-100A   
• 
Indication if an amendment to the protocol and/or consent form is recommended 
as a result   
9.  DATA SAFETY MONITORING PLAN  
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and  

 
  
41 
Safety Monitoring Plan that is in accordance with NCI regulations. The Data and Safety Toxicity 
Committee will review all serious adverse events and toxicity reports as well as annual reviews.  
10.  MEASUREMENT OF EFFECT  
10.1. Response Assessment  
Optimal guidelines for determining GBM response to therapy are not yet well established.  
The most accepted are the Macdonald criteria 44.  However, increasingly specific criteria are 
being developed by the Response Assessment in Neuro-Oncology (RANO) Group through the 
American Society of Clinical Oncology.  Using these developing guidelines, we have designed 
response criteria detailed in table below.  These are largely based on standardized response 
criteria using bi-dimensional measurements of the largest contrast-enhancing area 45.  However, 
it has been demonstrated that contrast-enhanced images can be altered by agents inhibiting 
angiogenesis with occasional progression of T2-weighted or FLAIR abnormality as well as 
clinical decline despite improvement in the contrast-enhancing signal 46-47.  In light of this, 
FLAIR imaging and clinical status will be part of the response criteria in addition to the widely 
used Macdonald criteria.  Hence, the largest cross-sectional area on the T1w contrast-enhanced 
images will be selected and measured in 2 dimensions with linear measures on the baseline MRI 
axial sequence.  In addition, the largest cross-sectional area of a contiguous hyperintense lesion 
on FLAIR sequences will be measured on the baseline MRI axial sequence.  All subsequent 
scans will be compared against these baseline measures (for both CE and FLAIR).  New foci of 
FLAIR signal abnormality will be recorded on each subsequent evaluation.  Response will be 
scored based on a combination of imaging and clinical features as defined by the modified 
RANO criteria.  
 

 
  
42 
  
3. Table: Modified RANO Response Criteria  
Response  
T1 Contrast  
Enhancement (CE)  
FLAIR Images  
Steroids  
Neurologic  
Exam  
Complete  
Response   
(CR)  
No residual CE 
(complete 
disappearance of all 
enhancing measurable 
disease for at least 4 
weeks; confirmatory 
MRI at 4 weeks is 
required to score as 
CR) and no new 
lesions.  
Stable or reduced area 
of FLAIR signal 
abnormality   
No steroids   
Stable or 
improved 
from prior 
evaluation   
Partial  
Response   
(PR)  
>50% reduction in 
sum of products of the 
perpendicular 
diameters of all 
measurable enhancing 
lesions sustained for at 
least 4 weeks and no 
new lesions or 
progression of 
nonmeasurable lesions   
Stable or reduced area 
of FLAIR signal 
abnormality   
Stable or 
reduced 
glucocorticoids  
from baseline  
MRI   
Stable or 
improved 
from prior 
evaluation  
Minor 
response 
(MR)  
>25% reduction in 
sum of products of the 
perpendicular 
diameters of all 
measurable enhancing 
lesions and no new 
lesions (confirmatory 
MRI at 4 weeks is  
required to score as  
PR)  
Stable or reduced area 
of FLAIR signal 
abnormality   
Stable or 
reduced 
glucocorticoids  
from baseline  
MRI   
Stable or 
improved 
from prior 
evaluation   
Stable  
Disease  
(SD)  
<25% reduction in 
area of CE maintained 
for at least 4 weeks 
duration.  Does not 
qualify for CR, PR or 
progression   
Stable or reduced area 
of FLAIR signal 
abnormality   
Stable or 
reduced 
glucocorticoids  
from baseline  
MRI   
Stable or 
improved 
from prior 
evaluation  

 
  
43 
Progressive  
Disease  
>25% in the sum of 
products of the 
perpendicular 
diameters of CE 
lesions; evidence of 
new lesion(s).   
Measurable increase 
in the sum of 
products of the 
perpendicular 
diameters of FLAIR 
signal abnormality 
from the baseline 
scan or the scan 
representing the best 
response (if there was 
a response) following 
therapy and not 
attributable to other 
co-morbid events 
(seizure, radiation, 
injury, infection, 
ischemia, etc.) OR 
presence of a new 
focus of FLAIR 
signal abnormality 
that cannot be 
explained by any 
other pathologic 
process.   
Stable or 
increased dose 
of  
glucocorticoids  
Stable or 
worsening 
neurologic 
symptoms   
  
Radiological tumor assessments will be performed at screening, as outlined in the 
Schedule of Assessments (XXX), and whenever disease progression is suspected.  
Another tumor assessment will be performed at the End of Study Visit if an assessment 
has not been performed within the prior 8 weeks.  All patient files and radiological 
images must be available for CRF source verification.      
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Appendix 1:  National cancer institute (NCI) common terminology criteria for adverse  
events (CTCAE)  
  
The NCI CTCAE (Version 4.0) should be used to assess Adverse Events and may be reviewed 
on-line at the following NCI website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf  
  
APPENDIX 2:  KARNOFSKY PERFORMANCE SCALE AND ECOG PERFORMANCE 
SCALE  
Status  
Karnofsky Grade 
ECOG  
Normal, no complaints  
100  
0  
Fully active, able to carry on all 
predisease performance without 
restriction 
Able to carry on normal activities. 
Minor signs or symptoms of disease 
90  
1  
Restricted in physically strenuous 
activity but ambulatory and able to carry 
out work of a  
 
 
Normal activity with effort  
80  
 
light or sedentary nature, e.g., light 
house work, office work  
Care for self. Unable to carry on 
normal activity or to do active work 
70  
2  
Ambulatory and capable of all self-care 
but unable to carry out any work 
activities. Up and  
about more than 50% of waking hours  
Requires occasional assistance, but 
able to care for most of his needs  
60  
Requires considerable assistance and 
frequent medical care  
50  
3  
Ambulatory and capable of all self-care 
but unable to carry out any work 
activities.  
 
 
Disabled. Requires special care and 
assistance  
40  
 
Up and about more than 50% of waking 
hours  
Severely disabled. Hospitalization 
indicated though death nonimminent 
30  
4  
Completely disabled. Cannot carry on 
any self-care. Totally confined to bed or 
chair  
Very sick. Hospitalization necessary. 
Active supportive treatment 
necessary  
20  
Moribund  
10  
Dead  
0  
  
  
  
  

 
  
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