Clinical trial NCT02343549
Conditions: Cancer of Brain and Nervous System
Sponsor: Wake Forest University Health Sciences
Start date: 2015-01-01; Completion date: 2020-07-11
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
All patients will complete best standard of care radiation, temozolomide and bevacizumab (6 weeks). Within two weeks of completion of this initial treatment period, study patients will be fitted with the NovoTTF-100A System and treated continuously. They will be treated with TTFields for 12 months for an average of 18 hours per day. The patient may elect to take a treatment break for a total of 3 days per month, for each month and still be in compliance. This will consist of wearing four electrically insulated electrode arrays on the head. The patients will also continue with maintenance temozolomide/ bevacizumab.

Detailed description:
This study will be carried out in two stages. The first stage will enroll a cohort of 22 patients. The FDA will review safety data of the first 15 patients during enrollment of the first cohort. Enrollment and interim analysis of the first cohort of patients will be completed within 15 months of study commencement. Upon FDA approval and favorable interim analysis followed by subsequent protocol/consent amendment (as applicable), the second stage will enroll a cohort of 24 patients and will be completed within 15 months of stage 2 commencement. The overall duration of the study is expected to be no longer than 30 months.

Arms: arm 1: Best standard of care radiation therapy (RT, 2 Gy given daily 5 days per week), temozolomide (TMZ, 75 mg/m2 administered daily), and bevacizumab (BEV, 10 mg/kg administered every 2 weeks as an IV infusion) for 6 weeks. After completion of chemoradiation, NovoTTF100A system was initiated, to be worn on average 18 hours or more a day for up to 12 months. The patients also continued with maintenance TMZ/BEV.
Interventions: intervention 1: NovoTTF100A intervention 2: Bevacizumab intervention 3: Temozolomide
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Protocol Number:  LCI-NEU-NOV-001 
Version 6: 05/05/2018  
 
 
Protocol #: LCI-NEU-NOV-001 
 
TITLE:  A PHASE II STUDY OF OPTUNETM SYSTEM IN COMBINATION WITH 
BEVACIZUMAB (BEV) AND TEMOZOLOMIDE (TMZ) IN SUBJECTS WITH NEWLY 
DIAGNOSED UNRESECTABLE GLIOBLASTOMA (GBM) 
 
LAY TITLE:  A PHASE II STUDY OF OPTUNETM, A DEVICE WORN ON THE HEAD 
IN COMBINATION WITH CHEMOTHERAPY TO TREAT GLIOBLASTOMA IN 
ADULTS 
 
Coordinating Center: 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
 
Sponsor-Investigator: 
Ashley L. Sumrall, MD, FACP 
Section Chief, Neuro-Oncology 
 Levine Cancer Institute 
Carolinas HealthCare System 
1021 Morehead Medical Drive, Suite 5300 
Charlotte, NC 28204 
 
Statistician: 
James Symanowski, PhD 
Department of Cancer Biostatistics 
Levine Cancer Institute 
Carolinas HealthCare System 
1100 Blythe Boulevard, Suite 1164 
Charlotte, NC 28203 
Phone:  (980) 442-2371 
Fax:  (704) 355-1353 
Email:  James.Symanowski@carolinashealthcare.org 
 
 
 
 
 
 
 
 
 
Investigational device: OptuneTM System 
Commercial agents:  Bevacizumab and Temozolomide 
 
 
Original Phase 2 / Version 6 / 05/05/2018 


Protocol Number:  LCI-NEU-NOV-001  
Version 6:  05/05/2018 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number:  LCI-NEU-NOV-001  
Version 6:  05/05/2018 
 
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TABLE OF CONTENTS 
 
SCHEMA ........................................................................................................................................ I 
1. 
OBJECTIVES ...................................................................................................................... 1 
1.1. Primary Objective ....................................................................................................................... 1 
1.2. Secondary Objective ................................................................................................................... 1 
1.3. Safety Objectives ......................................................................................................................... 1 
2. 
BACKGROUND .................................................................................................................. 1 
2.1. Study Disease ............................................................................................................................... 1 
2.2. Study Device: OptuneTM System ................................................................................................ 2 
2.3. Study Rationale ........................................................................................................................... 3 
2.4. Literature ..................................................................................................................................... 4 
3. 
SUBJECT SELECTION ..................................................................................................... 6 
3.1. Inclusion Criteria ........................................................................................................................ 6 
3.2. Exclusion Criteria ....................................................................................................................... 7 
3.3. Inclusion of Women and Minorities .......................................................................................... 8 
4. 
INVESTIGATIONAL PLAN ............................................................................................. 8 
4.1. Milestone Date Definitions ......................................................................................................... 8 
4.2. Overall Study Design and Plan .................................................................................................. 9 
4.3. Pre-Treatment ............................................................................................................................. 9 
4.4. Treatment .................................................................................................................................. 10 
4.5. End of Treatment ...................................................................................................................... 12 
4.6. Follow-Up................................................................................................................................... 12 
4.7. Off Study .................................................................................................................................... 12 
5. 
STUDY CALENDAR ........................................................................................................ 13 
6. 
TREATMENT PLAN ........................................................................................................ 14 
6.1. Temozolomide Administration ................................................................................................ 14 
6.2. Bevacizumab Administration................................................................................................... 15 
6.3. Radiation Therapy .................................................................................................................... 16 
6.4. OptuneTM System Administration ........................................................................................... 17 
6.5. Duration of Therapy ................................................................................................................. 21 


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6.6. Duration of Follow-Up .............................................................................................................. 21 
6.7. Criteria for Removal from Study ............................................................................................ 21 
7. 
TREATMENT- RELATED ADVERSE EVENTS ......................................................... 22 
7.1. Adverse Event Characteristics ................................................................................................. 22 
7.2. Adverse Events Considered Related to OptuneTM System .................................................... 22 
7.3. Adverse Events Considered Related to Temozolomide ......................................................... 23 
7.4. Adverse Events Considered Related to Bevacizumab ........................................................... 24 
8. 
SAFETY DATA COLLECTION,  RECORDING, AND REPORTING...................... 24 
8.1. Definitions .................................................................................................................................. 24 
8.2. Timing and Reporting .............................................................................................................. 28 
8.3 Other Reporting ........................................................................................................................ 29 
9. 
DATA AND SAFETY MONITORING PLAN ............................................................... 31 
9.1. Monitoring and Review ............................................................................................................ 31 
9.2. Communication Between Investigational Sites ...................................................................... 32 
9.3. Clinical Trial Registration........................................................................................................ 32 
10. MEASUREMENT OF EFFECT ...................................................................................... 32 
10.1. 
Antitumor Effect – Solid Tumors .................................................................................... 32 
10.2. 
Tumor Response Review .................................................................................................. 34 
11. STATISTICAL CONSIDERATIONS ............................................................................. 34 
11.1. 
Sample Size ........................................................................................................................ 34 
11.2. 
Endpoint Definitions ......................................................................................................... 35 
11.3. 
Analysis Populations ......................................................................................................... 36 
11.4. 
Analysis Methods .............................................................................................................. 36 
12. STUDY COMPLETION ................................................................................................... 37 
13. RETENTION OF RECORDS .......................................................................................... 37 
REFERENCES ............................................................................................................................. 39 
APPENDICES .............................................................................................................................. 40


Protocol Number:  LCI-NEU-NOV-001 
Version 6:  05/05/2018 
 
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1. 
OBJECTIVES 
 
1.1. Primary Objective 
 
The primary objective of this phase II study is to assess the efficacy of a treatment regimen 
that involves the administration of temozolomide and bevacizumab with concurrent use of 
the medical device, OptuneTM System, by evaluating the percentage of newly diagnosed 
unresectable glioblastoma (GBM) subjects who are alive at 12 months and compare to 
relevant historical controls. 
 
1.2. Secondary Objective 
 
The secondary objectives are to: 
• Evaluate progression free survival (PFS) 
• Evaluate objective response rate (ORR) and disease control rate (DCR) 
• Evaluate duration of response and disease control 
 
1.3. Safety Objectives 
 
 
The safety objectives are to evaluate: 
• Adverse events (AE) assessed by NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 
• Serious adverse events (SAE) and unanticipated adverse device effects (UADEs) 
including death on study 
 
2. 
BACKGROUND 
 
2.1. 
Study Disease 
 
Despite decades of intensive investigation, the prognosis for most patients with primary 
anaplastic, central nervous system (CNS) neoplasms remains very poor. Most high grade 
CNS tumors are highly resistant to currently available therapy. The addition of 
temozolomide to radiation therapy has improved survival compared to radiation therapy 
alone, but improvements are modest.[1] Median survival for adults with the most common 
form of CNS tumor, glioblastoma, has been reported as 9-15 months after diagnosis. Most 
recently, addition of OptuneTM to therapy for newly diagnosed glioblastoma (GBM) has 
demonstrated improved survival. In a cohort that included patients with resectable and 
unresectable glioblastoma, median progression-free survival from randomization was 6.7 
months in the TTFields + temozolomide group and 4.0 months in the temozolomide group 
(HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the 
TTFields + temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 
0.63; 95% CI, 0.53-0.76; P < .001). [2]. It has been documented that patients with 
unresectable disease have an even shorter survival. In the landmark EORTC study, patients 
who received diagnostic biopsy followed by temozolomide and radiation had a median OS 
of 5.1 months (95% CI: 4.47, 8.84). [1] Attempts to improve outcomes in the newly 
diagnosed setting by novel interventions have proven to be disappointing. In one study using 


Protocol Number:  LCI-NEU-NOV-001 
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ultrafractionated radiotherapy for unresectable tumors, an improvement in OS was not 
observed. [3, 4] Other attempts to improve survival have been modest. [4] 
 
Occasional responses to single or multiple agent chemotherapy are observed in the setting of 
recurrent tumor, but these responses are generally short in duration, and long-term survival 
is rare. Bevacizumab has been FDA-approved for recurrent glioblastoma, based on a 
randomized phase II trial. This led to additional work to evaluate bevacizumab in the newly 
diagnosed setting. In a small cohort of newly diagnosed patients, it was deemed safe to be 
administered with concurrent temozolomide and radiation therapy. In a phase II study 
examining patients with newly-diagnosed glioblastoma, the addition of bevacizumab to 
standard radiation therapy and daily temozolomide followed by the addition of bevacizumab 
and irinotecan to adjuvant temozolomide showed an improvement median overall survival 
to 21.2 months (95% CI: 17.2-25.4), and 65% of the patients were alive at 16 months (95% 
CI: 53.4-74.9). The median progression-free survival was 14.2 months (95% CI: 12-16). [5] 
This prompted larger, randomized studies. The mature PFS and OS results from AVAglio, a 
phase III trial evaluating bevacizumab added to standard radiation and temozolomide for 
newly-diagnosed GBM, were recently presented at the 2013 American Society of Clinical 
Oncology Annual Meeting. Unresectable tumors were included in this study. A 36% risk 
reduction in progression or death was observed. An improvement in median PFS by 4.4 
months was observed (HR 0.64, p<0.0001) in the bevacizumab treatment arm, and PFS in 
the control arm was 6.2 months. Stability or improvement in quality-of-life was also 
observed in the bevacizumab treatment arm, as well as maintenance of functional 
independence. Overall survival (OS) was not significantly prolonged.[6] RTOG 0825 also 
failed to demonstrate an improvement in OS. Of note, multifocal tumors were excluded 
from this study. In addition, 60% of the enrolled patients underwent gross total resection of 
glioblastoma.[7] From these studies, one can garner that bevacizumab appears to improve 
PFS and quality of life. The subset analyses from these studies are eagerly anticipated.  
 
Due to the dilemma of markedly poor prognosis for patients with unresectable disease, a 
novel approach is needed to improve long-term survival. An attempt to prolong survival in 
this cohort was documented by the efforts of Lou, Peters, Sumrall, et al. By administering 
upfront bevacizumab and temozolomide to patients with unresectable glioblastoma, OS was 
observed to be 11.7 months (95% CI:  7.4, 15.6). Minimal toxicities were observed.[8] 
 
2.2. 
Study Device: OptuneTM System 
 
The portable, battery-operated medical device, the OptuneTM System, delivers low intensity, 
intermediate frequency, alternating electric fields (TTFields (Tumor Treating Fields)) to the 
region of the malignant tumor.[9] The TTFields are applied 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.  This novel approach uses arrest of cell division in anaphase to 
augment cell death. It has been studied in combination with temozolomide and deemed safe 
for concurrent administration with chemotherapy in preclinical and clinical settings.[9] 


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Patients are evaluated for treatment with OptuneTM System by a qualified physician who has 
been specifically trained by Novocure. The device is to be worn for 18 hours on average 
each day for maximum effect. It has been FDA-approved for use as a treatment for adult 
patients with both newly-diagnosed and recurrent GBM after receiving chemotherapy and 
radiation therapy.  
 
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 change and recharge depleted 
device batteries and to connect to an external battery pack overnight. 
 
2.3. 
Study Rationale 
 
Typical patients with newly diagnosed, unresectable glioblastoma receive concurrent 
temozolomide and radiation therapy for approximately 6 weeks (Appendix A). Most of our 
patients without contraindications will also receive bevacizumab dosed at 10 mg/kg IV 
every 2 weeks in this setting.  Four weeks after completion of this phase, they will move 
forward to receive 12 months of adjuvant temozolomide and bevacizumab. 
 
OptuneTM Therapy has been studied in combination with temozolomide and deemed safe for 
concurrent administration with chemotherapy in preclinical and clinical settings.[10],[11] 
Based on the phase III trial evaluating the use of OptuneTM Therapy for recurrent GBM, an 
improved PFS-6 rate, improved response rate, and trend toward reduction of risk of death 
were observed. [12] This led to the FDA approval of the device. Furthermore, this treatment 
has been evaluated in the EF-14 trial, a randomized trial evaluating the efficacy of OptuneTM 
Therapy in combination with temozolomide in newly diagnosed, unresectable GBM 
patients. At the American Society of Clinical Oncology Annual Meeting in June 2015, 
analysis of this data was initially shared. A pre-specified, interim analysis of the first 315 
subjects concluded that the trial met its endpoints of superior PFS and OS. Analysis of the 
full trial cohort of 700 subjects confirmed this. Subjects treated with TTFields and 
temozolomide demonstrated a significant increase in PFS compared to temozolomide alone 
(median PFS of 7.1 months compared to 4.2 months, hazard ratio=0.69, p=0.001). Longer 
follow-up showed impressive results with an improvement in median progression-free 
survival from randomization of 2.7 months in the TTFields + temozolomide group. Median 
overall survival was improved by 4.9 months in the TTFields + temozolomide group (HR, 
0.63; 95% CI, 0.53-0.76; P < .001). [2] It is now FDA-approved for use in the adjuvant 
setting.  
 
OptuneTM therapy has also been shown to be safe when administered with bevacizumab. 
[13] To evaluate the effectiveness of the OptuneTM System, referencing a study in newly 
diagnosed unresectable GBM patients using the combination of temozolomide and 
bevacizumab for the historical controls is necessary.  One such study was conducted by Lou, 
Peters, and Sumrall, showing a median overall survival of 11.7 months (95% CI: 7.4, 
15.6).[8] 
 
 
 


Protocol Number:  LCI-NEU-NOV-001 
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2.4. 
Literature 
 
2.4.1. Pre-clinical studies 
 
In preclinical studies in vitro and in vivo, TTFields (Tumor Treating Fields) have 
been shown to safely and effectively slow tumor growth as an independent treatment 
modality, and in conjunction with chemotherapeutic agents.[9-11, 14, 15] In 2004, 
TTFields (Tumor Treating Fields) were first evaluated in over 500 culture dishes 
containing 11 different cancer cell lines, including human and rat glioma, as well as 
other human cancer cell types. [10] TTFields (Tumor Treating Fields) were delivered 
over a 24 hour period in a homogeneous manner.  Two mechanisms of action were 
identified:  1) interference with the proper formation of the mitotic spindle and 2) 
rapid disintegration of dividing cells. [14] TTFields (Tumor Treating Fields) 
frequency was delivered by internally implanted electrodes and optimal levels were 
found to vary by cancer type.  Optimal TTFields (Tumor Treating Fields) frequency 
was identified as 200k Hz in both human and rat glioma.[14] 
 
Building on this research, Kirson et al examined the effects of TTFields (Tumor 
Treating Fields) on additional human lung and breast carcinoma cell lines, as well as 
animal tumor models (melanoma and glioma), using externally applied transducer 
arrays.[11] Mechanisms of action and optimal TTFields (Tumor Treating Fields) 
frequency was consistent with previously reported research. In this study, 40 Fischer 
rats (inoculated intracranially with glioma cells) were treated with TTFields (Tumor 
Treating Fields) (200 kHz at 2 V/cm) for 6 days using external electrodes.  In 
comparison to a control arm, a 42.6% inhibition of tumor growth was observed with 
two directional TTFields (Tumor Treating Fields) (p < 0.01) and a 53.4% inhibition 
of tumor growth was observed with three directional TTFields (Tumor Treating 
Fields) (p < 0.01). The TTFields (Tumor Treating Fields) were positioned between 45 
and 90˚ of each other. [10] 
 
Next, the result of TTFields (Tumor Treating Fields) in conjunction with 
chemotherapeutic agents (paclitaxel, doxorubicin, cyclophosphamide, and 
dacarbazine (DTIC) treatments) were examined in human breast and glioma cell 
lines. [11] Four sets of experiments were conducted: control, TTFields (Tumor 
Treating Fields), chemotherapeutic agents, and TTFields (Tumor Treating Fields) 
with chemotherapy. Combined treatment (chemotherapeutic agent and 
TTFields (Tumor Treating Fields) treatment at 1.75 V/cm) over 72 hours resulted in 
50% decrease in cell proliferation compared to controls in the breast cancer cell lines. 
[11] 
 
In human glioma cell lines, a reduction in percent of viable cells was observed when 
adding TTFields (Tumor Treating Fields) treatment to DTIC.  Dose Reduction 
Indexes were calculated and indicated a reduction in dose in combination with 
TTFields (Tumor Treating Fields) delivery could be used to achieve the same level of 
efficacy.[11] As temozolomide is an imidazotetrazine derivative of the alkylating 
agent DTIC and has a similar in vivo mechanism, this data correlates well to those 
patients treated with temozolomide.  


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2.4.2 Clinical studies 
 
Due to the promising data from the preclinical studies, a small pilot sample was 
identified. Twenty patients with histologically confirmed GBM (ten newly diagnosed 
and ten recurrent) were included. They were treated for an average of 12 months (2.5 
to 24 months) with OptuneTM therapy. The ten newly-diagnosed patients had 
completed surgical resection and concurrent chemoradiotherapy with standard of care 
temozolomide and RT. OptuneTM therapy was administered with maintenance 
temozolomide. No serious adverse effects were observed. No additional toxicity was 
observed when temozolomide and OptuneTM therapy were combined. All patients 
were treated with multiple four-week treatment courses using continuous, 24-hour a 
day, 200 kHz, 0.7 V/cm TTFields. TTFields were applied through two sets of 
opposing insulated electrode arrays and alternated at a 1 second duty cycle between 
two perpendicular field directions through the tumor. Patients completed between 1 
and 17 treatment courses leading to maximal treatment duration of 16.5 months. 
Overall, more than 96, 4 week treatment courses were completed to date (> 9.6 
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 80% of the scheduled time. Considering the continuous nature of 
OptuneTM therapy (i.e., 24 hours a day for many months) this figure indicates that 
compliance with treatment 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 electrode gel in all 
patients during treatment. In most cases this dermatitis appeared for the first time 
during the second treatment course. The skin reaction improved with use of topical 
corticosteroids. Regular relocation of the electrode arrays was necessary in order to 
allow for continuous treatment.  Although the number of patients in this pilot trial 
was small, the excellent safety profile of this treatment modality and the highly 
promising efficacy data gathered so far indicate the potential of OptuneTM therapy as 
an effective therapy for newly diagnosed GBM patients.  It is noted that the patients 
involved had a Karnofsky performance score ≥ 70 and were required to wear the 
externally applied transducer arrays for 18 hours (on average) each day.  Median time 
to disease progression and overall survival of the patients was 26.1 months (range 
3.0-124.0) and 62.2 months (range 20.3-124.0), respectively, with two patients 
remaining progression free and three patients still alive at the end of the study period.  
One-year survival rate was 67.5%.[11] Treatment related adverse events included 
mild to moderate contact dermatitis in 18 of 20 patients (with good response to 
steroid cream and electrode relocation). In those ten newly diagnosed patients, the 
median progression free survival (PFS) exceeded concurrent and historical controls 
dramatically (greater than 18 months versus 7.1 months, respectively). Median 
overall survival from diagnosis is greater than 26 months at the moment (compared to 
14.6 months in historical controls).[14] 
 
Subsequent early clinical studies examined the addition of OptuneTM therapy to 
existing chemotherapy regimens. When OptuneTM therapy is used in conjunction with 
existing chemotherapy regimens, an additive effect was observed among 20 GBM 
subjects.[14] Half the subjects were newly diagnosed and received surgery, radiation, 


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6 
 
and temozolomide (TMZ) and were then treated with OptuneTM therapy concurrently 
with maintenance TMZ. The remaining 10 subjects were recurrent and received only 
OptuneTM therapy.  Progression free survival (PFS) and overall survival (OS) were 
increased in subjects treated with OptuneTM therapy.  Median PFS of subjects with the 
combined treatment (TMZ/OptuneTM therapy) was 155 weeks compared to 31 weeks 
for concurrent controls receiving TMZ alone.  OS was >39 months for subjects 
receiving the combined treatment, compared to 14.7 months in matched historical 
controls receiving TMZ alone.[14] No serious adverse events were reported, however 
dermatitis occurred in most (n=18) subjects, typically by the second month of 
treatment.  Dermatitis resolved completely within weeks of treatment 
termination.[14] 
 
The most recent study of OptuneTM therapy in cancer patients, a phase III multi-
institutional trial, examined 237 patients with recurrent glioblastoma, who were 
randomized in a 1:1 ratio to receive either OptuneTM therapy monotherapy or best 
standard of care chemotherapy.[12] Patients randomized to OptuneTM therapy 
(n=120) wore 4 transducer arrays on their shaved scalp that delivered 200 kHz 
TTFields to the brain at a field intensity of > 0.7 V/cm.  Patients wore the device, on 
average 20.6 hours each day.[12] Of the patients randomized to the best standard of 
care (n=117), 31% received a regimen containing bevacizumab or irinotecan (31%), 
followed by nitrosoureas (25%), carboplatin (13%), temozolomide (11%) or other 
regimen (5%).  Patients were followed for OS, PFS, quality of life and safety 
endpoints. Median survival was slightly higher in the OptuneTM therapy group 
compared to the chemotherapy only group (6.6 vs. 6.0 months, respectively).[12] 
One-year survival was equal in both groups (20%), however 2 and 3 year survival 
was slightly higher for the OptuneTM therapy treatment group compared to the 
chemotherapy only group (2-year: 8% vs. 4%; 3-year: 5% vs. 1%).[12] Those treated 
with OptuneTM therapy were 14% less likely to die compared to those treated with 
chemotherapy only (HR=0.86, 95% CI:  0.66-1.12, p=0.27).  This hazard ratio 
demonstrates that OptuneTM therapy alone may be at least as good as best standard of 
care chemotherapy in the treatment of recurrent glioblastoma.[12]Minimal adverse 
events were experienced by the OptuneTM therapy group and included grade 1 or 
grade 2 contact dermatitis on the scalp underneath the transducer arrays (16%), 
however this was completely resolved with corticosteroid treatment after treatment 
was stopped.[12]  Quality of life measures (cognitive and emotional functioning) 
were better for the OptuneTM therapy treated group.  While increased pain and fatigue 
was reported in the chemotherapy group, these symptoms were not reported in the 
OptuneTM therapy group.[12] 
 
3. 
SUBJECT SELECTION 
 
3.1. 
Inclusion Criteria 
 
a. At least 22 years of age 
b. Have undergone a brain biopsy via stereotactic or open technique. Biopsy is defined as 
less than 20% excision of the tumor. 
c. Pathological evidence of GBM using WHO classification criteria 


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d. Planned concurrent chemoradiotherapy post-biopsy concomitant with temozolomide 
(45-70Gy) 
e. Karnofsky scale ≥ 60 
f. Life expectancy at least 3 months 
g. Baseline hemoglobin of > 8.0 gm/dL 
h. Signed informed consent 
i. Able to start bevacizumab at least 2 weeks but no more than 4 weeks from date of 
biopsy  
j. Able to tolerate MRI of brain and have measurable disease 
k. Participants of childbearing potential must use effective contraception for at least 6 
months following completion of treatment. Acceptable forms of contraception are listed 
in section 4.4.1. 
 
3.2. 
Exclusion Criteria 
 
a. Enrolled in another clinical treatment trial 
b. Pregnant or breast-feeding 
c. No active malignancy within the past 2 years except for: 1) basal cell or squamous cell 
carcinoma of the skin, 2) a malignancy that requires hormonal therapy alone for 
management, and/or 3) an early-stage cancer that was cured by surgery 
d. Significant co-morbidities at baseline which would prevent maintenance temozolomide 
e. Platelet count < 100 x 103/μL 
f. Absolute neutrophil count < 1.5 x 103/μL 
g. CTC grade 4 non-hematological toxicity (except for alopecia, nausea, vomiting) 
h. AST or ALT > 3 times the upper limit of normal 
i. Total bilirubin > 2 times the upper limit of normal 
j. Serum creatinine> 1.7 mg/dL 
k. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other 
implanted electronic devices in the brain, or documented clinically significant 
arrhythmias. 
l. Infra-tentorial tumor 
m. Clinical evidence of increased intracranial pressure  
n. History of hypersensitivity reaction to temozolomide or a history of hypersensitivity to 
DTIC or hydrogel 
o. Inability to adequately cover treatment area with TTFields (Tumor Treating Fields) 
p. Unwillingness to wear OptuneTM System for an average of 18 hours per 24 hours 
q. Currently taking cytotoxic medications, non-steroidal anti-inflammatory drugs 
(NSAIDs), or enzyme inducing anticonvulsants. 
r. Currently taking anticoagulants or blood-thinners (Coumadin)  
s. Subjects meeting any of the following bevacizumab-specific contraindications are 
ineligible for study entry:   
• Inadequately controlled hypertension (defined as systolic blood pressure 150 
and/or diastolic blood pressure > 100 mmHg) 
• Prior history of hypertensive crisis or hypertensive encephalopathy 
• New York Heart Association (NYHA) Grade II or greater congestive heart failure  
• History of myocardial infarction or unstable angina within 6 months prior to study 


Protocol Number:  LCI-NEU-NOV-001 
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8 
 
enrollment 
• History of stroke or transient ischemic attack within 6 months prior to study 
enrollment  
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to study enrollment 
• History of hemoptysis (≥ ½ teaspoon of bright red blood per episode) within 1 
month prior to study enrollment  
• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation) 
• Major surgical procedure or significant traumatic injury within 28 days prior to 1st 
bevacizumab infusion or anticipation of need for major surgical procedure during 
the course of the study 
• Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 days prior to study enrollment 
• History of abdominal fistula, gastrointestinal perforation within 6 months prior to 
study enrollment 
• Serious, non-healing wound, active ulcer, or untreated bone fracture 
• Proteinuria at screening as demonstrated by either urine protein: creatinine (UPC) 
ratio   1.0 at screening OR urine dipstick for proteinuria ≥ 2+ (subjects discovered 
to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour 
urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). 
• Known hypersensitivity to any component of bevacizumab 
 
3.3. 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
3.4. 
Prerequisites for Initiation of OptuneTM Therapy: 
 
After successful completion of chemoradiation, the following criteria must be met: 
1. Adequate compliance of chemoradiation as documented by the investigator. 
2. Subject must be able to continue bevacizumab and maintenance temozolomide. 
3. Post-radiation MRI of the brain must be completed and fit to use for treatment 
planning for array placement. 
4. Subject must not have prohibitive skin changes which would not permit OptuneTM 
placement. 
 
4. 
INVESTIGATIONAL PLAN 
 
4.1. 
Milestone Date Definitions 
 
Eligibility date: the date of the last documented criterion that confirmed subject eligibility 
prior to initiation of treatment with radiation, temozolomide, and bevacizumab. 
Enrollment date: the date of initiation of treatment with radiation, temozolomide, or 
bevacizumab. If radiation, temozolomide, and bevacizumab is not initiated on the same date, 
the enrollment date will be defined as the initiation of the first study treatment administered. 


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Treatment discontinuation date: the date the Investigator decides to discontinue the 
subject from OptuneTM therapy (subjects who have OptuneTM device placed) or the date the 
Investigator decides that the subject will not have OptuneTM device placed (subjects who do 
not have OptuneTM placed).  
 
4.2. 
Overall Study Design and Plan 
 
This is an open label, single-arm, phase II protocol.  
 
All subjects will complete standard of care radiation, temozolomide, and bevacizumab 
(approximately 6 weeks). A post-radiation MRI of the brain will be completed within 2 
weeks after conclusion of radiation. Within 2 weeks of completion of this initial treatment 
period, study subjects will be fitted with the OptuneTM System and treated continuously. 
Planning for this therapy will be completed using the post-radiation MRI of the brain. They 
will be treated with TTFields for 12 months for an average of 18 hours per day. The subject 
may elect to take a treatment break for a total of 3 days per month, for each month and still 
be in compliance. This will consist of wearing four electrically insulated electrode arrays on 
the head.  The subjects will also continue with maintenance temozolomide/ bevacizumab for 
12 cycles. 
 
Upon completion of the OptuneTM therapy intervention phase, subjects will be followed for 
evaluation of PFS, OS, and safety objectives. 
 
This study will be carried out in two stages.  The first stage will enroll a cohort of 22 
subjects.  The Stage 1 analysis will be completed after all subjects in the first stage (n=22) 
have at least 12 months of follow-up time from the initiation of chemoradiation therapy (or 
have died). The second stage will enroll a cohort of 24 subjects (a total of 46 subjects).     
Study data will be collected and stored in the Clinical Trials Management System (CTMS). 
 
4.3. Pre-Treatment 
 
4.3.1. Registration Process  
 
Written informed consent will be obtained prior to any protocol specific pre-treatment 
assessments.  
 
Following informed consent, subjects will be registered in the CTMS and assigned a 
Study ID number. The Study ID number will begin with “LCI” and include a two 
digit number sequentially assigned to the subject (e.g. “LCI01” will be the Study ID 
number assigned to the first subject). 
 
After completion of chemoradiation, subjects will need to meet eligibility criteria as 
described in section 3.4 in order to continue participation in the study. 
 
Eligible subjects who receive the initial placement of the OptuneTM transducer arrays 
will be considered evaluable for efficacy analyses.   
 


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10 
 
4.4. Treatment 
 
4.4.1. Study Procedures 
Refer to the study calendar in Section 5 for when the following assessments will 
occur. 
 
Demographics and Medical History 
Demographics and information on baseline conditions will be collected during the 
screening visit. Medical history (oncological and relevant non-oncological) will be 
collected and recorded as standard in the medical record. GBM history will be obtained 
during screening and the following information will be recorded inthe medical record: 
• Date of first histological/cytological diagnosis 
• Primary tumor site 
• Tumor histology and characteristics, including analysis for MGMT and IDH1 
testing 
 
Physical Examination 
 
 
A physical exam should include the following: 
• Cardiopulmonary examination 
• Examination of the abdomen 
• Skin examination 
• Assessment of the mental and neurological status 
• Neurological exam to include cranial nerve, motor, and sensory examination 
 
Additional symptoms, which have not been reported during a previous examination, 
should be clarified. Wherever possible the same investigator should perform this 
examination. Physical exams will occur at the time points specified in the Study 
Calendar inSection 5. 
 
Performance Status 
Evaluation of KPS will be performed at the time points specified in the Study 
Calendar in Section 5. The KPS is found in Appendix B. 
Vital Signs and Body Weight 
Vital signs (blood pressure and pulse) and body weight will be recorded at the 
screening visit and at the time points specified in the Study Calendar in Section 5.  
Height will only be recorded at Screening. 
 
Compliance Assessment 
A device compliance report will be downloaded by Novocure and submitted to the 
prescribing physician monthly.  Subject compliance will be assessed by the 
prescribing physician.  Subjects will be considered non-compliant if their average 
monthly compliance rate is < 75% or if they take a treatment break for more than 3 
days in a month. Any non-compliance will be addressed with the subject and re-
education will occur as appropriate. Subjects who experience adverse events that 
result in the interruption of OptuneTM therapy will not be considered to be non-


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compliant.  See Section 6 for additional information. 
 
Concomitant Therapies and Diagnoses 
Concomitant diagnoses and/or therapies present during trial participation (between 
the Screening visit and at least until 28 days after the last administration of study 
device) will be recorded in the medical record. In case of medical or surgical 
procedures that would affect the assessment of the radiology findings, the Investigator 
has to describe the type and location of intervention as well as the results from biopsy 
or cytology assessment in the medical record. Any anti-cancer therapy administered 
after treatment discontinuation, including but not exclusive of RT, chemotherapy, 
targeted therapy, will be recorded in the medical record. 
 
 
MRI 
An MRI of the brain will be performed according to the schedule outlined in the 
Study Calendar in Section 5. 
 
Serum Pregnancy B-HCG 
A serum pregnancy B-HCG test for women of child-bearing potential will be 
performed during Screening. Subjects and partners of male subjects must use an 
effective form of contraception. 
 
Effective forms of contraception include:  
 
• True abstinence  
• Male sterilization (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). For female subjects, the vasectomized male 
partner should be the sole partner. 
• Placement of non-hormonal intrauterine device or intrauterine system 
• Condom with spermicidal foam/gel/film/cream/suppository 
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/film/cream/suppository 
 
Note: Unacceptable methods of contraception include: Periodic abstinence (e.g., 
calendar, ovulation, symptothermal post-ovulation methods), withdrawal, and tubal 
ligation. 
 
Adverse event assessment 
Adverse events listed in Section 7 will be monitored throughout the study as 
described in Section 8. 
 
Labs 
 Labs will be performed per the Study Calendar in Section 5.   
 


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4.5. End of Treatment 
 
The end of treatment (EOT) visit is done when the subject discontinues study treatment, for 
any reason. The decision to discontinue study treatment due to tumor progression must be 
based on the evaluation of imaging. If the decision to permanently discontinue study 
treatment is made during a scheduled visit, then the EOT visit should be performed instead 
of the scheduled visit. If the decision is made between scheduled visits, an EOT visit should 
be performed no later than 7 days after the last study treatment administration.  
 
 
 
4.6. Follow-Up 
 
Follow-up beyond the safety follow- up period is only required for subjects in the evaluable 
population for efficacy (subjects who have the OptuneTM device placed). These subjects 
should have the first follow-up visit (FUV1) 28 days (+/-7 days) after the EOT visit. 
Subsequent FUVs will take place monthly in the allowed window (+/- 7 days) outlined in 
the Study Calendar in Section 5. It is of utmost importance that subjects continue the 
imaging schedules until tumor progression.  At a minimum the following information 
should be collected at FUVs: 
 
• Survival status 
• Imaging 
• KPS 
• Initial subsequent anti-cancer therapy 
 
For subjects in the evaluable population for efficacy (subjects who have the OptuneTM 
device placed) who end treatment due to disease progression, monthly FUVs as described 
above will not be required. However, these subjects should be contacted (phone contact is 
acceptable) to assess survival every 3 months (+/- 14 days).  
 
Death information from public sources, e.g. death registry, obituary listing, etc. can also be 
used when it is available and verifiable. Refer to section 6.6 for duration of follow-up.  
 
4.7. Off Study 
 
Subjects will be removed from the study when any of the criteria listed in Section 6.7 
applies.  The reason for study removal and the date the subject was removed will be 
documented. 
 
 


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5. STUDY CALENDAR 
 
 
 
Screening 
(4 weeks)l 
XRT/TMZ/ 
BEV 
(Concurrent 
Chemoradiation 
Phase) (6 
weeks +/- 7 
days) 
Pre-
OptuneTM 
System 
Treatment 
(up to 2 
weeks) 
OptuneTM 
System 
Treatmentn    
/TMZ/BEV 
maintenance 
 
End of  
Treatmentj 
Follow-
Upi 
OptuneTM System 
planning and 
initial placement 
 
 
 X 
 
 
 
Informed 
consent/ 
Registration 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical historym 
X 
 
 
 
 
 
Physical exama 
X 
X 
X 
Xf 
X 
X 
OptuneTM System 
compliance 
 
 
 
Xf 
Xp 
 
Concomitant 
medications: 
documentation 
X 
X 
X 
Xf 
X 
 
Height 
X 
 
 
 
 
 
 Blood pressure 
and pulsek 
X 
X 
X 
X 
X 
 
Performance 
status (KPS)a 
X 
X 
X 
Xf 
X 
X 
MRIb 
X 
 
X 
Xg 
 
Xg 
Serum Pregnancy  
B-HCGc 
X 
 
 
 
 
 
Adverse event 
assessmento 
 
X 
X 
X 
X 
 
Labs 
Xe 
Xh 
Xh 
Xh 
Xh 
 
Confirmation of 
Prerequisites to 
Initiate Optune™ 
Therapyd 
 
 
Xd 
 
 
 
 
a: Physical exam must include weight, neurologic exam and KPS (every 2 weeks [± 3 days] during 
chemoradiotherapy and every 4 weeks [±3 days] during OptuneTM System Treatment) and required assessments as 
referenced in Section 4.4.1.  
b: Including tumor measurements 
c: In women of childbearing potential  
d: Confirm prerequisites for initiation of Optune™ therapy per section 3.4 
e: CBC with diff, lipid profile, CMP, U/A, PT, PTT, INR 
f: Every 4 weeks (+/- 3 days) 
g: Every 8 weeks +/- 7 days or as clinically indicated. Frequency to be based from previous MRI. 
h: CBC with diff weekly (+/- 2 days) during chemoradiotherapy. CBC with diff, CMP, and U/A every two weeks (+/- 
3 days) of each bevacizumab infusion and at the End of Treatment visit. CBC with diff day 21 (+/- 3 days) of every 
28 day maintenance cycle. 


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i: Follow-up beyond the safety follow-up period is only required for subjects in the evaluable population for efficacy 
(subjects who have the OptuneTM device placed). The first follow-up visit will be 28 days (+/- 7 days) from EOT visit 
per Section 4.6. Subsequent visits are monthly (+/- 7 days). For subjects who have disease progression, the only 
follow-up requirement is to contact to assess survival every 3 months (+/- 14 days).  
j: If the decision to permanently discontinue the device treatment is made during a scheduled visit, then the EOT visit 
should be performed instead of the scheduled visit. If the decision is made between scheduled visits, an EOT visit 
should be performed no later than 7 days after the last Optune™ treatment administration. 
k: Vital signs (blood pressure and pulse) to be documented during screening and then every two weeks (+/- 2 days) 
prior to bevacizumab infusion 
l. All screening procedures to be performed within 4 weeks of study treatment initiation unless otherwise noted 
m. To include documentation of baseline conditions 
n. OptuneTM System placement will occur after completion of chemoradiation and Pre-OptuneTM System Procedures 
(per the study calendar). TMZ and bevacizumab to be administered currently with OptuneTM System as 28 day cycles 
(12 cycles total during maintenance) with a +/- 3 day variation allowed for Day 1. 
o. Adverse event assessment to occur beginning with initiation of study treatment through 30 days after OptuneTM 
device is discontinued (or last dose of study treatment for subjects who do not have the OptuneTM device placed). 
p. Only required for subjects who had the OptuneTM System placed 
 
6. TREATMENT PLAN 
 
6.1. Temozolomide Administration 
 
Concurrent Chemoradiation Phase: Subjects will receive temozolomide at 75 mg/m2 daily 
concurrently with radiation therapy and bevacizumab.  
 
Maintenance Phase : At least four weeks after completing concurrent TMZ + RT + BEV, 
TMZ will be administered (with bevacizumab) for an additional 12 cycles (cycle = 28 days; 
± 3 day window allowed for Day 1). Dosage for cycle 1 will be TMZ 150 mg/m2 daily on 
days 1-5, followed by 23 days of rest. At the start of cycle 2, the dose will be escalated to 
200 mg/m2 if the following criteria are met:   
• CTC non-hematologic toxicities for Cycle 1 have resolved to Grade ≤2 (except for 
alopecia, nausea and vomiting),  
• Absolute neutrophil count (ANC) is ≥ 1.5 x 109/L, and  
• Platelet count is ≥ 100 x 109/L 
 
If the dose was not escalated at cycle 2, it may be escalated at cycle 3. After cycle 3, no dose 
escalations will be allowed.  
 
In the event of a treatment delay at the scheduled Day 1 of a cycle during maintenance, Day 
1 of that cycle will be delayed until TMZ is re-started. This may cause a cycle to extend to 
longer than 28 days. Day 1 will be defined as the day TMZ is re-started. 
If treatment is delayed for a TMZ-related toxicity, treatment with bevacizumab may 
continue per investigator discretion. If TMZ is held for greater than 4 weeks, the subject will 
be discontinued from study treatment. 
 
Dose delays or modifications not defined above will be done according to the most recent 
package insert. 
 


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15 
 
6.2. 
Bevacizumab Administration 
 
Concurrent Chemoradiation Phase: Bevacizumab will be administered every 2 weeks (+/- 3 
days) as an IV infusion dosed at 10 mg/kg concurrently with TMZ and radiation therapy. 
Every effort will be made to initiate bevacizumab and TMZ on the same day that radiation 
starts. Bevacizumab will only be administered if any existing surgical wound has fully healed. 
A maximum of 4 weeks after biopsy will be permitted.   
 
Dosing calculations should be based on body weight unless the subject’s weight on the day 
of dosing differs > 10% from the weight used to calculate the dose, then the dose must be 
recalculated. All doses should be rounded to the nearest milligram. 
 
The first infusion should be administered over 90 minutes. If the subject tolerates the first 
infusion, the second infusion will be administered over 60 minutes. All subsequent infusions 
will be administered over 30 minutes if the 60 minute infusion is tolerated. 
 
 
Refer to the package insert for recommended treatment modifications and supportive 
care for the following bevacizumab-related toxicities. 
 
Bevacizumab will be temporarily held for: 
• Elective surgery (hold at least 4 weeks prior to surgery and until wound is fully 
healed) 
• Severe hypertension defined as SBP > 160 and/or DBP > 100 mm Hg 
• Moderate to severe proteinuria  
o Hold for 3+ or greater urine dipstick reading 
o Resume when proteinuria is < 3+ on urine dipstick reading. A 24 hour 
urine may be ordered per investigator discretion. 
• Severe infusion reactions 
 
Bevacizumab will be permanently discontinued for: 
• Gastrointestinal perforation, including fistula formation involving an internal organ  
and intra-abdominal abscess 
• Surgery and wound healing complications including dehiscence and nectrotizing 
fasciitis 
• Serious hemorrhage 
• Severe arterial thromboembolic events 
• Grade 4 venous thromboembolic events, including pulmonary embolism that are 
determined to be life-threatening by the treating investigator 
• Hypertensive crisis or hypertensive encephalopathy 
• Posterior Reversible Encephalopathy Syndrome 
• Nephrotic syndrome 
 
Maintenance: After completing concurrent TMZ + RT + BEV, bevacizumab (with TMZ) 
will be administered every 2 weeks (+/-3 days) as an IV infusion dosed at 10 mg/kg for an 
additional 12 cycles (cycle = 28 days).  


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16 
 
 
If treatment is delayed for a bevacizumab-related toxicity, treatment with TMZ may 
continue per investigator discretion. 
In the event of a treatment delay at the scheduled Day 1 of a cycle during maintenance, Day 
1 of that cycle will be delayed until TMZ is re-started. This may cause a cycle to extend to 
longer than 28 days. Day 1 will be defined as the day the treatment is re-started. 
Missed doses will not be made up. If bevacizumab is held for greater than 4 weeks, the 
subject will be discontinued from study treatment. 
 
6.3. 
Radiation Therapy 
 
Intensity Modulated RT (IMRT) is allowed. Radiation therapy must begin ≤ 4 weeks after 
surgery. The modality chosen at registration MUST be used for the entire course of 
treatment 
6.3.1. Dose Specifications 
 
For both IMRT and 3D-CRT plans, one treatment of 2 Gy will be given daily 5 days 
per week for a total of 60 Gy over 6 weeks.  
 
6.3.2. Localization, Simulation, and Immobilization 
 
The subject shall be treated in the supine or other appropriate position for the location 
of the lesion. A head-holding device to ensure adequate immobilization during 
therapy and ensure reproducibility is strongly recommended.  
 
6.3.3. Initial Target Volume 
 
Target volumes will be based upon postoperative-enhanced MRI. Preoperative 
imaging should be used for correlation and improved identification. Two planning 
target volumes (PTV) will be defined, as outlined below. The initial gross tumor 
volume (GTV1) will be defined by either theT2 or the FLAIR abnormality on the 
post-operative MRI scan. The initial clinical target volume (CTV1) will be the GTV 
plus a margin of 2 cm.  
 
6.3.4. Boost Target Volume 
 
The boost gross tumor volume (GTV2) will be defined by the contrast-enhanced T1 
abnormality on the post-operative MRI scan. This must also include the surgical 
cavity margins. The boost clinical target volume (CTV2) will be the GTV plus a 
margin of 2.0 cm. The CTV2 margin maybe reduced to 0.5 cm around natural barriers 
to tumor growth such as the skull, ventricles, falx, etc, and also to allow sparing of the 
optic nerve/chiasm, if necessary.  
 


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6.3.5. Dose Guidelines 
 
The initial target volume will be treated to 46 Gy in 23 fractions. After 46 Gy, the 
conedown or boost volume will be treated to a total of 60 Gy, with seven additional 
fractions of 2 Gy each (14Gy boost dose).  
 
6.3.5.1. Treatment Interruption 
 
Up to 5 days of treatment interruption are permitted for any reason. 
Interruptions of 6 to 7 treatment days will be considered an acceptable protocol 
deviation. For interruptions of 8 days or greater, an unacceptable deviation will 
be assigned. 
 
6.3.6. Radiation Therapy Adverse Events 
 
6.3.6.1. Acute 
 
Expected acute radiation-induced toxicities include hair loss, fatigue, and 
erythema or soreness of the scalp. Potential acute toxicities include nausea and 
vomiting as well as temporary aggravation of brain tumor symptoms such as 
headaches, seizures, and weakness. Dry mouth or altered taste has been 
occasionally reported. 
 
6.3.6.2. Early Delayed 
 
Possible early delayed radiation effects include lethargy and transient 
worsening of existing neurological deficits occurring 1-3 months after 
radiotherapy treatment. 
 
6.3.6.3. Late Delayed 
 
Possible late delayed effects of radiotherapy include radiation necrosis, 
endocrine dysfunction, and radiation-induced neoplasms. In addition, 
neurocognitive deficits, which could lead to mental slowing and behavioral 
change, are possible. Cataracts can be encountered. 
 
6.4. 
OptuneTM System Administration 
 
6.4.1. Treatment Planning of TTFields (Tumor Treating Fields) 
 
Once the chemoradiation has been completed, the post-radiation MRI of the brain 
will be used for treatment planning of the transducer array layout. Only investigators 
trained by Novocure are involved in this study and training will be documented.  The 
treatment planning of the TTFields (Tumor Treating Fields) will be performed by the 
investigator via the NovoTALTM system. The investigator will plan the location of the 
treatment transducer arrays by using 3D software to encompass the target volume of 
tumor, and/or resection bed within the fields.  


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18 
 
 
6.4.2. Subject Preparation Prior to the Placement of OptuneTM System            
 
The subjects (and/or caregiver) will be trained in the use of the device by the 
investigator, a designated health care provider (eg. nurse), or a Novocure device 
support specialist.  All subjects will be required to shave their heads prior to initiating 
array placement and OptuneTM therapy.  Array placement will be performed based 
on the transducer array map calculated during treatment planning. 
 
6.4.3. Placement of OptuneTMSystem 
 
Upon completion of the treatment planning, the subject will have an appointment 
with the prescribing physician for the initial placement of the transducer arrays. 
Furthermore, the subject and caregiver(s) will be provided with educational material. 
They will receive extensive teaching in regard to usage and daily wear of the 
OptuneTM System.   
 
6.4.3.1. Transducer Array Placement Protocol 
 
The specific locations of each transducer array set will be pre-calculated by the 
investigator based on the post-radiation MRI of the brain. The transducer array 
layout will be approved by the treating investigator and determined according 
to tumor location. After transducer array placement, the OptuneTM System will 
be activated with pre-defined parameters which will be supplied by Novocure. 
 
6.4.3.2. Transducer Replacement 
 
During transducer array replacement, the skin below the transducer array will 
be inspected by the physician (during treatment visits) and by the subject 
himself or herself (or caregiver).  In the event of significant skin breakdown 
(leading to pain or bleeding) or evidence of infection, the transducer array will 
be moved to an alternate site.  Skin breakdown and/or infection will be treated 
according to the treating physician’s clinical judgment or based on a 
dermatologist's recommendation.  Adverse Events (AEs) of skin breakdown or 
evidence of infection, either of which requires a break in OptuneTM System 
treatment greater than 3 days, will be reported on the eCRF. Mild to moderate 
contact dermatitis is expected to appear beneath the transducer array gel during 
the first or second treatment course. This condition will be treated per 
instructions outlined under section 6.4.6. 
• Transducer array location will be shifted between two alternate sites at 
every transducer array change. At each array placement, 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. 
• Subjects will replace the transducer arrays two to three times per week 
with the help of a caregiver. At each array replacement, the subject’s 


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19 
 
scalp will be re-shaved and skin treated according to the guidelines 
specified in this protocol. 
 
 
6.4.4. Device Compliance 
 
The subject and caregiver(s) will be instructed on the length of daily wear (on average 
18 hours or more a day), the procedure for shaving subject’s scalp for preparation, 
and continued wearing of the device. Treatment with the device will be continuous, 
with breaks allowed for personal needs (eg: showering, array exchange).  The subject 
may elect to take a treatment break for a total of 3 days per month (may be non-
consecutive), for each month and still be in compliance. The treatment will be 
continued until disease progression, 12 months, a non-acceptable side effect to the 
subject, or consent withdrawal. Compliance with the OptuneTM System will be 
assessed through the use of a log generated by the device and will be assessed by the 
investigator or Novocure representative. Subjects who experience adverse events that 
result in the interruption of OptuneTM therapy will not be considered to be non-
compliant. 
 
6.4.5. Delivery of OptuneTM Therapy 
 
OptuneTM System will be programmed by Novocure to deliver 200kHz TTFields in 
two sequential, perpendicular field directions at a maximal intensity of 707mA RMS 
(otherwise known as the output current). There will be no adjustments made to the 
device by investigators or subjects/caregivers.  
 
6.4.6. Skin Care/Dose Modification for OptuneTM Therapy 
 
If the skin is inflamed and shows signs of allergic or irritant contact dermatitis, a 
topical corticosteroid such as triamcinolone 0.1% or clobetasol, at the physician’s 
discretion, will be applied to the irritated area twice daily, left on the scalp for 15 
minutes, and wiped away before the arrays are replaced. 
• In cases of irritant contact dermatitis, ceramide creams and/or bland 
emollients/moisturizers such as Eucerin Original Moisturizing fragrance-free 
lotion or cream (applied twice daily) or topical Aquaphor (applied once daily) 
may be recommended at the physician’s discretion. If a superficial infection 
develops, a topical antibiotic ointment may be added to the treatment regimen. 
• In cases of allergic contact dermatitis, calamine lotion or antipruritic lotions 
(i.e. topical diphenhydramine) may be recommended at the physician’s 
discretion. Severe cases of allergic contact dermatitis will be treated with a 2-
week course of systemic corticosteroids or corticosteroid injections. Topical 
immunomodulators may be used in cases where topical corticosteroids are 
unsafe. If a superficial infection develops, a topical antibiotic ointment may be 
added to the treatment regimen. 
• For folliculitis, topical antibiotic is recommended. Oral antibiotic may be 
advised if severe. Warm compresses or medicated shampoos may be advised. 


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20 
 
• For erosions (incomplete loss of epidermis), topical antibiotic is 
recommended. Oral antibiotics may be added for severe cases. Avoidance of 
erosions when placing arrays is recommended. The wounds may be dressed 
with gauzes, hydrogels, or hydrocolloids. Arrays will be removed from the 
site of the skin breach and bandages may be trimmed. 
• If the epidermis appears to be lost and dermis is affected, those lesions will be 
described as ulcers. Topical antibiotic is recommended. Oral antibiotics may 
be added for severe cases. Avoidance of erosions when placing arrays is 
recommended. Culture of open wound may be advised. The wounds may be 
dressed with gauzes, hydrogels, or hydrocolloids. Arrays will be removed 
from the site of the skin breach and bandages may be trimmed. 
 
If skin blistering occurs, silver sulfadiazine may be recommended to be applied to the 
affected areas. In subjects with sulfa allergy, a dermatology consult will be obtained 
to seek alternative courses of treatment. The subject or caregiver(s) may also apply 
cold, moist compresses for 20 minutes 3x a day. 
 
In any case where the subject does not notice an improvement in the skin reaction 
within 2 weeks of starting one of the treatments outlined above, the subject will be 
instructed to inform the investigator and a dermatological consult will be obtained. 
 
For all types of skin irritation (pruritis, erosion, ulcer, infection, or blister), the 
physician may determine that a temporary hold on the OptuneTM treatment may be 
necessary.  
 
There will be no “dose” adjustments to the device for adverse events. Reasons for 
breaks in treatment for longer than 3 days will be documented.  
 
6.4.7. Technical Support of the OptuneTM System 
 
The subject/caregiver(s) will be trained by a Novocure device support specialist 
and/or prescribing physician or other Novocure trained designee.  The 
subject/caregiver(s) will learn how to turn the device on/off and how to 
connect/disconnect the transducer arrays (through the connection cable).  The 
subject/caregiver(s) will also learn how to recharge and replace the device battery.   
 
The subject’s caregiver(s) will learn how to handle device error messages/device 
malfunctions themselves (using the troubleshooting section of the OptuneTM Patient 
Information and Operation Manual provided by Novocure) and will learn how to 
contact the Novocure device support specialist (or Novocure Technical Support Line) 
for issues they cannot resolve themselves.  They will also be instructed on when to 
contact the Novocure device support specialists versus when to call the prescribing 
physician. 
 
The subject/caregiver(s) will also be given extensive instruction on the treatment of 
expected adverse events.  
 


Protocol Number:  LCI-NEU-NOV-001 
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21 
 
All technical aspects of treatment can be handled by the Novocure device support 
specialists.  Examples of technical issues include, but are not limited to:  technical 
support of device for the subject (by phone or in person), training/re-training on 
correct use of the device, periodic download of device compliance log file (once 
every four weeks), replacement of faulty equipment, requests for replacements from 
Novocure and device, electrode and accessory accountability tracking. 
 
6.5. 
Duration of Therapy 
 
Study treatment will continue until one of the following criteria applies: 
• Completion of protocol therapy which is defined as completion of 12 months of 
OptuneTM therapy 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Subject decides to withdraw study consent  
• General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator 
• Study subject becomes pregnant 
 
NOTE: In the event the criteria for the final analysis are met, and there are subjects who 
have not yet been discontinued from study treatment, they will continue to receive therapy 
until one of the above criteria applies. 
 
6.6. 
Duration of Follow-Up 
 
Subjects in the evaluable population for efficacy (subjects who have the OptuneTM device 
placed) will be followed until all subjects have been on study five years from the date of 
enrollment, have died, or until the censoring rate reduces to 20%, whichever occurs first.  
Subjects who do have the OptuneTM device placed will be followed for the 30 day safety 
follow-up period as described in Section 8.2.1 and then removed from the study. 
 
6.7. 
Criteria for Removal from Study 
 
When subjects are removed from the study, the reason for study removal and date the 
subject was removed should be documented. Reasons a subject may be removed from the 
study include, but are not limited to: 
 
• Subject withdraws study consent 
• Investigator’s decision to withdraw the subject  
• Subject is lost to follow-up after three consecutive months of attempted contact 
• Death  
• Study completion 
 
Any subject removed from the study will remain under medical supervision until discharge 
or transfer is medically acceptable. Subjects that are Off Study will not participate in any 


Protocol Number:  LCI-NEU-NOV-001 
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22 
 
study related procedures, including data collection. 
 
 
7. 
TREATMENT- RELATED ADVERSE EVENTS 
 
 
 
 
7.1. 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting.   
 
Attribution of the AE: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.2. 
Adverse Events Considered Related to OptuneTM System 
 
Mild to moderate (grade 1 and grade 2) dermatitis has been reported on the scalp underneath 
the transducer arrays in patients receiving OptuneTM therapy.  This typically occurs by the 
second month of treatment and resolves with use of topical steroids and shifting of the 
arrays “back and forth” at each transducer array exchange.  Sometimes short treatment 
interruptions are required. Treatment with the OptuneTM System 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 sore, ulceration or blisters underneath the transducer arrays 
• Headache 
• Fatigue 
In the phase III trial of OptuneTM System monotherapy vs. physician’s choice chemotherapy 
in recurrent GBM the following moderate to severe adverse events (regardless of causality) 
were seen: 
 
Table 1 
 
 
 
OptuneTM Therapy (n=116) 
Active Control (n=91) 
System 
Adverse event term 
%  (% gr. 3+4) 
%  (% gr. 3+4) 


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23 
 
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) 
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 subsequently. 
7.3. 
Adverse Events Considered Related to Temozolomide 
 
Temozolomide has been well-tolerated by adults with the most common toxicity being mild 
myelosuppression.  Other, less likely, potential toxicities include nausea and vomiting, 


Protocol Number:  LCI-NEU-NOV-001 
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24 
 
constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, 
lethargy, and hepatotoxicity.  Hypersensitivity reactions have not yet been noted with 
temozolomide. As is the case with many anti-cancer drugs, temozolomide may be 
carcinogenic.   
 
7.4. 
Adverse Events Considered Related to Bevacizumab 
 
Patients receiving bevacizumab have experienced the following adverse events: 
• Grade 3/4 hypertension (including RPLS (confirmed by MRI) or 
 
hypertensive encephalopathy) 
• Grade ≥ 1 pulmonary or CNS hemorrhage 
• Grade 3 non-pulmonary and non-CNS hemorrhage 
• Grade 4 hemorrhage 
• Grade 3/4 asymptomatic venous thrombosis 
• Grade 4 symptomatic venous thrombosis 
• Any grade arterial thromboembolic 
• Grade 3/4 congestive heart failure (left ventricular systolic dysfunction) 
• Grade 3/4 proteinuria 
• GI perforation 
• Bowel obstruction 
• Wound dehiscence 
 
8. SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry values, regular 
measurement of vital signs and the performance of physical examinations.  Safety and tolerability 
will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. All adverse events (Grades 1 – 5) will be recorded. 
 
Serious adverse events (SAEs)/Unanticipated adverse device effects (UADEs) should be entered 
into the CTMS as soon as they occur, but no later than 24 hours of becoming aware of the event. 
Deviations should be entered into the CTMS as soon as they occur, but within no more than 5 
business days of becoming aware of the event. Any additional problems, such as study drug 
administration, or any other problem that could affect the validity/integrity of the study data 
should be tracked and submitted to the Sponsor-Investigator. SAEs/UADEs are also reported to 
the Levine Cancer Institute Data and Safety Monitoring Committee (DSMC) as soon as they 
occur, but no later than 24 hours of becoming aware of the event.   
 
8.1. 
Definitions 
 
8.1.1. Unanticipated Problem (UAP) Definition 
 
An UAP is any incidence, experience or outcome that is unexpected, given the 
information provided in research-related documentation (e.g investigator’s brochure, 
informed consent) and the study population characteristics that is related or possibly 


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25 
 
related to participation in the research study and places the participant at an increased 
risk.   
8.1.2. Adverse Event (AE) Definition  
 
An adverse event or adverse experience is any untoward medical occurrence in a 
study subject who is administered a study drug that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable 
and unintended sign, symptom, or disease temporally associated with the use of the 
study drug, whether or not considered related to the study drug.  Pre-existing 
conditions that increase in frequency or severity or change in nature during or as a 
consequence of use of a drug in human clinical trials are also considered adverse 
events.  Adverse events may also include pre- or post-treatment complications that 
occur as a result of protocol mandated- procedures (e.g., invasive procedures such as 
biopsies). 
 
Any continuing medical condition or clinically significant laboratory abnormality 
with an onset date before the first date of study drug/device administration should be 
considered pre-existing and should be documented at baseline. If the medical 
condition or clinical significant laboratory abnormality worsens while the subject is 
on study, it should be documented as an adverse event.  
 
An AE does not include: 
• relapse or progression of the underlying malignant disease; however, the 
 
associated signs, symptoms, or diagnoses should be recorded as adverse 
 
events (e.g., “jaundice” due to new or increasing liver metastases, or 
 
“tumor pain” or “bone pain” due to progressive disease); 
• medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
 
transfusion).  The condition that leads to the procedure is the adverse event; 
• situations where an untoward medical occurrence has not occurred 
 
(e.g., hospitalization for elective surgery, social and/or convenience 
 
admissions); 
• overdose of either study drug or concomitant medication without any signs 
 
or symptoms unless the subject is hospitalized for observation; or 
• pregnancy. 
 
Laboratory abnormalities are usually not recorded as adverse events; however, signs 
and/or symptoms that are associated with laboratory findings requiring study 
withdrawal, dose modification, or medical intervention (e.g., anemia requiring 
transfusions or hyperglycemia requiring treatment) or other abnormal assessments 
(e.g., ECG, radiographs, vital signs) must be recorded as adverse events if they meet 
the definition of an adverse event.  In addition, laboratory abnormalities marked as 
clinically significant by the investigator should also be recorded as adverse events in 
the eCRF.  The investigator will record the most severe grade of the clinically 
significant laboratory abnormality and will evaluate its relationship to the study drug 
and clinical condition if/when a clinically significant laboratory abnormality occurs.   
 


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26 
 
The relationship to study drug therapy should be assessed using the following 
definitions: 
 
Not Related:  Evidence exists that the AE has an etiology other than the study drug 
(eg, pre-existing condition, underlying disease, intercurrent illness, or concomitant 
medication).  This includes events that are considered remotely or unlikely related to 
study drug. 
 
Related:  A temporal relationship exists between the event onset and administration of 
the study drug.  It cannot be readily explained by the subject’s clinical state, 
intercurrent illness, or concomitant therapies.  In the case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge.  It should be 
emphasized that ineffective study drug treatment should not be considered as causally 
related in the context of AE reporting.  This includes events that are considered 
possibly, probably, or definitely related to study drug. 
 
All adverse events (including event name, grade, start/stop date and attribution) will 
be documented in the medical record and/or research chart and recorded on the 
electronic case report form for this protocol. 
 
The Investigator is responsible for verifying and providing source documentation for 
all adverse events and assigning the attribution for each event for all subjects enrolled 
on the trial. 
 
8.1.3. Suspected Adverse Reaction (SAR) Definition 
 
A SAR is an adverse event in which there is reasonable possibility that the study drug 
caused the adverse event as defined by 21 CFR 312.32.  The Investigator is 
responsible for judging whether it is a reasonable possibility that the study drug 
caused the adverse event. 
 
8.1.4. Unexpected Definition 
 
An AE or SAR is to be considered unexpected if the event is not listed in package 
insert, label or investigator brochure or is not listed in the severity or specificity 
observed. 
 
8.1.5. Serious AE or SAR 
 
An AE or SAR is to be considered serious if the Investigator (in consultation with the 
Sponsor-Investigator , if needed) deems it as such and the event results in any of the 
following outcomes: 
• Death; 
• Life-threatening situation (subject is at immediate risk of death); 
• Inpatient hospitalization or prolongation of an existing hospitalization 
 
(excluding those for study drug administration, protocol-related 


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procedures, palliative or hospice care, or placement of an indwelling 
 
catheter, unless associated with other serious events); 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect in the offspring of a subject who received 
study drug; 
• Any secondary malignancy (defined as new cancers, not transformation or 
progression of original disease). The pathology report documenting the 
new malignancy should be attached. 
• Other:  Important medical events that may not result in death, be 
 
immediately life-threatening, or require hospitalization, may be 
 
considered an SAE when, based upon appropriate medical judgment, 
 
they may jeopardize the subject or may require medical or surgical 
 
intervention to prevent one of the outcomes listed in this definition.  
 
Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for 
allergic bronchospasm; 
• 
Blood dyscrasias or convulsions that do not result in 
hospitalization; 
• 
Development of drug dependency or drug abuse. 
 
Questionable events: 
Any suspected adverse reaction can and should be reported as an SAE if deemed 
appropriate by the Sponsor-Investigator. 
 
Planned hospitalizations: 
Elective surgeries that have been planned prior to subject enrollment in the study or 
for conditions existing prior to study enrollment do not need to be captured as SAEs, 
unless complications occur or the conditions are worse than the subject’s baseline.   
 
Hospital admission for treatment required by the protocol (overnight chemotherapy, 
etc.) need not be reported as an SAE, unless a complication results that fits the 21 
CFR 312.32 definition of an SAE. 
 
The Investigator is responsible for verifying and providing source documentation for 
all SAEs and assigning the attribution for each event for all subjects enrolled on the 
trial. 
 
8.1.6. Unanticipated Adverse Device Effect (UADE) 
 
A UADE is defined as any serious adverse effect on the health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, 
problem or death was not previously identified in nature, severity or degree of 
incidence.  A UADE is also defined as any unanticipated serious problem associated 
with the device that is related to the rights, safety, or welfare of research subjects, 
according to 21 CFR 812.3. 
 


Protocol Number:  LCI-NEU-NOV-001 
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28 
 
8.2. 
Timing and Reporting 
8.2.1. 
Adverse Events  
 
All AEs from initiation of study treatment until 30 days after the OptuneTM device is 
discontinued will be documented (including event name, grade, start/stop date and 
attribution) and recorded in the CTMS. For subjects who do not have the OptuneTM 
device placed, AEs will be reported until 30 days after the last dose of study 
treatment.  Study treatment is defined as protocol-directed radiation, temozolomide, 
bevacizumab, and OptuneTM therapy. If radiation, temozolomide and/or bevacizumab 
are initiated on different days, the AE reporting period will start with the first study 
treatment administered. 
 
8.2.2. 
SAEs 
 
After informed consent but prior to initiation of study treatment, only SAEs caused 
by a protocol-mandated intervention will be reported (e.g. SAEs related to invasive 
procedures such as biopsies, medication washout).  
 
For any other experience or condition that meets the definition of an SAE, recording 
of the event must begin from initiation of study treatment until 30 days after the 
OptuneTM device is discontinued. For subjects who do not have the OptuneTM device 
placed, SAEs will be reported until 30 days after the last dose of study treatment.  
Study treatment is defined as protocol-directed radiation, temozolomide, 
bevacizumab, and OptuneTM therapy. If radiation, temozolomide and/or bevacizumab 
are initiated on different days, the SAE reporting period will start with the first study 
treatment administered. 
 
SAEs occurring greater than 30 days after last day of study treatment and thought to 
be possibly, probably, or definitely related to study treatment are reportable for the 
duration of the subject’s participation in the study. 
 
It is the responsibility of the Sponsor-Investigator, investigators and the protocol 
team to ensure SAEs are reported according to the Code of Federal Regulations 
(CFR), GCP, the protocol guidelines, IRB, and FDA policy.  
 
8.2.3. UADEs 
 
Any experience or condition that meets the definition of a UADE, recording of the 
event must begin from OptuneTM device placement and continue through the 30 days 
after OptuneTM System treatment is discontinued.  
 
UADEs occurring greater than 30 days after OptuneTM System discontinuation and 
thought to be possibly, probably, or definitely related to study treatment are 
reportable for the duration of the subject’s participation in the study. 
 


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29 
 
It is the responsibility of the Sponsor-Investigator, investigators and the protocol team 
to ensure UADEs are reported according to the Code of Federal Regulations (CFR), 
GCP, the protocol guidelines, IRB, and FDA policy.  
 
8.2.4. 
Reporting to the Sponsor-Investigator 
 
All SAEs and UADEs (including event name, grade, start/stop date and attribution) 
must be reported to the Sponsor-Investigator within 24 hours of awareness via the 
CTMS.  
 
8.2.5. Reporting to the FDA 
 
For Investigator-sponsored studies, reporting requirements for the FDA apply in 
accordance with the guidance set forth in 21 CFR 812.46, 21 CFR 812.150 and 21 
CFR 312.32. The following are required  to be submitted to the FDA in writing 
within 10 calendar days after the Sponsor-Investigator becomes aware of the event:  
• SAEs that are determined by the investigator to be related and unexpected to 
bevacizumab 
• All UADEs 
 
8.2.6. Reporting to the IRB 
 
All events occurring during the conduct of a protocol and meeting the definition of a 
UAP, SAE or UADE will be reported to the IRB per IRB reporting requirements. 
 
8.2.7. Reporting to the Funding Sponsoring Company (Novocure) 
 
Unanticipated adverse device events (UADEs) will be reported to Novocure promptly 
but no later than 10 working days of the Sponsor-Investigator learning of the event. 
 
Protocol deviations necessary to protect the safety, rights or welfare of subjects 
enrolled in the study will be reported to Novocure promptly but no later than 10 
working days from the time of identification of the protocol deviation by the Sponsor-
Investigator. 
 
8.3. 
Other Reporting 
 
Deviations from the investigational plan to protect the life or physical well-being of a 
subject in an emergency situation will be reported to the Sponsor-Investigator as soon as 
possible but no later than 5 working days after the emergency occurred and to the IRB per 
IRB reporting requirements.  Except in emergency situations, a planned protocol deviation 
requires prior sponsor approval; and if the deviation may affect the scientific soundness of 
the investigational plan or the rights, safety or welfare of study subjects, prior FDA and 
IRB approval are required. 
 
Descriptions of protocol deviations will be provided to the FDA by the Sponsor-
Investigator as part of the annual progress report and/or final report, as applicable. 


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30 
 
 
The FDA, IRB and Novocure will be notified in writing of other events according to the 
following schedule: 
 
Table 2 
Event 
Agency 
Timeframe for Reporting 
Minor changes to the 
investigational plan 
(prior FDA approval 
not required) 
FDA 
 
Within 5 working days after 
IRB approval/change 
implementation (known as 
5-Day Notice of IDE 
Change); or, changes 
submitted in next progress 
report (non-significant 
changes) 
IRB 
Within 90 days of S-I 
becoming aware of change 
Novocure 
 
Advance notice with 
confirmation of Novocure 
approval prior to IRB 
submission 
Major changes to the 
investigational plan 
(also known as 
supplements; prior 
approval required) 
FDA 
Advance notice and 30-day 
approval waiting period 
IRB 
Prior IRB approval required 
after receipt of FDA 
approval 
Novocure 
Advance notice with 
confirmation of Novocure 
approval prior to FDA 
submission 
Recall and device 
disposition 
FDA 
30 working days 
IRB 
10 working days 
Novocure 
Not applicable 
Withdrawal of IRB 
approval 
FDA 
5 working days after receipt 
of IRB withdrawal 
IRB 
Not applicable 
Novocure 
5 working days after receipt 
of IRB withdrawal 
 
Withdrawal of IDE 
FDA 
Not applicable 
IRB 
5 working days after receipt 
of IDE withdrawal 
Novocure 
5 working days after receipt 
of IDE withdrawal 
Current Investigator 
List 
FDA 
Every 6 months following 
FDA approval 


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31 
 
 
 
 
 
9. 
DATA AND SAFETY MONITORING PLAN 
 
This trial will be organized, performed, reported on and monitored in compliance with the 
study protocol, the Levine Cancer Institute (LCI) Data and Safety Monitoring Plan (DSMP), 
standard operating procedures (SOPs) of the LCI Clinical Trials department and Carolinas 
Healthcare System Office of Clinical and Translational Research, the FDA, IRB and other 
applicable regulations and guidelines (e.g. ICH and GCP).  Ultimately, it is the 
responsibility of the Sponsor-Investigator to monitor the safety data for this study. 
 
9.1. 
Monitoring and Review 
 
Monitoring and review of this clinical trial will occur at 3 levels as described in the LCI 
Data and Safety Monitoring Plan:  the Protocol Team, the Monitoring Team and the Data 
and Safety Monitoring Committee.   
 
The Protocol Team will meet to review subject consents, enrollment and retention, safety 
data for all subjects [including adverse events (AE’s) for all grades and attributions, serious 
adverse events (SAE’s), unanticipated adverse device effects], drug administration, and 
validity/integrity of the data at all research sites.  Following each Protocol Team meeting, a 
status report will be generated and will be kept on file. 
 
Routine internal monitoring of subject safety and data quality at all investigational sites will 
also be conducted at scheduled intervals (based on protocol risk level) by the Monitoring 
Team at LCI according standard operating procedures.  The Monitoring Team consists of 
members of the LCI Quality Assurance (QA) Department and other staff as needed. The 
Monitoring Team will be responsible for conducting initial, routine, and closeout 
monitoring visits according to the procedures defined in standard operating procedures. Data 
quality monitoring will be done by comparing source documentation to the eCRFs. The 
eCRFs will be reviewed and checked for omissions, apparent errors, and values requiring 
further clarification using computerized and manual procedures. Any variation between the 
IRB 
Only when the Principal 
Investigator changes  
Progress Report 
FDA 
Annually at time of FDA 
approval 
IRB 
Annually at time of IRB 
approval 
Final Report 
FDA 
Notify FDA within 30 
working days of study 
completion/termination.  
 
Final report submitted 
within 6 months. 
IRB 
At time of study 
completion. 
Novocure 
Final report submitted 
within 6 months. 


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32 
 
source document and the eCRF will be discussed with the Protocol Team. Data queries 
requiring clarification will be generated and addressed by Protocol Team. Only authorized 
personnel will make corrections to the protocol database and all corrections will be 
documented in an audit trail.  At the conclusion of each routine internal monitoring visit, the 
Monitoring Team will provide a report to the Protocol Team and QA Manager.  If at any 
monitoring visit subject safety risk, poor data quality or potential fraud or misconduct is 
identified, the Monitoring Team will notify the QA Manager and will follow the procedures 
outlined in the LCI standard operating procedures. 
 
The Monitoring Team will use the CTMS, status reports, and Monitoring Visit Reports to 
update the DSMC on the status of the trial (including toxicity assessment and outcomes 
data). This information will be reviewed by the Data and Safety Monitoring Committee 
(DSMC) at regular intervals depending on the accrual rate, and at the time of annual review. 
For immediate subject safety events, the Protocol and/or Monitoring Team will notify the 
QA Manager upon becoming aware of the concern. Additionally, the Protocol Team will 
notify the DSMC within 1 business day of becoming aware of the event to allow an ad hoc 
meeting, if deemed necessary. Based upon DSMC review, the Sponsor-Investigator and 
Protocol Team may be required to develop an action plan and then notify the DSMC Chair 
in writing within 4 business days.   
 
9.2. 
Communication Between Investigational Sites 
 
All investigational sites will report AEs, SAEs and UADEs using eCRFs and the SAE 
reporting function in the CTMS. Any additional problems that could affect subject safety or 
data validity should be communicated with the S-I by email and/or telephone as soon as 
they occur, but within 1 business day. 
 
9.3. 
Clinical Trial Registration 
 
The Sponsor-Investigator is solely responsible for determining whether the trial and its 
results are subject to the requirements for submission to ClinicalTrials.gov 
(http://www.clinicaltrials.gov). 
 
10. MEASUREMENT OF EFFECT  
 
10.1. Antitumor Effect – Solid Tumors 
 
In addition to a baseline scan, response and progression will be evaluated in this study using 
the Updated Response Assessment Criteria for High Grade Gliomas (RANO) (see section 
10.1.4).  
 
Subjects will have their response categorized as follows:  1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data).  [Note:  By arbitrary convention, category 9 usually designates 
the “unknown” status of any type of data in a clinical database.] 
 


Protocol Number:  LCI-NEU-NOV-001 
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33 
 
10.1.1. 
Disease Parameters 
 
Measurable disease:  As defined by the Updated Response Assessment Criteria for 
High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group 
(RANO), measurable disease is defined as bi-dimensionally contrast-enhancing 
lesions with clearly defined margins by MRI scan, with two perpendicular diameters 
of at least 10 mm, visible on two or more axial slices that are preferably, at most,5 
mm apart with 0-mm skip. All tumor measurements must be recorded in millimeters 
(or decimal fractions of centimeters). 
 
If there are multiple contrast-enhancing lesions, a minimum of two and a maximum 
of five of the largest lesions should be measured, and the sum of the products of the 
perpendicular diameters of these lesions should be determined for response. 
 
Note:  Tumor lesions that are situated in a previously irradiated area are considered 
measurable if accompanying clinical deterioration and new FLAIR changes are 
present.[16] 
 
Non-measurable disease:  Unidimensionally measurable lesions, masses with margins 
not clearly defined, or lesions with maximal perpendicular diameters <10 mm are 
considered non-measurable disease.[16] 
 
10.1.2. 
Methods of Evaluation for Measurable Disease (Target and Non- 
 
Target Lesions 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional MRI:  These techniques should be performed with cuts of 5 mm or less 
in slice thickness contiguously.[16] 
 
10.1.3. 
Response Criteria 
 
Complete response: 
Requires all of the following: complete disappearance of all enhancing measurable 
and non-measurable disease sustained for at least 4 weeks; no new lesions; stable or 
improved non-enhancing(T2/FLAIR) (fluid-attenuated inversion recovery) lesions; 
subjects must be off corticosteroids (or on physiologic replacement doses only); and 
stable or improved clinically. (Note: Subjects with non-measurable disease only 
cannot have a complete response; the best response possible is stable disease.)[16] 


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34 
 
 
Partial response: 
Requires all of the following: > 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for 
at least 4 weeks; no progression of non-measurable disease; no new lesions; stable or 
improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan; the corticosteroid dose at the time of the 
scan evaluation should be no greater than the dose at time of baseline scan; and stable 
or improved clinically. (Note: Subjects with non-measurable disease only cannot have 
a partial response; the best response possible is stable disease.)[16] 
 
Stable disease: 
Requires all of the following: does not qualify for complete response, partial 
response, or progression; stable non-enhancing (T2/FLAIR) lesions on same or lower 
dose of corticosteroids compared with baseline scan. In the event that the 
corticosteroid dose was increased for new symptoms and signs without confirmation 
of disease progression on neuroimaging, and subsequent follow-up imaging shows 
that this increase in corticosteroids was required because of disease progression, the 
last scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.[16] 
 
Progression: 
Defined by any of the following:  > 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions compared with the smallest tumor 
measurement obtained either at baseline (if no decrease) or best response, on stable or 
increasing doses of corticosteroids; significant increase in T2/FLAIR non-enhancing 
lesion on stable or increasing doses of corticosteroids compared with baseline scan or 
best response after initiation of therapy not caused by comorbid events (eg, radiation 
therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects); any new lesion; clear clinical deterioration not attributable to 
other causes apart from the tumor (eg, seizures, medication adverse effects, 
complications of therapy, cerebrovascular events, infection, and so on) or changes in 
corticosteroid dose; failure to return for evaluation as a result of death or deteriorating 
condition; or clear progression of non-measurable disease. (NOTE: All measurable 
and non-measurable lesions must be assessed using the same techniques as at 
baseline.) 
 
**Stable doses of corticosteroids include subjects not on corticosteroids.[16] 
 
10.2. Tumor Response Review 
 
Response will be reviewed by one neuro-oncologist and one neuro-radiologist independent 
of the study at the study’s completion.  Simultaneous review of the subjects’ files and 
radiological images is the best approach. 
  
11. STATISTICAL CONSIDERATIONS 
 
11.1. Sample Size 


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35 
 
 
To evaluate the effectiveness of the OptuneTM System, referencing a study in newly 
diagnosed unresectable GBM subjects using the combination of temozolomide and 
bevacizumab for the historical controls is necessary.  One such study was conducted by Lou, 
Peters, and Sumrall.  The survival results for this study showed that the lower limit of the 
95% CI for median OS was 7.4 months (median OS was 11.7 months).  The OptuneTM 
System will be considered worthy of further evaluation in this subject population if it is 
inferred that the median OS is superior to 7 months.  The primary objective is to evaluate 
the 12-month overall survival rate.  Assuming the median OS is 7 months, it is estimated 
that the 12-month survival rate would be 0.30.  A Simon optimal 2-stage design will be used 
to test the hypothesis that the 12-month OS rate is less than or equal to 0.30.  With treatment 
using the OptuneTM System, an improvement in 12-month survival by 20% would be 
clinically notable. In the first stage, 22 subjects will be enrolled.  If at least 8 subjects are 
surviving at 12 months, then an additional 24 subjects will be enrolled (total of 46 subjects).  
If at least 18 of 46 subjects are surviving at 12 months, the null hypothesis will be rejected 
and the addition of the OptuneTM System to chemoradiation therapy may be considered for 
further evaluation.  Assuming 1-sided alpha = 0.10 significance level, this sample size will 
provide 90% power to reject the null hypothesis, assuming the true 12-month survival rate is 
0.50. 
 
11.2. Endpoint Definitions 
 
11.2.1. 12-Month Survival 
Twelve-month survival will be determined for each subject as a binary variable indicating 
whether or not the subject is alive at 12 months. Determination of this endpoint occurs 
after the subject has at least 12 months of follow-up, unless they have died sooner. 
 
11.2.2. Overall Survival 
Overall survival is defined as the duration from the initiation of chemoradiation therapy to 
the date of death from any cause. Subjects who are alive or lost to follow-up at the time of 
the analysis will be censored at the last known date they were alive. 
 
11.2.3. Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from initiation of 
chemoradiation therapy to first occurrence of either progressive disease or death. Disease 
progression must be objectively determined as per Section 10.1, where the date of PD is 
the date of the radiologic assessment that identified progressive disease. If the subject died 
without documented disease progression, the date of progression will be the date of death. 
For surviving subjects who do not have documented disease progression, PFS will be 
censored at the date of last radiologic assessment. For subjects who receive subsequent 
anti-cancer therapy prior to documented disease progression, PFS will be censored at the 
date of last radiologic assessment prior to the commencement of subsequent therapy (note 
that this situation will not apply to cases where the subject discontinues OptuneTM therapy 
but continues treatment with TMZ or BEV). Subjects who have an initial PFS event 
immediately following 2 or more consecutive missed assessments will be censored at the 
date of the last assessment prior to those missed assessments. For participants with only 
one missed assessment, the documented progressive disease status and assessment date 


Protocol Number:  LCI-NEU-NOV-001 
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36 
 
will be used. 
 
11.2.4. Objective Response 
Objective response will be determined for each subject as a binary variable indicating 
whether or not the subject achieved a best overall response of CR or PR as determined by 
the response criteria in Section 10.1. 
 
11.2.5. Duration of Response 
The duration of response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first occurrence of either progressive disease 
or death. The date of PFS events and the censoring mechanism for duration of response 
will be the same as those described for PFS. 
 
11.2.6. Disease Control 
Disease control will be determined for each subject as a binary variable indicating whether 
or not the subject achieved stable disease or better (CR, PR, or stable disease) as 
determined by the response criteria in Section 10.1. 
 
11.2.7. Duration of Disease Control 
Duration of disease control is measured from the time of initiation of chemoradiation 
therapy until the first occurrence of either progressive disease or death. The date of PFS 
events and the censoring mechanism for duration of disease control will be the same as 
those described for PFS. Duration of disease control will be calculated only for those 
subjects with a best overall response of SD or better. 
 
11.3. Analysis Populations 
 
All subjects who receive the initial treatment with chemoradiation therapy will be included 
in the safety population. Subjects who receive initial placement of the OptuneTM System 
transducer arrays will be included in the evaluable population for efficacy. The enrollment 
requirements for the 2-stage design as described in Section 11.1 apply to the evaluable 
population for efficacy. Subjects in the evaluable population with measurable disease will 
be included in the analysis of objective response, duration of response, disease control, and 
duration of disease control. 
 
11.4. Analysis Methods 
 
11.4.1. Timing of Analysis 
The Stage 1 analysis will be conducted after all evaluable subjects in the first stage (n=22) 
have been on study for at least 12 months from the initiation of chemoradiation therapy or 
have died. The primary analysis of the second stage will occur after all evaluable subjects 
(n=46) have been on study for at least 12 months from the initiation of chemoradiation 
therapy or have died. An updated analysis will occur when all subjects have been on study 
for at least 2 years or are off study otherwise. A final analysis will occur when the OS 
censoring rate reaches 20%, or after all surviving subjects have been on study for at least 5 
years after initiation of chemoradiation or are off study otherwise, whichever occurs first. 
 


Protocol Number:  LCI-NEU-NOV-001 
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37 
 
11.4.2. Subject Disposition 
An accounting of all consenting subjects will be provided at the end of the study. This will 
include a breakdown of subjects who consented, were treated with chemoradiation therapy, 
were treated with OptuneTM, discontinued treatment, died, and were lost to follow-up or 
withdrew consent. 
 
11.4.3. Baseline Subject and Disease Characteristics 
A summary of baseline subject and disease characteristics will be completed. Counts and 
proportions will be used for binary and categorical variables. Means, medians, and ranges 
will be used for quantitative measures. 
 
11.4.4. Efficacy Analyses 
11.4.4.1. Primary Analysis 
The frequency and proportions of subjects who are alive at 12 months will be summarized 
and corresponding 95% confidence intervals will be calculated using the Clopper-Pearson 
method. A one-sided test for binomial proportions using the rejection regions described in 
Section 11.1 will be carried out, testing the null hypothesis that the 12 months survival rate 
is less than 30%. 
 
11.4.4.2. Secondary Analyses 
Overall survival, progression-free survival, duration of response, and duration of disease 
control will be analyzed using Kaplan Meier techniques. Medians, 25th, and 75th percentiles 
will be estimated. Selected landmarks will be estimated using the product limit function. 
The frequency and proportions will be used to summarize objective response rate and 
disease control rate. Corresponding 95% confidence intervals will be calculated using the 
Clopper-Pearson method. Cox multiple regression models and logistic regression models 
will be used to evaluate the impact of baseline factors on outcomes. 
 
11.4.5 Safety Analyses 
 
The proportion of subjects experiencing AEs, SAEs, UADEs and death on study will be 
summarized by arm and corresponding 95% confidence intervals will be calculated using 
the Clopper-Pearson method. Safety data collected from date of initiation of chemoradiation 
therapy until the date of transducer arrays placement will be analyzed separately from safety 
data collected after the date of transducer arrays placement. 
 
12. STUDY COMPLETION 
 
The study will be considered complete when one or more of the following conditions is met: 
• 
All subjects have completed all study visits 
• 
All subjects have discontinued from the study 
• 
The IRB, FDA, Sponsor-Investigator or Novocure discontinues the study 
 
because of safety considerations 
• 
The Sponsor-Investigator defines an administrative or clinical cut-off date 
 
13. RETENTION OF RECORDS 


Protocol Number:  LCI-NEU-NOV-001 
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38 
 
 
Documentation of adverse events, records of drug and device accountability, and all IRB 
correspondence should be retained for at least 2 years after the investigation is completed. 


Protocol Number:  LCI-NEU-NOV-001 
Version 6:  05/05/2018 
 
39 
 
REFERENCES 
 
1. Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma. N Engl J Med, 2005. 352(10): p. 987-96. 
2. Stupp, R.,  et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs 
Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A 
Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23): p. 2306-2316. 
3. Beauchesne, P., et al., Prolonged survival for patients with newly diagnosed, inoperable 
glioblastoma with 3-times daily ultrafractionated radiation therapy. Neuro Oncol, 2010. 
12(6): p. 595-602. 
4. Nieder, C., et al., Treatment of unresectable glioblastoma multiforme. Anticancer Res, 
2005. 25(6C): p. 4605-10. 
5. Vredenburgh, J.J., et al., The addition of bevacizumab to standard radiation therapy and 
temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly 
diagnosed glioblastoma. Clin Cancer Res, 2011. 17(12): p. 4119-24. 
6. Fine, H. PFS and health-related QOL in AVAglio, a phase III study of bevacizumab, 
temozolomide, and radiotherapy in newly diagnosed glioblastoma. in ASCO Annual 
Meeting. 2013. Chicago, IL. 
7. Gilbert, M. RTOG 0825: Phase III double-blind placebo-controlled trial evaluating 
bevacizumab in patients with newly diagnosed GBM. in ASCO Annual Meeting. 2013. 
Chicago, IL. 
8. Lou, E., et al., Phase II trial of upfront bevacizumab and temozolomide for unresectable 
or multifocal glioblastoma. Cancer Med, 2013. 2(2): p. 185-95. 
9. 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. 
10. Kirson, E.D., et al., Disruption of cancer cell replication by alternating electric fields. 
Cancer Res, 2004. 64(9): p. 3288-95. 
11. 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. 
12. Stupp, R., et al., NovoTTF-100A versus physician's choice chemotherapy in recurrent 
glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer, 
2012. 48(14): p. 2192-202. 
13. Grace Elzinga, A.C., Eric Wong, Safety analysis of bevacizumab plus NovoTTF-100A in 
patients with recurrent malignant glioma, in ASCO Annual Meeting2013: Chicago, IL. 
14. 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. 
15. Kirson, E.D., et al., Chemotherapeutic treatment efficacy and sensitivity are increased by 
adjuvant alternating electric fields (TTFields). BMC Med Phys, 2009. 9: p. 1. 
16. Wen, P.Y., et al., Updated response assessment criteria for high-grade gliomas: response 
assessment in neuro-oncology working group. J Clin Oncol, 2010. 28(11): p. 1963-72. 
 
 
 
 
 


Protocol Number:  LCI-NEU-NOV-001 
Version 6:  05/05/2018 
 
40 
 
APPENDICES 
 
APPENDIX A: Standard of Care for Newly Diagnosed Glioma Patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number:  LCI-NEU-NOV-001 
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41 
 
APPENDIX B: Karnofsky Performance Scale 
 
 
Karnofsky Performance Scale 
Percent 
Description 
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 to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
0 
Dead. 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
Official Title: A Phase II Study of Optune (NovoTTF) in Combination With Bevacizumab 
(BEV) and Temozolomide (TMZ) in Patients With Newly Diagnosed Unresectable 
Glioblastoma (GBM)
NCT02343549
IRB-Approved Date: 3/7/2018


Ashley Sumrall, MD 
Chesapeake IRB Approved Version 7 Mar 2018 
 
 
 
 
 
 
 
CAROLINAS HEALTHCARE SYSTEM 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
 
 
Sponsor / Study Title: 
  
Levine Cancer Institute, A Phase II Study of OptuneTM in 
Combination with Bevacizumab (BEV) and Temozolomide 
(TMZ) in Patients with Newly Diagnosed, Unresectable 
Glioblastoma (GBM) 
 
 
Protocol Number: 
 
LCI-NEU-NOV-001 
Principal Investigator: 
 
Ashley Sumrall, MD 
Telephone: 
 
 (24 Hours) 
 (24 Hours Toll Free) 
 
Address: 
Levine Cancer Institute 
 
 
 
INTRODUCTION 
 
Dr. Ashley Sumrall and her associates are asking you to participate in this research study of 
OptuneTM and bevacizumab at Levine Cancer Institute (LCI) and Carolinas HealthCare System 
(CHS).  You are being asked to take part because you are 22 years of age or older and have a newly 
diagnosed, unresectable glioblastoma (GBM).  The purpose of this study is find out if using 
OptuneTM will improve survival.   
 
Temozolomide (TMZ) is a chemotherapy drug that is currently approved by the FDA for use in 
newly diagnosed GBM patients (like you).  Bevacizumab (BEV) is a chemotherapy drug that is 
currently Food and Drug Administration (FDA) approved for use in GBM that has progressed.  
OptuneTM in combination with BEV and TMZ is considered investigational and is not FDA 
approved.   
 
You will be one of approximately 46 people involved in this research project at CHS. Your 
participation will last until your disease gets worse, you no longer wish to participate, or your study 
doctor removes you from the study. 
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about taking part. You have also been told that you have the option not to participate. You 


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Ashley Sumrall, MD 
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may discuss your decision with your friends and family. You can also discuss it with your health care 
team. If you have any questions, you can ask your study doctor for more explanation. 
  
This study is being carried out under the sponsorship of Levine Cancer Institute (LCI).  Novocure is 
the company that developed OptuneTM that will be used in this study. 
 
WHY IS THIS STUDY BEING DONE? 
 
The main purpose of this study is to see if adding OptuneTM and bevacizumab to the standard 
medical treatment plan for GBM will increase the number of people who are alive after 12 months.   
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
A total of approximately 46 subjects will take part in this study and will be enrolled in 
two groups.  In the first group, 22 subjects will be enrolled.  If adding OptuneTM and 
bevacizumab to regular care shows an improvement in survival in the first group, the 
study will continue and will enroll the additional group of 24 patients.  If adding 
OptuneTM and bevacizumab to regular care does not show an improvement in survival 
in the first group, the 24 additional subjects will not be enrolled. 
 
 
 
HOW THE STUDY WORKS 
 
Before you begin the study (Pre-Study Treatment): 
You will need to have the following tests and procedures done to determine if you can 
be in the study.  These exams, tests, and procedures are part of regular cancer care and 
may be done even if you do not join the study. If you have had some of them recently, 
they may not need to be repeated. This will be up to your study doctor. 
 
• Demographics and medical history 
• Physical and neurological (pertaining to the nervous system) examinations; including vital 
signs (heart rate, blood pressure, temperature) and height/weight measurements 
• 
Performance status assessments (assesses daily living abilities) 
• Magnetic Resonance Imaging (the use of magnetic waves to look at the soft tissues of 
the body) (MRI) of your brain 
• Pregnancy test if able to get pregnant 
• Documentation of any side effects you are experiencing 
• Blood work for blood counts and biochemistry (electrolytes [salts or chemicals in the 
blood] and kidney and liver functions).  
 
During study treatment (Intervention):  
If the exams, tests, and procedures show that you can be in the study, and you choose 
to take part, then you will receive the investigational treatment, OptuneTM and 
bevacizumab, in addition to the standard medical treatment for newly diagnosed GBM 


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patients.  The current standard medical treatment typically begins with radiation therapy, 
along with the chemotherapy drug TMZ.  You will first receive radiation therapy for 
five days each week for a total of six weeks.  During this time, you will also take the oral 
study drug (pill) TMZ daily for six weeks and receive the intravenously injected (IV) 
drug BEV every two weeks, for approximately six weeks.  At the end of this initial six 
week period, you will continue BEV every two weeks. After about four weeks, you will 
resume TMZ (daily on days 1-5 of each cycle) and continue BEV (every two weeks) for 
twelve cycles. A cycle is 28 days.   
 
At this time, you will also begin study treatment with OptuneTM.  You will be asked to 
shave your head and wear the device for at least 18 hours a day (on average) for twelve 
months.  While you are wearing the device, insulated transducer arrays (a ceramic disc 
coated with gel) will be attached to your shaved scalp using a bandage-like adhesive.  
The insulated transducer arrays produce alternating electric fields that interfere with the 
rapid cell division of cancer cells.  At the end of the twelve months, you will stop 
wearing the device, but may continue to receive TMZ and BEV therapy at your 
physician’s discretion.   
 
During the study, you will need the following exams, tests, and procedures. Most of 
these exams, tests, and procedures are part of regular cancer care: 
 
• Physical and neurological examinations  
• Performance status assessment  
• MRI scan of your brain  
• Documentation of any side effects you experience  
• Blood work for blood counts and biochemistry  
 
After you complete study treatment (End of Study Treatment visit): 
When your study doctor discontinues your treatment with OptuneTM(or if applicable, at 
the time of your doctor’s decision that you will not be able to have the device placed) 
you will return for your End of Treatment visit.  During this visit, the following 
procedures and tests will be done: 
• Physical and neurological examinations; including vital signs (heart rate, blood 
pressure, temperature) 
• Performance status assessment 
• Documentation of any side effects you have experienced from study treatment 
• Blood work for blood counts and biochemistry 
 
Follow-up: 
When you have completed your End of Study Treatment visit, you will enter the follow-
up period.  You will remain in the follow-up period for the rest of your life, until you 
choose to quit the study, or until your study doctor removes you from the study. 


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For subjects who have OptuneTM placed during the study, the following procedures and 
tests will be done monthly during follow-up: 
 
• Physical and neurological examinations; including vital signs (heart rate, blood pressure, 
temperature) 
• Performance status assessment 
• MRI scan of your brain (approximately every 8 weeks or as clinically indicated) 
• Documentation of any side effects you are experiencing from study treatment 
 
For subjects who have OptuneTM placed during the study who show evidence of cancer 
worsening, the procedures listed above will no longer be required for follow-up. The 
following will be done approximately every 3 months during follow-up: 
 
• Phone contact by the study team if you have not been seen by a healthcare 
provider around the time your 3-month follow-up contact is due   
 
For subjects who are not able to have OptuneTM placed during the study, you will be 
followed to monitor for side effects until 30 days after your last dose of study treatment. 
After this follow-up period has been completed, you will be removed from the study 
and will not be required to have any more follow-up visits for the purposes of the study. 
 
YOUR ROLE IN THE STUDY 
 
Taking part in a research study can be an inconvenience to your daily life.  Please consider the study 
time commitments and responsibilities as a research subject when you are deciding to take part.  
Your responsibilities as a study subject include the following: 
 
• Tell the truth about your medical history and current conditions. 
• Tell the study doctor if you have been in a research study in the last 30 days or are in another 
research study now. 
• Tell the study doctor about any problems you have during the study. 
• Use the study drug and study device as directed by the study doctor and study staff. 
• Do not share the study drug and study device with anyone else.  Keep the study drug and 
study device out of the reach of children and persons of limited capacity to read or 
understand. 
• The study doctor or study staff will talk to you about any food or medicines that you should 
not take while in this study. 
• Use care when driving or using machinery while you are taking the study drug and using the 
study device.   
• Accurately fill out your TMZ pill diary and return it. 
 
 


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RISKS 
 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may happen. 
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. Many side effects go away soon after you stop taking the drugs, change the 
position of the transducer arrays or stop wearing the device. In some cases, side effects can be 
serious, long lasting, or may never go away. A severe side effect rarely may be life threatening. 
Although the risk of death is low, you should tell your study doctor immediately if you experience 
any side effects. 
 
All side effects will be treated in the best way possible and this may involve anti-nausea 
medications, hospitalization to receive antibiotics (medications to fight infections), platelet (small 
cells in the blood that stop bleeding) transfusions (getting blood cells from another person), stool 
softeners or laxatives, and steroids or antihistamines for allergic reactions. There are guidelines 
for reducing the doses of chemotherapy drugs or eliminating them altogether should you 
experience serious or intolerable side effects. To avoid potential drug interactions, you should 
consult your physician or pharmacist before taking any new medications, including over the 
counter (non-prescription) medications.  
 
This study has several risks.  First, it is possible that you will get the new study treatment but do less 
well than you have been doing.  Second, because the study treatment is new, we may not yet know 
all the side effects and something unexpected could happen.  The following known side effects of 
radiation, OptuneTM, BEV and TMZ are listed below. 
 
Risks and side effects of Radiation: 
Likely 
• Scalp redness or soreness 
• Hair loss, which may be temporary or permanent 
• Ear/ear canal reactions, possibly resulting in a short-term hearing loss 
• Fatigue (tiredness) 
• Lethargy (sleepiness) 
• Difficulty with concentration 
• Temporary aggravation of brain tumor symptoms such as headaches, seizures, or 
 
weakness 
 
 
Less Likely 
• Neurocognitive (thinking and understanding) problems, including memory deficits (loss), 
that could be permanent 
• Permanent hearing loss 
• Cataracts (clouding of the lens of the eye) 
• Behavioral change 


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• Nausea 
• Vomiting 
• Temporary worsening of existing neurological deficits, such as decreased vision,  
drowsiness, and weakness of your arms and legs 
• Endocrine problems causing abnormalities in the level of some hormones (chemicals in 
the body) related to changes to the pituitary gland (produces hormones) 
• Dry mouth or altered (changed) taste 
 
Rare but Serious 
• Severe local damage to normal brain tissue, a condition called necrosis (tissue injury) 
• Radiation necrosis can mimic recurrent (happens again) brain tumor and may require 
surgery for diagnosis and treatment 
• Injury to the eyes with the possibility of blindness 
• Development of other tumors (either benign [non-cancerous] or malignant [cancerous]) 
 
Risks and side effects of OptuneTM: 
Likely 
• Local heat and tingling “electric” sensation beneath the transducer array 
• Mild to moderate contact dermatitis (sore, red or inflamed skin) underneath the device 
 
Less Likely   
• Skin irritation or skin breakdown 
• Infection at the sites of transducer array contact with the skin 
• Open sore, ulceration or blisters underneath the transducer arrays 
• Headache 
• Fatigue 
• Weakness 
• Convulsions 
• Thinking changes 
Rare but Serious 
• None previously reported 
 
 
 


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Risks and side effects of Bevacizumab (BEV): 
Likely  
• Loss of the normal functioning of the ovaries in a woman that can result in temporary or 
permanent menopause; the impact on fertility is unknown  
• High blood pressure  
 
Less Likely  
• Lack of enough red blood cells (anemia)  
• Fever associated with dangerously low levels of a type of white blood cell (neutrophils)  
• Fast heartbeat that usually starts in an area located above the ventricles  
• Feeling of spinning or whirling  
• Belly pain  
• Inflammation (swelling and redness) of the large bowel (colon)  
• Constipation  
• Diarrhea  
• Heartburn  
• Bleeding in some organ(s) of the digestive tract  
• Blockage in an organ(s)/part(s) of the digestive tract  
• Partial or complete blockage of the small and/or large bowel 
• Irritation or sores in the lining of the mouth  
• Nausea or the urge to vomit 
• Vomiting  
• Fatigue or tiredness  
• Reaction that can occur during or following infusion of the drug. The reaction may include 
fever, chills, rash, low blood pressure, and difficulty breathing 
• Chest pain that is not heart-related  
• Pain  
• Allergic reaction by your body to the drug product that can occur immediately or may be 
delayed. The reaction may include hives, low blood pressure, wheezing, swelling of the 
throat, and difficulty breathing  
• Infection 
• Infection (collection of pus) around the rectum  
• Premature opening of a wound along surgical stitches after surgery  
• Increased blood level of a liver enzyme (ALT/SGPT)  
• Increased level of a liver or bone enzyme (alkaline phosphatase)  
• Increased blood level of a liver enzyme (AST/SGOT)  
• Increased blood level of a liver pigment (bilirubin) often a sign of liver problems  
• Increased blood level of a heart muscle protein (troponin I) indicating damage to the heart 
muscle 
• Decreased number of a type of white blood cell (neutrophil/granulocyte)  


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• Weight loss 
• Decrease in the total number of white blood cells (leukocytes)  
• Loss of appetite  
• Joint pain  
• Abnormal changes in the growth plate that may affect the growth of long bones in very 
young children. This side effect appeared to be reversible after the treatment was stopped 
but has not been assessed with long-term use of the bevacizumab drug.  
• Muscle pain  
• Destruction or death of jawbone  
• Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness)  
• Headache or head pain  
• Inflammation (swelling and redness) or degeneration of the peripheral nerves (those nerves 
outside of brain and spinal cord) causing numbness, tingling, burning  
• Fainting  
• Blood in the urine  
• More protein leaking into the urine than usual, often a sign of kidney disease  
• Bleeding in the vagina  
• Stuffy or runny nose, sneezing  
• Cough  
• Shortness of breath  
• Nose bleed  
• Hoarseness  
• Itching  
• Skin rash with the presence of macules (flat discolored area) and papules (raised bump)  
• Hives  
• Formation of a blood clot that plugs the blood vessel; blood clots may break loose and travel 
to another place, such as the lung  
 
Rare but Serious  
• Damage of or clots in small blood vessels in the kidney that can cause complications, some 
of which are serious including abnormal destruction of red blood cells (hemolysis) or 
platelets (that help to clot blood) and kidney failure  
• Collection of signs and symptoms that indicate sudden heart disease in which the heart does 
not get enough oxygen. Sudden symptoms such as chest pain, shortness of breath, or 
fainting could indicate heart disease and should be reported right away.  
• Heart failure: inability of the heart to adequately pump blood to supply oxygen to the body 
• Decrease in heart's ability to pump blood during the "active" phase of the heartbeat (systole)  
• Heart attack caused by a blockage or decreased blood supply to the heart  
• Irregular heartbeat resulting from an abnormality in the one of the lower chambers of the 
heart (ventricle)  


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• Ventricular fibrillation: irregular heartbeat that involves the lower chambers of the heart 
(ventricles) that results in uncoordinated contraction of the heart; life threatening and 
potentially fatal, needing immediate attention  
• Gastrointestinal fistula: Abnormal hole between an organ of the digestive tract and another 
organ or tissue  
• Gastrointestinal perforation: A tear or hole in the stomach or gut that can lead to serious 
complications and may require surgery to repair  
• Sore (ulcer) somewhere in the digestive tract  
• Serious, life-threatening allergic reaction requiring immediate medical treatment by your 
doctor. The reaction may include extremely low blood pressure, swelling of the throat, 
difficulty breathing, and loss of consciousness.  
• Leakage from stomach due to breakdown of an anastomosis (surgical connection of two 
separate body structures)  
• Bleeding in the brain 
• Stroke caused by decreased blood flow to the brain 
• Abnormal changes in the brain that can cause a collection of symptoms including headache, 
confusion, seizures, and vision loss associated with MRI imaging findings (RPLS)  
• Sudden decrease of kidney function  
• A condition in which the kidneys leak a large amount of protein into the urine that can cause 
complications including swelling and kidney failure  
• Abnormal hole between part of the urinary system and another organ or tissue 
• Abnormal hole between the vagina and another organ or tissue  
• Abnormal hole between the lower breathing tube and the body cavity that surrounds the 
lungs  
• Bleeding from the lungs  
 
• Hole in the wall that separates the nostrils of the nose  
• Abnormal hole between the breathing tube (windpipe) and the tube that goes from mouth to 
stomach through which food passes (esophagus). This is life-threatening and potentially 
fatal.  
• Blockage or narrowing of a blood vessel (artery) that can cause damage or loss of function 
including a heart attack or stroke  
 
Risks and side effects of Temozolomide (TMZ): 
Likely 
• Nausea and/or vomiting 
• Decreased appetite 
• Headache 
• Constipation 
• Drowsiness/Fatigue 
• Inability to sleep 
 


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Less Likely 
• Decrease in blood counts that may cause infection, bleeding, and bruising 
• Diarrhea 
• Fever 
• Sores in your mouth 
• Rash 
• Elevated liver enzymes (chemicals in the liver) [reversible] 
• Swelling in your arms and legs 
• Memory loss 
• Itchiness 
• Increased need to urinate 
• Weakness 
• Back pain 
• Dizziness 
• Tingling/burning in your arms and legs 
• Anxiety 
• Depression 
• Stomach pain 
 
Rare but Serious 
• Decreased ability to carry out daily activities 
• Convulsions 
• Weakness on one side of your body 
• Abnormal coordination 
• Paralysis (inability to move) 
• Myelodysplastic syndrome (problem with the bone marrow [soft tissue inside the bone] that 
causes decreased production of red cells, white cells, or platelets that can sometimes turn 
into blood cancer) 
 
Women Who Can Get Pregnant or Are Breastfeeding 
 
You may not take part in this study if you are breastfeeding, are pregnant, think that you 
may be pregnant, or are trying to get pregnant.  If you are pregnant or breastfeeding, 
there may be risks to you and the baby that are not known at this time.  Women who 
can get pregnant will be tested for pregnancy during the study. 
 
You must avoid getting pregnant in order to take part in this research study.  You 
should not have sexual intercourse or you should use a method of birth control that is 
acceptable to you, the study doctor, and the sponsor during the study and six months 
after completion of the study treatment. 
 


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It is important for you to tell the study doctor at once if you get pregnant or think that 
you might be pregnant while you are in the research study.  If this happens, the study 
doctor will discuss with you what you should do.  If you get pregnant, you will be asked 
to stop taking part in the study.  You may also be asked questions about your pregnancy 
and the baby. 
 
Men  
 
The effects of BEV and TMZ on male sperm is unknown.  In rare cases, drugs may 
damage sperm in ways that affect a child that is fathered.  Affected sperm may be 
present in the semen for about 2 months.  In this study, however, it is recommended 
that males are to avoid fathering a child for 6 months after the last dose of the study 
treatment. 
 
You should not have sexual intercourse or you should use a method of birth control 
that is acceptable to you, the study doctor, and the sponsor.  If you think that you have 
gotten a woman pregnant, you must tell the study doctor at once.  If your partner gets 
pregnant during the study, you may be asked questions about the pregnancy and the 
baby.   
 
Blood Draw/IV/Catheter Insertion Risks 
 
You may have pain or bruising at the site where the blood is drawn or IV/catheter is 
inserted.  You may feel faint.  An infection at the site of the blood draw or IV/catheter 
insertion is possible. 
 
Allergic Reaction Risks 
 
As with taking any drug, there is a risk of allergic reaction.  If you have a very serious 
allergic reaction, you may be at risk of death.  Some symptoms of allergic reactions are:   
 
• Rash 
• Wheezing and difficulty breathing  
• Dizziness and fainting 
• Swelling around the mouth, throat or eyes 
• A fast pulse 
• Sweating 
 
Please seek treatment immediately and tell the study doctor and study staff if you have 
any of these symptoms, or any other side effects, during the study. 
 
If you have problems that might be related to the drugs or device, you study doctor may remove you 
from the study. 


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EXCLUSION CRITERIA 
 
The following conditions may prevent you from enrolling on this study. This is not a complete list. 
Your study doctor will review your medical record and the complete list of exclusion criteria in the 
study to see if they are applicable to you. 
 
• Enrolled in another clinical treatment trial 
• Pregnant or breast-feeding 
• Any other cancer within the past 2 years aside from the following: localized basal cell or 
squamous cell carcinoma of the skin, cancer requiring hormonal therapy alone for 
management, and/or an early stage cancer that was cured by surgery 
• Significant health conditions which would prevent you from taking temozolomide 
• Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other 
implanted electronic devices in the brain, or documented clinically significant arrhythmias. 
• History of an allergy to bevacizumab, temozolomide, DTIC, or hydrogel 
• Unwillingness to wear OptuneTM for an average of 18 hours per 24 hours 
• New York Heart Association (NYHA) Grade II or greater congestive heart failure  
• History of heart attack or unstable angina (chest pain) within the last 6 months  
• History of stroke or transient ischemic attack (TIA) within the last 6 months  
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent 
peripheral arterial thrombosis) within the last 6 months  
• History of coughing up blood within the last month  
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior 
to 1st bevacizumab infusion or anticipation of need for major surgical procedure during the 
course of the study 
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to study enrollment 
• History of abdominal fistula, gastrointestinal perforation within the last 6 months  
• Serious, non-healing wound, active ulcer, or untreated bone fracture 
 
WILL I BENEFIT FROM PARTICIPATING IN THIS STUDY? 
 
This study may or may not improve your condition.  The information gained from your 
participation may benefit others with your condition. 
 
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
 
Your other choices may include: 
• Getting treatment or care for your brain tumor without being in a study; this could 
include bevacizumab plus the standard medical therapy (radiation plus temozolomide). 
• Taking part in another research study 


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• Getting no treatment other than close observation and follow-up 
 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
 
Novocure, the manufacturer of OptuneTM, will attempt to seek reimbursement from your insurance 
company for use in this clinical trial. Depending on your insurance company, you may have coverage 
for OptuneTM while participating in this clinical trial. If your insurance company does not provide 
coverage for OptuneTM or your out of pocket financial cost share would be unaffordable, you may 
be eligible for financial assistance. It is recommended that you contact Novocure prior to signing 
this consent at 
 in order to understand your potential financial responsibility. 
 
You and/or your health plan/insurance will need to pay for some or all of the costs related to your 
radiation therapy and chemotherapy treatment (bevacizumab and temozolomide).  
 
Certain tests and examinations will need to be done regularly to monitor your safety and to measure 
the effects of chemotherapy and OptuneTM. These tests include physical exams, scans, urine tests, 
and blood tests. Costs for these tests and examinations will be billed to you and/or your health 
plan/insurance. The use of medications or other types of treatment to help control side effects you 
might have could also result in added costs to you and/or your health plan/insurance.  
 
You will not receive payment for taking part in this study. For more information on clinical trials 
and insurance coverage, you can visit the National Cancer Institute’s web site at 
http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a copy of the 
“Clinical Trials and Insurance Coverage” information from this web site.  Another way to get the 
information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.  
 
STUDY STAFF PAYMENT/FINANCIAL DISCLOSURE 
 
The manufacturer of OptuneTM, Novocure, will give and has given the study doctor, Dr. Ashley 
Sumrall, money or other benefits to be used for the cost of conducting the study.   
 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
 
If you become ill or are hurt while you are in the study, get the medical care that you need right 
away. 
 
In the event that you are harmed as a result of your participation in this study, inform your study 
doctor immediately so you can access medical treatment. You and/or your health plan will be 
charged for this treatment in the usual manner. The study will not pay for standard medical 
treatment.  
 
You still have the right to make a claim through the legal system even if you sign this form, accept 
medical care, or accept payment for medical expenses. 


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We will tell you about new medical findings that may affect your willingness to continue in the 
study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
 
CONFIDENTIALITY 
 
The records of this study will be kept private.  In any sort of report we might publish, we will not 
include any information that will make it possible to identify a patient.  Your record for this study 
may, however, be reviewed and/or photocopied by the drug/device manufacturer/sponsor, by 
Carolinas HealthCare System, or by representatives of the Food and Drug Administration or other 
government agencies.  To that extent, confidentiality is not absolute. 
 
To ensure that your information collected for this study will be kept private, your name will not be 
used whenever possible.  A code will be used instead of your name.  All of your study data will be 
kept in a secure location. 
 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
If you wish to take part in this clinical study, you will be asked to sign this consent form.  It allows 
the study sponsor and the study investigator to collect, process and pass on to the sponsor 
organizations any relevant personal health information collected from you during the study.  These 
are activities routinely carried out during all clinical studies. 
 
You have been told that personal information about you (including sensitive personal health 
information, such as your medical history and your racial/ethnic origin if relevant to the study) will 
be reviewed, collected on a computer database, stored in electronic or manual files, audited, and/or 
otherwise processed by: 
 
• the study doctor and study staff, 
• the study sponsor and/or its associated companies, Levine Cancer Institute, Novocure 
• regulatory or other governmental authorities of the United States and other countries, 
• other persons authorized by the study sponsor, 
• Carolinas HealthCare System employees, 
• other persons or agencies as required by law or allowed by federal regulations. 
 
You have been told that your personal data are being collected and processed to: 
 
• check your suitability to take part in the study, 
• monitor your treatment with the study drugs/device, 


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• compare and pool study treatment results with those of other subjects in clinical studies, 
• support the development of the study drugs, 
• support the licensing application for regulatory approval of the study drugs or device in the 
world  
• support the marketing, distribution, sale and use of the study drugs or device anywhere in 
the world.    
 
You have been told that your personal information may be processed within the U.S. or elsewhere in 
the world or transferred to or from the U.S. for review, processing and/or storage by an associated 
company or a carefully selected third-party organization.  By signing this document, you explicitly 
consent to the transfer of your personal information, including sensitive personal information, 
collected during this clinical study, for review, processing and/or storage.  Your personal health 
information may be further shared by the groups above.  If shared by them, the information will no 
longer be covered by the Privacy Rule.  However, the groups are committed to keeping your 
personal health confidential. 
 
You may refuse this authorization to transfer your personal information.  If you choose not to agree 
to this authorization, you might be ineligible to participate in the study.  If you decide not to sign 
this authorization, that will not harm your relations with your doctors or with Carolinas HealthCare 
System.   
 
You have the right to inspect your medical record at any time. Your research record may be 
unavailable until the conclusion of the study. At that point, it will be available.  Please speak with the 
study doctor if you desire to access your record. 
 
You have been told whenever your personal information is processed; it will be kept confidential 
and secure, to the best of our ability.  It will be used only for the purpose for which it was collected. 
 
This Authorization does not have an expiration date. You have been told that according to the 
guidelines for good clinical practice, the study investigator and sponsor will keep your personal 
information for at least 6 years. If you do not withdraw this Authorization in writing, it will remain 
in effect indefinitely.  If you wish to revoke authorization to use your personal information, you will 
notify the study doctor in writing at the address and telephone number listed on the first page of this 
form. Some of the data obtained from your record prior to your revocation may still be used if 
considered necessary for the study.   
 
 
 


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GETTING ANSWERS TO YOUR QUESTIONS ABOUT THE STUDY 
 
You can ask questions about this consent form or the study (before you decide to start the study or 
at any time during the study).  Questions may include: 
 
• Who to contact in the case of a research-related injury or illness 
• Any payment for being in the study 
• Your rights and your responsibilities as a study subject 
• Other questions 
 
Contact the study doctor or study staff at Carolinas HealthCare System with any questions or 
concerns.  Their telephone number is printed on the first page of this form.  If you have any 
questions or complaints about your rights as a research subject, contact:  
 
• By mail: 
 
 
Study Subject Adviser 
 
 
 
 
 
 
 
 
• or call toll free: 
 
• or by email:    
 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00010270. 
 
If you seek emergency care, or if hospitalization is required, please inform the treating doctor that 
you are participating in a clinical trial. 
 
If any new information becomes available during the course of this study that may affect your 
willingness to participate, you will be informed.  
 
BEING A STUDY VOLUNTEER AND WITHDRAWING FROM THE STUDY 
 
Your participation in this study is completely voluntary. You should feel under no pressure to be in 
the study.  If you decide not to be in the study that will not in any way harm your relations with 
your doctors or with Carolinas HealthCare System.  You are free to stop being in the study if you 
change your mind after entering it.  This would not harm your relations with your doctors or 
Carolinas HealthCare System. 
 
• You may always say no.  You do not have to take part in the study. 
• If you start a study, you may stop at any time.  You do not need to give a reason. 
• If you do not want to be in a study or you stop the study at a later time, you will not be 
penalized or lose any benefits. 


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• If you stop, you should tell the study staff and follow the instructions they may give you. 
 
Your part in the research may stop at any time for any reason, such as: 
 
• The sponsor or the study doctor decides to stop the study. 
• The sponsor or the study doctor decides to stop your part in the study for your safety. 
• You need additional medicine. 
• You do not follow the study rules. 
• You have a new injury or illness. 
• You decide to stop. 
 
You may be asked to stop the study even if you do not want to stop.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STATEMENT OF CONSENT   
 
I have read this form and its contents were explained to me. I agree to be in this research study for 
the purposes listed above.  All of my questions were answered to my satisfaction.  I will receive a 
signed and dated copy of this form for my records.  I am not giving up any of my legal rights by 
signing this form.  
 
___________________________________ 
____/____/____  _________ 
Signature of Research Subject 
 
Date 
 Time 
 
___________________________________ 
Printed Name of Research Subject 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject the nature and purpose of the above study.  There has been 
an opportunity for the subject to ask questions about this research study.  I have been available to 
answer any questions that the subject has about this study. 
 
___________________________________ 
____/____/____  _________ 
Signature of Person Explaining Consent 
Date 
 Time 
 
___________________________________ 
Printed Name of Person Explaining Consent