A Phase 2, Historically Controlled Study Testing the Efficacy of TTFields (Optune®) With Adjuvant Temozolomide in High Risk WHO Grade II and III Astrocytomas (FORWARD)
Phase: PHASE2
Conditions: Astrocytoma, Grade II, Astrocytoma, Grade III
Sponsor: University of Florida

A PHASE 2, HISTORICALLY 
CONTROLLED STUDY TESTING 
THE EFFICACY OF TTFIELDS 
(OPTUNE®) WITH ADJUVANT 
TEMOZOLOMIDE IN HIGH-RISK 
WHO GRADE II AND III 
ASTROCYTOMAS (FORWARD) 
UF IRB Protocol Number: 201800600 
National Clinical Trial (NCT) Identified Number:  NCT03906448 
UFHCC ID: OCR17711 
Study Chair: David Tran, MD, PhD 
Coordinating Center: University of Florida 
UF Principal Investigator: Ashley Ghiaseddin, MD 
IDE Sponsor: University of Florida 
IDE Number: G190054 
Funded by: Novocure, Ltd. 
Version Number:  v.2.3 
24 January 2020 
 
Summary of Changes from Version 2.1 to 2.3: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
5.2 
Revised Exclusion Criteria 
FDA Reviewer Suggestion 
10.3 
Addition of  contemporaneous cohort 
explanation 
IRB reviewer suggestion 
11.1.9.2 
Clarification of data de-identification 
timeline 
Survival Follow-up data will be collected for the 
duration of the study (5 years) 

  
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Table of Contents 
1 
STATEMENT OF COMPLIANCE ................................................................................................. 1 
2 
PROTOCOL SUMMARY ............................................................................................................... 1 
2.1 
Synopsis ................................................................................................................................. 1 
2.2 
Schema ................................................................................................................................... 3 
2.3 
Schedule of Activities (SoA) ................................................................................................ 4 
3 
INTRODUCTION ............................................................................................................................ 6 
3.1 
Study Rationale ..................................................................................................................... 6 
3.1.1 
High-risk Grade II and III Gliomas .................................................................... 6 
3.1.2 
Background ........................................................................................................ 11 
3.1.3 
Risk/Benefit Assessment ................................................................................. 15 
4 
OBJECTIVES AND ENDPOINTS .............................................................................................. 18 
5 
STUDY DESIGN ........................................................................................................................... 19 
5.1 
Overall Design ..................................................................................................................... 19 
5.1.1 
Hypothesis .......................................................................................................... 19 
5.1.2 
Description ......................................................................................................... 19 
5.1.3 
The 2016 World Health Organization (WHO) Classification of Grade II 
and III gliomas 
 ............................................................................................................... 20 
5.1.4 
Study Sites ......................................................................................................... 20 
5.2 
Scientific Rationale for Study Design ............................................................................... 20 
5.3 
Justification for Dose .......................................................................................................... 21 
5.3.1 
Temozolomide ................................................................................................... 21 
5.3.2 
Optune  ............................................................................................................... 21 
5.4 
End of Study Definition ....................................................................................................... 21 
6 
STUDY POPULATION ................................................................................................................. 21 
6.1 
Inclusion Criteria.................................................................................................................. 21 
6.2 
Exclusion Criteria ................................................................................................................ 22 
6.3 
Additional Considerations .................................................................................................. 23 
6.4 
Screen Failures ................................................................................................................... 23 
6.5 
Strategies for Recruitment and Retention ....................................................................... 23 
6.5.1 
Screening ........................................................................................................... 24 
6.5.2 
Registration ........................................................................................................ 24 
7 
STUDY INTERVENTION ............................................................................................................. 25 
7.1 
Study Intervention(s) Administration ................................................................................ 25 
7.1.1 
Study Intervention Description ........................................................................ 25 
7.1.2 
Dosing and Administration ............................................................................... 32 
7.2 
Preparation/Handling/Storage/Accountability ................................................................. 36 
7.2.1 
Acquisition and accountability ......................................................................... 36 
7.2.2 
Formulation, Appearance, Packaging, and Labeling ................................... 36 
7.2.3 
Product Storage and Stability .......................................................................... 36 
7.2.4 
Preparation ......................................................................................................... 37 
7.3 
Correlative Studies .............................................................................................................. 37 
7.3.1 
Tumor Tissue Specimens ................................................................................ 37 
7.3.2 
Electric Field Modeling ..................................................................................... 38 
7.4 
Study Intervention Compliance ......................................................................................... 40 

  
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7.5 
Concomitant Therapy ......................................................................................................... 41 
8 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................... 41 
8.1 
Discontinuation of Study Intervention .............................................................................. 41 
8.2 
Procedures for Orderly Termination of Participation ..................................................... 41 
8.3 
Lost to Follow-Up ................................................................................................................ 41 
9 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 42 
9.1 
Efficacy Assessments ........................................................................................................ 42 
9.1.1 
Day 0 – Start of TMZ Treatment Cycle 1 ....................................................... 42 
9.1.2 
Week 4 (-3/+7 days) - Start of Subsequent TMZ Treatment Cycles, repeat 
every 4 weeks up to 12 cycles .................................................................................................. 42 
9.1.3 
Week 8 (+/- 1 week) – repeat MRIs every 8 weeks only, until treatment 
stop 
 
 ............................................................................................................... 43 
9.1.4 
Progression ........................................................................................................ 43 
9.2 
Safety and Other Assessments ........................................................................................ 43 
9.2.1 
After Treatment Stop ........................................................................................ 43 
9.2.2 
Survival Follow-up ............................................................................................. 44 
9.3 
Adverse Events and Serious Adverse Events ................................................................ 44 
9.3.1 
Definition of Adverse Events (AE) .................................................................. 44 
9.3.2 
Definition of Serious Adverse Events (SAE) ................................................. 44 
9.3.3 
Classification of an Adverse Event ................................................................. 44 
9.3.4 
Summary of AE Reporting Requirements for Site Investigators ................ 46 
9.3.5 
Time Period and Frequency for Event Assessment and Follow-Up ......... 46 
9.3.6 
Adverse Event Reporting ................................................................................. 47 
9.3.7 
Serious Adverse Event Reporting .................................................................. 47 
9.3.8 
Reporting Events to Participants .................................................................... 47 
9.3.9 
Events of Special Interest ................................................................................ 48 
9.3.10 
Reporting of Pregnancy ................................................................................... 48 
9.4 
Unanticipated Problems ..................................................................................................... 48 
9.4.1 
Definition of Unanticipated Problems (UP).................................................... 48 
9.4.2 
Unanticipated Problem Reporting ................................................................... 48 
9.4.3 
Reporting Unanticipated Problems to Participants ...................................... 49 
10 
CONTROL COHORT ................................................................................................................... 49 
10.1 
Control Cohort Rationale ................................................................................................... 49 
10.2 
Control Cohort Inclusion Criteria....................................................................................... 49 
10.3 
Control Cohort Exclusion Criteria ..................................................................................... 50 
10.4 
Control Cohort Lifestyle Considerations .......................................................................... 50 
10.5 
Control Cohort Limited Data Collection ........................................................................... 50 
11 
STATISTICAL CONSIDERATIONS ........................................................................................... 51 
11.1 
Statistical Hypotheses ........................................................................................................ 51 
11.2 
Sample Size Determination ............................................................................................... 52 
11.2.1 
Analysis of Primary and Secondary Endpoints and Correlative Studies .. 53 
11.3 
Populations for Analyses ................................................................................................... 53 
11.4 
Safety Analyses ................................................................................................................... 54 
12 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............. 55 
12.1 
Regulatory, Ethical, and Study Oversight Considerations ............................................ 55 

  
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12.1.1 
Informed Consent Process .............................................................................. 55 
12.1.2 
Study Discontinuation and Closure ................................................................ 56 
12.1.3 
Confidentiality and Privacy .............................................................................. 56 
12.1.4 
Future Use of Stored Specimens and Data .................................................. 57 
12.1.5 
Key Roles and Study Governance ................................................................. 57 
12.1.6 
Safety Oversight ................................................................................................ 57 
12.1.7 
Clinical Monitoring ............................................................................................. 58 
12.1.8 
Quality Assurance and Quality Control .......................................................... 58 
12.1.9 
Data Handling and Record Keeping ............................................................... 58 
12.1.10 
Protocol Deviations ........................................................................................... 59 
12.1.11 
Publication and Data Sharing Policy .............................................................. 60 
12.1.12 
Conflict of Interest Policy ................................................................................. 60 
12.2 
Additional Considerations .................................................................................................. 60 
12.2.1 
Guidance on Contraception ............................................................................. 60 
12.2.2 
Enrollment Documentation Requirements .................................................... 60 
12.3 
Abbreviations ....................................................................................................................... 62 
12.3.1 
Summary of Figures ......................................................................................... 64 
12.4 
Protocol Amendment History ............................................................................................ 65 
13 
REFERENCES .............................................................................................................................. 66 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with Good Clinical Practice (GCP), applicable United States (US) 
Code of Federal Regulations (CFR), state laws and local requirements. The Principal Investigator will 
assure that no deviation from, or changes to the protocol will take place without prior agreement from 
the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor, funding agency and 
documented approval from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study have 
completed Human Subjects Protection and GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
1 PROTOCOL SUMMARY 
1.1 Synopsis  
Title: 
A Phase 2, Historically Controlled Study Testing the Efficacy of TTFields (Optune®) 
with Adjuvant Temozolomide in High-risk WHO Grade II and III Astrocytomas 
(FORWARD) 
Study Description: 
Phase 2, multi-institutional, open-label historically controlled study. The 
hypothesis of this study is that the addition of TTFields treatment to adjuvant 
temozolomide (TMZ) will significantly increase overall survival (OS) in patients 
with newly diagnosed Grade II and III astrocytoma with Telomerase Reverse 
Transcriptase (TERT) promoter mutations only compared to historical controls. 
Objectives: 
Primary Objective: 
1. 
To determine whether TTFields combined with adjuvant temozolomide 
increases OS in patients with newly diagnosed Grade II and III astrocytoma with 
TERT promoter mutation only, compared to historical (dating back to 2016) and 
contemporaneous controls at the same project sites. 
Secondary Objectives:  
1. 
To determine whether the combination of TTFields and adjuvant 
temozolomide is safe in the newly diagnosed high-risk Grade II and III 
astrocytoma. 

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2. 
To determine whether TTFields combined with adjuvant temozolomide 
increases progression-free survival (PFS) in patients with newly diagnosed Grade II 
and III astrocytoma with TERT promoter mutation only, as compared to historical 
(dating back to 2016) and contemporaneous controls at the same project sites. 
3. 
To evaluate quality of life (QOL) using Karnofsky Performance Status 
(KPS), Mini-Mental Status Examination (MMSE), and European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire - Cancer and 
Brain (EORTC QLQ-C30/BN20) scale in patients treated with TTFields combined 
with adjuvant temozolomide, compared to historical (dating back to 2016) and 
contemporaneous controls at the same project sites. 
Exploratory Objectives: 
1. 
To determine whether the addition of TTFields to adjuvant 
temozolomide significantly increases mutation burden, as compared to historical 
(dating back to 2016) and contemporaneous controls in samples from the same 
project sites. 
2. 
To determine whether TTFields increases immune cell infiltration. 
3. 
To determine whether TTFields induces immunogenic cell death in 
tumor. 
Endpoints: 
Primary Endpoint: Overall survival (OS) 
Secondary Endpoints: Progression free survival (PFS), safety and quality of life 
Study Population: 
Patients with tissue-based diagnosis of high-risk Grade II or III astrocytomas, 18 
years or older, of both genders after surgery or biopsy followed by radiation 
therapy with concurrent temozolomide. 
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
This study is being conducted in a consortium of 10-20 high volume brain tumor 
centers in the U.S.  
Description of Study 
Intervention: 
Treatment with TTFields (Optune®) with Adjuvant Temozolomide: TT Fields are 
applied through surface transducer arrays placed directly on the shaved head. 
Temozolomide is available in either tablet or IV infusion.  
Study Duration: 
60 months: 36 months enrollment plus 24 months follow-up/study completion 

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Accrual Goal: 
100 interventional subjects and up to 100 historical and contemporaneous control 
subjects 
Participant Duration: 
24 months (study treatment) plus follow-up until death or until the study is 
complete/terminates.  
1.2 Schema 
 
Figure 1. This is a phase 2, Single Arm, Historically Controlled Study of the Combination of Adjuvant 
Temozolomide plus TTFields in Patients with Newly Diagnosed Grade 2 and 3 Glioma with TERT Promoter 
Mutation Only  The interventional arm will combine TTFields with adjuvant TMZ after the completion of 
definitive chemoradiotherapy. Study treatment may continue past first tumor recurrence. The primary 
endpoint will be overall survival. TMZ = Temozolomide; RT = Radiation Therapy.  
 
 

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1.3 Schedule of Activities (SoA) 
 
TABLE 1: SCHEDULE OF ACTIVITIES: INTERVENTIONAL SUBJECTS 
Study Procedure: 
 
Screening ≤14 days prior 
to Day 0 
Day 0 : Begin TMZ 
Treatment 
Week 4 (-3/+7 days) 
and every 4 weeks until 
treatment stop 
Week 8 (±7 days) 
and every 8 weeks only 
until treatment stop 
Progression 
After Treatment Stop 
(Week 4 (+/- 7 days) 
from end of  treatment) 
Survival follow-up 
Informed Consent 
X 
 
 
 
 
 
 
Medical History, Demographics 
X 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
MGMT methylation status 
X 
 
 
 
 
 
 
Tumor Tissue Sample9 
X 
 
 
 
 
X 
 
 
MRI of the brain1 
X 
 
 
X 
X 
 
 
Physical Exam 
X 
 
X 
 
X 
X 
 
Neurological status, KPS 
X 
 
X 
 
X 
X 
 
CBC w/diff 
X10 
 
X 
 
X 
X 
 
Pregnancy test (urine or serum) 
X10 
 
 
 
 
 
 
Biochemistry Panel6 
X10 
 
X 
 
X 
X 
 
Record Steroid Dose 
X 
 
X 
 
X 
 
 
Quality of Life Questionnaires2 
X 
 
 
X 
X 
 
 
RANO 
X 
 
 
X 
X 
 
 
Temozolomide Cycle 
 
X7 
X8 
 
 
 
 

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Study Procedure: 
 
Screening ≤14 days prior 
to Day 0 
Day 0 : Begin TMZ 
Treatment 
Week 4 (-3/+7 days) 
and every 4 weeks until 
treatment stop 
Week 8 (±7 days) 
and every 8 weeks only 
until treatment stop 
Progression 
After Treatment Stop 
(Week 4 (+/- 7 days) 
from end of  treatment) 
Survival follow-up 
Optune Therapy4 
 
X 
X 
 
X 
 
 
Optune Compliance4 
 
 
X 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
 
Telephone Interview 
 
 
 
 
 
 
X5 
DICOM Images shipped for electric 
fields mapping11 
 
X 
 
 
X 
 
X 
1) Screening MRI should be done within 21 days of study treatment start. MRI of the brain will be performed 
routinely at baseline and again every 8 weeks +/- 7 days until treatment termination or second progression, 
whichever is first. An MRI of the head will be obtained within 21 days in the event of clinical signs of 
progression. 
After the post-treatment follow up visit and the patient has not progressed by treatment termination, patient 
will have contrast-enhanced brain MRI every 3 +/- 1 months for 12 months, then every 6 +/- 2 months for 24 
months, then yearly +/- 1 month thereafter or until disease progression, whichever comes first. 
All MRI scans should be performed with and without contrast and include the scalp.  
2) Quality of Life will be measured using the EORTC QLQ-C30/BN20 and MMSE every 8 weeks +/- 7 days for the 
first 2 years then every 3 months thereafter. 
3) Screening visit should occur within 14 days of adjuvant temozolomide start, with the exception of MRI which 
can be within 21 days (3 weeks) of adjuvant temozolomide start. 
4) Optune therapy should start within two weeks of start of adjuvant temozolomide, but not more than 7 weeks 
from the end of temozolomide/RT and will be continuous throughout study. Compliance documentation will be 
obtained every 4 weeks +/- 7 days. 
5) Every 3 months until death. The only data required during survival follow-up is DOD. 
6) Biochemistry panel will include electrolytes, creatinine, bilirubin, liver enzymes. 
7) Patients will begin treatment with temozolomide at 4 weeks (+14 days) from end of radiotherapy.  Cycle 1 will 
be dosed at 150mg/m2 daily for 5 consecutive days of a 28-day cycle. 

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Study Procedure: 
 
Screening ≤14 days prior 
to Day 0 
Day 0 : Begin TMZ 
Treatment 
Week 4 (-3/+7 days) 
and every 4 weeks until 
treatment stop 
Week 8 (±7 days) 
and every 8 weeks only 
until treatment stop 
Progression 
After Treatment Stop 
(Week 4 (+/- 7 days) 
from end of  treatment) 
Survival follow-up 
8) Patients will begin treatment with temozolomide Cycle 2 and subsequent cycles every 4 weeks (-3/+7 days) at 
200mg/m2 PO daily for 5 consecutive days, if CTC hematologic toxicity for cycle 1 is grade < 1 and the CTC non-
hematologic toxicity for cycle 1 is grade ≤ 2.  If dose escalation is not appropriate, the dose should remain at 150 
mg/m2 PO daily for 5 consecutive days for Cycle 2 and onward. 
9) Verification of tissue availability and location should be determined at screening visit. When available, 
formalin fixed and paraffin embedded (FFPE), pathology slides and/or frozen samples will be obtained for 
primary tumors and first recurrent tumors. 
10) Labs to be completed within 3 days for pre-TMZ cycles. Screening and other labs are within the visit 
windows noted. Pregnancy Test required for WOCBP only at Screening.  
11) DICOM images will be shipped to Beth Israel Deaconess Medical Center for electric field mapping analysis at 
baseline, first progression and second progression.  Imaging performed between shipping time points should be 
included in the next shipment.  
 
2 INTRODUCTION 
 
2.1 Study Rationale  
2.1.1 High-risk Grade II and III Gliomas 
A long-standing observation in neuro-oncology concerns a group of Grade II and III gliomas that appear relatively 
indolent histologically but are highly aggressive and resistant to standard chemoradiation therapy with an overall 
survival rate similar to that of Grade IV astrocytomas (glioblastoma - GBM). Recent therapeutic advancements in 
low-risk Grade II and III gliomas have further shined the spotlight on this high-risk group, widely recognized as a 
major remaining roadblock to achieving long-term survival in all Grade II and III gliomas. In recent years, molecular 
and genomic reclassification of gliomas has identified this high-risk group of Grade II and III tumors that require 
special attention as new treatment modalities are developed in the hope of improving its outcomes. Addressing 
this unmet need is the overarching goal of this protocol. 
Common point mutations at the R132 position of the cytosolic NADP+-dependent isocitrate dehydrogenase gene 1 
(IDH1) occur in a majority of Grade II and III gliomas (70-80% in oligodendrogliomas and 60-70% in astrocytomas) 
and secondary GBM (~10%) [1-3] and confer better prognosis and response to therapy. At this position, the R132H 
mutation accounts for approximately 90% of all IDH1 mutations [1, 3]. Mutations in the related mitochondrial IDH 
gene IDH2 are much less common and exclusive of IDH1 mutations and occur at the pos ition R172 with the R172K 
mutation accounting for nearly 65% of all IDH2 mutations [1].  

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Another important recurrent mutation that occurs exclusively in Grade II and III oligodendrogliomas is the 1p/19q 
co-deletion [per the new WHO grading system for brain tumors-[4]], which carries both positive prognostic and 
predictive values [5-7]. By this new classification, astrocytomas lack 1p/19q co-deletion and fare much worse 
compared to oligodendrogliomas, especially those without IDH mutations. New efforts have been directed at 
further defining these high-risk subgroups of astrocytomas, including ATRX mutations in alpha-thalassemia/mental 
retardation syndrome X-linked (ATRX) gene [8-10], which impair non-homologous end joining (NHEJ) repair and are 
correlated with the alternative lengthening of telomeres (ALT) phenotype, but are mutually exclusive with 1p/19q 
co-deletion  (therefore, for the purpose of this study, the presence of ATRX mutations is considered equivalent to 
the absence of 1p/19q co-deletion)leading to improved response to cytotoxic treatment, and more recently 
mutations in the promoter of telomerase reverse transcriptase (TERT), the catalytic subunit of the enzyme 
telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of 
the telomerase complex. TERT promoter mutation increase telomerase activity and occur in both astrocytomas 
and oligodendrogliomas of all grades [11, 12]. 
Until recently, treatment standards for WHO Grade II and III gliomas were poorly defined as few phase 3 clinical 
trials were available to delineate a role for adjuvant therapy after radiotherapy (RT), which historically had 
demonstrated a PFS, but not OS, benefit in several studies [13, 14]. In the last five years, however, three large 
phase 3 studies (two for Grade III and one for Grade II) have established an important role for adjuvant 
chemotherapy for the standard treatment for these tumors [15-17].  
Similar to Grade II oligodendrogliomas, the addition of the chemotherapy regimen PCV to RT in Grade II 
astrocytomas increased both PFS and OS (Fig. 2A and 2C), although the magnitude of benefit in astrocytomas is 
significantly less compared to the more favorable oligodendroglioma subtype. As projected, the presence of IDH1 
R132H mutation predicted for better response to PCV (Fig. 2B and 2D). However, since there was no breakdown in 
the fraction of IDH1 R132H mutation in astrocytomas and oligodendrogliomas in this study because the number of 
tumors lacking a IDH mutation was too few to assess the association with treatment [11], the assumption is that 
the predictive value of the IDH1 R132H mutation is of equal importance in both of these histologic subtypes. In 
addition, it is unclear, whether other mutations at positions R132 of IDH1 and R172 of IDH2 carry similar predictive 
value.  

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Figure 2. Role of IDH1 R132H Mutation in Grade II Astrocytoma. (A-B) PFS comparison of RT alone (RT) or RT + PCV 
in Grade II astrocytoma (A) and in all Grade II gliomas (both oliodendrogliomas and astrocytomas) (B) with IDH1 
R132H mutation. (C-D) OS comparison of RT alone (RT) or RT + PCV in Grade II astrocytoma (C) and in all Grade II 
gliomas (both oliodendrogliomas and astrocytomas (D) with IDH1 R132H mutation. (Adapted from Buckner JC et al. 
N Engl J Med 2016;374:1344-1355).  
Of note, information on 1p/19q co-deletions was not available in this study; however, it can be assumed that there 
would be a strong correlation between the presence of 1p/19q co-deletions and better response to PCV and 
prognosis compared to those without 1p/19q codeletions, as demonstrated for Grade III gliomas. In summary, 
Grade II tumors without 1p/19q co-deletions (i.e. astrocytomas per new classification scheme [4]) and IDH 
mutations fare much worse compared to their counterparts with either or both of these recurrent alterations.  
In Grade III gliomas, the predictive roles of 1p/19q co-deletions and IDH mutations, specifically the IDH1 R132H 
mutation, are better defined thanks to two large phase 3 studies [16, 17].  The presence of 1p/19q co-deletions 
(i.e. oligodendrogliomas per new classification [4]) significantly increased response to PCV chemotherapy and 
prolonged survival compared to 1p/19q intact tumors (i.e. astrocytomas) (Fig. 3). The additive presence of the 
IDH1 R132H mutation further defined 3 distinct groups of tumors with the combined 1p/19q co-deletions and IDH 
mutations group fairing the best, the double negative the worst, and the single positive group in the intermediate 
(Fig. 4). 

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Figure 3. Role of 1p, 19q Codeletions in Grade III Glioma. OS comparison of RT alone (RT) or RT + PCV in Grade III 
gliomas with 1p, 19q codeletions (A) or without 1p, 19q codeletions (B). (Adapted from Gregory Cairncross et al. 
JCO 2013; 31:337-343). 
 
 
Figure 4. Role of 1p, 19q Codeletions and IDH1 R132H mutations in Grade III Glioma. Kaplan-Meier estimates of OS 
for patients with a Grade III glioma (orange) or without 1p, 19q codeletions and with (blue) or without 1DH1 R132H 
mutation after PCV + RT (A) or RT Alone (B). (Adapted from Gregory Cairncross et al. JCO 2013;31:337-343). 
 

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Figure 5. TERT Promoter Mutation only is associated with the worst prognosis in Grade II and III Glioma. The 
presence of IDH mutations and/or 1p/19q codeletions were able to rescue the poor prognosis associated with TERT 
promoter mutation. Triple-positive: IDH mutations, 1p/19q codeletions, and TERT promoter mutation; Triple-
negative: No IDH mutations, 1p/19q intact, and no TERT promoter mutations. (Adapted from Eckel-Passow JE et al. 
N Engl J Med 2015;372:2499-2508). 
 
2.1.1.1 Reclassification of WHO grade II and III astrocytomas with high-risk molecular features 
to molecular GBM 
To further delineate and stratify risks within the double negative group of astrocytomas that are resistant to 
current standard chemoradiation therapy and whose survival approaches that of GBM, Eckel-Passow et al. scored 
1087 gliomas, of which 596 were Grade II and III tumors, as negative or positive for the three biomarkers: 1p/19q 
co-deletions, IDH mutations, and TERT promoter mutations [11]. Using 11,590 controls, association between these 
genotypic groups and clinical data were examined. As previously demonstrated, TERT promoter mutation occurred 
in both the most aggressive form of gliomas (GBM) and the best prognostic group (oligodendrogliomas with 
1p/19q codeletions and an IDH mutation) (Fig. 5).  Importantly, astrocytomas that lacked the 1p/19q co-deletions 
and IDH mutations, and possessed TERT promoter mutation, exhibited the worst overall survival rate that was not 
dissimilar to that of GBM, suggesting that these tumors represent a molecular continuum with GBM even though 
histologically they are Grade II or III.  
 
Beside the Eckel-Passow report [18], a large growing body of literature over the past decade confirms this distinct 
group of diffuse astrocytomas WHO grade II and III carrying the same molecular high risk features as primary 
astrocytomas WHO grade IV (i.e. GBM), despite their histologic appearance similar to regular WHO grade II and III 
tumors. This high-risk group of astrocytomas invariably carry isolated TERT promoter mutations without the 
presence of IDH mutations [19]. Recently the c-IMPACT-NOW consortium reaffirmed the central role of the poor 
prognostic indication of diffuse astrocytomas with TERT promoter mutations in the absence of IDH mutations [20], 
while others support the reclassification of this high-risk diffuse astrocytomas to represent molecular GBM [21], 
with an aggressive clinical course essentially similar to histologic primary GBM, and treated as regular GBM [3, 18, 

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21-24]. Although PCV has demonstrated efficacy in combination with radiotherapy in both grade II and III diffuse 
gliomas, including both regular-risk and high-risk astrocytomas [15-17], TMZ is increasingly being used in place of 
PCV because of 1) TMZ’s proven activity against newly diagnosed GBM [25] and newly diagnosed grade III 
astrocytomas [26]; 2) TMZ given sequentially before or after RT resulting in similar positive impact on PFS in 
gliomas, just as PCV [27]; 3) a systematic review of 19 studies, including 2 randomized control trials and 1407 
patients, demonstrating that RT/TMZ is at least as efficacious, and in many cases more efficacious, specifically in 
high-risk Grade II and III astrocytomas as compared to RT/PCV [28]; and 4) the lower toxicity profile and higher 
ease of administration of TMZ compared to PCV observed in these various trials.   
Therefore, these high-risk Grade II and III astrocytomas (1p/19q intact, IDH wild-type, TERT promoter mutated) are 
increasingly being grouped with primary GBM and managed and treated as aggressively as molecular GBM, and 
new approved therapies that have shown to be effective against primary GBM (e.g. TMZ and TTFields) or novel 
experimental approaches designed to treat GBM should be tested in this high-risk group of diffuse astrocytomas.  
 
2.1.1.2 Generalizability of results 
Brain and other nervous system cancer is most frequently diagnosed among people ages 55-64 according to the 
National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER). The percent of brain and 
other nervous system cancer deaths is highest among people aged 65-74, with the median age 58 at diagnosis and 
65 at death. Given the impact of brain and nervous system cancer on the general older patient population, results 
from this investigation will be additive to the cancer knowledge landscape for scientists and investigators going 
forward.   
2.1.2 Background  
 
2.1.2.1 Introduction to Electric Fields 
In the laboratory setting and in clinical practice, alternating electric fields show a wide range of effects on living 
tissues. At very low frequencies (under 1 kHz), alternating electric fields stimulate excitable tissues through 
membrane depolarization [29]. The transmission of such fields by radiation is insignificant and therefore they are 
usually applied directly by contact electrodes, though some applications have also used insulated electrodes. Some 
well-known examples of such effects include nerve, muscle and heart stimulation by alternating electric fields [29, 
30]. In addition, low frequency pulsed electric fields have been claimed to stimulate bone growth and accelerate 
fracture healing [31]. However, as the frequency of the alternating electric field increases above 1 kHz, the 
stimulatory effect diminishes. Under these conditions although a greater fraction of the fields penetrates the cells, 
due to the parallel resistor-capacitor nature of all biological membranes, the stimulatory power greatly diminishes 
as the alternating cell membrane hyper–depolarization cycles are integrated such that the net effect is nulled. 
At very high frequencies (e.g. MHz), while the integration becomes even more effective, a completely different 
biological effect is observed. At these frequencies tissue heating becomes dominant due to dielectric losses. This 
effect becomes more intense as field intensity or tissue dissipation factor increase [32]. This phenomenon serves as 
the basis for some commonly used medical treatment modalities including diathermy and radio frequency tumor 
ablation, which can be applied through insulated electrodes [33]. 
Intermediate frequency electric fields (i.e., tens of kHz to MHz), alternate too fast for causing nerve-muscle 
stimulation and involve only minute dielectric losses (heating). Such fields, of low to moderate intensities, are 
commonly considered to have no biological effect [32]. However, a number of non-thermal effects, of minor 
biological consequence, have been reported even at low field intensities. These include microscopic particle 
alignment (i.e., the pearl chain effect [34]) and cell rotation [35, 36]. With pulsed relatively strong electric fields, > 

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103 V/cm and 100 ms pulse length, reversible pore formation appears in the cell membrane, a phenomenon usually 
called electroporation [37]. 
2.1.2.2 Novocure’s Tumor Treating Electric Fields (TTFields) 
Novocure has shown [38] that when properly tuned, very low intensity, intermediate frequency electric fields 
(TTFields) stunt the growth of tumor cells. This inhibitory effect was demonstrated in all proliferating cell types 
tested, whereas, non-proliferating cells and tissues were unaffected. Interestingly, different cell types showed 
specific intensity and frequency dependences of TTField inhibition. It has been shown that two main processes occur 
at the cellular level during exposure to TTFields: arrest of proliferation and dividing cell destruction. The damage 
caused by TTFields to these replicating cells was dependent on the orientation of the division process in relation to 
the field vectors, indicating that this effect is non-thermal. Indeed, temperature measurements made within culture 
dishes during treatment and on the skin above treated tumors in-vivo, showed no significant elevation in 
temperature compared to control cultures/mice. Also, TTFields caused the dividing cells to orient in the direction of 
the applied field in a manner similar to that described in cultured human corneal epithelial cells exposed to constant 
electric fields [39]. At the sub-cellular level, it was found that TTFields disrupt the normal polymerization-
depolymerization process of microtubules during mitosis. Indeed, the described abnormal mitotic configurations 
seen after exposure to TTFields are similar to the morphological abnormalities seen in cells treated with agents that 
interfere directly [40, 41] or indirectly [42-44] with microtubule polymerization (e.g. paclitaxel). 
2.1.2.3 The Optune Device 
The Optune system (NovoTTFTM Therapy) is a portable battery- operated device, which produces TTFields within the 
human body by means of surface transducer arrays [45-47]. 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. All the treatment parameters are pre-set by Novocure so there are no electrical output 
adjustments available to the patient. Patients and their caregivers are instructed on proper procedures for changing 
and recharging depleted service batteries and connecting the device to an external battery pack overnight. 
Optune is currently FDA-approved as a single modality treatment for recurrent GBM when both surgical and 
radiotherapy options have been exhausted. In the pivotal EF-11 trial in recurrent GBM, overall survival (OS) of 
patients treated with the device was equivalent to those treated with standard chemotherapy alone [46]. Six-month 
progression-free survival (6PFS) analysis favored the TTFields arm compared to the chemotherapy arm, although not 
statistically significant. Safety and toxicity profile favored the Optune arm compared to the chemotherapy control 
arm. No device-specific grade 3 and 4 toxicities were identified for hematologic, gastrointestinal, vascular, renal and 
respiratory disorders. There were also no increased grade 3 and 4 central nervous system adverse events. The most 
common device specific adverse event was skin rash due to the transducer arrays. In 2017, Optune was approved in 
combination with first-line adjuvant temozolomide for newly diagnosed GBM (see below). 
2.1.2.4 Effect of Optune on Newly Diagnosed GBM Patients - A Phase 3 Study 
Six-hundred ninety-five patients from 83 centers across the world were treated.  All patients underwent surgery and 
radiotherapy for the primary tumor. All patients received temozolomide as adjuvant chemotherapy and were then 
randomized to standard adjuvant temozolomide chemotherapy (for 6-12 cycles) with or without concomitant 
administration of TTFields.  There was a 2.7- month PFS increase with a median PFS of 6.7 months compared to 4.0 
months in the control group (HR, 0.63; 95% CI, 0.52-0.76; P < .001) [47, 48]. Median overall survival results increased 
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(HR, 0.63; 95% CI, 0.53-0.76; P < .001). [48]Systemic adverse event frequency was 48% vs. 44% in the combination 
arm vs. temozolomide alone arm, respectively.  These results established a new standard treatment for newly 
diagnosed GBM [47, 48]. 
2.1.2.5 Temozolomide 
Adjuvant temozolomide and radiation therapy following surgery has been shown to improve survival by about 
20%. According to the temozolomide package insert adjuvant temozolomide treatment delays disease progression 
(from 5 to 6.9 months) and improves overall survival (from 12.1 to 14.6 months) in classical GBM histology [25]. 
2.1.2.6 Correlative Study Background 
2.1.2.6.1 THE IMMUNOLOGICAL BASIS BEHIND TTFIELDS 
Although immunotherapy, especially immune checkpoint inhibitors (ICIs), has proven to be efficacious against 
many cancers including lung, head and neck, renal and urothelial cancers, melanoma and lymphoma, their 
activities against poorly immunogenic cancers such as malignant gliomas remain less defined. Several intratumoral 
factors have been identified to correlate with responses to ICIs. 1) Mutational burden and landscape have been 
demonstrated to predict response to ICIs in several cancers, through various mechanisms including correlation 
between high mutational burden and higher checkpoint ligand expression [49-51], and the observation that 
effective anti-tumor immune response can be elicited against tumor neoantigens, which are more abundant in 
tumors with higher mutational burden [52, 53]. Tumors with high mutational burden due to microsatellite 
instability and/or defective mismatch repair mechanisms have some of the highest response rates to ICIs [54-61]. 
2) The presence of tumor infiltrating lymphocytes (TILs), particularly CD8+ TILs, has also been correlated with 
response to ICIs [62]. TILs may help drive expression of PD-L1 expression in tumors [63]. However, the composition 
of TILs is emerging as a more reliable predictor of outcomes and response to ICIs. TILs composed mostly of type 1 T 
cells with high TBET expression and type 1 interferon response are associated with better outcomes, whereas TILs 
enriched in regulatory T cells expressing the forkhead box transcription factor (Foxp3) (Tregs) confer a significantly 
poor prognosis and severe resistance to ICIs [64].  
Gliomas are generally considered to have low mutation burden compared to ICI-sensitive tumors [65]. The 
combination of radiotherapy and temozolomide, an alkylating agent, has been suggested to increase mutation 
burden in gliomas [66], however it remains unclear if this modest increase was sufficient to improve response to 
ICIs. Early clinical experience of ICIs in recurrent malignant gliomas showed minimal efficacy [67, 68]. However 
high-grade gliomas with a hypermutant phenotype, such as in patients with germline biallelic mismatch repair 
deficiency, demonstrated significant and durable response to ICIs [69], indicating that very high mutation burden 
may improve gliomas’ response to ICIs. Recent study in an animal model of lung cancer suggested that TTFields 
targeted DNA repair mechanisms [70], which potentially could greatly enhance mutation burden in treated tumors 
over time. These results raise the possibility that the addition of TTFields to chemoradiotherapy in glioma 
treatment may be sufficient at increasing mutation burden above the threshold of necessary for meaningful and 
durable response to ICIs. Although immunotherapy and ICIs are not the focus of the current protocol, we propose 
to determine whether TTFields can indeed increase mutation burden since the results will have significant impact 
for future trials and treatment development for gliomas in general. Tumor mutational burden will be assessed by 
standard clinical DNA sequencing on pre-treatment (i.e. at initial surgery) and post-treatment (i.e. first 
radiographic recurrence while receiving adjuvant temozolomide and TTFields and any subsequent recurrences, 
where available from standard care procedures) tumor specimens. These results will be compared to historical and 
concurrent data available on patients with malignant gliomas similarly treated at participating institutions with 
radiation and temozolomide only and without TTFields. Both microsatellite status and mutation burden, expressed 
as number of mutations per Mb, will be obtained and compared between the 2 groups. 

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Radiographic responses to TTFields have been noted to be delayed, in many instances, for >4 months after 
treatment initiation. In fact, most responders to TTFields experienced transient increases in enhancement, FLAIR 
and vasogenic edema within 2-4 months of treatment initiation, followed by a gradual decrease in enhancement 
and edema (EF-11 and EF14 study) [46, 47]. These observations suggest a possibility that TTFields may induce an 
inflammatory reaction in the tumor. In animal models of cancer, TTFields therapy to the primary tumors induced a 
considerable increase in peri- and intra-tumoral immune cell infiltration, including both CD4+ and CD8+ 
lymphocytes, compared to sham-treated control tumors [71]. Although the mechanism remains unclear, it is 
presumably through its anti-mitotic activities causing immunogenic cell death of cancer cells, leading to an 
increase in cancer-associated antigen or neoantigen presentation and immune activation, including type 1 
interferon responses. In this protocol, we will seek to confirm these observations using patients’ tissue samples 
with an eye toward future combinations of TTFields and immunotherapy. 
2.1.2.6.2 THE PHYSICS THAT GOVERNS TTFIELDS 
TTFields are lower frequency electromagnetic energies operating at 200 kHz and they are  administered externally 
on the scalp by the Optune® device that consists of two pairs of transducer arrays positioned orthogonally from 
each other and are connected to a portable electric field generator [72].  The distribution of these electric fields 
within the intracranial space is governed by the laws of physics, specifically Coulomb’s Law, Gauss’ Law, Ohm’s Law 
and the principles of continuity and capacitance. Derivatives of these laws also comprise principles such as 
capacitive reactance and specific absorption rate, which are critical for the characterization of the respective 
electric field distribution and power absorption rate within the brain [73].  Furthermore, the distribution of 
TTFields are dependent on tissue characteristics, such as physical density, geometry, electric conductivity and 
relative permittivity, which in turn determine the changing magnitude and direction of the flow of electric charges 
flow through different regions of the brain as a function of time.  Preclinical experiments have shown that TTFields 
at 200 kHz interfere with dividing cancer cells as they undergo the metaphase-to-anaphase transition in mitosis 
with evidence that they may perturb the functions of α/β Tubulin and Septin 2,6,7 protein complex, both of which 
possess high dipole moments, leading to cellular stress, transcriptional alteration and dysfunctional DNA repair 
[38, 70, 74].  However, the modeling of TTFields in the brain and therefore treatment verification requires complex 
computational simulation and modeling of electromagnetic wave propagation, which entails added difficulties due 
to the different conductivity and relative permittivity values of various intracranial tissues and cavities [73, 75, 76]. 
In order to visualize the distribution of TTFields in the tumor and the surrounding brain tissues, the coupled 
Maxwell equations must be solved using numerical approximations such as finite element modeling.  These 
computer modeling procedures involve the segmentation of various brain tissues as seen on patient MRI datasets, 
the application of appropriate initial and boundary conditions and material properties and finding the solution to 
the coupled Maxwell equations using finite element analysis.  A heatmap of the electric field distribution within 
the human brain can be derived as well as the electric field-volume and specific absorption ratio-volume 
histograms can be constructed [73].  From these histograms, the electric field parameters, including EAUC, EV150, E95% 
and E50%, as well as specific absorption ratio parameters, including SARAUC, VSAR7.5, SAR95% and SAR50%, can then be 
used to compare the dosage applied to different patients.  Past effort has shown that the electric field strength 
estimated by computer modeling was within 10% of that measured directly [45].  However, aggregate analysis is 
lacking on a larger homogeneous patient population that has been treated by TTFields.  Therefore, in this protocol, 
we will perform computer modeling of electric field and energy deposition in the tumor and then perform 
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2.1.3 Risk/Benefit Assessment   
 
2.1.3.1 Known Potential Risks  
 
2.1.3.1.1 POTENTIAL ADVERSE EVENTS: OPTUNE 
Treatment with the Optune is not expected to cause any serious side effects. However, it is possible that treatment 
may cause any of the following: 
• 
Local warmth and tingling “electric” sensation beneath the transducer array 
• 
Allergic reaction to the adhesive or the gel 
• 
Skin irritation or skin breakdown 
• 
Infection at the sites of electrode contact with the skin 
• 
Transducer array overheating leading to pain and/or local skin burns 
• 
Headache 
• 
Fatigue 
2.1.3.1.2 POTENTIAL ADVERSE EVENTS: TEMOZOLOMIDE 
Treatment with temozolomide commonly (>30%) causes the following adverse events:  
• 
Headache 
• 
Fatigue 
• 
Nausea 
• 
Vomiting 
• 
Constipation 
Treatment with temozolomide commonly (10-30%) causes the following adverse events: 
• 
back, abdominal and/or stomach pain, breast pain 
• 
diarrhea  
• 
alopecia (hair loss) 
• 
dry skin, skin redness, itching and/or rash, 
• 
erythema multiforme (a skin condition that is similar to a bad rash) 
• 
swelling of extremities (arms, legs, fingers, or toes) 
• 
inflammation or swelling of the mouth, throat and/or sinuses 
• 
confusion, amnesia, dizziness, fever, and/or weakness 
• 
anxiety, depression 
• 
joint and muscle pain 
• 
hemiparesis 
• 
asthenia 
• 
coordination abnormal 
• 
viral infection 
• 
insomnia 
• 
changes in sense of taste 
• 
changes in vision such as double or blurred vision 
• 
coughing or shortness of breath, respiratory tract infection 
• 
urinary incontinence/frequency, urinary tract infection 
• 
weight increase 

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• 
seizures, hemiparesis (weakness on one side of the body) 
• 
adrenal hypercorticisim (elevated hormone levels) 
• 
allergic reactions, sometimes severe 
• 
hepatotoxicity 
• 
lymphopenia, thrombocytopenia, neutropenia, and leukopenia 
• 
anorexia 
• 
convulsions 
• 
Very rare side effects have included secondary cancers (including leukemia and myelodysplastic syndrome 
(MDS)) 
2.1.3.1.3 POTENTIAL ADVERSE EVENTS: TEMOZOLOMIDE PLUS OPTUNE 
In earlier clinical trials using temozolomide plus Optune, common side effects where Optune and temozolomide 
were used together were: 
• 
low platelet count 
• 
nausea 
• 
constipation 
• 
vomiting 
• 
fatigue 
• 
medical device site reaction 
• 
headache 
• 
seizures 
• 
depression 
In earlier clinical trials where Optune and temozolomide were used together, additional side effects were seen.  
• 
seizure and consecutive seizures 
• 
decrease or loss of ability to carry out daily activities 
• 
neurological decline or death 
2.1.3.1.4 ADDITIONAL POTENTIAL RISKS  
2.1.3.1.4.1 DISEASE PROGRESSION 
Adverse events and complications associated with the underlying disease process, which are unlikely but unknown 
if related to treatment with Optune together with adjuvant temozolomide include the following adverse events: 
• 
Seizure, including Status Epilepticus 
• 
Neurological and functional decline 
• 
Headaches, nausea and/or vomiting 
• 
Death 
2.1.3.1.4.2 CEREBRAL EDEMA 
Cerebral edema may be secondary to the disease process itself, the surgical procedure, necrosis from previous 
radiation, or inflammation due to immune infiltration of the brain or destruction of tumor cells.  Symptoms may 
include, but are not limited to, severe headache, confusion, lethargy, unresponsiveness, coma, or focal 
neurological deficits.  Patients will be monitored throughout the course of the study and those with any signs or 
symptoms of cerebral edema may need their steroid doses increased, treatment with an osmotic diuretic, or 
surgical decompression.  Edema that fails to respond to aggressive therapy may lead to permanent neurological 
impairment.  The probability of this risk can be predicted to some degree based upon tumor size, location and pre-
operative neurological impairment. Patients will be monitored throughout the course of the study. 

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2.1.3.1.4.3 PHLEBOTOMY 
Drawing blood or inserting an intravenous catheter into an arm vein may result in bruising or swelling in the area 
of the insertion, bleeding at the site of the needle puncture, light headedness, fainting and very rarely, local 
infection, which may be severe.  
2.1.3.1.4.4 MRI 
The risks and/or discomforts associated with the performance of MRI include the anxiety produced from being in a 
tight, enclosed space (claustrophobia). In addition, the machine operates using a large and powerful magnet. The 
magnetism of the machine attracts certain metals: therefore, people with these metals in their bodies (specifically 
pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods or plates) will be excluded from 
the study. Patients will also be checked to make sure that they do not bring any metal objects into the MRI facility. 
Dental fillings are less affected by the magnetic fields generated and are therefore permitted. It will be asked that 
patients let the physicians conducting this study know of any metal in their bodies other than dental fillings. 
2.1.3.1.4.5 ALLERGIC REACTIONS TO CONTRAST AGENTS 
During the MRI, patients will be given a contrast agent.  The agent is given routinely to obtain enhanced MRI scans 
of the brain.  The agent is administered through the vein and requires the placement of an IV catheter.  The 
catheter placement is similar to drawing blood except that the catheter remains in the vein during the time the 
agent is actively delivered.  The risks of a blood draw and insertion of a catheter are similar.  There have been a 
few, rare cases of allergies to the agent used in MRI contrast-enhanced scans. Patients with any known severe 
allergies to contrast agents will be scanned using CT instead of MRI.  Patients with mild allergies (i.e., rash only) will 
be pretreated with Tylenol and Benadryl prior to injection of the contrast agent. 
2.1.3.1.4.6 CONFIDENTIALITY 
Participation in research may result in a loss of confidentiality.  All data will be coded to protect the patient’s 
identity; however, records will be made available to individuals involved with the study, the clinical staff 
administering the study, and regulatory representatives such as the IRB, FDA, OHRP and funding agency. Any 
publications resulting from this study will not use patient identifying data. 
2.1.3.2 Known Potential Benefits  
 
Based on previous studies in GBM with TMZ, increased survival is an potential benefit of Optune in this population 
of patients with high-risk Grade II and III Astrocytoma.  
2.1.3.3 Assessment of Potential Risks and Benefits  
Optune is currently FDA-approved as a single modality treatment for recurrent GBM when both surgical and 
radiotherapy options have been exhausted as well as combination with adjuvant temozolomide for newly 
diagnosed GBM. In the pivotal EF-11 trial in recurrent GBM, overall survival of patients treated with the device was 
equivalent to those treated with standard chemotherapy alone [72]. Six-month progression-free survival (6PFS) 
analysis favored the TTFields arm compared to the chemotherapy arm, although not statistically significant. Safety 
and toxicity profile favored the Optune arm compared to the chemotherapy control arm. No device-specific grade 
3 and 4 toxicities were identified for hematologic, gastrointestinal, vascular, renal and respiratory disorders. There 
were also no increased grade 3 and 4 central nervous system adverse events. The most common device specific 
adverse event was skin rash due to the transducer arrays.  
Up to 100 patients will be exposed to TTFields treatment during the current trial. Considering the minimal 
toxicity and promising efficacy seen in the previous trials, the small number of patients exposed to this 

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treatment in the current study and the poor outcome of these patients despite Temozolomide treatment, we 
conclude that the possible benefits of TTFields treatment drastically exceed its potential risks. 
2.1.3.3.1 EF-14 STUDY EXPERIENCE 
Six hundred and ninety five patients from 83 centers across the world were treated. All patients underwent 
surgery and radiotherapy for the primary tumor. All patients received temozolomide as adjuvant chemotherapy 
and were then randomized to standard adjuvant TMZ chemotherapy (for 6-12 cycles) with or without concomitant 
administration of TTFields. During a pre-specified interim and futility analysis after 315 randomized patients 
reached a minimum follow-up of 18 months there was a 3.1-month PFS increase with a median PFS of 7.1 months 
compared to 4.0 months in the control group [37].  
Increased PFS in the TTFields arm subsequently led to the recommendation from the independent data monitoring 
committee to terminate the trial early for success and allow standard of care patients to cross over to the TTFields 
group.  The percentage of patients alive at 2 years following enrollment was 43% in the TTFields plus 
temozolomide group compared to 29% in the temozolomide alone group.    
Overall survival results increased from 15.6 months in the temozolomide alone group to 20.5 months in the 
TTFields plus adjuvant temozolomide group establishing a new standard treatment for newly diagnosed GBM [37]. 
3 OBJECTIVES AND ENDPOINTS 
TABLE 2: OBJECTIVES & ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine whether TTFields 
combined with adjuvant temozolomide 
increases OS in patients with newly 
diagnosed Grade II and III astrocytoma 
with TERT promoter mutation only 
compared to historical and 
contemporaneous controls. 
 
OS measured in days from Study Day 0 
until death. If the study ends and the 
participant is still living, OS will be 
measured in days from Study Day 0.  
 
OS remains the primary 
concern within this 
patient population. Intent 
to Treat analysis will be 
used to determine if this 
objective is met.  
Secondary 
 
 
• To determine whether the 
combination of TTFields and adjuvant 
temozolomide is safe in the newly 
diagnosed high-risk Grade II and III 
astrocytoma. 
• To determine whether TTFields 
combined with adjuvant temozolomide 
increases PFS in patients with newly 
diagnosed Grade II and III astrocytoma 
with TERT promoter mutation only 
compared to historical and 
contemporaneous controls. 
• To evaluate QOL using KPS, EORTC 
QLQ-C30/BN20, and MMSE in patients 
treated with TTFields combined with 
adjuvant temozolomide compared to 
• PFS measured in days from Day 0 to 
progression 
• Safety measured by incidence and 
severity of Adverse Events and 
Toxicities.  
• Quality of life measured by KPS, EORTC 
QLQ-C30/BN20, and MMSE 
• Correlation between % Compliance 
with TTFields and OS 
 
Safety, Efficacy, and 
Quality of Life measures 
for a more complete view 
of the effects of the study 
treatment(s).  

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historical and contemporaneous 
controls. 
 
Tertiary/Exploratory  
 
 
• To determine whether the addition 
of TTFields to adjuvant temozolomide 
significantly increase mutation burden, 
compared to historical and 
contemporaneous controls. 
• To determine whether TTFields 
increases immune cell infiltration. 
• To determine whether TTFields 
induces immunogenic cell death in 
tumor. 
• 
Mutation burden before and after 
TTFields, compared to historical and 
contemporaneous controls 
• 
Immune cell infiltration before and 
after TTFields, compared to 
historical and contemporaneous 
controls 
• 
Immunogenic cell death marker 
before and after TTFields, compared 
to historical and contemporaneous 
controls 
• 
Computer modeling of electric field 
and energy deposition 
To add key 
immunological and 
mutational information 
to the information about 
these specific tumors.  
4 STUDY DESIGN  
 
4.1 Overall Design 
 
4.1.1 Hypothesis 
The hypothesis of this study is that addition of TTFields treatment to adjuvant temozolomide will significantly 
increase OS in patients with newly diagnosed Grade II and III astrocytoma with TERT promoter mutation only 
compared to historical and contemporaneous controls. 
 
4.1.2 Description 
This is a phase 2, multi-institutional, open-label, historically controlled, study of 100 patients with newly diagnosed 
high-risk Grade II and III astrocytoma combining TTFields with adjuvant temozolomide compared to historical and 
contemporaneous controls after the completion of definitive chemoradiotherapy. The primary endpoint will be 
overall survival. This high-risk astrocytoma subgroup constitutes approximately 10% of all Grade II and III gliomas 
(Fig. 6). Therefore, in order to achieve targeted accrual goals, this study is being conducted in a consortium of 10-
20 high volume brain tumor centers in the U.S.  

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Figure 6 Prevalence of TERT Promoter Mutation in Grade II and III Glioma. (Adapted from Eckel-Passow JE et al. N 
Engl J Med 2015;372: 2499-2508). 
 
4.1.3 The 2016 World Health Organization (WHO) Classification of Grade II and III 
gliomas 
 
This new classification provides extensive updates to the previous version from 2007 [77]. For WHO grade II and III 
gliomas, astrocytomas are now defined by the absence of 1p19q codeletions as determined by FISH, while 
oligodendrogliomas are defined by the presence of 1p19q codeletions AND IDH1/2 mutation as determined by 
next generation sequencing (NGS). The concordance rate between 1p19q codeletions and IDH1/2 mutation is 
extremely high. Gliomas with 1p19q codeletions and without IDH1/2 mutation represents an exceedingly rare 
entity. In fact, in the Eckel-Passow et al. study, of the 1087 infiltrating gliomas, Pisapia found no case with whole 
arm 1p19q codeletions was associated with wild-type IDH1/2 [18, 78]. Even when partial arm deletions were 
included, only 0.3% of cases with partial deletions of 1p19q was without IDH1/2 mutation [18, 78]. In fact, per 
WHO guidelines, oligodendrogliomas should not be diagnosed in the absence of IDH1/2 mutation (and/or 1p19q 
codeletions) regardless of histologic appearance since the lack of IDH1/2 mutation is equivalent to the absence of 
1p19q codeletions. Thus, the absence of IDH1/2 mutation is mutually exclusive of 1p19q codeletions in the vast 
majority of cases. Therefore, for the purpose of this study, WHO grade II and III gliomas without IDH1/2 mutation 
as determined by NGS (rare variants of unknown significance are excluded and not considered to be pathologic 
mutations) will be considered to also have intact 1p19q (i.e. without codeletions) and a FISH test to determine 
1p19q codeletions status will not be required. 
4.1.4 Study Sites 
 
A complete list of study sites will be maintained by the Coordinating Center.  
 
4.2 Scientific Rationale for Study Design 
 
See section entitled Study Rationale.  

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4.3 Justification for Dose 
 
4.3.1 Temozolomide 
Dosing instructions are consistent with the usage guidelines for refractory anaplastic astrocytoma listed in the 
package insert. See package insert for full details.  
 
4.3.2 Optune 
Usage instructions are consistent with the usage guidelines approved for Optune by FDA for GBM.  
 
4.4 End of Study Definition 
 
A participant is considered to have completed the study if he or she withdraws consent, is withdrawn by the 
investigator, is declared lost to follow-up, or dies.  
5 STUDY POPULATION 
5.1 Inclusion Criteria 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
A. Willing and able to provide written informed consent 
B. Stated willingness to comply with all study procedures and availability for the duration of the study  
C. Male or female, 18 years or older  
D. Life expectancy of at least 3 months 
E. Histologic confirmation of WHO Grade II or III astrocytoma 
a. mixed oligoastrocytomas are permitted 
F. Mutational identity determined by CLIA-certified sequencing including: 
a. IDH1/2 wildtype (i.e. lack of detectable mutations on the sequencing report, variants of unknown 
significance or non-synonymous single nucleotide polymorphisms deviating from wild-type sequence 
do not apply)  
AND 
b. TERT promoter mutation(s) 
G. Karnofsky performance status ≥70% 
H. Maximal safe resection 
a. biopsy alone is allowed 
I. 
Completed standard chemoradiation with total RT dose of at least 40 Gy and concurrent temozolomide 
(75mg/m2 daily dose with 80% prescribed dose completed) 
a. Patients with a tumor that was biopsied or resected in the past followed by observation only 
without definitive chemoradiation and/or chemotherapy given will be eligible, as long as: repeat 
maximal surgical resection (biopsy only allowed) has been performed, definitive temozolomide/RT 
treatment meets the criteria above, and adjuvant temozolomide treatment is planned  
J. Candidate for adjuvant high dose temozolomide per investigator’s clinical judgement 
K. Adjuvant Temozolomide start date at least 4 weeks, but not more than 6 weeks, from the later of last dose 
of concomitant temozolomide or radiotherapy 
L. No evidence of early disease progression per RANO criteria at the time of enrollment 
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avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug to minimize 
the risk of pregnancy.  
a. Prior to study enrollment, women of childbearing potential must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  
b. Refer to section 10.2.1 for guidance on highly effective contraceptive methods acceptable in this 
study. 
c. 
WOCBP include any woman who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) 
or who is not post-menopausal. Post-menopause is defined as: 
i. Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or  
ii. For women with irregular menstrual periods who are taking hormone replacement 
therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater 
than 35 mIU/mL. 
N. Males with female partners of child-bearing potential must agree to use physician-approved contraceptive 
methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving 
children for 24 weeks following the last dose of study drug. 
O. Patient must agree to wear the Optune device. If patient declines to wear the Optune device for personal 
and non-medical reasons (except for history of known allergy to hydrogel) and the plan is to treat the 
patient with adjuvant TMZ alone, the patient can be considered for enrollment in the contemporaneous 
control cohort (See Section 9, Control Cohort). 
 
5.2 Exclusion Criteria 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
A. Prior treatment with anti-angiogenic agents including bevacizumab. 
B. Prior treatment with TTFields. 
C. Progressive disease (according to RANO criteria) after temozolomide/RT.  
D. Actively participating in another clinical treatment trial intended to treat the underlying astrocytoma. 
E. Females who are pregnant or breastfeeding. 
F. Significant co-morbidities at baseline (within 2 weeks prior to adjuvant temozolomide start) which would 
prevent adjuvant temozolomide treatment: 
a. Thrombocytopenia (platelet count < 100 x 103/μL) 
b. Neutropenia (absolute neutrophil count < 1.5 x 103/μL) 
c. 
CTC grade 4 non-hematological toxicity (except for alopecia, nausea, vomiting) 
d. Significant liver function impairment - AST or ALT > 5 times the upper limit of normal 
e. Total bilirubin > 2 times upper limit of normal 
f. 
Significant renal impairment (GFR ≤ 30 ml/min) 
G. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted 
electronic devices in the brain, or documented clinically significant arrhythmias. 
H. A skull defect such as missing bone with no replacement 
I. 
Bullet fragments embedded the skull 
J. Tumors located in the brain stem and/or the cerebellum. 
K. History of hypersensitivity reaction to temozolomide, Dacarbazine (DTIC) or hydrogel. 
 

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5.3 Additional Considerations 
• 
Operable patients (biopsy alone allowed) must undergo surgery prior to enrollment.  
• 
All patients must have received radiation therapy with concomitant temozolomide prior to 
enrollment.  
• 
Patients receiving steroids to control edema may be included in the trial; however, any change in 
steroid dose must be documented during the follow- up visits.  
• 
Disease status will be determined by comparing screening MRI to the immediate post-surgical MRI. If 
unavailable, an immediate post-surgical CT can be used for the same purpose.  
• 
Patients who have progressive disease at screening (compared to the immediate post-surgical MRI) 
are not candidates for this study.  
• 
In the case of local radiological suspicion of pseudoprogression, the patient is still eligible for the study 
per RANO criteria. However, other imaging modalities (e.g. brain PET, perfusion in addition to T1 
weighted MRI) can be obtained to assess biological activity of the tumor if desired but not required by the 
study. 
 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but do not meet the 
criteria for participation in this trial. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants, to meet publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details and eligibility criteria. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may not be rescreened. 
Participants may repeat individual lab tests within the screening window, but no modifications to the screening 
window or I/E criteria are permitted. No protocol exceptions are permitted and no waivers will be granted for 
enrollment into this protocol.  
This protocol estimates a 10% screen failure rate.  
 
5.5 Strategies for Recruitment and Retention 
Potentially eligible patients scheduled to undergo maximal surgical resection of a Grade II or III astrocytoma will be 
identified through direct referral at participant sites. PHI will be reviewed by the PI(s) and/or Study Coordinator 
but not recorded in order to pre-screen patients for eligibility for this trial.  The pre-screening PHI will consist of a 
review of the medical records to confirm new diagnosis in adults age 18 years or older, as well as tumor 
cytogenetic and DNA sequencing characteristics (Mutational identity determined by CLIA-certified sequencing as 
possessing a IDH1/2 wildtype and TERT promoter mutated genotype). 
Since high-risk astrocytomas are only approximately 10% of all Grade II and III gliomas, only those patients who 
have appropriate tumor characteristics after biopsy will be approached about the study. Potential subjects will be 
approached well in advance of study commencement to ensure sufficient time for review of the informed consent 
form and other logistical coordination.  
Since the primary outcome of the study is overall survival, each patient’s Legally Authorized Representative (LAR) 
will be recorded at enrollment. In the event that the subject loses capacity to consent for himself/herself during 
the course of the study, the LAR will be approached for the Survival Follow-up items (only) for that subject.  

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Information on this study will be posted on ClinicalTrials.gov. Recruitment is planned for 36 months in total.  
 
5.5.1 Screening  
• 
Patients with newly diagnosed high-risk Grade II or II astrocytoma must undergo maximal safe resection 
(biopsy alone may be eligible).  
• 
Patients must undergo chemoradiotherapy: concomitant 75mg/m2 daily temozolomide with 80% 
prescribed dose completed and RT with minimal RT dose of 40 Gy delivered.   
• 
Within three weeks prior to beginning adjuvant temozolomide, all patients will undergo a Baseline 
contrast-enhanced MRI of the brain. 
• 
Within two weeks prior to beginning adjuvant temozolomide, all patients will undergo the following 
assessments: 
o 
Medical History and demographics 
o 
Medication History 
o 
Steroid Dose (recorded) 
o 
MGMT methylation status (if feasible, required for stratification) 
o 
Tumor Tissue sample – verify availability of FFPE, pathology slides, and/or frozen sample(s) 
o 
RANO assessment 
o 
Complete physical examination 
o 
Neurological status and KPS 
o 
CBC with differential 
o 
Pregnancy test (urine or serum) – WOCBP only 
o 
Biochemistry panel (Electrolytes, creatinine, bilirubin, liver enzymes) 
o 
Quality of life questionnaires (EORTC QLQ-C30/BN20, and MMSE) 
No study-specific procedures may be performed prior to obtaining informed consent.  However, assessments 
performed according to standard of care, prior to consent, may be used to fulfill the screening requirement if they 
are part of the patient’s medical record within the specified timeframe.   
See Section “Enrollment Documentation Requirements” for a complete list of patient enrollment documentation.  
5.5.1.1 Mini-Mental Status Exam 
The Mini-Mental Status Exam is a standardized tool to measure neurocognitive function. The MMSE is scored on a 
scale of 0 to 30. Throughout this protocol, a cutoff score of 23 or less shall prompt study staff to report the score to 
the treating physician for clinical decision-making. 
5.5.2 Registration 
Per UFHCC policy, patients must be registered into UF’s OnCore within one business day of consent. Status 
changes must also be updated within one business day.  
Sites should notify the Coordinating Center by one of the following: 

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• 
Enter into eCRF (REDCap) 
• 
Email to Forward-study@ufl.edu 
• 
Fax to (352) 392-8413 with phone confirmation to (352) 294-8836 
 
A minimum amount of data is required for registration and status changes. CRFs will be provided to all sites via the 
eCRF.  
6 STUDY INTERVENTION 
 
6.1 Study Intervention(s) Administration 
 
6.1.1 Study Intervention Description 
6.1.1.1 Treatment Plans – Optune (TTFIELDS) + temozolomide 
Patients will begin study treatment with temozolomide and TTFields within 2 weeks of the baseline evaluation, 
and no later than 6  weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the 
two). A minimum of 6 and a maximum of 12 cycles of adjuvant temozolomide will be given, depending on 
tolerability and toxicity. 
6.1.1.2 Periodic Evaluation until Treatment Termination 
Patients will be seen and examined before each cycle of temozolomide. After a maximum of 12 cycles of adjuvant 
temozolomide, patients will be seen every 8 weeks. Brain MRI and QoL assessments will be performed every 8 
weeks following the baseline MRI for the first 2 years then every 3 months thereafter until second progression 
(when TTFields treatment will be terminated).  
Patients will undergo the following studies or review every month until treatment termination: 
• 
Physical examination 
• 
Neurological status and performance status (KPS) 
• 
Blood exams  
• 
Optune Compliance 
• 
Record of Adverse Events, concomitant medications and steroid dose  
Patients will undergo the following studies or review every 8 weeks +/- 7 days until treatment termination: 
• 
Quality of Life Questionnaires (EORTC QLQ-C30/BN20, and MMSE) 
• 
Contrast-enhanced MRI 
Screening MRI should be done within 21 days of study treatment start. MRI of the brain will be performed 
routinely at baseline and again every 8 weeks +/- 7 days until treatment termination or second progression, 
whichever is first. In case of clinical progression, an MRI will be performed within 21 days. 
All MRI scans should be performed with and without contrast. 
The data collection for patients who remain on Optune (on-study treatment) and begin 2nd line therapy should 
include labs and visits adjusted as appropriate for the standard care of that patiet’s 2nd line therapy.  

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6.1.1.3 Disease Progression 
The following will be considered disease progression for determination of PFS using the updated response 
assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group 
guideline [79]. 
This study will apply the RANO criteria for high grade gliomas to assess radiographic disease status. These criteria 
specify assessment of enhancing disease to define progression and response. It is likely that a significant number of 
subjects eligible for the proposed study will have non-enhancing disease. For subjects without enhancing disease 
to be eligible for the study, the RANO allowance for FLAIR will be utilized for non-enhancing disease. FLAIR 
considerations are detailed in the tables below.  
6.1.1.3.1 CRITERIA FOR DETERMINING FIRST PROGRESSION DEPENDING ON TIME FROM INITIAL 
CHEMORADIOTHERAPY 
TABLE 3. RANO CRITERIA FOR DETERMINING FIRST PROGRESSION 
First Progression 
Definition 
Progressive disease <12 weeks 
after completion of 
chemoradiotherapy 
 
Progression can only be defined using diagnostic imaging if there is new 
enhancement outside of the radiation field (beyond the high-dose region or 80% 
isodose line) or if there is unequivocal evidence of viable tumor on 
histopathologic sampling (e.g., solid tumor areas [i.e., > 70% tumor cell nuclei in 
areas], high or progressive increase in MIB-1 proliferation index compared with 
prior biopsy, or evidence for histologic progression or increased anaplasia in 
tumor). Note: Given the difficulty of differentiating true progression from 
pseudoprogression, clinical decline alone, in the absence of radiographic or 
histologic confirmation of progression, will not be sufficient for definition of 
progressive disease in the first 12 weeks after completion of concurrent 
chemoradiotherapy.  
Progressive disease ≥ 12 
weeks after 
chemoradiotherapy 
completion  
 
1. New contrast-enhancing lesion outside of radiation field on decreasing, 
stable, or increasing doses of corticosteroids.  
2. Increase by ≥ 25% in the sum of the products of perpendicular diameters 
between the first post-radiotherapy scan, or a subsequent scan with smaller 
tumor size, and the scan at 12 weeks or later on stable or increasing doses of 
corticosteroids.  
3. Clinical deterioration not attributable to concurrent medication or comorbid 
conditions is sufficient to declare progression on current treatment but not for 
entry onto a clinical trial for recurrence.  
4. For patients receiving antiangiogenic therapy, significant increase in T2/FLAIR 
non-enhancing lesion may also be considered progressive disease. The increased 
T2/FLAIR must have occurred with the patient on stable or increasing doses of 
corticosteroids compared with baseline scan or best response after initiation of 
therapy and not be a result of comorbid events (e.g., effects of radiation 
therapy, demyelination, ischemic injury, infection, seizures, postoperative 
changes, or other treatment effects).  
 

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6.1.1.3.1.1 CRITERIA FOR RESPONSE ASSESSMENT INCORPORATING MRI AND CLINICAL FACTORS 
Criteria for Response Assessment Incorporating MRI and Clinical Factors (Adapted from JCO 2010) 
 
TABLE 4. RESPONSE EVALUATION AFTER A COMPLETE RESECTION 
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) lesions. 
• 
Patients must be off corticosteroids (or on physiologic replacement doses only) and 
stable or improved clinically. Note: Patients with non-measurable disease only cannot 
have a complete response; the best response possible is stable disease.  
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. 
• 
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. 
• 
Stable or improved clinically. Note: Patients with non-measurable disease only cannot 
have a partial response; the best response possible is stable disease.  
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.  
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*. 
The absolute increase in any dimension must be at least 5mm when calculating the 
products. 
• 
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 (e.g. radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment 
effects). 
• 
Any new measureable lesion. 
• 
Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
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.  
• 
All measurable and non-measurable lesions must be assessed using the same techniques as at baseline. 

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• 
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery. 
• 
Stable doses of corticosteroids include patients not on corticosteroids.  
The determination of whether to stop treatment due to progression will be based on the investigator's 
evaluation of the patient's clinical condition. TTFields treatment will be continued for 24 months or until 
second progression whichever occurs first unless the patient's clinical condition prohibits this. In the case of 
radiological progression based on local evaluation, temozolomide treatment will be stopped and a second line 
treatment chosen instead. The following treatments or any combination of these treatments are considered 
second line therapy in this protocol: 
• 
Re-operation 
• 
Local radiation therapy  
• 
Second line therapy 
• 
Combination of the above 
6.1.1.3.1.2 DISEASE PARAMETERS 
Measurable disease:  Bi-dimensionally measurable lesions with clearly defined margins by MRI scan.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).   
Non-measurable or evaluable disease:  Uni-dimensionally measurable lesions or lesions with margins not clearly 
defined such as areas of T2/FLAIR signal abnormality or poorly defined enhancing abnormality.  
Note: For cystic lesions, the only measurable part is any enhancement area around the cyst that is clearly defined 
and bi-dimensionally measurable. The cyst itself should not be considered measurable or non-measureable disease. 
Target lesions: All measurable lesions that are seen at baseline MRI. Target lesions should be selected on the basis 
of their size (lesions with the longest diameter), but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, which can be measured reproducibly should be 
selected.  When there are too many measurable lesions, choose the largest 3 lesions as target lesions to follow.  The 
other measurable lesions should be considered evaluable for the purpose of objective status determination. 
Non-target lesions:  All non-measurable lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
6.1.1.3.1.3 METHODS FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler. All baseline MRI evaluations should 
be performed as closely as possible to Study Day 0. An MRI should be collected and evaluated after any surgical 
procedure (surgical resection/debulking) but not biopsy.   
Clinical lesions:  Clinical lesions will only be considered measurable on brain MRI when they are  10 mm (1 cm) in 2 
perpendicular measurements in each of 2 perpendicular planes (i.e., axial and coronal) as assessed using a ruler. 
Histology:  This technique can be used to differentiate between partial responses (PR) and complete responses (CR) 
in rare cases when biopsy or surgical resection of a measureable lesion is clinically indicated.  
Perfusion/CBV: This advanced brain MRI technique can be used as an adjunct test to determine treatment response 
or disease status.  However, it should not be used as the primary or sole method to determine response or disease 
status.  

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Brain FDG-PET coupled with head CT or brain MRI and brain spectroscopy: These advanced metabolic imaging 
techniques can be used as an adjunct test to determine response or disease status. However, they should not be 
used as the primary or sole method of determining response or disease status. 
6.1.1.3.1.4 EVALUATION OF TARGET LESIONS 
Complete Response (CR):  Disappearance of all target lesions. 
Partial Response (PR):  ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters 
of all target lesions sustained for at least 4 weeks. 
Progressive Disease (PD):  At least a 25% increase in the sum of products of perpendicular diameters of at least 1 
target lesion, taking as reference the smallest sum of products of perpendicular diameters on study (this includes 
the baseline sum if that is the smallest on study).  The absolute increase in any dimension must be at least 5mm 
when calculating the products of perpendicular diameters. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum of products of perpendicular diameters while on study. 
 
6.1.1.3.1.5 EVALUATION OF NON-TARGET LESIONS 
Complete Response (CR):  Disappearance of all non-target lesions.  
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s). 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after 
initiation of therapy* not caused by comorbid events (e.g. Radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects). Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician 
should prevail in such circumstances, and the progression status should be confirmed at a later time by the Study 
Chair. 
6.1.1.3.1.6 EVALUATION OF BEST OVERALL RESPONSE 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on the achievement of both measurement 
and confirmation criteria. 
TABLE 5. SUMMARY OF THE RANO RESPONSE CRITERIA (ADAPTED FROM JCO 2010) 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ 
≥ 25% ↑* 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA† 
Clinical status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓* 
Requirement for response 
All 
All 
All 
Any* 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, partial response; 
SD, stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion recovery; NA, not applicable.  

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* Progression occurs when this criterion is present.  
† Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration.  
NOTE: Patients may continue on treatment and remain under close observation and evaluation at 4-8 week 
intervals if there is uncertainty regarding whether pseudoprogression may be present as determined by the 
investigators. If subsequent radiographic or clinical assessments suggest that the patient is in fact experiencing 
progression, then the date of progression should be the time point at which this issue was first raised.  Similarly, 
stable disease may be assigned in cases of presumed “pseudoprogression” associated with decreased steroid 
use. 
6.1.1.3.1.7 DURATION OF RESPONSE 
Duration of overall response:  The duration of overall response is measured from the time measurement criteria are 
met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented.  
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
6.1.1.3.1.8 NEUROLOGICAL EXAM AND PERFORMANCE STATUS 
Patients will be graded using the Karnofsky Performance Status scale and their neurological function evaluated as 
improved, stable or deteriorated in addition to objective measurement of tumor size. These parameters will be 
used to deter mine the overall response assessment. 
The Karnofsky Scale has been adapted for use in many areas, including hospices, cancer clinics, etc., as well as used 
by various CFS researchers and physicians (Leonard Jason, PhD; Jay A. Goldstein, MD). 
The 10-point scale is a quick and easy way to indicate how you are feeling on a given day, without going through 
several multiple-choice questions or symptom surveys. 
TABLE 6: KARNOFSKY SCALE 
100 
Able to work. Normal; No complaints; No evidence of disease. 
90 
Able to work. Able to carry on normal activity; Minor symptoms. 
80 
Able to work. Normal activity with effort; Some symptoms. 
70 
Independent; not able to work. Cares for self; Unable to carry on normal activity. 
60 
Disabled; dependent. Requires occasional assistance; cares for most needs. 
50 
Moderately disabled; dependent. Requires considerable assistance and frequent care. 

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40 
Severely disabled; dependent. Requires special care and assistance. 
30 
Severely disabled. Hospitalized, death not imminent. 
20 
Very sick. Active supportive treatment needed. 
10 
Moribund. Fatal processes are rapidly progressing. 
 
6.1.1.3.1.9 PROGRESSION-FREE SURVIVAL  
PFS is defined as the duration of time from start of adjuvant treatment (TMZ C1D1) to time of progression or death, 
whichever occurs first. 
 
6.1.1.3.2 RESPONSE EVALUATION AFTER A COMPLETE RESECTION 
A complete resection will be defined as contiguous contrast-enhancement <10 mm in 2 perpendicular 
measurements in each of 2 perpendicular planes (i.e., axial and coronal).  Because neither the RECIST[80] nor 
MacDonald [81] criteria are completely appropriate for patients with minimal residual disease, a modified version 
of these criteria will be used as outlined below. 
6.1.1.3.2.1 COMPLETE RESPONSE 
Complete disappearance of enhancing tumor on consecutive CT or MRI images at least 1 month apart, and 
neurologically stable or improved and at the same or a lower steroid dose.  To be assigned a status of “Complete 
Response” as a best overall response, changes in tumor measurements must be confirmed by repeat assessments 
that should be performed no less than 4 weeks after the criteria for response is first met. 
6.1.1.3.2.2 PARTIAL RESPONSE 
Partial response is not assessable in patients without sufficient measurable disease. 
6.1.1.3.2.3 STABLE DISEASE 
Insufficient change to qualify for Complete Response or Progressive disease. 
6.1.1.3.2.4 PROGRESSIVE DISEASE 
At least a 25% increase in the longest diameter on an axial image of any enhancing tumor on consecutive CT or 
MRI images with a minimum of ≥ 5mm of contiguous contrast-enhancement in 2 perpendicular measurements in 
each of 2 perpendicular planes (i.e., axial and coronal). 
6.1.1.3.2.5 NOT ASSESSABLE 
Progression has not been documented and one or more sites have not been assessed. 

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6.1.1.3.2.6 POST-TREATMENT EVALUATION 
After treatment termination the patient will be seen at an outpatient clinic for one additional visit within 30 days 
+/- 7 days. Physical and neurological examination, blood tests (CBC and Biochemistry panel) will be performed 
during this visit. Patient mortality and adverse events will be documented on the case report forms.  
After the post treatment follow up visits, if the patient has not progressed by treatment termination, patient will 
have contrast-enhanced brain MRI every 3 +/- 1 months for 12 months. Then MRIs every 6 +/- 2 months for 24 
months, then yearly +/- 1 month thereafter or until disease progression, whichever comes first.  
In case of clinical progression an MRI will be performed within 21 days. After the end of study therapy visit 
post disease progression, the patient will not be required to return to the clinic for follow-up but will be 
followed until death by telephone every 3 months to monitor their status. 
 
6.1.2 Dosing and Administration 
 
6.1.2.1 Adjuvant Temozolomide Treatment  
All patients will receive adjuvant temozolomide. 
 
6.1.2.2 Adjuvant Phase Cycle 1:  
Four to six weeks after completing the temozolomide + RT phase, the temozolomide is administered for an 
additional 12 cycles of adjuvant treatment. Dosage in Cycle 1 (adjuvant) is 150 mg/m2 once daily for 5 days 
followed by 23 days without treatment. 
 
6.1.2.3 Adjuvant Cycles 2-12:  
At the start of Cycle 2, the dose is escalated to 200 mg/m2, if the CTC non- hematologic toxicity for Cycle 1 is 
Grade ≤2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/L, and the 
platelet count is ≥ 100 x 109/L.  
The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle unlessunless toxicity occurs. 
If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. 
 
6.1.2.4 Temozolomide Dose Reduction or Discontinuation 
Dose reductions during the adjuvant phase should be applied according to Tables 7 and 8 below. Cycle 1 Day 1 
should not start until the ANC is above 1.5 x 109/L (1,500/μL) and the platelet count exceeds 100 x 109/L 
(100,000/μL). If unable to start within the Cycle 1 start window, the patient will be considered a screen fail.  

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The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. Dose 
reductions during the next cycle should be based on the lowest blood counts and worst non-hematologic toxicity 
during the previous cycle. Dose reductions or discontinuations during the adjuvant phase should be applied 
according to Tables 7 and 8. Routine blood monitoring should be conducted in accordance with local site 
procedures.  
 
TABLE 7. TEMOZOLOMIDE DOSE LEVELS FOR ADJUVANT TREATMENT 
 
Dose Level 
Dose (mg/m2/day) 
Remarks 
–1 
100 
Reduction for prior toxicity 
0 
150 
Dose during Cycle 1 
1 
200 
Dose during Cycles 2-12 in absence of toxicity 
 
 
TABLE 8. TEMOZOLOMIDE DOSE REDUCTION OR DISCONTINUATION DURING ADJUVANT TREATMENT 
 
Toxicity 
Reduce temozolomide by 1 Dose 
Levela 
Discontinue 
temozolomide 
Absolute Neutrophil Count 
<1.0 x 109/L 
See footnote b 
Platelet Count 
<50 x 109/L 
See footnote b 
CTC Non-hematological Toxicity 
(except for alopecia, nausea, 
vomiting) 
CTC Grade 3 
See footnote b 
a: temozolomide dose levels are listed in table 7. 
b: temozolomide is to be discontinued if dose reduction to <100 mg/m2 is required or if the same Grade 3 non-
hematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. 
CTC = Common Toxicity Criteria. 
 
6.1.2.5 Treatment after temozolomide discontinuation 
Following temozolomide discontinuation due to toxicity or radiological disease progression (based on local 
interpretation of MRI), patients will be offered second line therapy for their disease. The following treatment 
options may be considered based on the patient's clinical condition per the treating physician’s discretion: 
1. Re-operation (TTFields treatment will be interrupted for at least 2 weeks after reoperation or until wound 
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2. Local radiation therapy 
3. Second line therapy (at the discretion of the treating physician and not limited to traditional cytotoxic 
chemotherapy) 
4. Combination of the above 
TTF treatment will continue concomitant with second line treatments until second disease progression for TTFields 
+ temozolomide patients. 
 
6.1.2.6 Optune (TTFields) + temozolomide 
Optune treatment will be initiated in an outpatient clinic by the investigator’s team at each center or at home by 
Novocure’s device support specialists (DSS). 3D mapping of tumors using the FDA-approved NovoTAL software will 
be completed by a NovoTAl-certified treating physician or by Novocure. Scalp shaving, array placement and all 
device support services (including patients’ and families’ education of device operation, downloading and 
processing of technical and compliance data, and troubleshooting device malfunction) will be provided by the DSS 
for the first placement. Patients and/or their caregivers will continue treatment at home after being trained in 
device use with the support of DSS as needed.  
TTFields will start within 2 weeks of the first cycle of adjuvant temozolomide but must be within 7 weeks after end 
of temozolomide/RT. Adjuvant Temozolomide will continue for a minimum of 6 and a maximum of 12 cycles. 
Optume will continue for a maximum of 2 years. At first progression, patients will be allowed to continue with 
TTFields therapy with any other therapy per standard of care. Patients will receive up to 12 one-month courses of 
continuous Optune treatment together with standard adjuvant temozolomide.  The decision to add each 
additional treatment course will depend on the lack of treatment related serious adverse events which reappear 
upon re-challenge and lack of clinical disease progression. All technical aspects of the Optune device are handled 
by the DSS.  
During Optune treatment the patient will be permitted to interrupt treatment for personal needs with the goal 
of achieving approximately 75% of the time over each 4-week period. Compliance reports with TTFields will be 
obtained by Novocure’s DSS per usual clinical treatment procedures.  If a patient’s compliance is below 75% of the 
time over any 4-week period, the patient will be trained on the importance of compliance and any barriers to 
compliance will be addressed by the DSS. If a patient’s compliance is below 50% of the time over any 4-week 
period, the patient will be trained on the importance of compliance and any barriers to compliance will be 
addressed by the DSS and study staff. 
Approximately once per month, from baseline until treatment termination, all patients will report to an outpatient 
clinic where they will be assessed clinically and undergo routine laboratory examinations. The follow-up 
window for these visits is -3/+ 7 days for the Adjuvant TMZ follow-up window of approximately 12 months. The 
follow- up window after discontinuation of Adjuvant TMZ will be +/- 1 month. If patients are removed from 
study therapy due to toxicity and/or disease progression prior to the 2-year study treatment, the patients will 
have an end of study therapy visit within 1 month +/- 7 days. After this end of study therapy visit, patients will 
be followed by telephone interview every 3 months until death. 
 

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6.1.2.6.1 RECOMMENDATIONS FOR USE OF OPTUNE 
All patients treated with Optune will be required to shave their heads to initiate array placement and Optune 
therapy. Array placement will be performed based on the transducer array map calculated during treatment 
planning. It is recommended that treatment with the device be continuous with breaks allowed for personal needs 
(e.g., showering, array exchange). Breaks should be no more than 1 hour twice daily.  
Use compliance is aimed at a minimum of 50% (12 hours) with the goal of achieving at least 75% (18 hours) of the 
time per day on average. In addition, investigators may grant brief breaks in device treatment that last no more 
than 3 days in any 30-day period at the investigator’s discretion. Subjects should be counseled by study staff if 
compliance reports show less than 50% compliance.  
Optune is programmed by Novocure to deliver 200 kHz TTFields in two sequential, perpendicular field directions at 
a maximal intensity of 707 mARMS. There will be no adjustments made to the device by investigators or 
patients/caregivers.  
It is recommended that patients replace the transducer arrays 2-3 times per week with the help of a caregiver. At 
each array replacement, it is recommended that the patient’s scalp be re-shaved and skin treated according to the 
guidelines in section “Skin Care Guidelines.” 
There will be no dose adjustments to the device for adverse events. Reasons for breaks in treatment for longer 
than 24 hours will be documented. 
Optune therapy will be stopped in the following cases: 
• 
The occurrence of serious adverse events probably or definitely related to treatment with TTFields 
• 
Clinical and functional deterioration considered by the investigator to be prohibitive of continuing 
treatment. 
• 
After 24 months or after second progression, whichever occurs first. 
Treatment with the Optune does not need to be terminated in the following situations: 
• 
Toxicity due to temozolomide treatment 
• 
Radiological progression alone will not lead to termination of TTFields treatment, but to replacement 
of the temozolomide treatment with best standard of care second line therapy: 
o 
Re-operation 
o 
Local radiation therapy  
o 
Second line therapy 
 
6.1.2.6.2 SKIN CARE GUIDELINES 
If the skin beneath the transducer arrays is inflamed, it is recommended that a prescription strength steroid 
ointment (e.g. 3% hydrocortisone or 0.05-0.1% Clobatasol) be prescribed to the patient. The patient or caregiver 
should apply the ointment after removing the arrays and cleaning the scalp with baby oil and gentle soap. The 
ointment should be left on the scalp for at least 30 minutes prior to washing the skin with a mild shampoo and 
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At each array replacement, it is recommended that the new set of arrays be shifted by approximately 2 cm 
compared to the previous layout so that the array discs are placed between the areas of skin irritation. At the next 
array replacement, the arrays should be shifted back to their original location.  
If the dermis is breached (ulcers, open sores, punctate lesions, cuts, etc.), it is recommended that an antibiotic 
ointment (e.g. bactroban) be prescribed and used in place of the steroid ointment.  
 
6.2 Preparation/Handling/Storage/Accountability 
 
6.2.1 Acquisition and accountability 
 
Temozolomide is a standard of care therapy widely available throughout the U.S. Each site will utilize their 
hospital/local pharmacies for this study.   
 
Optune devices will be delivered to patients and maintained by the Novocure network of Device Site Specialists 
across the U.S. Subjects will be met at their house and trained on device use. Device supplies will be delivered 
directly to the subject. The DSS will revisit as required for usage/compliance reporting, device maintenance, 
resupply, and to answer any questions the patient has about the device.  
 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
 
The complete package insert for temozolomide will accompany this protocol in lieu of an Investigator’s Brochure.  
 
The complete Optune Instructions for Use and Device Manual will accompany this protocol in lieu of a Device 
Manual.  
 
Additionally, the Optune DSS may provide the patient with Optune Patient Information and Operation Manual, 
Optune Travel Support Brochure, Optune Patient Scalp Care Guidelines, etc. These are educational resources 
published by Novocure to better assist patients in understanding and using the device.  
 
6.2.3 Product Storage and Stability 
6.2.3.1 Temozolomide 
Storage 
• 
Store (temozolomide) Capsules at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)  
• 
Store (temozolomide) for Injection refrigerated at 2-8°C (36-46°F).  
o 
After reconstitution, store reconstituted product at room temperature (25°C [77°F]). 
Reconstituted product must be used within 14 hours, including infusion time. 
The above storage guidelines are taken from the package insert; please see full insert for full details.  
 
6.2.3.2 Optune 
6.2.3.2.1 STORAGE CONDITIONS 
• 
Temperature range: 23°F to 104°F for the device and additional parts 
• 
Temperature range: 41°F to 81°F for the transducer arrays 

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• 
Relative humidity range: 15-75% for the device and additional parts 
• 
Relative humidity range: 35-50% for the transducer arrays 
6.2.3.2.2 TRANSPORT CONDITIONS 
Transportation of the device and additional parts is possible using air/ground transportation in weather protected 
conditions as specified below: 
• 
Temperature range: -13°F to 104°F 
• 
Maximal relative humidity 15-75% 
• 
No direct exposure to water 
Transportation of the transducer arrays is possible using air/ground transportation in weather protected 
conditions as specified below: 
• 
Temperature range: 32°F to 104°F 
• 
Maximal relative humidity 15-75% 
• 
No direct exposure to water 
 
Please see the Optune Instructions for Use and Device Manual for full details.  
 
6.2.4 Preparation 
No preparation of either temozolomide or the Optune device is required by study staff. Temozolomide is 
administered per package insert. Optune is delivered, set-up, trained, and maintained by the Novocure DSS in the 
site’s local area per clinical standard of care.  
 
6.3 Correlative Studies 
6.3.1 Tumor Tissue Specimens 
6.3.1.1 Collection of specimens 
Formalin fixed and paraffin embedded (FFPE) samples will be obtained from pathology or research tissue banks 
from primary tumors and first recurrent tumors, when available. One FFPE tissue block or fifteen slides of 20 µm 
thick section will be required for analysis. At least 20 pairs of primary tumors and first recurrent tumors from 
patients treated only with RT and concurrent temozolomide followed by adjuvant temozolomide, and not with 
TTFields or any other modalities (drug, radiation or device), are needed.  
The Coordinating Center will obtain at least 20 historical paired samples from patients with the same tumor type 
or GBM before and after being treated with temozolomide and RT, but not with TTFields, over the last 5 years at 
the same participating institutions.  
Sequencing analyses will be obtained by standard of care sequencing (immunohistochemistry or next-generation 
sequencing), from which mutation burden data will be obtained. Mutation burden will be expressed as number of 
mutations per Mb and will be extracted from sequencing reports for primary tumors and first recurrent tumors, 
where available. 
 

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6.3.1.2 Handling of specimens 
FFPE samples, or pathology slides, will be used for standard H&E and immunohistochemical (IHC) staining for 
biomarkers for TILs and immunogenic cell death to be performed at the University of Florida.  
IHC will be performed for the following, but not limited to, biomarkers: CD4, CD8, CD19, and CD45 (immune cells), 
AIM2, ACS and cGAS (immunogenic cell death), ISG15, INFalpha, and INFbeta (type 1 interferon response). Results 
will be expressed as percentage of cells with positive staining for each marker. 
 
6.3.1.3 Shipping of specimens 
FFPE or slide samples will be transported or mailed at ambient temperature to the University of Florida at the 
address below: 
FORWARD Trial 
c/o David Tran 
1149 S Newell Drive, L3-132 
Gainesville, FL 32610  
 
Contact persons for tissue shipping and delivery: 
Annie Allen:  
Anne.Allen@neurosurgery.ufl.edu 
phone #: 352-294-8836 
Sonisha Warren:  
Sonisha.Warren@neurosurgery.ufl.edu 
phone #: 352-273-9000 
Alexandra Sherman: 
Nagheme Thomas:  
Alexandra.sherman@neurosurgery.ufl.edu 
Nagheme.Thomas@neurosurgery.ufl.edu 
phone #: 352-273-6997 
phone #: 352-273-6997 
Shipments details should be logged into REDCap as soon as possible, and no later than 14 days from date of 
shipment. 
 
6.3.2 Electric Field Modeling 
Tumor Treating Fields are alternating electric fields at 200 kHz that can penetrate from the surface of the scalp into 
the brain to exert their anti-mitosis effect on dividing tumor cells.  They have to first pass through the calvarium 
and subarachnoid space where they are attenuated by resistive property of bone and the conductive property of 
the cerebrospinal fluid.  The remaining fields then reach the gray and white matters where they are either 
augmented or attenuated, depending on the local tissue properties and the geometry of structures such as the 
frontal, temporal and posterior horns of the lateral ventricles.  As a result of these interferences, the amount of 
electric fields that reaches the gross tumor volume cannot be calculated precisely but can only be approximated 
numerically by methods such as finite element analysis [62].  
6.3.2.1 Secondary imaging analyses 
In addition, secondary analyses will be performed to determine the extent of correlation with respect to patient 
age, Karnofsky Performance Status, dexamethasone dosage, other non-therapeutic supportive medications and 
the number of cycles of chemotherapy, targeted therapy, biological agents or immune therapies received.  
Additional analyses will be conducted to also determine the correlation with fluctuations in laboratory values in 
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parameters, such as Ki67, presence or absence of IDH-1 mutation, MGMT methylation status and/or somatic 
mutations found in next generation sequencing. 
6.3.2.2 MRI Acquisition and DICOM images 
The process of numerical estimation of electric field strength at the gross tumor volume consists of a number of 
steps.  First, gadolinium-enhanced MP RAGE sequences will be acquired using MRI in one axis and reconstructed in 
the other two axes resulting in axial, coronal and sagittal images.  Standard T2, FLAIR and pre-gadolinium 
sequences will also be obtained per local care standards.  The field of view of the images should include the 
surface of the scalp (Fig. 7).  These images will be exported as DICOM images.   
Second, the DICOM images will be imported into a tissue segmentation software program as previously described 
[69].  Third, both intracranial and extracranial structures, including scalp, skull, dura, cerebrospinal fluid, gray 
matter, white matter and bilateral ventricles, will be segmented and meshed before solving using finite element 
methods [62].   
Lastly, the electric field strength and the specific absorption ratio at the gross tumor volume will be tabulated using 
various electric field strength parameters, including EAUC, EV150, E95% and E50%, and specific absorption ratio 
parameters, including SARAUC, VSAR7.5, SAR95% and SAR50%.  Together, these parameters will allow the 
comparison among patients of the electric field strength, as well as the amount of energy deposited, at the tumor. 
 The electric field and specific absorption ratio parameters will be correlated with measures of clinical outcome, 
including response rate, progression free survival and overall survival.  Spearman rank-order correlation will be 
performed between the non-parametric electrical and clinical outcome variables.   
The DICOM images will be obtained for analysis at baseline, each two months per protocol, and at the time of first 
and second progression.  These analyses will be performed at Beth Israel Deaconess Medical Center. Analysis will 
be completed within two years of the last patient’s enrollment.   
                             
 
Figure 7. MRI image samples demonstrating field of view of the images must include the surface of the scalp. 
Incorrect image on the left does not include full scalp surface where indicated by arrows. The correct image at the 
right does include the surface of the scalp around the entire head.  

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6.3.2.3 Shipping of DICOM images 
Anonymized DICOM images will be burned onto a compact disc coded with the following study information: 
subject’s study number, Date of Service, and Site Number.  
The following shipment time points will be used for each patient:  
1. Baseline 
2. First Progression 
3. Second Progression 
 
Images collected between shipping time points should be sent at the next shipment time point. Shipment 
information should be entered into the eCRF. 
The CDs should be mailed to: 
Brain Tumor Center 
c/o Eric T Wong 
Beth Israel Deaconess Medical Center 
330 Brookline Avenue 
Boston, MA  02215 
Tel: 617-667-1665; Fax: 617-667-1664 
 
Contact person: 
Dr. Eric Wong:  
ewong@bidmc.harvard.edu 
 
6.4 Study Intervention Compliance 
 
Temozolomide compliance will be measured by subject self-report.  
 
Optune compliance will be measured on each device and a monthly report provided to the subject and Site 
Investigator by the DSS.  
Optune compliance will be addressed according to the following table: 
TABLE 9: OPTUNE COMPLIANCE REQUIREMENTS 
Subject Compliance in previous 4-
week period per device report 
DSS 
Study Staff 
≥ 75% 
n/a 
Reinforce good compliance report 
74% to 50% 
o 
Re-train patient on device 
compliance requirements 
o 
barriers to compliance will 
be addressed 
n/a 
≤ 49% 
o 
Re-train patient on device 
compliance requirements 
o 
barriers to compliance will 
be addressed 
Counsel subject during study visit 
re: need for additional use of 
device and identify any remaining 
barriers 
 

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6.5 Concomitant Therapy 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are concomitant 
prescription medications, over-the-counter medications and supplements.  
 
Medication History should include the Chemoradiation treatment window, or at least 90 days of Medication 
History, whichever is greater.  
7 STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 Discontinuation of Study Intervention 
 
Discontinuation from study treatment does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is identified 
(including, but not limited to changes from baseline) after enrollment, the investigator or qualified designee will 
determine if any change in participant management is needed.  
 
Any serious adverse event deemed life threatening by the treating physician that is definitely related to the study 
device will be cause for immediate cessation of treatment for the patient. Patient follow up will continue after 
such an event. 
 
7.2 Procedures for Orderly Termination of Participation 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
The investigator may remove a patient from the study in case of not complying with study protocol. 
• 
If any clinical adverse event (AE), including a laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best interest of the 
participant 
The reason for participant discontinuation or withdrawal from the study will be recorded on the electronic Case 
Report Form (eCRF). Subjects who sign the informed consent form and do not receive the study intervention may 
be replaced.  Subjects who sign the informed consent form, and receive the study intervention, and subsequently 
withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
 
7.3 Lost to Follow-Up 
A participant will be considered lost to follow-up (LTFU) if he or she fails to return and is unable to be contacted by 
the study site staff for up to 180 days following his/her final visit or call.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 

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• 
The site will attempt to contact the participant and reschedule the missed visit within the visit window, 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to 
regain contact with the participant (where possible this will include 3 telephone call attempts and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
 
Since the participant may be incapacitated, the LAR will be contacted in the event the participant cannot be 
reached.  
 
Should the participant continue to be unreachable with no known outcome, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 Efficacy Assessments  
8.1.1 Day 0 – Start of TMZ Treatment Cycle 1 
 
• 
Patients will begin treatment with temozolomide at 4 weeks (+14 days) from end of radiotherapy.   
• 
Cycle 1 will be dosed at 150mg/m2 daily for 5 consecutive days of a 28-day cycle. 
• 
Optune therapy should start within two weeks of start of adjuvant temozolomide, but not more than 7 
weeks from the end of temozolomide/RT and will be continuous throughout study.  
• 
Review Concomitant Medications 
• 
Update Adverse Events 
 
8.1.2 Week 4 (-3/+7 days) - Start of Subsequent TMZ Treatment Cycles, repeat 
every 4 weeks up to 12 cycles 
• 
Physical Exam 
• 
Patients will begin treatment with temozolomide cycle 2 and subsequent cycles every 4 weeks (-3/+7 
days) at 200 mg/m2, if the CTC non-hematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, 
nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 109/L, and the platelet count is ≥ 100 x 
109/L.  
o 
The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle unless 
toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in 
subsequent cycles. 
• 
Neurological status and KPS 
• 
CBC with differential 
• 
Biochemistry Panel (electrolytes, creatinine, bilirubin, liver enzymes) 
• 
Steroid Dose (recorded) 
• 
Optune therapy will be continuous throughout study. Compliance documentation will be obtained every 4 
weeks (-3/+ 7 days). 
• 
Review Concomitant Medications 
• 
Update Adverse Events 

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8.1.3 Week 8 (+/- 1 week) – repeat MRIs every 8 weeks only, until treatment stop 
• 
Contrast-enhanced MRI of the brain 
• 
Quality of life questionnaires (EORTC QLQ-C30/BN20, and MMSE) 
• 
RANO assessment 
• 
Review Concomitant Medications 
• 
Update Adverse Events 
 
8.1.4 Progression 
If progression is identified, the following procedures should be performed: 
• 
Contrast-enhanced MRI of the brain 
• 
Physical Exam 
• 
Neurological status and KPS 
• 
CBC with differential 
• 
Steroid Dose (recorded) 
• 
Biochemistry panel (Electrolytes, creatinine, bilirubin, liver enzymes) 
• 
Quality of life questionnaires (EORTC QLQ-C30/BN20, and MMSE) 
• 
RANO assessment 
• 
Optune Therapy – confirm continuation (See Recommendations for Use of Optune) 
• 
Optune Compliance 
• 
Review Concomitant Medications 
• 
Update Adverse Events  
• 
Tumor Tissue sample – determining availability of FFPE, pathology slides and/or frozen sample(s) for first 
recurrence 
8.2 Safety and Other Assessments 
 
The following labs are collected for safety by the investigator or his/her designee:  
• 
CBC with differential 
• 
Pregnancy Test (urine or serum) – WOCBP only 
• 
Biochemistry (electrolytes, creatinine, bilirubin, liver enzymes) 
Lab results should be reviewed promptly.  
 
8.2.1 After Treatment Stop  
Week 4 (+/- 7 days) from treatment stop 
The following will be performed 4 weeks (+/- 7 days) from treatment stop: 
• 
Physical exam 
• 
Neurological status and KPS 
• 
CBC with differential 
• 
Biochemistry Panel (electrolytes, creatinine, bilirubin, liver enzymes) 
• 
Review Concomitant Medications 
• 
Update Adverse Events 
 

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8.2.2 Survival Follow-up 
Every 3 months +/- 14 days 
After the final visit is conducted, subjects will be followed every 90 days (3 months) +/- 14 days, either by phone or 
in-person.  
See the Survival Follow-up Telephone Script for specific questions.  
8.3 Adverse Events and Serious Adverse Events 
 
8.3.1 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 Definition of Serious Adverse Events (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
8.3.3 Classification of an Adverse Event 
 
8.3.3.1 Severity of Event 
AEs will be assessed according to the CTCAE version 5.0 (term and grade) and documented.  If CTCAE term does 
not exist, the PI should select the most appropriate CTC category and indicate “other”.   
If CTCAE grading does not exist for an AE, the severity of the AE will be graded as: 
1. Mild - Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
2. Moderate - Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
3. Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating.  Of note, the 
term “severe” does not necessarily equate to “serious” 
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5. Fatal 
8.3.3.1.1 CEREBRAL EDEMA TOXICITY EXCEPTION: 
NCI CTCAE criteria categorize all cerebral edema as grades 3-5. Cerebral edema, with or without mass effect, 
normally presents in glioma patients as part of the disease process and can be exacerbated by standard of care 
chemotherapy and radiation. Therefore, cerebral edema, for purposes of this protocol, although ranked grades 3-5 
by NCI CTCAE criteria, will be graded with the full range of toxicities in order to accurately capture the AE: (1) Mild 
(2) Moderate (3) Severe (4) Life Threatening (5) Fatal.    
8.3.3.1.2 CLINICAL SIGNIFICANCE OF LAB RESULTS 
Only clinically significant lab abnormalities will be recorded as AEs.  
 
Abnormal laboratory results shall be assessed by the Site investigator (or designee) promptly for clinical 
significance. Laboratory reports should be initialed and dated by the evaluator.  
 
An abnormal lab value should be deemed clinically significant if both of the following conditions are met:  
• 
The abnormality suggests a disease and/or organ toxicity that is new or has worsened from baseline.  
• 
The abnormality is of a degree that requires additional active management, e.g., change of dose, 
discontinuation of the drug, close observation, more frequent follow-up assessments, or further 
diagnostic investigation. 
 
8.3.3.2 Relationship to Study Intervention 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the site investigator 
(clinician) who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study intervention must always be suspect. 
 
• 
Definitely Related (Definite) – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related (Probable) – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related (Possible) – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other factors 
may have contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event 
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drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related (Unrelated) – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician.] 
 
8.3.3.3 Expectedness  
 
Site Investigators will be responsible for determining whether an adverse event (AE) is expected or unexpected.   
 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with the 
risk information previously described for the study intervention.  
 
8.3.4 Summary of AE Reporting Requirements for Site Investigators 
 
8.3.4.1 Adverse Event Reporting 
All Adverse Events CTCAE Grades 1 and 2 should be entered into the eCRF within 14 days of discovery by the site if 
possibly, probably, or definitely related to the study treatment in the opinion of the site investigator. 
All Adverse Events CTCAE Grade 3 and higher should be entered into the eCRF within 14 days of discovery by the 
site. 
8.3.4.2 Serious Adverse Event Reporting 
 
All SAEs should be reported to the Coordinating Center within 24 hours of discovery by the site.   
 
Per UF DSMB policy, all SAEs will be reported to the UFHCC Data Integrity and Safety Committee (DISC) within 5 
days. 
 
8.3.5 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. 
Any medical condition that is present at the time that the participant is screened will be considered as baseline 
and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, 
it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration 
of each episode. 
Study Staff will record all reportable events with start dates occurring any time after the start of study treatment 
for 30 days after the After Treatment Stop Visit.  At each study visit, the investigator or his/her designee will 
inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until 
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During Survival Follow-up, AEs and SAEs will not be collected. Only Progression status and survival outcomes will 
be monitored during this stage of the study.  
 
8.3.6 Adverse Event Reporting  
 
Adverse Events shall be recorded and entered into the eCRF within 14 days. The Coordinating Center will report 
the events to the DSMB for review per policy.  
The site investigator is responsible for informing the local IRB of adverse events per local requirements. 
 
8.3.7 Serious Adverse Event Reporting  
 
The site investigator must report any serious adverse event, whether or not considered study intervention related, 
including those listed in the protocol, package insert, or device use manual to the Coordinating Center within 24 
hours of discovery and must include an assessment of whether there is a reasonable possibility that the study 
intervention caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately 
report the event to the Coordinating Center. 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator deems 
the event to be chronic or the participant is stable. Supporting documentation of the event may be requested by 
the Coordinating Center and should be provided as requested. 
8.3.7.1 Unanticipated Adverse Device Effect 
 
The investigational device exemption (IDE) regulations define an unanticipated adverse device effect (UADE) as 
“any serious adverse effect on 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 in the investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects” 
(21 CFR 812.3(s)). UADEs must be reported by the clinical investigator to the Coordinating Center and the 
reviewing IRB, as described below:  
 
Investigators are required to submit a report of a UADE to the Coordinating Center within 24 hours after the 
investigator first learns of the event.   
 
The IDE Sponsor will conduct an evaluation of a UADE and will report the results of the evaluation to FDA, all 
reviewing IRBs, and participating investigators within 10 working days after the sponsor first receives notice of the 
effect.  
 
The site investigator is responsible for informing the IRB of the UADE per local requirements. 
The IDE sponsor will make reports to FDA as required by §812.150. 
 
8.3.8 Reporting Events to Participants  
 

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If additional risks are identified, the protocol will be amended and Informed Consent Form revision(s) 
implemented.  
 
8.3.9 Events of Special Interest  
 
This section is not-applicable. There are no events of special interest for this study. All adverse events CTCAE Grade 
3 and above, and serious adverse events shall be collected and reported as describe in this protocol.  
 
8.3.10 Reporting of Pregnancy  
 
Pregnancy of any female subject including pregnancies that occur in the female partner of a male study subject 
should be reported to the Coordinating Center within 24 hours of discovery. All pregnancies must be followed to 
outcome. 
The subject will be withdrawn from the study and the site investigator will continue safety follow-up. 
 
8.4 Unanticipated Problems 
 
8.4.1 Definition of Unanticipated Problems (UP) 
 
Unanticipated problems involving risks to participants or others includes, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-approved 
research protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect on 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 in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 
8.4.2 Unanticipated Problem Reporting  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board (IRB) per 
local policy and to the Coordinating Center within 24 hours of discovery. The UP report will include the following 
information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome;  

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• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents 
an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
An investigator shall submit  to the reviewing Institutional Review Board (IRB) a report of any unanticipated 
adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working 
days after the investigator first learns of the effect (21 CFR 812.150(a)(1) and to the Coordinating Center within 24 
hours of discovery.  
 
The IDE sponsor who conducts an evaluation of an unanticipated adverse device effect under 812.46(b) will report 
the results of such evaluation to the Food and Drug Administration (FDA) and to all reviewing IRB's and 
participating investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter 
the IDE sponsor shall submit such additional reports concerning the effect as FDA requests (21 CFR 812.150(b)(1)).    
 
8.4.3 Reporting Unanticipated Problems to Participants  
 
If additional risks are identified, the protocol will be amended and Informed Consent Form revision(s) 
implemented. 
9 CONTROL COHORT 
This trial will include a control cohort that includes both historical and contemporaneous control patients. A 
minimum of 90 and a maximum of 100 patients will be enrolled in the control cohort. This is a non-interventional 
control group (data collection only). All patients in the control cohort will be enrolled at the same participating 
institutions.  Risks associated with participation of the control cohort are minimal. 
Historical controls will be gathered via chart review of patients completing chemo/RT after 1/1/2016 and 
before 5/20/2019; 5/20/2019 is the initial date of IRB approval for the coordinating center and first 
opened study site. Control patients completing chemo/RT after 5/20/2019 will be enrolled as 
contemporaneous controls. 
Control subjects (contemporaneous or historical) will be enrolled via informed consent if consent is 
practicable. An IRB waiver of consent will be requested for historical control patients who may be 
deceased, no longer being followed or lost to follow-up.  
9.1 Control Cohort Rationale 
Identification of a homogeneous historical cohort for comparing the investigational device data to historical data is 
of critical importance to this study’s design and scientific rigor. This historical and contemporaneous cohort will 
include patients completing radiation and chemotherapy treatment no earlier than January 1, 2016, when 
chemotherapy became the care standard in these tumor subtypes [16].  
9.2 Control Cohort Inclusion Criteria 
In order to be eligible to enroll in the control cohort, an individual must meet all of the following criteria: 
A. Willing and able to provide written informed consent or eligible for inclusion under an IRB-approved 
waiver of consent 
B. Male or female, 18 years or older  

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C. Histologic confirmation of WHO Grade II or III astrocytoma 
a. mixed oligoastrocytomas are permitted 
D. Mutational identity determined by CLIA-certified sequencing including: 
a. IDH1/2 wildtype (i.e. lack of detectable mutations on the sequencing report, variants of unknown 
significance or non-synonymous single nucleotide polymorphisms deviating from wild-type 
sequence do not apply)  
AND 
b. TERT promoter mutation(s) 
E. Karnofsky performance status ≥70% 
F. 
Maximal safe resection 
a. biopsy alone is allowed 
G. Completed standard chemoradiation and concurrent temozolomide and adjuvant temozolomide. 
a. Patients with a tumor that was biopsied or resected in the past followed by observation only 
without definitive chemoradiation and/or chemotherapy given will be eligible, as long as: repeat 
maximal surgical resection (biopsy only allowed) has been performed, definitive temozolomide/RT 
treatment meets the criteria above, and adjuvant temozolomide treatment was given (or planned 
for the contemporaneous cohort)  
H. Candidate for adjuvant high dose temozolomide per investigator’s clinical judgement (for the 
contemporaneous cohort) 
I. 
No evidence of early disease progression per RANO criteria upon completion of Chemo/RT and beginning 
adjuvant temozolomide 
 
9.3 Control Cohort Exclusion Criteria 
At time of starting adjuvant (first-line) therapy: 
L. Prior treatment with anti-angiogenic agents including bevacizumab. 
M. Progressive disease (according to RANO criteria) after temozolomide/RT, at time of starting adjuvant 
therapy.   
N. Actively participating in another clinical treatment trial intended to treat the underlying astrocytoma at 
start of adjuvant Temozolomide treatment. 
 
9.4 Control Cohort Lifestyle Considerations 
• 
Patients enrolled in the control cohort must not have any past, present, or planned TT Fields treatment. 
9.5 Control Cohort Limited Data Collection 
Data collected for the historical and contemporaneous control group will be distinct from data collected for 
interventional patients in this study, as described below. Data for control patients is designed to be collected 
exclusively from chart review. 
 
All control cohort documentation should be uploaded into the eCRF within 45 days of collection. Data extracted 
from the medical record shall be defined as collected on the day of extraction.  
 
1. Informed Consent or waiver 
2. Demographics 

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3. Pathology   
4. Date of and extent of operation (GTR, partial, or biopsy) 
5. Summary of Concurrent Chemo/RT 
6. KPS 
7. Summary of Adjuvant Chemotherapy (TMZ dates, number of cycles) 
8. Summary of Additional Therapies (therapy types, dates, number of cycles) 
9. Date(s) of Progression 
10. Date of Death (if applicable) 
11. Tumor tissue samples (optional) 
 
Tumor Tissue samples are optional for control cohort patients. Adverse Events are not collected, and not reportable 
for control patients. MRI Correlative Study does not include control cohort participants. Concomitant Medications 
will not be maintained for control patients, although applicable steroid doses may be recorded as part of the RANO 
form.  
10 STATISTICAL CONSIDERATIONS  
 
10.1 Statistical Hypotheses 
 
• 
Primary Efficacy Endpoint: overall survival (OS) 
Control arm: the control arm will consist of both historical and contemporaneous control patients. Historical 
controls will consist of TERT mutation-only astrocytoma patients treated and followed by the participating sites 
between January 1, 2016 and May 20, 2019. As described above, these patients will have received standard 
treatment and would have met first tier inclusion/exclusion criteria for the study. Data for these patients will be 
collected via chart review. Contemporaneous controls will also consist of patients who qualify for the trial and 
receive standard treatment but decide not to proceed with the Optune experimental treatment because of 
personal preference. This personal preference must be non-medical in nature. Based on clinical experience, most 
commonly this non-medical patient personal preference preventing Optune use will be unwillingness to shave 
his/her head and/or unwillingness to wear a visible medical device on his/her head most of the day.   
• 
N = 90 patients total in an expected mixture ranging between 80 historical controls and 10 
contemporaneous controls to 60 historical controls and 30 contemporaneous controls. 
• 
Assumed median survival = 22 months (based on Figure 3A in Eckel-Passow et al [12]) 
• 
Follow-up = up to 60 months for the historical controls, up to 60 months for the contemporaneous 
controls 
Experimental treatment arm: TERT mutation-only astrocytoma patients who will receive standard treatment plus 
TTFields therapy at one of 15 participating centers. 
• 
N = 90 patients 

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• 
Assumed accrual rate = 2.5 patients/month accumulated over 15 centers 
• 
Accrual period = 36 months 
• 
Follow-up period after the end of accrual = 24 months 
• 
Assumed survival time distribution = Weibull with accelerating hazard and proportional hazards 
 
10.2 Sample Size Determination 
To assess sample size requirements for detecting an improvement in median overall survival (OS) in the 
experimental treatment arm relative to the historical control arm, we initially assumed 60 to 90 patients receiving 
standard treatment and follow-up between 1-2016 and 5-2019 would be available for chart review. We assumed 
that these historical control patients would have a maximum follow-up time of 60 months. For the experimental 
treatment, we assumed an accrual rate of 2.5 patients per month across 15 participating centers and an accrual 
period of 36 months, yielding an enrollment of 90 patients in the experimental arm. The patients in the 
experimental arm would be followed for an additional 24 months after the end of accrual. We considered 
improvements in median survival ranging from 4 to 8 months to be of clinical interest. We also assumed that 
survival times would follow a Weibull distribution with proportional hazards and an accelerating hazard function 
(shape parameter k=2.0, estimated from Figure 3A in Eckel-Passow et al [12]. We also considered a more slowly 
accelerating Weibull shape parameter of k=1.8. Under these assumptions, the power to detect improvements in 
median OS using a one-sided log-rank test (one-sided alpha=0.05) are summarized in Table 10 for selected 
combinations of historical control sample size, Weibull shape parameter, and number of months improvement in 
median OS [detectable effect size methodology adapted from (Wu and Xiong, 2014)]. We then explored the effect 
of mixing historical and contemporaneous controls in select mixtures into a single control arm, noting a very slight 
improvement in power to detect improvements in survival. Overall, a control arm sample size of 90 patients, in 
historical/contemporaneous control mixtures of 90+0, 80+10, 70+20, and 60+30 all have at least 80% power to 
detect improvements in survival between 6 and 8 months. 
 
TABLE 10: POWER TO DETECT M MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL UNDER SELECTED SCENARIOS 
                                                      Power to detect M months 
                                                      improvement in median OS 
                                 Hx Ctl+                 at one-sided α=0.05 
Accrual  Accrual Follow-up       Contemp               using the log-rank test 
  rate   period   period   Trial   Ctl   Weibull   ----------------------------- 
 (N/mo)  (mos)    (mos)       N     N    shape k   M = 4     5     6     7     8 
-------------------------------------------------------------------------------- 
   2.5     36       24       90   50+ 0    2.0     0.525 0.667 0.782 0.866 0.922 
   2.5     36       24       90   60+ 0    2.0     0.565 0.711 0.823 0.899 0.946 
   2.5     36       24       90   70+ 0    2.0     0.598 0.745 0.853 0.922 0.962 
   2.5     36       24       90   80+ 0    2.0     0.626 0.773 0.876 0.938 0.972 
   2.5     36       24       90   90+ 0    2.0     0.649 0.796 0.894 0.950 0.979 
-------------------------------------------------------------------------------- 
-------------------------------------------------------------------------------- 
   2.8     36       24       90   80+10    2.0     0.650 0.796 0.894 0.950 0.979 
   3.1     36       24       90   70+20    2.0     0.651 0.797 0.895 0.951 0.979 

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   3.3     36       24       90   60+30    2.0     0.652 0.798 0.895 0.951 0.979 
================================================================================ 
   2.5     36       24       90     50     1.8     0.447 0.577 0.692 0.787 0.858 
   2.5     36       24       90     60     1.8     0.483 0.620 0.737 0.828 0.892 
   2.5     36       24       90     70     1.8     0.513 0.654 0.771 0.858 0.916 
   2.5     36       24       90     80     1.8     0.538 0.683 0.798 0.880 0.933 
   2.5     36       24       90     90     1.8     0.560 0.707 0.820 0.898 0.946 
   2.5     36       24       90    100     1.8     0.579 0.727 0.838 0.912 0.955 
-------------------------------------------------------------------------------- 
-------------------------------------------------------------------------------- 
   2.8     36       24       90   80+10    1.8     0.561 0.708 0.821 0.899 0.946 
   3.1     36       24       90   70+20    1.8     0.562 0.709 0.822 0.899 0.947 
   3.3     36       24       90   60+30    1.8     0.563 0.710 0.823 0.900 0.947 
 
10.2.1 Analysis of Primary and Secondary Endpoints and Correlative Studies 
We will compare OS and progression-free survival (PFS) between historical control and experimental treatment 
arms using the log-rank test (we will also collect PFS data via chart review for the historical control patients). For 
our correlative studies, we will use the independent-sample t test to compare mean mutation burden between 
patient samples treated with RT+temozolomide or RT+temozolomide+TTFields. We may perform the same 
comparison within a linear regression framework if the need arises to adjust for any potential confounders for the 
effect of TTFields in our correlative studies. 
To investigate the influence of electric field and energy deposition in the tumor on outcomes, we will use the 
Wilcoxon rank sum test to compare the electric field and specific absorption ratio parameters between: 
responders and non-responders; subjects with progression-free survival ≥ and < 1 year; subjects with overall 
survival ≥ and < 2 years; and subjects with overall survival ≥ and < 1.5 years.  We will estimate Pearson correlation 
coefficients to assess the correlation of OS and PFS with electric field or specific absorption ratio parameters. 
We may stratify the patients by MGMT methylation status, extent of resection, or a combination of the two.  
10.3 Populations for Analyses 
 
The historical control arm will consist of patients with tissue-based diagnosis of Grade II or III astrocytomas, 18 
years or older, of both genders, after surgery or biopsy followed by radiation therapy with concurrent 
temozolomide. As described above, these patients will have received standard treatment and would have met first 
tier inclusion/exclusion criteria for the study. Data for these patients will be collected via chart review. 
Contemporaneous controls will also consist of patients who qualify for the trial and receive standard treatment but 
decide not to proceed with the Optune experimental treatment because of personal preference. This personal 
preference must be non-medical in nature. Based on clinical experience, most commonly this non-medical patient 
personal preference preventing Optune use will be unwillingness to shave his/her head and/or unwillingness to 
wear a visible medical device on his/her head most of the day.   
 
The interventional patient population will consist of patients with tissue-based diagnosis of Grade II or III 
astrocytomas, 18 years or older, of both genders after surgery or biopsy followed by radiation therapy with 
concurrent temozolomide and subsequent TTFields therapy plus temozolomide. 
 

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10.4 Safety Analyses 
 
Clinical and laboratory test parameters monitored for the purpose of identifying severe adverse events (SAEs) will 
be summarized at the end of the trial using standard summary statistics and confidence intervals. The cumulative 
incidence of SAEs will be monitored continuously within the framework of a stopping rule.  
Stopping Rule: We will use separate sequential Pocock-type boundaries [82] to monitor continuously for 
chemotherapy-related and device-related SAEs. If the cumulative number of patients experiencing an SAE is equal 
to or exceeds the relevant boundary indexed by the number of patients currently enrolled, a halt in enrollment will 
be triggered for further evaluation, to determine if the study should be discontinued for safety reasons.  
The maximum acceptable toxicity rate will be set at 25% for device-related SAEs, and 50% for chemotherapy-
related SAEs.  
Each type of SAE will have its own boundary, which will be specified so that the overall probability of stopping the 
trial early for each type of SAE is 0.05 when the true device-related rate is less than 25% or the true chemotherapy-
related rate is less than 50%. 
 
TABLE 11: POCOCK BOUNDARY STOPPING RULE FOR DEVICE-RELATED SAE MONITORING 
(SAE target rate=25%, N=90 patients in the treatment arm) 
Number of Patients    1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 
SAE Boundary          -  -  -  4  5  5  6  6  7  7  7  8  8  9  9  9 10 10 10 11 
 
Number of Patients   21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
SAE Boundary         11 11 12 12 13 13 13 14 14 14 15 15 15 16 16 16 17 17 17 18 
 
Number of Patients   41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 
SAE Boundary         18 18 19 19 19 20 20 20 21 21 21 22 22 22 23 23 23 23 24 24 
 
Number of Patients   61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 
SAE Boundary         24 25 25 25 26 26 26 27 27 27 28 28 28 28 29 29 29 30 30 30 
 
Number of Patients   81 82 83 84 85 86 87 88 89 90 
SAE Boundary         31 31 31 32 32 32 32 33 33 33 
(Stop trial if cumulative number of patients experiencing a device-related SAE is equal to or exceeds the SAE event 
boundary) 
 
TABLE 12. POCOCK BOUNDARY STOPPING RULE FOR CHEMOTHERAPY-RELATED SAE MONITORING 

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(SAE target rate=50%, N=90 patients in the treatment arm; will be expanded to include contemporaneous controls 
if enrolled) 
Number of Patients    1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 
SAE Boundary          -  -  -  -  -  -  7  8  9 10 10 11 12 12 13 14 14 15 15 16 
 
Number of Patients   21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
SAE Boundary         17 17 18 19 19 20 20 21 22 22 23 23 24 25 25 26 27 27 28 28 
 
Number of Patients   41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 
SAE Boundary         29 29 30 31 31 32 32 33 34 34 35 35 36 36 37 38 38 39 39 40 
 
Number of Patients   61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 
SAE Boundary         41 41 42 42 43 43 44 45 45 46 46 47 47 48 49 49 50 50 51 51 
 
Number of Patients   81 82 83 84 85 86 87 88 89 90 
SAE Boundary         52 52 53 54 54 55 55 56 56 57 
(Stop trial if cumulative number of patients experiencing a device-related SAE is equal to or exceeds the SAE event 
boundary) 
 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 
11.1 Regulatory, Ethical, and Study Oversight Considerations 
 
11.1.1 Informed Consent Process 
 
11.1.1.1 Consent/assent and Other Informational Documents Provided to participants 
  
Consent forms describing in detail the study intervention, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering study 
intervention.  The following consent materials are submitted with this protocol: 
• 
Informed Consent Form – Coordinating Center Template 
• 
Informed Consent Form (Control Arm) – Coordinating Center Template 
11.1.1.2 Consent Procedures and Documentation 
 

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No clinical investigator may involve a human being as a subject in research unless the investigator has obtained the 
legally effective informed consent from the subject, unless waived by the IRB. Informed consent is a process that is 
initiated prior to the individual’s agreeing to participate in the study and continues throughout the individual’s 
study participation. Consent forms will be Institutional Review Board (IRB)-approved and the participant will be 
asked to read and review the document. The investigator will explain the research study to the participant and 
answer any questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or surrogates 
or think about it prior to agreeing to participate. The participant will sign the informed consent document prior to 
any procedures being done specifically for the study. Participants must be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the form signed, before the participant undergoes 
any study-specific procedures.  
 
11.1.2 Study Discontinuation and Closure 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause.  
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding sponsor, the and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Site Principal Investigator (PI) will promptly 
inform study participants and the Institutional Review Board (IRB) and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy 
the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
 
11.1.3 Confidentiality and Privacy  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological samples, MRI 
images, and genetic tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the Coordinating Center.  
 
All research activities should be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the University of Florida, representatives of the 
Institutional Review Board (IRB), or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) for the 
participants in this study. The clinical study site will permit access to such records. 
 

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The study participant’s contact information will be securely stored at each clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB and Institutional policies. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the University of Florida. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by the 
University of Florida research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the University of Florida. 
 
11.1.4 Future Use of Stored Specimens and Data  
11.1.4.1 MRI Data 
MRI Data collected for this study will be analyzed and stored at Beth Israel Deaconess Medical Center. After the 
study is completed, the de-identified, archived data will be stored per local institution guidelines. Permission to 
transmit data to the Beth Israel Deaconess Medical Center will be included in the informed consent.  
11.1.4.2 Tissue samples 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified biological 
samples will be shipped to the University of Florida for analysis. These samples could be used to research the 
causes of glioma, its complications and other conditions for which individuals with glioma are at increased risk, and 
to improve treatment. The researchers will also be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant during laboratory analyses. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological 
specimens collected. However, withdrawal of consent to biosamples already collected will not be possible after 
analysis is underway. 
 
When the study is completed, access to study data will be provided through the University of Florida. Residual 
samples will be returned or destroyed per standard practice.  
 
 
11.1.5 Key Roles and Study Governance 
 
Study Chair 
Coordinating Center PI 
David D. Tran, MD, PhD 
Ashley Ghiaseddin, M.D. 
University of Florida  
University of Florida  
PO Box 100265 
Gainesville, FL 32610 
PO Box 100265 
Gainesville, FL 32610 
(352) 273-9000 
(352) 273-9000 
David.Tran@neurosurgery.ufl.edu 
Ashley.Ghiaseddin@neurosurgery.ufl.edu 
 
 
11.1.6 Safety Oversight 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of individuals 
with the appropriate expertise, including oncology expertise. Members of the DSMB should be independent from 
the study conduct and free of conflict of interest, or measures should be in place to minimize perceived conflict of 

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interest.  The DSMB will meet at least annually to assess safety and efficacy data on each arm of the study. The 
DMSB will operate under the rules of an approved charter that will be written and reviewed at the organizational 
meeting of the DSMB. At this time, each data element that the DSMB needs to assess will be clearly defined. The 
DSMB will provide its input to the Principal Investigator and IRB.  
 
11.1.7 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with Good Clinical Practice (GCP), and with 
applicable regulatory requirement(s).  
 
• 
Monitoring and auditing for this study will be performed by the UF Coordinating Center.   
• 
Details of ongoing site monitoring are documented in a Clinical Monitoring Plan (CMP).  
o 
A blend of centralized and on-site monitoring may be utilized based on site enrollment. 
o 
 Monitoring will focus on targeted validation of primary outcome measures and any key safety 
measures determined throughout the study by DSMB. Validation will take place in the REDCap 
database, which will serve as the eCRF and source document repository for the study. 
• 
Independent audits will be conducted by the UF Health Cancer Center at least annually.  
o 
Details of the auditing plan are documented in the UF Health Cancer Center manual. 
 
11.1.8 Quality Assurance and Quality Control 
 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  An individualized quality management plan should be on file to 
describe a site’s ongoing quality management activities. 
 
Quality control (QC) procedures will be implemented by the Coordinating Center beginning with the data entry 
system and data QC checks. Any missing data or data anomalies will be communicated to the site(s) for 
clarification/resolution; these data items should be addressed within 14 days of site notification.  
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted 
and data are generated and biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, Good Clinical Practice  (GCP), and applicable regulatory requirements.  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.  
 
11.1.9 Data Handling and Record Keeping  
 
11.1.9.1 Data Collection and Management Responsibilities  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording 
data for each participant enrolled in the study.  Data recorded in the electronic case report form (eCRF) derived 

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from source documents should be consistent with the data recorded on the source documents. It is permissible to 
use site worksheets or EMR records in place of visit worksheets if the same information is documented. 
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture system provided by 
the University of Florida Coordinating Center. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
Clinical data will be entered directly from the source documents.  
 
Data should be entered into REDCap, including uploading related source documents, within 14 days of data 
collection.  
 
For urgent data transmissions (Serious Adverse Events, etc.), fax and/or secure email transmission is acceptable 
with separate notification to the Coordinating Center confirming receipt of the records for review. 
 
Fax: (352) 392-8413 
Separate notification via email: Forward-study@ufl.edu  or via phone: (352) 294-8836. 
 
 
 
11.1.9.2 Study Records Retention  
 
Study documents should be retained for at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study intervention. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these documents no longer need 
to be retained. 
 
Patients will be followed for survival status until death, loss to follow-up, withdrawal, or until study data collection 
is concluded. As stated earlier, it is anticipated that data collection will be complete in 5 years. At that time, the 
data set will then be cleaned and locked, and identifiable patient data will be coded for analysis.  
 
11.1.10 
Protocol Deviations  
 
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The noncompliance may be 
either on the part of the participant, the investigator, or the study site staff. As a result of deviations, corrective 
actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with GCP:  
• 
Compliance with Protocol  
• 
Quality Assurance and Quality Control  
• 
Identification and correction of Noncompliance  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations within 14 
days of identification of the protocol deviation, or within 14 days of the scheduled protocol-required activity.  All 
deviations must be addressed in study source documents, and reported to Coordinating Center via the eCRF. 
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing IRB requirements.  
 

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11.1.11 
Publication and Data Sharing Policy 
 
The results of the clinical investigation will be made publicly available in case of positive or negative results following 
the completion of the trial.  
 
11.1.12 
Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical.  Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial.  The study leadership in conjunction with the University of 
Florida has established policies and procedures for all study group members to disclose all conflicts of interest and 
will establish a mechanism for the management of all reported dualities of interest. 
 
Dr. David Tran, the Study Chair and Sub-Investigator at the University of Florida, is a paid member of the medical 
advisory board of Novocure which provides funding for the study.   
 
11.2 Additional Considerations 
 
11.2.1 Guidance on Contraception 
For the purposes of the proposed study, “highly effective” contraceptive methods are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1 percent per year) when used consistently and 
correctly, and include the following: 
• 
Surgical sterilization at least 6 months before Study Drug administration 
• 
Implants 
• 
Levonorgestrel (LNG) and Copper T IUDs 
• 
Sexual abstinence 
Subjects who prefer methods which evidence a higher (6-9%) failure rate with typical use will be required to 
employ at least two methods of contraception concurrently.  These methods include the following: 
• 
Injectable hormone depos 
• 
Oral contraceptive pill 
• 
Hormone patch 
• 
Vaginal ring 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT 
acceptable methods of contraception. 
http://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/contraceptive_methods_508.pdf for a list of 
contraceptive methods and effectiveness. 
 
11.2.2 Enrollment Documentation Requirements  
 

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The following documentation is required for subject enrollment. All documents should be uploaded into the eCRF 
within 14 days of enrollment. 
 
1. Signed and dated Informed Consent Form 
2. Documentation of consent 
3. Pathology Report including MGMT methylation status. If not feasible or indeterminate, must be stated. 
Indeterminate methylation status will be considered unmethylated.   
4. Immunohistochemistry or next-generation sequencing Report (e.g. Foundation Medicine, TEMPUS, Caris, 
or similar CLIA-certified sequencing service) 
5. Operative Report of biopsy or resection 
6. Chemo/Radiation Radiology Report confirming total Gy delivered 
a. An isodose map of the treatment area may be required (to adjudicate cases with 
suspected/possible new lesions outside the RT treatment field) before eligibility can  be 
confirmed 
7. Oncology Screening Visit Note 
8. Screening MRI Report; RANO forms are not required at time of enrollment. 
9. Screening labs with local lab reference ranges, reviewed and signed by local investigator 
10. Relevant medical history 
11. Concurrent medications 
12. Steroid dose 
13. Signed and dated enrollment checklist 
 
11.2.2.1 Control Cohort Enrollment Documentation Requirements 
The following documentation is required for control subject enrollment. All documents should be uploaded into 
the eCRF within 45 days of enrollment. 
 
1. Signed and dated Informed Consent Form 
2. Documentation of consent checklist 
3. Pathology Report including MGMT methylation status. If not feasible or indeterminate, must be stated. 
Indeterminate methylation status will be considered unmethylated.   
4. Immunohistochemistry or next-generation sequencing Report (e.g. Foundation Medicine, TEMPUS, Caris, 
or similar CLIA-certified sequencing service) 
5. Screening MRI Report; RANO forms are not required at time of enrollment. 
6. Signed and dated enrollment checklist 
 
Additionally, the following data shall be entered into the eCRF at enrollment and source documentation 
included: 
a. KPS 
b. Resection Summary 
c. 
Chemo/Radiation Summary 
 
 

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11.3 Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
Case report form 
CT 
Computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DICOM 
Digital Imaging and Communications in Medicine 
DISC 
Data Integrity and Safety Committee 
DOB 
Date of birth 
DSMB 
Data and Safety Monitoring Board 
DSS 
Device Support Specialist 
DTIC 
Dacarbazine 
eCRF 
Electronic case report form 
EGFR 
Estimated Glomerular Filtration Rate 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 
Cancer 
EORTC QLQ-
BN20 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 
Brain 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed and paraffin embedded 
FISH 
Fluorescence In Situ Hybridization 
FLAIR 
Fluid Attenuated Inversion Recovery 
FSH 
Follicle-stimulating hormone 
GBM 
Glioblastoma multiforme 
HRT 
Hormone replacement therapy 
ICIs 
Immune checkpoint inhibitors 
IDH 
Isocitrate dehydrogenase 
IHC 
Immunohistochemical 
IRB 
Institutional Review Board 
kHz 
kilohertz 
KPS 
Karnofsky performance status 
LAR 
Legally Authorized Representative 
LTFU 
Lost to Follow-up 
MGMT 
O6-alkylguanine DNA alkyltransferase 
MHz 
Megahertz 
MMSE 
Mini-Mental State Examination 
MP RAGE 
Magnetisation-prepared rapid gradient-echo 
MRI 
Magnetic resonance imaging 
NHEJ 
Non-Homologous End Joining 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PCV 
Procarbazine/CCNU/vincristine 

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PFS 
Progression-free survival 
PT 
Prothrombin time 
PTT 
Partial thromboplastic time 
QoL 
Quality of Life 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RR 
Radiological Response 
RT 
Radiation Therapy 
SAE 
Serious adverse event 
WOCBP 
Women Of Child-Bearing Potential 
 
 
 

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11.3.1 Summary of Figures 
FIGURE 1. THIS IS A PHASE 2, MULTI-INSTITUTIONAL, OPEN-LABEL, HISTORICALLY CONTROLLED, STUDY OF 200 PATIENTS WITH NEWLY-
DIAGNOSED HIGH-RISK GRADE II AND III ASTROCYTOMA. THE INTERVENTIONAL ARM WILL COMBINE TTFIELDS WITH ADJUVANT TMZ 
AFTER THE COMPLETION OF DEFINITIVE CHEMORADIOTHERAPY. STUDY TREATMENT MAY CONTINUE PAST FIRST TUMOR RECURRENCE. 
THE PRIMARY ENDPOINT WILL BE OVERALL SURVIVAL. TMZ = TEMOZOLOMIDE; RT = RADIATION THERAPY. ................................ 3 
FIGURE 2. ROLE OF IDH1 R132H MUTATION IN GRADE II ASTROCYTOMA. (A-B) PFS COMPARISON OF RT ALONE (RT) OR RT + PCV IN 
GRADE II ASTROCYTOMA (A) AND IN ALL GRADE II GLIOMAS (BOTH OLIODENDROGLIOMAS AND ASTROCYTOMAS) (B) WITH IDH1 
R132H MUTATION. (C-D) OS COMPARISON OF RT ALONE (RT) OR RT + PCV IN GRADE II ASTROCYTOMA (C) AND IN ALL GRADE II 
GLIOMAS (BOTH OLIODENDROGLIOMAS AND ASTROCYTOMAS (D) WITH IDH1 R132H MUTATION. (ADAPTED FROM BUCKNER JC ET 
AL. N ENGL J MED 2016;374:1344-1355). ................................................................................................................. 8 
FIGURE 3. ROLE OF 1P, 19Q CODELETIONS IN GRADE III GLIOMA. OS COMPARISON OF RT ALONE (RT) OR RT + PCV IN GRADE III 
GLIOMAS WITH 1P, 19Q CODELETIONS (A) OR WITHOUT 1P, 19Q CODELETIONS (B). (ADAPTED FROM GREGORY CAIRNCROSS ET AL. 
JCO 2013; 31:337-343). ......................................................................................................................................... 9 
FIGURE 4. ROLE OF 1P, 19Q CODELETIONS AND IDH1 R132H MUTATIONS IN GRADE III GLIOMA. KAPLAN-MEIER ESTIMATES OF OS FOR 
PATIENTS WITH A GRADE III GLIOMA (ORANGE) OR WITHOUT 1P, 19Q CODELETIONS AND WITH (BLUE) OR WITHOUT 1DH1 R132H 
MUTATION AFTER PCV + RT (A) OR RT ALONE (B). (ADAPTED FROM GREGORY CAIRNCROSS ET AL. JCO 2013;31:337-343). .... 9 
FIGURE 5. TERT PROMOTER MUTATION ONLY IS ASSOCIATED WITH THE WORST PROGNOSIS IN GRADE II AND III GLIOMA. THE PRESENCE 
OF IDH MUTATIONS AND/OR 1P/19Q CODELETIONS WERE ABLE TO RESCUE THE POOR PROGNOSIS ASSOCIATED WITH TERT 
PROMOTER MUTATION. TRIPLE-POSITIVE: IDH MUTATIONS, 1P/19Q CODELETIONS, AND TERT PROMOTER MUTATION; TRIPLE-
NEGATIVE: NO IDH MUTATIONS, 1P/19Q INTACT, AND NO TERT PROMOTER MUTATIONS. (ADAPTED FROM ECKEL-PASSOW JE ET 
AL. N ENGL J MED 2015;372:2499-2508). ............................................................................................................... 10 
FIGURE 6 PREVALENCE OF TERT PROMOTER MUTATION IN GRADE II AND III GLIOMA. (ADAPTED FROM ECKEL-PASSOW JE ET AL. N ENGL 
J MED 2015;372: 2499-2508). .............................................................................................................................. 20 
FIGURE 7. MRI IMAGE SAMPLES DEMONSTRATING FIELD OF VIEW OF THE IMAGES MUST INCLUDE THE SURFACE OF THE SCALP. INCORRECT 
IMAGE ON THE LEFT DOES NOT INCLUDE FULL SCALP SURFACE WHERE INDICATED BY ARROWS. THE CORRECT IMAGE AT THE RIGHT 
DOES INCLUDE THE SURFACE OF THE SCALP AROUND THE ENTIRE HEAD. ............................................................................... 39 
 
 
 

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11.4 Protocol Amendment History 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a description of 
the change and rationale. A Summary of Changes table for the current amendment is located in the Protocol Title 
Page.  
 
Version 
Date 
Section 
Description of Change  
Brief Rationale 
1.1 
5 April 
2019
 
 
Title Page 
Addition of NCT and IDE 
numbers 
Updates flowing from IDE 
approval 
1.1 
5 April 
2019
 
 
1.1 
Clarification/Correction of 
enrollment vs. participant 
timelines 
Response to FDA initial review 
question 
1.1 
5 April 
2019
 
 
2.1.1.1 
Addition of generalizability of 
results section 
Clarification of potential benefits 
to the Medicare population from 
study results 
1.1 
5 April 
2019
 
 
10.1.11 
Revision of Publication Policy 
Updated to reflect the current 
study contract 
1.1 
5 April 
2019
 
 
1.3, 5.5.1, 6.3.1, 8.1.4 
Consistent description of 
acceptable tissue sample 
types 
FFPE, pathology slides, or frozen  
samples are acceptable for onsite 
tissue verification; only FFPE and 
pathology slides may be shipped 
2.1 
16 Dec 
2019 
1.1, 9, 10, 10.3, 11.1.1 
Addition of Control Cohort 
Methodological improvement in 
the historical control for this study 
2.1 
16 Dec 
2019 
4.1.3, 5.1, 5.5 
Removal of Inclusion criteria 
regarding 1p/19q and/or 
ATRX 
Update of WHO Classification of 
Grade II and III criteria for 
gliomas 
2.1 
16 Dec 
2019 
5.1 
Addition of Inclusion criteria 
Clarify patients appropriate for 
Optune 
2.1 
16 Dec 
2019 
1.1, 10.3 
Removal of Stupp Protocol 
specification 
Avoid any specific Gy 
requirement assumption 
analogous with Stupp 
2.1 
16 Dec 
2019 
6.1.1.3 
Addition of RANO 
clarification regarding non-
enhancing disease 
Clarification of criteria for non-
enhancing disease via FLAIR 
2.1 
16 Dec 
2019 
10.2.1 
Addition of stratification by 
extent of resection 
Implementation of FDA 
suggestion 
2.1 
16 Dec 
2019 
1.3, 5.1, 5.4, 6.1, 6.2, 
6.3, 8.1.2 
Minor Typographical Updates 
Clarification 
2.1 
16 Dec 
2019 
11.1.6, 11.1.7 
Update DSMB audit 
frequency 
Updated to reflect current study 
approved risk level (moderate) 
and related annual DSMB audit 
frequency 
2.1 
16 Dec 
2019 
Sections not 
applicable to this 
protocol (and 
therefore intentionally 
left blank) 
Removed to avoid confusion 
Implementation of SRMC 
suggestion for readability. 
 
 
 

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Hartmann, C., et al., Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and 
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2. 
Parsons, D.W., et al., An integrated genomic analysis of human glioblastoma multiforme. Science, 2008. 
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3. 
Yan, H., et al., IDH1 and IDH2 mutations in gliomas. N Engl J Med, 2009. 360(8): p. 765-73. 
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Louis, D.N., et al., The 2016 World Health Organization Classification of Tumors of the Central Nervous 
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8. 
Leeper, H.E., et al., IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas. Oncotarget, 
2015. 6(30): p. 30295-30305. 
9. 
Kannan, K., et al., Whole exome sequencing identifies ATRX mutation as a key molecular determinant in 
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Koschmann, C., et al., ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA 
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Eckel-Passow, J.E., et al., Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. 
New England Journal of Medicine, 2015. 372(26): p. 2499-2508. 
12. 
Killela, P.J., et al., TERT promoter mutations occur frequently in gliomas and a subset of tumors derived 
from cells with low rates of self-renewal. Proceedings of the National Academy of Sciences, 2013. 110(15): 
p. 6021-6026. 
13. 
Karim, A.B., et al., Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the 
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14. 
Yeh, S.A., et al., Treatment outcomes and prognostic factors in patients with supratentorial low-grade 
gliomas. The British journal of radiology, 2005. 78(927): p. 230-235. 
15. 
Buckner, J.C., et al., Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. New 
England Journal of Medicine, 2016. 374(14): p. 1344-1355. 
16. 
Cairncross, G., et al., Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term 
Results of RTOG 9402. Journal of Clinical Oncology, 2013. 31(3): p. 337-343. 
17. 
van den Bent, M.J., et al., Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly 
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