Proposed Pilot Study of Combined Optune+ Bevacizumab, and Hypofractionated Stereotactic Irradiation for Bevacizumab-Naive Recurrent Glioblastoma
Phase: NA
Conditions: RECURRENT GLIOBLASTOMA, Brain Tumor
Sponsor: University of Maryland, Baltimore

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GCC 1344 / HP-00056719 
 
PILOT STUDY OF COMBINED OPTUNE (NOVOTTF-100A), BEVACIZUMAB, AND 
HYPOFRACTIONATED STEREOTACTIC IRRADIATION FOR BEVACIZUMAB-
NAIIVE, RECURRENT GLIOBLASTOMA 
 
Version: Mar2018 
 
 
 
Principle Investigators:  
 
Young Kwok, MD1 (University of Maryland) 
 
 
 
 
 
 
 
 
 
 
 
Mark Mishra, MD (University of Maryland) 
 
 
Co-Investigators:  
 
 
Minesh Mehta, MD (Miami Cancer Institute) 
William Regine, MD1 
  
Edward Sausville, MD, PhD2 
Howard Eisenberg, MD3 
Graeme Woodworth, MD3 
Jack Hong, MD1 
Alexander Engelman, MD1 
 
 
Statistician:   
 
 
Alex Hanlon, PhD 
 
 
Contact: 
 
 
 
Young Kwok, MD 
University of Maryland Medical Center 
Department of Radiation Oncology - GGJ20 
22 South Greene Street 
Baltimore, MD 21201 
410-328-6080 
 
 
 
 
 
 
 
 
 
 
1.  Department of Radiation Oncology 
2.  Department of Medicine Division of Hematology and Oncology 
3.  Department of Neurosurgery 

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TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
 
 
 
Schema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    3 
 
 
 
Eligibility Checklist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    4 
 
1.0 
 
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   7 
 
2.0 
 
Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  12 
 
3.0 
 
Eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   12 
 
4.0 
 
Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    15 
 
5.0 
 
Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    16 
 
6.0 
 
Bevacizumab Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   19 
 
7.0 
 
Optune Therapy . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .  20 
 
8.0 
 
Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  21 
 
9.0 
 
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   22 
 
10.0 
 
Patient Protocol Discontinuation . . . . . . . . . . . . . . . . . . . . . . . . . . . .    24 
 
11.0 
Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   24 
 
12.0 
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   25 
 
Appendix I 
M. D. Anderson Symptom Inventory – Brain Tumor (MDASI-BT) . . . .  26 
 
Appendix II 
Tables and Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    28 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
*  Pre-Cycle 1 treatment is optional and can consist of up to 2 cycles of bevacizumab 
administered at University of Maryland Medical System or an outside institution. 
 
**  Cycle 1 of treatment will consist of bevacizumab and Optune and will be 28 days.  
Bevacizumab will be given on days 1 and 15 (+/- 3 days).  Optune will be worn 
continuously (or as tolerated by the patient) and will begin before Cycle 1, day 1 infusion 
of bevacizumab.  Upon completion of Cycle 1, patients will have a brain MRI with 
contrast to evaluate for disease progression; if there is no disease progression the 
patient will proceed to Cycle 2. 
 
***  Cycle 2 of bevacizumab and Optune will include hypofractionated radiation therapy 
(RT). The duration of this cycle will also be 28 days.  Cycle 2 will begin on day 29 (+/- 3 
days) of treatment.  Bevacizumab will be given on days 1 and 15 (+/- 3 days).  Optune 
will be worn continuously (or as tolerated by the patient).  RT will be initiated within the 
CYCLE 2*** 
Bevacizumab, Optune, and 
Hypofractionated Radiation 
Therapy (RT) 
 
Bevacizumab - Days 1 and 15 
 
Optune - Continuous starting 
day 1 
 
RT - For 2-3 weeks 
CYCLE 1** 
Bevacizumab and Optune 
 
Bevacizumab - Days 1 and 15 
 
Optune - Continuous starting day 1 
CYCLE 3 and ONWARDS**** 
Bevacizumab and Optune 
 
Bevacizumab - Days 1 and 15 
 
Optune - Continuous starting day 1 
 
If no disease 
progression on 
brain MRI with 
contrast 
Pre-CYCLE 1* (optional) 
Up to 2 cycles of 
Bevacizumab with or without 
Optune 
 
Received at UMMS or outside 
hospital 

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first 10 days of Cycle 2 and will continue for 2-3 weeks based on which regimen the 
treating radiation oncologist selects; either 30 Gy in five fractions of 6 Gy each (given at 
least 48 hours apart) or 35 Gy in ten consecutive fractions of 3.5 Gy each. 
 
****  Cycle 3 treatment and any subsequent cycles (28 days +/- 3 days) will mirror Cycle 
1 treatment with bevacizumab and Optune.  Patients will be evaluated by a physician 
prior to starting each new cycle and will continue treatment until disease progression. 

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GCC 1344:  PILOT STUDY OF COMBINED OPTUNE, BEVACIZUMAB, AND HYPOFRACTIONATED 
STEREOTACTIC IRRADIATION FOR BEVACIZUMAB-NAIIVE, RECURRENT GLIOBLASTOMA 
 
ELIGIBILITY CHECKLIST 
 
(Y)  
1.  Does the patient have histologically proven diagnosis of original glioblastoma or other variant 
of WHO grade IV malignant glioma? 
 
(Y) 
2.  Does the patient have disease progression on contrast-enhanced brain MRI within 30 days 
prior to registration? 
 
(N)  
3.  Does the patient have a recurrent or persistent enhancing tumor greater than 8 cm in 
maximum diameter? 
 
(N) 
4.  Does the patient have any significant CNS hemorrhage (greater than 1 cm in diameter) seen 
on the brain MRI with contrast? 
 
(Y/N) 
5.  Has the patient had prior therapy with bevacizumab or an inhibitor of VEGF or VEGFR? 
 
 
 
(Y/NA)  Has the patient received two or less cycles of bevacizumab? 
 
 
 
(N/NA)  Has the patient received a different inhibitor of VEGF or VEGFR? 
 
(Y)  
6.  Was a history and physical with neurological examination obtained within 30 days prior to 
registration? 
 
(Y)  
7.  Is the Karnofsky performance status greater than or equal to 70% within 30 days prior to 
registration? 
 
(Y)  
8.  Is the patient’s age greater than or equal to 22? 
 
(Y)  
9.  Was a CBC with differential, CMP, and Urinalysis obtained within 14 days prior to 
registration showing adequate bone marrow, liver, and renal function as defined in the eligibility 
criteria? 
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
 
Platelets ≥ 100 x 109/L. 
 
Hemoglobin (Hgb) ≥ 9.0 g/dL (Note the use of transfusion or other intervention to 
achieve Hgb ≥ 9.0 is acceptable). 
 
Serum total bilirubin ≤ 1.5 x ULN. 
 
ALT and AST ≤ 3.0 x ULN. 
 
Adequate Renal Function: BUN and Cr < 2 x ULN. 
 
 (Y) 
10.  Is there an interval of 12 weeks or greater between completion of prior radiotherapy and 
registration? 
 
(Y)  
11.  Does the patient have a prior history of CNS radiation as defined in the eligibility criteria? 
 
(Y/N) 
12.  Did the patient have a recent resection, major surgery (e.g. intra-thoracic, intra-abdominal 
or intra-pelvic), open biopsy or significant traumatic injury in the last 4 weeks prior to 
registration? 
 
(Y/NA)  Has the patient recovered from the effects of surgery? 
 
(Y/N) 
13.  Did the patient have a minor procedure, percutaneous biopsy or placement of vascular 
access device in the last 1 week prior to registration? 
 

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(Y/NA)  Has the patient recovered from the effects of the procedure? 
 
 
GCC 1344:  PILOT STUDY OF COMBINED OPTUNE, BEVACIZUMAB, AND HYPOFRACTIONATED 
STEREOTACTIC IRRADIATION FOR BEVACIZUMAB-NAIIVE, RECURRENT GLIOBLASTOMA 
 
ELIGIBILITY CHECKLIST 
 
(Y/N) 
14.  Did the patient receive prior investigational agent(s) and/or prior cytotoxic drug therapy? 
 
(Y/NA)  Was there a minimum time of 3 weeks since last non-cytotoxic therapy? 
 
(Y/NA)  Was there a minimum time of 3 weeks since the completion of a non-nitrosourea-
containing chemotherapy regimen? 
 
(Y/NA)  Was there a minimum time of 6 weeks since the completion of a nitrosourea-containing 
chemotherapy regimen? 
 
(Y/NA) 
15.  Has patient recovered from the toxic effects of any prior surgery/procedure and/or 
investigational agent/drug/cytotoxic therapy so that in the opinion of the treating physici an the 
patient could tolerate study treatment? 
 
(Y) 
16.  Did the patient provide informed consent prior to registration? 
 
(Y)  
17.  Is the patient willing to practice effective contraception while on study treatment and for 6 
months after? 
 
Questions 18-19 pertain only to female patients 
 
(N) 
18.  Is the patient pregnant or breast-feeding? 
 
(Y/NA)  19.  Was a negative pregnancy test obtained within 14 days prior to registration for women of 
child-bearing potential? 
 
(Y/N) 
20.  Has the patient had prior invasive malignancy (except non-melanomatous skin cancer; 
does not apply to glioblastoma or recurrent glioblastoma)? 
 
(Y/NA)  Has the patient been disease free for a minimum of 1 year? 
 
(Y) 
21.  Is the patient maintained on a stable or decreasing corticosteroid regimen from the time of 
their baseline scan until registration? 
 
(Y/N) 
22.  Is the patient on full dose anticoagulants? 
 
(Y/NA)  Is there an in-range INR (usually between 2 and 3) on a stable dose of oral 
anticoagulant or on a stable dose of low molecular weight heparin? 
 
(N/NA)  Does the patient have active bleeding or a pathological condition that carries a high risk 
of bleeding (e.g. tumor involving major vessels or known varices)? 
 
(N) 
23.  Does the patient have severe active co-morbidity as defined in the eligibility criteria (e.g. 
cardiac impairment, cirrhosis, viral issues, HIV, GI issues, infection, uncontrolled diabetes, 
etc.)? 
 
 
 

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GCC 1344:  PILOT STUDY OF COMBINED OPTUNE, BEVACIZUMAB, AND HYPOFRACTIONATED 
STEREOTACTIC IRRADIATION FOR BEVACIZUMAB-NAIIVE, RECURRENT GLIOBLASTOMA 
 
ELIGIBILITY CHECKLIST 
 
(N) 
24.  Does the patient have an active implanted medical or electronic device, or bullet 
fragments?  (Examples of implanted devices include: deep brain stimulators, spinal cord 
stimulators, vagus nerve stimulators, pacemakers, defibrillators, and programmable shunts.) 
 
(N) 
25.  Is there evidence of multifocal, infratentorial or leptomeningeal spread of disease? 
 
(N) 
26.  Does the patient have a history of allergy or sensitivity to conductive hydrogels like the gel 
used on electrocardiogram (ECG) stickers or TENS (transcutaneous electrical nerve 
stimulation) electrodes? 
 
(N) 
27.  Was the patient treated on any other therapeutic clinical protocols within 3 weeks of 
registration? 
 
(Y/N) 
28.  Does the patient have data regarding MGMT methylation status? 
 
What was the result of the MGMT analysis? 
 
(N) 
29.  Has the patient had gastrointestinal bleeding or any other hemorrhage/bleeding event 
(CTCAE v.4) grade 3 or greater within 30 days prior to registration? 
 
 
This Eligibility Checklist must be completed in its entirety prior to registration.  The completed, signed, and 
dated checklist used for study registration must be retained in the patient’s study file. 
 
 
 
For use during screening of subjects: 
 
______________________________________                            ____________________ 
Name of Subject 
 
 
 
Reviewed and subject acceptable for study:          ___  YES          ___  NO 
 
______________________________________ 
                 ____________________ 
Signature of Principal Investigator 
 
 
                               Date 
 
 

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1.0  INTRODUCTION 
This protocol is designed to generate and provide preliminary data to determine the 
safety and activity of combination therapy using Optune (tumor treating fields (TTFields; 
NovoTTF-100A; Novocure, Haifa, Israel)), a novel FDA-approved therapy utilizing 
alternating electric fields to inhibit tumor cell growth, along with bevacizumab (Avastin; 
Genentech, San Francisco, CA), a humanized monoclonal antibody that inhibits 
vascular 
endothelial 
growth 
factor 
(VEGF), 
and 
hypofractionated 
stereotactic 
radiotherapy, a highly-focal abbreviated course of brain irradiation, in the treatment of 
patients with bevacizumab-naive recurrent glioblastoma (GBM).  Each of these 
individual therapies, and also several combinations in doublets, has already 
demonstrated safety and efficacy but prospective clinical data for the concurrent 
combination of all three therapies are lacking. 
 
1.1  Background Information 
Glioblastoma remains the most prevalent primary malignant brain tumor in adults. 
Despite optimal treatment, median survival is only < 15 months with the majority of 
patients developing recurrence at a median of < 8 months post treatment (Stupp 2005).  
At the time of disease recurrence, treatment options for glioblastoma patients are limited 
and prognosis is poor.  Various treatment modalities have been evaluated in the 
recurrent setting including resection, chemotherapy, targeted agents, irradiation, and 
combinations of modalities. 
 
Bevacizumab for the treatment of recurrent glioma 
After initial progression, phase II trials of chemotherapy have resulted in 6-month 
progression-free survivals of 9-19% and median survivals of 6-8 months (Wong 1999, 
Chang 2003).  Bevacizumab (BVZ), a humanized monoclonal antibody targeting VEGF, 
was approved by the FDA as a single agent for recurrent glioblastoma. Vascular 
proliferation is a common feature in glioblastoma and anti-VEGF therapy can inhibit new 
vessel growth, lead to vascular regression and vascular normalization, as well as 
directly affect tumor cell function (Ellis 2008).  Antiangiogenic therapies may decrease 
vasogenic edema as well as corticosteroid use and has been shown to be effective in 
the treatment of radiation necrosis (Levin 2011).  Several phase II trials using 
Bevacizumab have shown promising results with 6-month progression-free survival 
rates ranging from 29-42%1.  In spite of this improvement in PFS, clinical trials of 
bevacizumab for recurrent glioblastoma to date have not shown a substantial 
improvement in overall survival (OS). 
 
Hypofractionated Stereotactic Radiation Therapy for Recurrent Glioma 
Salvage re-irradiation is another well-studied treatment modality with historical results 
conferring 6-month progression-free survival ranging from 28-39% and a median 1-year 
overall survival of 26%, ranging from 18-46% (Combs 2005, Nieder 2008).  
Hypofractionated stereotactic radiotherapy (HFSRT) offers an acceptable safety profile 
and abbreviated schedule while exploiting several radiobiological advantages of an 
increase in dose-per-fraction and accelerated time course of radiotherapy.  One recent 
retrospective analysis of one hundred forty seven patients with recurrent HGG treated 
with HFSRT (median dose 35 Gy in 3.5 Gy fractions) reported median survival of 11 

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months and found 1/3 of patients able to reduce corticosteroid dose (Fogh 2010).  
Patients with shorter-interval recurrence and those receiving > 35 Gy re-irradiation may 
stand to benefit more from treatment.  While toxicities have been associated with an 
increased rate of radiation necrosis and subsequent re-operation, previous studies of 
HFSRT have resulted in comparable and possibly increased survival rates2. 
 
Combination Bevacizumab and HFSRT for Recurrent Glioma 
Putative benefits to the combination of bevacizumab and hypofractionated stereotactic 
radiotherapy include the ability of anti-angiogenic agents to sensitize tumor endothelium 
to RT, targeting of radio-resistant cancer stem cells by disrupting vascular niches, and 
vascular stabilization leading to reduced toxicity by reducing risk of radiation necrosis 
(Gutin 2009).  This combination has recently been evaluated in a phase II study as 
treatment for recurrent malignant gliomas.  Gutin et al. reported on twenty-five patients 
with recurrent grade III-IV glioma who received bevacizumab concurrently with HFSRT 
and found a 6-month progression-free survival of 65% and median overall survival of 
12.5 months; results which compare very favorably to historic controls.  Additionally, an 
overall response rate of 50% for the GBM cohort was seen.  This treatment was well 
tolerated with no incidence of radiation necrosis and no additional need for 
corticosteroids following radiation. 
 
Single institution retrospective data also suggests a benefit to the addition of 
bevacizumab to highly focal radiation (Cuneo 2012).  In patients with Grade IV glioma, 
SRS with adjuvant bevacizumab resulted in 1-year OS of 50% vs. 22% for patients not 
receiving adjuvant bevacizumab (p = 0.005). Median progression-free survival (PFS) for 
patients who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for 
patients who did not (p = 0.014).  Treatment-related Grade 3/4 toxicity for patients 
receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58). 
 
Tumor Treatment Fields 
Optune (formerly NovoTTF) represents a novel, promising therapeutic option for 
patients with recurrent glioblastoma as well as other malignancies.  This FDA-approved 
therapy utilizes low-intensity intermediate-frequency alternating electric fields delivered 
via non-invasive transducer arrays to inhibit tumor cell growth.  These fields physically 
interfere with microtubule subunit polymerization in the mitotic spindle and alter 
intracellular macromolecule movement during telophase leading to disturbance in 
chromosome segregation and cell death (Lee 2011).  The morphological abnormalities 
seen after exposure to TTFields are analogous to those seen in cells treated with 
agents that interfere directly or indirectly with microtubule polymerization, e.g. paclitaxel, 
with well-studied safety and efficacy data when used in concert with other 
chemotherapies (Rowinsky 1995).  Indeed, favorable combination and dose reduction 
indices from combination of paclitaxel and NovoTTF suggest similarity and synergism in 
a pre-clinical study (Kirson 2009). 
 
Tumor Treatment Fields for Recurrent Glioma 
In upfront setting, NovoTTF-100A has been preliminarily evaluated with concurrent 
maintenance temozolomide for patients with newly-diagnosed glioblastoma following 

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resection and chemoradiation.  In a study of 10 patients with median follow-up of 40 
months, concurrent electric field therapy and maintenance temozolomide resulted in 
actuarial median PFS of 155 weeks and median OS of > 39 months without serious 
adverse event and with no change from the expected toxicity of temozolomide alone 
(Kirson 2009).  These results, in albeit a small and well-selected population, are 
profoundly heartening when compared to historic controls of 31 week PFS and 14.7 
month OS with temozolomide alone. 
 
In a phase III trial of patients with recurrent grade IV glioma, NovoTTF-100A as 
monotherapy demonstrated comparable efficacy to chemotherapy with a more favorable 
safety profile and quality of life benefit (Stupp 2012)3.  In a cohort of heavily pretreated 
patients, NovoTTF use afforded a median overall survival of 6.6 months, 1-year survival 
rate of 20%, and a PFS-6 of 21.4%; an effect equal to that of physician’s-choice 
chemotherapy without many of the attendant, often severe, treatment-limiting side 
effects of chemotherapy.  NovoTTF-100A subjects experienced fewer adverse events in 
general, significantly fewer treatment related adverse events, and significantly lower 
gastrointestinal, 
hematological 
and 
infectious 
adverse 
events 
compared 
to 
chemotherapy controls.  The only device-related adverse events seen were a mild to 
moderate skin irritation beneath the device transducer arrays, which was easily treated 
with topical ointments.  Finally, quality of life measures (EORTC - QLQ C30 symptom 
and general scales) were better in NovoTTF-100A subjects as a group when compared 
to subjects receiving effective best standard of care chemotherapy. 
 
Based on these data, and the continued overall poor outcomes for this population, 
combinations of the various therapies demonstrating activity are logically being pursued 
in various formats.  For example, for newly diagnosed GBM the combination of 
temozolomide and NovoTTF as adjuvant therapy following initial post-resection 
radiotherapy with concomitant temozolomide is the thrust of a major international 
ongoing phase III trial.  Within the Radiation Therapy Oncology Group (RTOG), two 
randomized phase II trials are either ongoing or planned to specifically test the survival 
advantage 
from 
combinations 
of 
these 
therapies 
(hypofractionated RT plus 
bevacizumab for recurrent, bev-naïve GBM; and NovoTTF plus bevacizumab for 
recurrent bev-refractory GBM).  However, the three-modality combination, although 
used off-label, has not been evaluated in a prospective trial. 
 
1.2  Rationale for Multimodality Therapy: NovoTTF-100A, Bevacizumab, and 
HFSRT 
The population of patients with recurrent glioblastoma represents a diverse group, with 
subsets of both salvage-naïve patients and patients who have exhausted numerous 
therapeutic options.  The combination of hypofractionated RT and bevacizumab in 
bevacizumab-naïve recurrent glioblastoma is currently the subject of a randomized 
prospective phase II trial (RTOG 1205).  Phase III data of the clinical impact of tumor 
treatment fields has to date been evaluated in patients toward the end of their clinical 
course, often having progressed on multiple regimens.  In the pivotal multinational trial 
published by Stupp, 91% of patients had progressed 2 or more times with 43% on their 

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3rd or greater recurrence.  Patients who retain salvage-naiveté may harbor the potential 
for a more substantial benefit from this promising new modality. 
 
Combination of NovoTTF-100A and Bevacizumab 
NovoTTF has already demonstrated safety and efficacy in combination with multiple 
chemotherapeutic regimens.  Dose-reduction was possible in vitro with addition of 
NovoTTF to paclitaxel, doxorubicin, and cyclophosphamide (Kirson 2009).  The 
potential combination of TTFields with bevacizumab is enhanced by the fact that the 
mechanism of action of NovoTTF is not limited by the normalization of the blood-brain 
barrier caused by use of concomitant bevacizumab, a factor that limits the potential 
combinatorial effect of bevacizumab and traditional systemic chemotherapies.  Studies 
of bevacizumab in concert with paclitaxel (like NovoTTF an inhibitor of normal 
microtubular function with similar mitotic effects) have shown improvements in PFS in 
randomized controlled trials of multiple disease sites including non-small-cell lung 
cancer, ovarian cancer, and metastatic breast cancer (Perren 2011). 
 
Given the clinical interest and widespread use of bevacizumab in the setting of recurrent 
GBM, an exploratory survival analysis of the phase III NovoTTF trial was performed in a 
subset of patients who had progressed on prior bevacizumab (20% of patients 
evaluated).  In patients with bevacizumab-refractory disease, median OS was 
significantly longer when treated with NovoTTF-100A compared to chemotherapy (6.3 
vs. 3.3 months; hazard ratio (HR) 0.39; p = 0.01).  Building on these exploratory results, 
the RTOG has a developing phase II randomized trial (RTOG 1301) to test the 
hypothesis that combination of tumor treating fields with bevacizumab will improve 
survival compared with treatment using bevacizumab and pre-specified investigator 
choice chemotherapy for patients with bevacizumab-refractory recurrent GBM.  There is 
without doubt great promise to the combination of systemic therapy and TTF; however 
the full potential for benefit from concurrent therapy alongside TTF will require testing 
the right combination of modalities in the right populations.  It is an unfortunate reality of 
this disease process that patients who have progressed to the point at which they would 
be eligible for this trial likely represent those who harbor treatment-resistant clonogens 
or in whom multiple treatments have selected a more aggressive phenotype.  Patients 
with recurrence that maintain the therapeutic option of bevacizumab represent a key 
first step in transitioning NovoTTF therapy earlier in this disease course and offer the 
possibility of enhanced therapeutic effect for those in such great need of improved 
outcomes. 
 
Combination of NovoTTF-100A and Radiation Therapy 
NovoTTF may sensitize cells to the effects of irradiation.  The mitotic arrest seen with 
electric field therapy and the mechanism of interrupted microtubule assembly create two 
avenues for radiosensitization.  Arrest in M phase increases the proportion of cells in G2 
and M phases and thus in radiosensitive portions of the cell cycle, enhancing the 
therapeutic ratio.  This effect may be more dramatically realized at the increased doses 
per fraction seen with HFSRT.  Additionally, interruption of tubule polymerization (in the 
form of taxol-based chemotherapy) is a well-established radiosensitizing mechanism.  
Phase III randomized evidence from a myriad of disease sites have demonstrated 

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improvement with the addition of taxol-based regimens to radiation therapy.  
Hypofractionated stereotactic radiation has been evaluated with concurrent paclitaxel in 
patients with recurrent glioblastoma (Lederman 2000).  The regimen was well tolerated 
and suggested benefit for patients with small tumors (< 30 cm3). 
 
NovoTTF may potentiate the effects of irradiation.  Radiation therapy is known to exert a 
large portion of its antitumor effects via double-strand DNA damage.  DNA acts as an 
inducible dipole in the presence of electric fields.  Double-strand breakage fragments 
produced by ionizing radiation, in the presence of TTFields, experience both rotational 
and migrational forces.  These mechanical forces can interfere with DNA repair 
mechanisms such as homologous and non-homologous end joining pathways resulting 
in decreased potentially lethal damage repair and enhanced biologic effect.  Preclinical 
data support the concept of delayed repair4.  COMET assays were performed on MCF-7 
breast cancer cells after 8 Gy single dose irradiation, 1, 2, or 24-hour TTF exposure, 
and the combination.  Irradiation alone was associated with DNA fragmentation which 
returned to near control-levels within two hours.  As compared to control, TTF alone, 
and RT alone, cells exposed to TTFields within 5 minutes following irradiation 
demonstrated persistence of fragmentation for the duration of TTF use.  The 
persistence of radiation-induced DNA fragmentation suggests delayed or inhibited 
repair mechanisms raising the potential for enhanced biologic effect. 
 
Radiation therapy may also enhance the effects of NovoTTF use.  Chromosomal 
abnormalities caused by irradiation may enhance the cytotoxic mechanisms of TTF, 
again by altered dipole moment and differential in centripetal migration of intracellular 
components during cytokinesis.  The potential for therapeutic benefit with concurrent 
TTFields and irradiation is promising, especially when considered with NovoTTF’s track 
record of safety without significant additive toxicity. 
 
Novel multimodality therapy: NovoTTF-100A, Bevacizumab, and HFSRT 
The combination of NovoTTF with the active regimen of bevacizumab and 
hypofractionated stereotactic radiotherapy bases the addition of an effective new 
treatment in the setting of a safe regimen with favorable survival reports.  To date, no 
clinical data are available on the interaction of concomitant tumor treating fields with 
radiation therapy either with or without bevacizumab.  TTF and radiation both have the 
potential to enhance the other’s therapeutic ratio though synergistic mechanisms of 
action.  The addition of bevacizumab to this regimen has both therapeutic and 
improved-toxicity implications.  A trial combining NovoTTF-100A with the proven 
regimen of HFSRT and bevacizumab for recurrent glioblastoma affords an avenue to 
demonstrate safety in a population who may more readily derive a benefit from novel 
multimodality therapy and explore the great potential for synergistic effect.  The 
endpoint of efficacy would clearly need to be more definitively addressed in a future 
categorical trial, which would be the logical positive outcome of this pilot study. 
 

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2.0  OBJECTIVES 
The study will enroll 32 patients, expecting to accrue 27 evaluable patients.  The 
assumption is that at least 16 patients (60%) will receive the proposed tri-modality 
treatment without undue treatment related toxicity.  After 9 patients have been enrolled 
the study will be evaluated to determine whether the treatment is feasible and safe.  If at 
least 6 out of the 9 patients have completed the tri-modality treatment without undue 
treatment related toxicity, the trial will move on to the second stage so that a total of 27 
patients will be evaluable.  For evaluation purposes, patients who initiate therapy with 
bevacizumab and Optune, but experience disease progression before initiating 
radiotherapy will be deemed not evaluable.  In addition, patients without undue 
treatment related toxicity who do not initiate tri-modality treatment will be deemed not 
evaluable.  If the total number of patients completing the tri-modality treatment without 
undue treatment related toxicity is at least 16 of 27, the treatment will deemed safe and 
will be considered for further study.  If 3 or fewer patients of the first 9, or 15 or fewer 
patients total, complete the tri-modality treatment without undue treatment related 
toxicity respectively, then modification of the protocol will be considered, including 
possibly proceeding to the tri-modality phase earlier. 
 
2.1  Primary Objective 
The ability to complete protocol treatment (i.e. tri-modality treatment) without undue 
treatment related acute toxicity as defined below: 
2.1.1  Safety: < 40% rate of Grade 3 or higher non-hematologic treatment related 
toxicity. 
2.1.2  Safety: < 15% rate of Grade 4 or higher non-hematologic treatment related 
toxicity. 
2.1.3  Safety: < 5% rate of Grade 4+ scalp dermatitis. 
2.1.4  Safety: < 50% rate of Grade 2-3 scalp dermatitis. 
2.1.5  Early stopping rules: Two or more Grade 2 or higher symptomatic CNS 
hemorrhages; Eight treatment-related Grade 3 or higher non-hematologic or Grade 4 
or higher hematologic treatment related toxicities. 
 
2.2  Secondary Objectives 
2.2.1  Progression-Free Survival at 6 months. 
2.2.2  Median Progression-Free Survival. 
2.2.3  Median Overall Survival. 
2.2.4  1-year Overall Survival. 
2.2.5  Overall Response Rate. 
2.2.6  Quality of Life assessment. 
 
 
3.0  ELIGIBILITY 
 
3.1  Inclusion criteria 
3.1.1  Patients with recurrent or progressive glioblastoma or other grade IV 
malignant glioma (e.g. glioblastoma, gliosarcoma, giant cell glioblastoma, etc.) who 
have failed prior radiation but who have not progressed/recurred on bevacizumab.  

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Patients will be eligible if the original histology was lower-grade glioma and 
subsequent diagnosis of glioblastoma or gliosarcoma is made. 
3.1.2  Patients with any number of recurrences are allowed. 
3.1.3  Brain MRI with contrast demonstrates an enhancing tumor ≤ 8 cm in largest 
diameter within 30 days prior to registration. 
3.1.4  History and physical including neurological exam, height, weight, cranial skin 
exam, and Karnofsky performance status ≥ 70% within 30 days prior to registration. 
3.1.5  Age ≥ 22 years old. 
3.1.6  Patients must have the following laboratory values within 14 days prior to 
registration (by CBC w/ differential, CMP, Urinalysis, and PT/INR for patients on 
anticoagulants): 
 Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. 
 Platelets ≥ 100 x 109/L. 
 Hemoglobin (Hgb) ≥ 9.0 g/dL (Note the use of transfusion or other 
intervention to achieve Hgb ≥ 9.0 is acceptable). 
 Serum total bilirubin ≤ 1.5 x ULN. 
 ALT and AST ≤ 3.0 x ULN. 
 Adequate Renal Function: BUN and Cr < 2 x ULN. 
3.1.7  Minimum interval since completion of radiation treatment is 12 weeks. 
3.1.8  History of CNS radiotherapy: radiation of 60 Gy in 30 fractions, 59.4 Gy in 1.8 
Gy fractions, 75 Gy in 30 fractions or equivalent or lower doses.  
3.1.9  Minimum interval since last major surgery (e.g. intra-thoracic, intra-abdominal 
or intra-pelvic), open biopsy, or significant traumatic injury is 4 weeks prior to 
registration.  Minimum interval since minor procedures, percutaneous biopsies or 
placement of vascular access device is 1 week prior to registration.  Patients must 
have recovered from side effects of such procedure or injury prior to registration. 
3.1.10  Minimum interval since last investigational agent and/or prior cytotoxic drug 
therapy (patient must have also recovered from the toxic effects of any prior 
therapy): 
 3 weeks since last non-cytotoxic therapy. 
 3 weeks must have elapsed since the completion of a non-nitrosourea-
containing chemotherapy regimen. 
 6 weeks since the completion of a nitrosourea-containing chemotherapy 
regimen. 
3.1.11  Patients must have signed an approved informed consent. 
3.1.12  Patients with the potential for pregnancy or impregnating their partner must 
agree to practice effective contraceptive methods to avoid conception while on study 
and for 6 months after study completion. 
3.1.13  Female patients of child-bearing potential must have a negative pregnancy 
test within 14 days prior to study registration. 
3.1.14  Patients with history of prior invasive malignancy (except non-melanomatous 
skin cancer and glioblastoma diagnosis) must have been disease free for a minimum 
of 1 year. 
3.1.15  Patients must be maintained on a stable or decreasing corticosteroid 
regimen from the time of their baseline scan until registration. 

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3.1.16  Patients on full-dose anticoagulants (e.g., warfarin or LMW heparin) must 
meet both of the following criteria: 
 No active bleeding or pathological condition that carries a high risk of 
bleeding (e.g., tumor involving major vessels or known varices). 
 In-range INR (max ≤ 3) on a stable dose of oral anticoagulant for greater than 
1 month or on a stable dose of low molecular weight heparin. 
 
3.2  Exclusion criteria 
3.2.1  Greater than two cycles of bevacizumab or any prior therapy with an inhibitor 
of VEGF or VEGFR. 
3.2.2  Any significant CNS hemorrhage defined as > 1 cm diameter of blood seen on 
the pre-registration brain MRI with contrast scan.  If > 1 cm of acute blood is 
detected, the patient will be ineligible for this trial. 
3.2.3  Patients with impaired cardiac function or clinically significant cardiac 
diseases, including any of the following: 
 History or presence of serious uncontrolled ventricular or significant 
arrhythmias. 
 Any of the following within 6 months prior to registration: myocardial infarction 
(MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), 
Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient 
Ischemic Attack (TIA), Pulmonary Embolism (PE). 
 Uncontrolled hypertension (defined by a SBP ≥ 160 mmHg or DBP ≥ 100 
mmHg while on anti-hypertensive medications) or history of hypertensive 
crisis or hypertensive encephalopathy, stroke, TIA, symptomatic peripheral 
vascular disease, or grade 2 CHF. 
3.2.4  Patients with cirrhosis, or active viral or non-viral hepatitis. 
3.2.5  Patients with peptic ulcer, abdominal fistula, gastrointestinal perforation, intra-
abdominal abscess within 6 months of registration. 
3.2.6  Patients with active implanted medical or electronic device or bullet fragments 
including pacemakers, defibrillators, deep brain stimulators, spinal cord stimulators, 
vagus nerve stimulators, and programmable shunts. 
3.2.7  Infratentorial, leptomeningeal, or multifocal tumor. 
3.2.8  Known sensitivity or allergy to conductive hydrogels (like the gel used on 
electrocardiogram (ECG) stickers or TENS (transcutaneous electrical nerve 
stimulation) electrodes). 
3.2.9  Known diagnosis of human immunodeficiency virus (HIV) infection (please 
note that HIV testing is not mandatory). 
3.2.10  Other concurrent severe and/or uncontrolled concomitant medical conditions 
(e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause 
unacceptable safety risks or compromise compliance with the protocol. 
3.2.11  Pregnant or breast-feeding women. 
3.2.12  Patients treated on any other therapeutic clinical protocols within 3 weeks of 
registration. 
3.2.13  Patients with gastrointestinal bleeding or any other hemorrhage/bleeding 
event (CTCAE v.4) grade 3 or greater within 30 days prior to registration will be 
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4.0  TRIAL DESIGN 
 
4.1  Treatment Overview 
Patients with recurrent or progressive grade IV malignant glioma who have failed prior 
radiation but who have not progressed/recurred on bevacizumab and who meet the 
specified inclusion/exclusion criteria will be eligible for participation. 
 
The date of registration/enrollment is considered to be the day the Eligibility Checklist is 
signed by the verifying physician.  Once a patient is enrolled, a unique case number will 
be assigned to the patient. 
 
Patients will have baseline contrast-enhanced brain MRI within 30 days prior to 
registration.  MR diffusion and spectroscopy studies may be performed to better define 
and characterize areas of recurrent disease, as per physician discretion and institutional 
guidelines.  Patients will also undergo complete physical and neurological exam within 
30 days prior to registration, and blood and urine tests within 14 days prior to 
registration. 
 
Patients will receive bevacizumab at a dose of 10 mg/kg IV every 14 days on days 1 
and 15 (+/- 3 days) of 28 day cycles until treatment failure (disease progression).  
Bevacizumab is standard of care for recurrent GBM and can be administered at an 
outside institution. 
 
Starting on or before day 1 of cycle 1, patients will initiate Optune with frequency of 200 
kHz electric fields and field intensity set at > 0.7 V/cm (at the center of the brain) in 2 
perpendicular directions, 1 second in each direction sequentially, with goal use of 
greater than 18 hours/day.  Optune therapy will consist of 28 day courses of continuous 
Optune treatment until progression.  Patients will be permitted to take 2-3 days off 
treatment near the end of each 28 days of treatment but should resume Optune therapy 
with the start of radiotherapy. 
 
At the end of the first cycle of concurrent bevacizumab and Optune (ideally days 21-28 
or as close as is reasonably possible), patients will undergo a repeat contrast-enhanced 
brain MRI as well as repeat physical and neurological exam.  If patients have a 
response or stable findings on MRI they will proceed to radiation therapy.  Patients with 
progressive disease will come off study and will not be evaluable for protocol therapy 
and endpoints. 
 
Hypofractionated Stereotactic Radiation Therapy (HFSRT) will be determined at the 
discretion of the treating physician from one of the following regimens: 
 
A.  Contrast enhancing lesion: 6 Gy x 5 = 30 Gy 
Residual FLAIR after 1st cycle of bevacizumab, Optune: 4 Gy x 5 =20 
 
OR 

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B.  Contrast enhancing lesion: 3.5 Gy x 10 = 35 Gy 
Residual FLAIR after 1st cycle of bevacizumab, Optune: 2.5 Gy x 10 =25 
 
Radiation treatments will start within the first 10 days of cycle 2 of concurrent 
bevacizumab and Optune and will be delivered over a 2-3 week period.  During 
radiotherapy, patients will remove Optune treatment arrays immediately prior to 
radiation treatments and will resume as soon as is reasonably possible on each day 
following completion of radiation treatment. 
 
After completion of cycle 2 with the tri-modality treatment, patients will resume 28 day 
cycles of bevacizumab and Optune until disease progression.  These subsequent 
cycles will mirror cycle 1. 
 
Please note that dose modifications, delays, and discontinuations of bevacizumab, 
Optune, and radiotherapy are at the physician’s discretion and per institution guidelines.  
If bevacizumab is interrupted, treatment with Optune and radiotherapy will continue as 
planned, and this follows for the other treatment modalities. 
 
5.0  RADIATION THERAPY 
 
5.1  Dose Specifications 
Choice of radiation therapy regimen is at the treating physician’s discretion. For an 
enhancing tumor greater than 5 cm in maximum diameter, Regimen B should be 
followed. 
 
Regimen A:  30 Gy in five fractions of 6 Gy each delivered to the contrast enhancing 
lesion, with 20 Gy in five fractions of 4 Gy each delivered to the residual FLAIR signal 
abnormality remaining after the initial cycle of bevacizumab and Optune.  Treatments 
will be delivered with at least 48 hours between fractions; maximum of 3 fractions per 5 
day treatment week. 
 
OR 
 
Regimen B:  35 Gy in ten fractions of 3.5 Gy each delivered to the contrast enhancing 
lesion, with 25 Gy in ten fractions of 2.5 Gy each delivered to the residual FLAIR signal 
abnormality remaining after the initial cycle of bevacizumab and Optune.  Treatments 
will be delivered once daily on consecutive treatment days (typically 5 fractions per 
week). 
 
Radiation treatments will start within the first 10 days of cycle 2 of concurrent 
bevacizumab and Optune and will be delivered over a 2-3 week period. 
 
5.2  Coverage Goals 
Volume of PTV (planning target volume) covered by the prescription dose:  Greater than 
or equal to 95% of the PTV should receive greater than or equal to 100% of the planned 

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total prescription dose.  Acceptable deviation will include greater than or equal to 90% 
of the PTV receiving greater than or equal to 100% of the planned total prescribed dose. 
 
Minimum dose to the PTV (0.03 cc):  Greater than or equal to 90% of the planned total 
prescription dose.  Acceptable deviations will include minimum PTV dose greater than 
or equal to 80% of the prescription dose as well as minimum PTV doses less than 80% 
of the prescription dose if these areas occur due to OAR-PTV overlap. 
 
Maximum dose to the PTV (0.03 cc): Less than or equal to 110% of the prescription 
dose.  Acceptable deviation will include maximum dose less than or equal to 115% of 
the prescription dose. 
 
5.3  Localization, Immobilization, Simulation, and Imaging 
MRI with contrast is required for treatment planning.  CT simulation of the patient 
immobilized in treatment position should have image resolution of no worse than 1.5 
mm slice thickness.  Immobilization must be rigid (e.g. thermoplastic mask, with bite 
block preferred if patient able to tolerate).  For daily treatment, localization will include 
the steps of a) immobilization with the same device used for simulation, and b) daily 
image guidance using at a minimum orthogonal pairs of radiographs aligned to digitally 
reconstructed radiographs (DRRs) (use of CBCT alignment is permitted as well but not 
mandatory). 
 
Image fusion of both the pre-study-entry MRI: “MRI-1” and the pre-RT (ideally end of 
cycle 1) MRI: “MRI-2” will be made with the planning CT simulation scan and used for 
target delineation per protocol and institutional guidelines. 
 
5.4  Technical Factors 
Treatment shall be delivered with megavoltage machines of a minimum energy of 6 MV 
photons.  Selection of the appropriate photon energy(ies) should be based on 
optimizing the radiation dose distribution within the target volume and minimizing dose 
to non-target normal tissue.  Source skin distance for SSD techniques or source axis 
distance for SAD techniques must be at least 80 cm.  Electron, particle, planned 
radiosurgery or implant boost is not permissible.  Intensity-modulated Radiation Therapy 
(IMRT) is required; any of the methods of IMRT may be used. Proton therapy is 
permitted at the discretion of the treating physician. 
 
5.5  Treatment Planning/Target Volumes 
5.5.1  Initial Target Volume (PTV1):  Treatment volumes will be defined by the pre-RT 
MRI (MRI-2). Gross tumor volume (GTV1) will be equal to clinical tumor volume (CTV1).  
CTV1 will be defined by either the T2 or the FLAIR abnormality on MRI-2.  This must 
also include any volume included in GTV2 (described below).  The initial planning target 
volume (PTV1) is an additional margin of 3 to 5 mm, depending upon localization 
method and reproducibility, however, this may be reduced to as low as 0 cm around 
natural barriers to tumor growth or to allow sparing of normal tissues. 
 

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The dose to PTV1 for regimen A will be 4 Gy per fraction for 5 fractions, total dose 20 
Gy. The dose to PTV1 for regimen B will be 2.5 Gy per fraction for 10 fractions, total 
dose 25 Gy. 
 
5.5.2  Boost Target Volume (PTV2):  In order to account for the described phenomena 
of pseudo-response seen with bevacizumab and pseudo-progression seen with 
NovoTTF,  the gross tumor volume (GTV2) will represent a composite of the pre-study-
entry MRI (MRI-1) and the pre-RT MRI (MRI-2). GTV2 will be defined by the contrast-
enhancing T1 abnormality according to the following provisions: 
a) if the contrast-enhancing lesion on MRI-2 is smaller than MRI-1, the extent of 
disease on MRI-1 will be used 
b) if the contrast-enhancing lesion on MRI-2 is reasonably larger than MRI-1 (but 
not meeting the criteria for progressive disease), the extent of disease on MRI 2 
will be used 
c) if the contrast-enhancing lesion on MRI-2 is significantly larger than MRI-1 (but 
not meeting the criteria for progressive disease), the portion of enhancement felt 
to represent pseudo-progression will be excluded and the extent of disease on 
MRI-2 will be edited to include, at a minimum, the extent of disease on MRI-1. 
 
The post-operative resection cavity will be outlined if no residual enhancing tumor is 
noted.  The boost clinical target volume (CTV2) will be the gross tumor volume (GTV2) 
plus an optional margin of no more than 5 mm if this is a new lesion.  The CTV2 margin 
may be reduced to as low 0 cm around natural barriers to tumor growth such as the 
skull, ventricles, falx, etc, and also to allow sparing of the normal tissues, if necessary.  
The boost planning target volume (PTV2) is an additional margin of 3 to 5 mm, 
depending upon localization method and reproducibility, however this may be reduced 
to as low as 0 cm around natural barriers to tumor growth or to allow sparing of normal 
tissues. 
 
The dose to PTV2 for regimen A will be be 6 Gy per fraction for 5 fractions, total dose 
30 Gy. The dose to PTV2 for regimen B will be 3.5 Gy per fraction for 10 fractions, total 
dose 35 Gy. 
 
5.6  Critical Structures 
Normal tissues to be contoured will include the brainstem, optic nerves, chiasm, retina, 
cochlea, lenses, and lacrimal gland.  The treatment parameters should be modified to 
optimize the conformity of the prescription isodose volume to the target volume while 
minimizing dose to critical structures.  The dose limits for both regimens A and B are 
given below. 
 
Normal Tissue Dose Limits 
 
Regimen A 
 
Critical Structure 
Dose Constraint 
Acceptable Deviation 

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Maximum 
Dose 
to 
Optic 
Nerves and Chiasm (0.03 cc) 
Less than or equal to 15 Gy 
Greater than 15 Gy but less 
than or equal to 18 Gy  
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or equal to 17 Gy 
Greater than 17 Gy but less 
than or equal to 22 Gy 
Mean Dose to Cochlea 
Less than or equal to 22 Gy 
Greater than 22 Gy 
Maximum Dose to Lens 
Less than or equal to 5 Gy  
Greater than 5 Gy 
Mean Dose Lacrimal Gland 
Less than or equal to 12 Gy  
Greater than 12 Gy 
 
Regimen B 
 
Critical Structure 
Dose Constraint 
Acceptable Deviation 
Maximum 
Dose 
to 
Optic 
Nerves and Chiasm (0.03 cc) 
Less than or equal to 20 Gy  
Greater than 20 Gy but less 
than or equal to 25 Gy 
Maximum Dose to 
Brainstem (0.03 cc) 
Less than or equal to 24 Gy 
Greater than 24 Gy but less 
than or equal to 30 Gy 
Mean Dose to Cochlea 
Less than or equal to 30 Gy  
Greater than 30 Gy 
Maximum Dose to Lens 
Less than or equal to 7 Gy  
Greater than 7 Gy 
Mean Dose Lacrimal Gland 
Less than or equal to 20 Gy  
Greater than 20 Gy 
 
6.0 BEVACIZUMAB THERAPY 
 
6.1  Drug Definition, Description, and Storage 
Bevacizumab (human-mouse monoclonal rhuMAb-VEGF γ-chain anti-human vascular 
endothelial growth factor) is a humanized IgG1 monoclonal antibody (MAb) that binds 
biologically active isoforms of human VEGF (VEGF-A) and prevents interaction of 
VEGF with its receptors (Flt-1, KDR) on the surface of endothelial cells resulting in 
inhibition of angiogenesis.  The antibody consists of human IgG1 framework regions 
and murine complementarity-determining antigen-binding regions.  Vials contain 
bevacizumab with phosphate, trehalose, polysorbate 20, sterile water for injection, USP.  
Vials contain 25 mg/mL concentrate and should be diluted in 0.9% sodium chloride.  Do 
not administer or mix with dextrose solutions.  Vials contain no preservative and are 
suitable for single use only.  Diluted solution may be stored at 2-8°C for up to 8 hours, 
do not freeze; protect from light. 
 
6.2  Dose Administration 
Bevacizumab will be administered at a dose of 10 mg/kg every 2 weeks (+/- 3 days).  
Doses will be adjusted if there is a > 10% change in weight.  Bevacizumab should be 
administered as a continuous intravenous infusion using a rate-regulating device per 
institutional guidelines with associated pre-medications and not as an IV push or bolus.  
Administer the initial dose over a minimum of 90 minutes.  If no adverse reactions 
occur, administer the second dose over a minimum of 60 minutes.  If no adverse 
reactions occur after the second dose, administer subsequent doses over a minimum of 
30 minutes.  Bevacizumab has been administered safely over shorter infusion times 

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(0.5 mg/kg per minute), but is not recommended to be administered in shorter than 30 
minutes.  If infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated.  Dose modifications, 
delays, and discontinuations are at the discretion of the treating medical oncologist and 
per institutional standards. 
 
6.3  Timing of Therapy 
The initial cycle of bevacizumab (concurrent with Optune initiation) must start within 14 
days of registration.  A cycle will consist of a dose on day 1 and day 15 (+/- 3 days).  
Subsequent cycles will be administered every 28 days (+/- 3 days) until disease 
progression. 
 
7.0  OPTUNE THERAPY 
 
7.1  Description 
The Optune (formerly NovoTTF-100A) System is an FDA (Food and Drug 
Administration) approved device developed by Novocure.  It is a portable battery or 
power supply operated device which produces alternating electric fields (tumor 
treatment fields or TTF) which are applied to the patient by electrically-insulated surface 
transducer arrays.  The Optune System is comprised of two main components: an 
Electric Field Generator (the Optune device) and INE Insulated Transducer Arrays (the 
transducer arrays).  In addition, the following components are also included in the 
Optune Treatment Kit: power supply, portable battery, battery rack, battery charger, 
connection cable and carrying case.  The patient must change and recharge depleted 
device batteries and connect unit to an external power supply overnight.  In addition, the 
transducer arrays need to be replaced once to twice a week and the scalp re-shaved at 
least weekly in order to maintain optimal contact. 
 
7.2  Treatment Parameters 
Treatment parameters are preset by Novocure such that there are no electrical output 
adjustments available to the patient.  Electric field intensity will be set at > 0.7 V/cm at 
the center of the brain and frequency set at 200 kHz.  Two intersecting field directions 
will be used with transducer array arrangements designed by Novocure to encompass 
the highest proportion of treatable orientations.  Each field will operate in alternating 
sequence at 1 second duty cycles. 
 
7.3  Treatment Application 
As is standard clinical practice, patients will be supplied with multiple sterile transducer 
arrays as well as the Optune treatment unit and associated cables, equipment, and 
instruction.  Patients will have four transducer arrays placed on the shaved scalp in an 
arrangement pattern specified by Novocure and connected to a portable, battery or 
power supply operated device (Optune) set to sequentially generate perpendicular 
alternating electric fields.  Patients will be trained on how to operate the device and will 
then continue treatment at home.  Treatment will be continuous while maintaining 
normal daily activity.  Transducer arrays are to be replaced by the patients, their 
caregivers or device technicians once or twice a week.  Prior to placement, the scalp 

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will be carefully re-shaved as needed with an electric razor in order to avoid skin 
irritation or wounding.  Uninterrupted treatment is recommended with goal treatment 
time of greater than 18 hours per day.  Patients will remove transducer arrays 
immediately prior to each radiotherapy treatment and will resume therapy as soon as is 
reasonably possible (ideally within about 30 minutes) following completion of that day’s 
radiation treatment.  Patients will be allowed to take treatment breaks of up to an hour, 
twice per day, for personal needs (e.g. shower).  In addition, patients will be allowed to 
take 2-3 days off treatment at the end of each 28 day cycle of treatment. 
 
8.0  ASSESSMENTS 
 
8.1  Clinical Follow-Up 
Patients will undergo clinical assessments including neurologic exam and blood and 
urine tests prior to each cycle of treatment.  Patients will be evaluated for toxicities 
weekly for the duration of radiotherapy as well as prior to each new cycle.  NCI 
Common Toxicity Criteria version 4 scoring will be used for toxicity grading. 
 
8.2  Imaging Assessment 
8.2.1  Imaging Schedule 
Patients will undergo contrast-enhanced brain MRI scanning after the first cycle of 
treatment with bevacizumab and Optune.  After completion of radiotherapy, MRIs 
will be performed every 2-3 months (+/- 2 weeks).  MRIs may be performed earlier if 
clinically warranted. 
 
8.2.2  Measurement of Response 
Response to treatment will be determined by contrast-enhanced brain MRI and 
neurological status according to three pre-defined scales: RECIST, Macdonald, and 
RANO (in expectation that the utilization of the appropriate scale for recurrent GBM 
will likely change in the near-future); however, for “actionable” results, only the 
Macdonald criteria will be utilized for this trial. 
 Complete Response (CR) requires all of the following:  Complete 
disappearance of the measurable enhancing lesion sustained for at least 4 
weeks; no new lesions; and on a stable or reduced corticosteroid dose. 
 Partial Response (PR) requires all of the following: ≥ 50% decrease 
compared with baseline in the sum of products of perpendicular diameters of 
the measurable enhancing lesion sustained for at least 4 weeks; no new 
lesions; and stable or reduced corticosteroid dose. 
 Stable Disease (SD) requires all of the following:  Does not qualify for 
complete response, partial response, or progression and is receiving stable or 
decreasing doses of steroids.  This will not require a confirmatory scan. 
 Progression (P) is defined by any of the following: ≥ 25% increase in sum of 
the products of perpendicular diameters of enhancing lesions provided that 
the patient has not had his/her dose of steroids decreased since the last 
evaluation period; and any new lesions.  A concomitant decrease in steroid 
dose will rule out progression during the initial 12 weeks after completion of 
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 Pseudo-Progression (PP):  The effect of large dose per fraction as well as 
combined modality treatment with Optune may result in imaging changes 
indicative of treatment effect or pseudo-progression.  As such, in the absence 
of neurologic decline OR a new distant area of tumor, the initial post-radiation 
scan should NOT be used to declare progression.  Spectroscopy and 
perfusion sequences, as per standard clinical practice guidelines, may be 
used to better define imaging uncertainty.  Progressive worsening on 
subsequent imaging studies usually distinguishes true progression from 
pseudo-progression; and if determined by subsequent imaging, then the date 
of progression returns to the earlier date with increasing mass. 
 
8.3  Quality-of-Life Assessment 
As part of a planned exploratory endpoint, patients will be given the opportunity to 
undergo a quality of life assessment with the M. D. Anderson Symptom Inventory - 
Brain Tumor (MDASI-BT) Module at the time of study entry, prior to initiating 
radiotherapy, upon completion of radiotherapy, at 1 month post treatment, as well as 
every 8 weeks (+/- 1 week) thereafter.  MDASI-BT assessment may be performed by 
telephone interview.  The MDASI-BT assessment tool is detailed in Appendix I. 
 
 
9.0  SAFETY 
Safety will be measured by the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
 
9.1  Radiation Therapy Related Adverse Events 
Particular side effects and risks from therapy will change based on the location of 
recurrent disease and previous treatment specifics.  The following are some commonly 
encountered adverse events. 
9.1.1  Acute 
Expected acute radiation-induced toxicities include, fatigue, hair loss, scalp or 
erythema or soreness.  Potential acute toxicities include nausea and vomiting, 
temporary aggravation of brain tumor symptoms such as headaches, seizures, and 
weakness, as well as erythema and/or soreness of the ears or in the ear canals 
potentially resulting in short-term hearing impairment, dry mouth, or altered taste. 
9.1.2  Early Delayed 
Possible early delayed radiation effects include fatigue and lethargy as well as 
potential worsening of existing neurological deficits occurring 1-3 months after 
radiotherapy treatment. 
9.1.3  Late Delayed 
Possible late delayed effects of radiotherapy include risk of radiation necrosis, 
hormonal impairment, cataract formation, and neurocognitive deficits which could 
lead to mental slowing and behavioral changes.  Permanent hearing impairment and 
visual damage are rare. 
 
9.2  Bevacizumab Related Adverse Events Including Likely (> 20%) and Less-
Likely Events (< 20% - > 3%) 

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9.2.1  Blood and lymphatic system disorders:  Anemia, febrile neutropenia. 
9.2.2  Cardiac disorders: Supraventricular tachycardia. 
9.2.3 Ear and labyrinth disorders:  Vertigo. 
9.2.4  Gastrointestinal disorders:  Abdominal pain, colitis, constipation, diarrhea, 
dyspepsia, gastrointestinal hemorrhage, gastrointestinal obstruction, ileus, oral 
mucositis, nausea, vomiting. 
9.2.5  General disorders and administration site conditions:  Fatigue, infusion related 
reaction, non-cardiac chest pain, pain. 
9.2.6  Immune system disorders:  Allergic reaction. 
9.2.7  Infections and infestations: Infection, peri-rectal abscess. 
9.2.8  Injury, poisoning and procedural complications: Wound dehiscence. 
9.2.9  Investigations: Increased alanine aminotransferase, increased alkaline 
phosphatase, increased aspartate aminotransferase increased blood bilirubin, 
increased cardiac troponin i, decreased neutrophil count, weight loss, decreased 
white blood cell count. 
9.2.10  Metabolism and nutrition disorders: Anorexia. 
9.2.11  Musculoskeletal and connective tissue disorders: Arthralgia, bone 
metaphyseal dysplasia, myalgia, osteonecrosis of jaw. 
9.2.12  Nervous system disorders: Dizziness, headache, peripheral sensory 
neuropathy, syncope. 
9.2.13  Renal and urinary disorders: Hematuria, proteinuria. 
9.2.14  Reproductive system and breast disorders: Ovarian failure, vaginal 
hemorrhage. 
9.2.15  Respiratory, thoracic and mediastinal disorders: Allergic rhinitis, cough, 
dyspnea, epistaxis, hoarseness. 
9.2.16  Skin and subcutaneous tissue disorders: Pruritus, maculo-papular rash, 
urticaria. 
9.2.17  Vascular disorders: Hypertension, thromboembolic event. 
 
9.3  Optune Related Adverse Events 
Adverse events deemed as related to Optune reported in the recurrent GBM setting 
include: device site reaction (rash under transducer arrays), headache, malaise, muscle 
twitching, falls, skin ulcers, other skin and subcutaneous tissue disorders (such as skin 
breakdown, infections, pain, blisters), as well as other musculoskeletal and connective 
tissue disorders. 
 
9.4  Adverse Event Reporting 
9.4.1  Data and Safety Monitoring / Quality Assurance Committee  
This study will be governed by the UMGCC Data Safety Mointoring / Quality 
Assurance Committee (DSMQAC).  The study will be sent to the DSMQAC for a 
mandatory interim review after the first 9 patients have been accrued.  Once the 
DSMQAC has reviewed and approved the initial 9 patients on the study, 23 
additional patients will be enrolled.  The study will be reviewed by the DSMQAC on 
an annual basis and a report will be uploaded in the continuing review submitted to 
the Institutional Review Board (IRB). 
9.4.2  Anticipated Toxicities 

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All anticipated toxicities are listed in this protocol document (sections 9.1-9.3) and 
the informed consent document. 
9.4.3  Toxicity Reporting 
The research team and the treating physicians/PI will review the toxicities and record 
them in Oncore.  Attribution of toxicity to protocol and clinical relevance will be 
reviewed. 
 
If an undue treatment related toxicity or other significant medical event is 
unexpected and probably related to study treatment, then it will be submitted to the 
IRB via the Reportable New Information (RNI) guidelines.  All AE’s entered into 
Oncore will be submitted for review on an annual basis. 
 
Patients that are withdrawn from protocol treatment will be followed for adverse 
events for 30 days after discontinuation of protocol treatment. 
 
 
10.0  PATIENT PROTOCOL DISCONTINUATION 
Imaging evidence confirming disease progression or occurrence of an undue treatment 
related toxicity (Grade 3 or higher non-hematologic adverse event or Grade 4 or greater 
hematologic adverse event) will serve as criteria for discontinuation of protocol 
treatment.  If protocol treatment is discontinued, follow-up and data collection will 
continue at the treating physician’s discretion. 
 
 
11.0  STATISTICS 
A two phase design will allow for evaluation after enrollment of the initial nine patients.  
A Grade 3 or higher non-hematologic Adverse Event or Grade 4 or greater hematologic 
Adverse Event as measured by the NCI Common Terminology Criteria for Adverse 
Events (CTCAE version 4.0) will be termed an undue toxicity.  Should three or fewer 
patients complete the tri-modality treatment without undue toxicity, the study will be 
terminated and the treatment protocol modified.  Should the study progress to the 
second phase and fifteen or fewer patients complete tri-modality treatment without 
undue acute toxicity, the treatment will be rejected and modification of the protocol will 
be considered. 
 
If P = patient completes tri-modality treatment without undue toxicity, the two-stage 
design to test the null hypothesis that the probability of P < = 0.35 versus the alternative 
that P > = 0.60 has an expected sample size of 16 and a probability of early termination 
of 0.609.  If the treatment is actually not feasible and/or safe there is a 0.046 probability 
of concluding that it is (the target for type II error being β < 0.05).  If the treatment is 
actually feasible and safe, there is a 0.195 probability of concluding that it is not (the 
target for type I error α < 0.200).  After treating 9 patients in the first stage, the study will 
be terminated and the current treatment protocol rejected if 3 or fewer patients complete 
the tri-modality treatment without undue acute toxicity.  If the study goes on to the 
second stage, a total of 32 patients will be enrolled (with at least 27 evaluable patients).  
If the total number of patients completing the tri-modality treatment without undue acute 

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toxicity is less than or equal to 15, the treatment is rejected and modification of the 
protocol will be considered.  

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REFERENCES 
 
1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. 
2. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in 
recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 
1999;17:2572-8. 
3. Chang Yi W, Allen PK, Maor MH, et al. International Journal of Radiation 
Oncology, Biology, Physics 2003;56(2):519-528. 
4. Combs SE, Thilmann C, Schulz-Ertner D J, et al. Efficacy of fractionated 
stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients 
treated in a single institution. J Clin Oncol. 2005;23(34):8863-9. 
5. Stupp R, Wong ET, Gutin PH. et al. NovoTTF-100A versus physician's choice 
chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel 
treatment modality. Eur J Cancer. 2012;48(14):2192-202. 
6. Lederman G, Wronski M, Wrzolek M, et al. Treatment of recurrent glioblastoma 
multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. 
Am J Clin Oncol. 2000;23(2):155-9. 
7. Kirson ED, Gurvich Z, Schneiderman R, et al. Disruption of cancer cell replication 
by alternating electric fields. Cancer Res 2004;64:3288-95. 
8. Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for 
phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80. 
9. Kirson E, Dbaly V, Palti Y, et al. Alternating electric fields arrest cell proliferation 
in animal tumor models and human brain tumors. PNAS 2007;104:10152-57. 
10. Kirson E, Schneiderman RS, Palti Y, et al. Chemotherapeutic treatment efficacy 
and sensitivity are increased by adjuvant alternating electric fields (TTFields). 
BMC Medical Physics 2009;9:1-13. 
11. Gutin P, Iwamoto F, Abrey L, et al. Safety and efficacy of bevacizumab with 
hypofractionated stereotactic irradiation for recurrent malignant gliomas. IJROBP 
2009;75:156-163. 
12. Friedman H, Prados M, Cloughesy T, et al. Bevacizumab alone and in 
combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-
40. 
13. Simon, R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled 
Clinical Trials 1989; 10:1-10. 
 

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APPENDIX I 
M. D. Anderson Symptom Inventory – Brain Tumor (MDASI-BT) 
 
 

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APPENDIX I 
M. D. Anderson Symptom Inventory – Brain Tumor (MDASI-BT) 
 
 
 

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APPENDIX II 
Tables and Figures 
 
1. Outcomes with Bevacizumab in Recurrent GBM 
 
Study 
Pts 
(n) 
Treatment 
mOS 
mPFS 
PFS-6 
ORR 
Kreisl JCO 2009 
48 
Bevacizuma
b 
7.8 
mo 
16 
wks 
29% 
35% 
Nagane JCO 2012 29 
Bevacizuma
b 
10.5 
mo 
13 
wks 
34% 
27.6% 
Gilbert JCO 2009 
57 
Bev 
+ 
CPT11 
 
 
37% 
 
Vrendenburgh Clin 
Ca Res 2007 
23 
GBM 
Bev 
+  
CPT11 
9.2 
mo 
20 
wks 
38% 
61% 
Friedman 
JCO 
2009  
82 
Bev 
+  
CPT11 
8.7 
mo. 
24 
wks 
50.2% 
37.8% 
Freidman 
JCO 
2009 
85 
Bevacizuma
b 
9.2 
mo 
18 
wks 
42.6% 
28.2% 
 
2. Outcomes of Re-irradiation in Recurrent GBM 
 
Study 
Pts 
(n) 
Gy/Fx's 
Median OS 
ORR 
Severe 
Tox/Re-op 
rate 
Shepherd 
IJROBP 
1997 
29 
20-50Gy/5 Fx 
11 months 
 
36% 
Hudes 
IJROBP 
1999 
19 
30Gy/10 Fx 
10.5 
months 
22% 
0% 
Vordermark BMC 
Cancer 2005 
9 
30Gy/6 Fx 
7.4 months 
 
26% 
Ernst-Stecken  J 
Neuro Onc 2006 
15 
35Gy/5 Fx 
11 months 
27% 
0% 
Fokas 2009 
52 
30Gy/10 Fx 
9 months 
 
0% 
Gutin IJROBP 2009 
20 
30Gy/5 
Fx 
(+Bev) 
12.5 
months 
50% 
12% (Gr 4) 
Fogh JCO 2010 
147 
35Gy/10 Fx 
11 months 
10% 
0% 

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APPENDIX II 
Tables and Figures 
 
3. Overall Survival and PFS for patients treated with TTF in Stupp 2012 trial.  
4.