Clinical trial NCT02743078
Conditions: Glioblastoma Glioma Gliosarcoma
Keywords: Glioblastoma Glioma Gliosarcoma Optune TTFields
Sponsor: RTOG Foundation, Inc.
Start date: 2017-05-09; Completion date: 2019-10-15
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial will investigate the efficacy and safety of the addition of Optune (Tumor Treating Fields \[TTFields\] Therapy) to bevacizumab for patients with bevacizumab-refractory recurrent glioblastoma.

Detailed description:
Patients that have recurrent glioblastoma that has progressed on bevacizumab continue to receive bevacizumab with the addition of Tumor Treating Fields Therapy. Treatment is given until disease progression or the development of adverse events that require complete discontinuation.

Arms: arm 1: Bevacizumab starts on the first day (+/- 1 day) of Tumor Treating Fields (TTFields) therapy. Treatment is given until disease progression or the development of adverse events that require complete discontinuation.
Interventions: intervention 1: Bevacizumab intervention 2: TTFields Therapy
Intervention descriptions: intervention 1: 10 mg/kg every 2 weeks intravenously over 30 minutes. intervention 2: Device is worn continuously at least 18 hours a day on average, with 1-3 days off every four weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
1 
RTOG 3503 version date: December 12, 2017 
 
 
 
RTOG Foundation Collaboration With Novocure 
 
RTOG 3503 
 
A Limited Participation Study 
 
PHASE II TRIAL OF OPTUNE® PLUS BEVACIZUMAB IN BEVACIZUMAB-REFRACTORY RECURRENT 
GLIOBLASTOMA 
 
Protocol Version Date: December 12, 2017 
Amendment Number 5 
 
Sponsor: RTOG Foundation 
 
 
Principal Investigator/Neuro-Medical Oncology 
Manmeet Ahluwalia, MD, FACP 
 
 
 
 
 
Study Co-Chairs 
 
Neuro-Medical Oncology 
Karan Dixit, MD 
 
 
 
Senior Statistician 
James Dignam, PhD 
 
 
Protocol Acceptance 
On behalf of the RTOG Foundation, Inc. 
 
 
 
 
 
 
 
 
 
 
 
  December 12, 2017 
Walter J. Curran, Jr., MD 
RTOG Foundation Chairman  
 
Date 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
RTOG FOUNDATION STUDY 3503 
(ClinicalTrials.gov NCT # NCT02743078) 
 
 
 
PHASE II TRIAL OF OPTUNE® PLUS BEVACIZUMAB IN BEVACIZUMAB-REFRACTORY RECURRENT 
GLIOBLASTOMA 
 
 
Limited Participation Study  
 
 
Study Chairs (12-DEC-2017) 
 
Principal Investigator/Neuro-Medical Oncology 
Manmeet Ahluwalia, MD, FACP 
Cleveland Clinic 
9500 Euclid Avenue, S73 
Cleveland, OH 44185 
216-444-6145/FAX 216-444-0924 
ahluwam@ccf.org 
 
Neuro-Medical Oncology Co-Chair 
Karan Singh Dixit, MD 
Northwestern University 
710 N. Lake Shore Drive 
Chicago, IL 60611 
312-503-4724/FAX 312-908-5073 
kdixit@nm.org 
 
 
 
 
 
 
Senior Statistician 
James Dignam, PhD 
University of Chicago 
RTOG Foundation, Inc. 
1818 Market Street, Suite 1720 
Philadelphia, PA 19013 
773-834-3162 
jdignam@uchicago.edu   
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
  
 
PHASE II TRIAL OF OPTUNE® PLUS BEVACIZUMAB IN BEVACIZUMAB-REFRACTORY RECURRENT 
GLIOBLASTOMA 
 
 
 
RTOG Headquarters Contact Information (12-DEC-2017) 
 
Data Managers:   
For questions concerning eligibility or data submission 
Liz Wise, 215-574-3221, lwise@acr.org 
or 
Sylvia Solakov, 215-717-0830, ssolakov@acr.org 
 
 
Serious Adverse Event Coordinator: 
For questions concerning serious adverse event reporting 
procedures, timelines, and queries 
Sara McCartney, 267-940-9404, 
smccartney@acr.org 
 
 
Project Managers:  
For questions concerning regulatory documentation and 
RTOG website access. 
Lynne Hallman, 215 574-3224, lhallman@acr.org 
and 
Treena Davis-Trotman, 215-574-3205, 
ttrotman@acr.org 
 
Clinical Trials Administration:  
For questions concerning contracts and reimbursement 
RTOG-Membership@acr.org 
 
 
Protocol Agents 
 
Agent/Device 
Supply 
IND/IDE # 
Optune®  
Novocure* 
IDE #G150275 
Bevacizumab 
Commercial 
Exempt 
*Obtained through commercial prescription process, with forms submitted to Novocure; see Protocol Section 7.3 
for details. 
 
 
Document History 
 
Version Date 
Amendment 5 
December 12, 2017 
Amendment 4 
October 31, 2016 
Activation, with Amendment 3 
February 24, 2016 
Amendment 3 
February 24, 2016 
Amendment 2 
November 19, 2015 
Amendment 1 
August 4, 2014 
Initial 
May 30, 2014 
 
  


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
 
TABLE OF CONTENTS 
 
 
SCHEMA ....................................................................................................................................................................5 
1.0 
INTRODUCTION ............................................................................................................................................6 
1.1 
Introduction to Electric Fields .....................................................................................................................7 
1.2 
Novocure’s Tumor Treating Electric Fields (TTFields) or TTFields Therapy .............................................7 
1.3 
Mechanisms of Action of TTFields Therapy ...............................................................................................8 
1.4 
In Vivo Effects of TTFields Therapy ........................................................................................................ 10 
1.5 
The Optune Device .................................................................................................................................. 12 
1.6 
Effect of Optune on Newly Diagnosed GBM Patients – Clinical Pilot Study ........................................... 12 
1.7 
Effect of Optune on Recurrent GBM Patients – Clinical Pilot Study ....................................................... 13 
1.8 
Effect of Optune on Recurrent GBM Patients – Pivotal Study ................................................................ 13 
2.0 
OBJECTIVES .............................................................................................................................................. 16 
2.1 
Primary Objective .................................................................................................................................... 16 
2.2 
Secondary Objectives .............................................................................................................................. 16 
3.0 
PATIENT SELECTION ................................................................................................................................ 17 
3.1 
Conditions for Patient Eligibility ............................................................................................................... 17 
3.2 
Conditions for Patient Ineligibility ............................................................................................................. 18 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT .................................................................................. 19 
4.1 
Recommended Evaluations/Management............................................................................................... 19 
5.0 
REGISTRATION PROCEDURES ............................................................................................................... 19 
5.1 
Regulatory Pre-Registration Requirements ............................................................................................. 19 
6.0 
RADIATION THERAPY ............................................................................................................................... 19 
7.0 
DRUG AND DEVICE THERAPY ................................................................................................................. 19 
7.1 
Treatment: Bevacizumab Plus Optune .................................................................................................... 19 
7.2 
Bevacizumab Treatment Guidelines  ....................................................................................................... 19 
7.3 
Optune Treatment Guidelines  ................................................................................................................ 20 
7.4 
Dose Modifications .................................................................................................................................. 22 
7.5 
Modality Review ....................................................................................................................................... 25 
7.6 
Adverse Events ........................................................................................................................................ 25 
7.7 
Serious Adverse Event (SAE) Reporting Requirements ......................................................................... 26 
8.0 
SURGERY ................................................................................................................................................... 29 
9.0 
OTHER THERAPY ...................................................................................................................................... 29 
9.1 
Permitted Supportive Therapy ................................................................................................................. 29 
9.2 
Non-Permitted Supportive Therapy ......................................................................................................... 29 
10.0 
TISSUE/SPECIMEN SUBMISSION ............................................................................................................ 29 
11.0 
PATIENT ASSESSMENTS.......................................................................................................................... 30 
11.1 
Study Parameters .................................................................................................................................... 30 
11.2 
Measurement of Response/Progression/Recurrence ............................................................................. 30 
11.3 
Criteria for Discontinuation of Protocol Treatment .................................................................................. 31 
12.0 
DATA COLLECTION ................................................................................................................................... 32 
12.1 
Summary of Data Submission ................................................................................................................. 32 
13.0 
STATISTICAL CONSIDERATIONS ............................................................................................................ 33 
13.1 
Primary Endpoint ..................................................................................................................................... 33 
13.2 
Secondary Endpoints ............................................................................................................................... 33 
13.3  
Sample Size and Power Justification ...................................................................................................... 33 
13.4 
Analysis Plan ........................................................................................................................................... 33 
13.5 
Gender and Minorities ............................................................................................................................. 34 
REFERENCES ........................................................................................................................................................ 35 
APPENDIX I ............................................................................................................................................................. 37 
APPENDIX II ............................................................................................................................................................ 40 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
  
 
RTOG FOUNDATION STUDY 3503 
 
Phase II Trial of Optune® Plus Bevacizumab in Bevacizumab-Refractory Recurrent Glioblastoma 
 
 
 
 
 
SCHEMA  
 
Recurrent GBM That Has 
Progressed on 
Bevacizumab 
 
Bevacizumab continuation every 2 weeks + Optune*  
 
 
*See Section 7 for full treatment details. 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
 
Histologically proven diagnosis of glioblastoma or other grade IV malignant glioma (including variants of 
glioblastoma ie, gliosarcoma, giant cell glioblastoma, etc.). 
 
Confirmation of tumor recurrence or progression on contrast MRI (with and without gadolinium contrast) 
as determined by RANO criteria within 14 days prior to registration for patients who did not have recent 
resection of their glioblastoma or only had a stereotactic biopsy 
 
Failure on bevacizumab (either as a monotherapy or a combination) as most recent regimen confirmed by 
tumor recurrence on MRI. The patient must have failed no more than one regimen of bevacizumab. The 
patient must not have received bevacizumab as an upfront treatment in newly diagnosed glioblastoma 
 
Required Sample Size: 85 patients 
  
 
 
 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
1.0 
INTRODUCTION 
Despite advances in surgery, radiation therapy, and chemotherapy, including establishment of concurrent 
radiation and temozolomide followed by temozolomide as standard of care, GBM remains an incurable 
disease with a dismal median overall survival (OS) of 15-18 months (Stupp 2005).   
 
Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a humanized monoclonal antibody that 
inhibits VEGF and is the first antiangiogenic therapy to be approved for use in patients with cancer. The 
BRAIN study, a phase II randomized trial, evaluated the role of bevacizumab (alone or in combination 
with irinotecan) in 167 patients with recurrent GBM (Friedman 2009). The progression-free survival (PFS) 
at 6 months (PFS-6) was 42.6% and 50.3%, objective response rate (ORR) was 28.2% and 37.8% and 
median overall survival (OS) was 9.2 months and 8.7 months in the monotherapy and combination arms, 
respectively. In a study done at the National Cancer Institute (NCI), 48 patients with recurrent 
glioblastoma multiforme (GBM) were treated with bevacizumab, producing a response rate (RR) of 35%, 
PFS-6 of 29% and a median OS of 31 weeks (Kreisl 2009). Clinical benefit was evident with decreasing 
cerebral edema, tapering steroid doses, and improvement in neurological function in nearly half of the 
patients. Addition of irinotecan to patients who progressed following bevacizumab did not provide any 
additional benefit. 
 
The results of these two studies compared favorably to historic controls of PFS-6 of 15% for GBM (Wong 
1999), and the FDA approved bevacizumab for patients with recurrent GBM in May 2009 as a 
monotherapy.  However, the duration of effect of bevacizumab appears to be limited and there are 
growing concerns about the long-term efficacy of bevacizumab. To date, clinical trials with bevacizumab 
with recurrent GBM have shown an improvement of PFS without substantial improvement in OS. There is 
no effective therapy for patients with recurrent GBM after progression on bevacizumab. Various studies 
have reported PFS of 5 to 8 weeks and OS of 3 to 5 months, emphasizing the dismal prognosis of these 
patients and an urgent need for options in this setting of bevacizumab-refractory recurrent GBM (Kreisel 
2009; Iwamoto 2009; Norden 2008; Quant 2009; Hovey 2015; Magnuson 2014).  
 
Studies of Patients With Recurrent GBM Who Have Progressed on Bevacizumab 
Author 
N 
Treatment 
Median 
PFS, Wks 
6-Mo PFS, 
% 
Median 
OS, 
(months) 
Norden 
2008 
23 
Bevacizumab + a different 
chemotherapy (most often 
carboplatin) 
7 
2 
NS 
Kreisl 
2009 
19 
Bevacizumab + irinotecan 
4 
0 
NS 
Hovey 
2015 
23 
Bevacizumab + carboplatin 
7 
3 
3.4 
Iwamoto 
2009 
19 
Bevacizumab + chemotherapy 
8 
0 
5.2 
 
Bevacizumab has been associated with prolonged OS in phase III trials of metastatic colorectal and non-
small-cell lung cancers and with prolonged PFS in metastatic breast and renal cancers in combination 
with chemotherapy or biologics. Except GBM, all the approved indications for bevacizumab have been in 
combination with chemotherapy. However, based on the results of the BRAIN study, bevacizumab was 
approved as a monotherapy. One hypothesis for the lack of survival benefit in GBM with the addition of 
chemotherapy to bevacizumab is that treatment with bevacizumab leads to normalization of the blood 
brain barrier (BBB) and this may decrease peritumoral edema, producing short-term benefit. 
 
 
Novocure (Haifa, Israel) has developed a novel therapy (Optune) utilizing alternating electric fields and 
has shown that when properly tuned, very low intensity, intermediate frequency electric fields (TTFields 
Therapy) inhibit the proliferation of tumor cells (including glioma).  Given its mechanism of action, Optune 
is not dependent on the BBB for its efficacy (explained in detail with both preclinical and clinical data 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
provided below). The inhibitory effect with TTFields Therapy has been demonstrated in all proliferating 
cancer cell types tested, whereas non-proliferating cells and normal tissues were unaffected. Promising 
clinical results have been demonstrated in pilot studies of both newly diagnosed GBM in combination with 
temozolomide as well as recurrent GBM when treated with the Optune System.  In a phase III trial Optune 
monotherapy demonstrated comparable efficacy to chemotherapy with a more favorable safety profile 
and quality of life benefit in the recurrent GBM setting, resulting in FDA approval of Optune. A subset 
post-hoc analysis generated the hypothesis that survival could putatively be lengthened in bevacizumab-
refractory recurrent GBM (data presented below).   
 
1.1 
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. (Palti 1966; Polk 1995) 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. (Palti 1966; Polk 1995) In addition, low 
frequency pulsed electric fields have been claimed to stimulate bone growth and accelerate fracture 
healing. (Basset 1985). However, as the frequency of the alternating electric field increases above 1 kHz, 
the stimulatory effect diminishes. Under these conditions although a greater fraction of the fields 
penetrates the cells, due to the parallel resistor-capacitor nature of all biological membranes, the 
stimulatory power greatly diminishes as the alternating cell membrane hyper–depolarization cycles are 
integrated such that the net effect is nulled.  
 
At very high frequencies (i.e., above many MHz), while the integration becomes even more effective, a 
completely different biological effect is observed. At these frequencies tissue heating becomes dominant 
due to dielectric losses. This effect becomes more intense as field intensity or tissue dissipation factor 
increase. (Elson 1995) This phenomenon serves as the basis for some commonly used medical 
treatment modalities including diathermy and radiofrequency tumor ablation, which can be applied 
through insulated electrodes. Chou 1995)  
 
Intermediate frequency electric fields (i.e., tens of kHz to MHz) alternate too fast to cause nerve-muscle 
stimulation and involve only minute dielectric losses (heating). Such fields, of low to moderate intensities, 
are commonly considered to have no biological effect. (Elson 1995) However, a number of non-thermal 
effects of minor biological consequence have been reported even at low-field intensities. These effects 
include microscopic particle alignment (i.e., the pearl chain effect [Takashima 1985]) and cell rotation. 
Holzapfel 1982) With pulsed relatively strong electric fields, > 103 V/cm and 100 ms pulse length, 
reversible pore formation appears in the cell membrane, a phenomenon usually called electroporation. 
(Pawlowski 1993) 
 
The relevance of electric fields in oncology may not be immediately obvious but under closer examination 
it is apparent that biological molecules are dipoles (composed of positive and negative charges), and with 
the application of an external electric field, dipole movement can occur.  In situations where biological 
processes require precise spatial alignment, such as mitosis, externally applied electric fields can disrupt 
this process. This was the hypothesis that led to the initial work to evaluate the ability of electric fields to 
disrupt mitosis in cancer cells.  
 
1.2 
Novocure’s Tumor Treating Electric Fields (TTFields) or TTFields Therapy  
Preclinical studies have shown that when properly tuned, very low intensity, intermediate frequency 
electric fields (TTFields Therapy) inhibit the growth of tumor cells (Figure1) (Kirson 2004). This inhibitory 
effect was demonstrated in all proliferating cancer cell types tested, whereas non-proliferating cells and 
normal tissues were unaffected. Interestingly, different cell types showed specific intensity and frequency 
dependencies of TTField inhibition. It has been shown that two main processes occur at the cellular level 
during exposure to TTFields Therapy: arrest of proliferation and dividing cell destruction. The damage 
caused by TTFields Therapy 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 Therapy 
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. (Zhao 1999) At the sub-


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
cellular level it was found that TTFields Therapy disrupt the normal polymerization-depolymerization 
process of microtubules during mitosis. Indeed, the described abnormal mitotic configurations seen after 
exposure to TTFields Therapy (Figure 2) are similar to the morphological abnormalities seen in cells 
treated with agents that interfere directly (Jordan 1992; Rowinsky 1995) or indirectly (Kline-Smith 2002; 
Kapoor 2000; Maiato 2002) with microtubule polymerization (e.g., paclitaxel). 
 
Figure 1. Time-lapse microphotography of malignant melanoma cells exposed to TTFields Therapy. A, an 
example of a cell in mitosis arrested by TTFields Therapy. Contrary to normal mitosis, the duration of 
which is less than 1 h, the depicted cell is seen to be stationary at mid-cytokinesis for 3 h. B and C, two 
examples of disintegration of TTFields Therapy-treated cells during cytokinesis. Three consecutive stages 
are shown: cell rounding (left); formation of the cleavage furrow (middle); and cell disintegration (right). 
Scale bar = 10 μm. 
 
Figure 2. Immunohistochemical staining of abnormal mitotic figures in TTFields Therapy-treated cultures. 
Malignant melanoma cultures (n = 4) were treated for 24 h at 100 kHz and then stained with monoclonal 
antibodies for microtubules (green), actin (red), and DNA (blue). The photomicrographs show exemplary 
abnormal mitoses including: polyploid prophase (A); rosette (B); ill separated metaphase (C); 
multispindled metaphase (D); single-spindled metaphase (E); and asymmetric anaphase (F).  
 
1.3 
Mechanisms of Action of TTFields Therapy 
In order to explain how TTFields Therapy cause orientation-dependent damage to dividing cells and 
disrupt the proper formation of the mitotic spindle Novocure modeled the forces exerted by TTFields 
Therapy on intracellular charges and polar particles using finite element simulations. Two main 
mechanisms by which the electric fields may affect dividing cells were recognized. The first relates to the 
field effect on polar macromolecule orientation. Within this framework, during the early phases of mitosis, 
i.e., in pre-telophase, when tubulin polymerization-depolymerization drives the proliferation process, the 
electric field forces any tubulin dimers, positioned further than 14 nm away from the growing end of a 
microtubule, to orient in the direction of the field (Figure 3). This force moment, (10-5 pN) acting on the 
dimers, is sufficient to interfere with the proper process of assembly and disassembly of microtubules that 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
is essential for chromosome alignment and separation. (Gagliardi 2002) This effect can explain the mitotic 
arrest of TTField treated cells. (Fishkind 1996)  
 
Figure 3. Tumor treating fields mechanism of action: (A) Disruption of the formation of the mitotic spindle 
in metaphase, and (B) Positive dielectrophoresis during anaphase. 
 
The second mechanism, which interferes with cell division and is most likely to play an important role in 
cell destruction, becomes dominant during cleavage. As seen in simulations, the electric field within 
quiescent cells is homogenous, whereas the field inside mitotic cells, during cytokinesis, is not 
homogenous. An increased field line concentration (indicating increased field intensity) is seen at the 
furrow, a phenomenon that highly resembles the focusing of a light beam by a lens. This in-homogeneity 
in-field intensity exerts a unidirectional electric force on all intracellular charged and polar entities 
(including induced dipoles), pulling them towards the furrow (regardless of field polarity). For example, for 
a cleavage furrow that reached a diameter of 1 µm in an external field of only 1 V/cm, the force exerted 
on the microtubules is in the order of 5 pN. This magnitude is compatible with the reported forces 
necessary to stall microtubule polymerization that is 4.3 pN. (Dogterom 1997) With regards to other 
particles, such as cytoplasmic organelles, they are polarized by the field within dividing cells. Once 
polarized, the forces acting on such particles may reach values up to an order of 60 pN, resulting in their 
movement towards the furrow at velocities that may approach 0.03 m/sec. At such velocity, cytoplasmic 
organelles would pile up at the cleavage furrow within a few minutes, interfering with cytokinesis and 
possibly leading to cell destruction. It has also been found that the electric forces acting on intracellular 
particles are maximal when the axis of division is aligned with the external field. This is consistent with the 
dependence of the destructive effect of TTFields Therapy on the angle between division axis and the 
field, as demonstrated experimentally. The calculated dependence of the magnitude of this force on 
frequency is consistent with the experimentally determined frequency dependence of the inhibitory effect 
of TTFields Therapy on melanoma and glioma cell proliferation (120 kHz vs. 200 kHz, respectively). 
Finally, cells that progress to anaphase show evidence of structural disruption and violent membrane 
blebbing (Figure 4). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4.  Microscopic evidence of membrane blebbing. HeLa cells treated with TTFields during mitosis 
exhibit both moderate and violent membrane blebbing soon after the appearance of metaphase plates 
within the cells. (Lee 2011) 
 
1.4 
In Vivo Effects of TTFields Therapy 
Novocure has shown that TTFields Therapy can be applied effectively to animals through electrodes 
(transducer arrays) placed on the surface of the body. (Kirson 2004; Kirson 2007) Using a special type of 
electrically insulated transducer array, significant inhibition of the growth of both intradermal melanoma 
(B16F1, Figure 5 A-F) in mice and intracranial glioma (F-98, Figure 5 G-H) in rats was seen after less 
than one week of treatment. This growth inhibition was accompanied by a decrease in angiogenesis 
within the tumor, due to inhibition of endothelial cell proliferation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
 
 
 
Figure 5 A-F. In vivo effects of TTFields on intradermal tumors in mice. Malignant melanoma (A) and 
adenocarcinoma (B) tumor cells were injected in two parallel locations intradermally on the back of each 
mouse. Only the tumor on the left side of the mouse was treated. After 4 days of TTFields treatment (at 
100 kHz), no tumor can be discerned on the treated side, whereas on the untreated side a large tumor 
has grown. C–F, histological sections of TTFields-treated intradermal melanoma versus a control 
(untreated) melanoma on the same mouse. C, after H&E staining, a large (5 mm diameter) nodule of 
melanoma cells can be seen in the dermis of the control tumor (×40). Note that due to the large size of 
the tumor, its deep portion has been lost in preparation. D, treated tumor; only two small (<0.4 mm 
diameter) nodules are present (scale bar = 0.5 mm). The nontumor structures of the dermis are 
morphologically intact. E, control tumor, malignant melanoma cells appear intact and viable (×200). 
(Scale bar = 100 μm). F, only necrotic tissue and cellular debris are seen in the treated tumor.  
 
Figure 5 G-H. TTFields inhibition of the growth of intracranial glioma. (G and H) Exemplary T1 weighted 
coronal MRI sections (after IV injection of Gd-DTPA) of the heads of a control and a TTFields treated (200 
kHz, two-directional TTFields) rat, respectively. In both examples, the section shown is that with the 
largest diameter tumor. Head simulations are 3.1 × 1.9 cm ellipsoid; skin thickness, 0.4 mm (σ = 0.00045 
S/m; ε = 1,120); skull thickness, 1.1 mm (σ = 0.015 S/m; ε = 16); thickness of the CSF surrounding the 
brain, 0.5 mm (σ = 2 S/m; ε = 109); and brain itself has the properties of a uniforms white matter (σ = 0.15 
S/m; ε = 3,200). The electrodes placed over a 0.5-mm layer of hydrogel. Note the almost uniform field 
intensity in most brain volume. (Scale bars, 1 cm.) 
 
Extensive safety studies in healthy rabbits and rats exposed to TTFields Therapy for protracted periods of 
time have shown no treatment-related side effects.  The reasons for the surprisingly low toxicity of 
TTField treatment can be explained in the light of the known passive electric properties of normal tissues 
within the body and the effects of electric fields applied via insulated transducer arrays. More specifically, 
two types of toxicities may be expected in an electric field–based treatment modality. First, the fields 
could interfere with the normal function of excitable tissues within the body, causing, in extreme cases, 
cardiac arrhythmias and seizures. However, this is not truly a concern with TTFields Therapy since, as 
frequencies increase above 1 kHz, excitation by sinusoidal electric fields decreases dramatically due to 
the parallel resistor-capacitor nature of the cell membrane (with a time constant of about 1 ms).  Thus, as 
expected, in both acute and chronic application of TTFields Therapy to healthy animals, no evidence of 
abnormal cardiac rhythms or pathologic neurological activity was seen.  
Secondly, the antimitotic effect of TTFields Therapy might be expected to damage the replication of 
rapidly dividing normal cells within the body (bone marrow, small intestine mucosa). Surprisingly, no 
treatment-related toxicities were found in any of the animal safety trials performed by Novocure, even 
when field intensities, 3-fold higher than the effective antitumoral dose were used. The lack of damage to 
G 
H 
G 
H 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
intestinal mucosa in TTField-treated animals is probably a reflection of the fact that the small intestine 
mucosal cells have a slower replication cycle than neoplastic cells and that the intestine itself most likely 
changes its orientation in relation to the applied field quite often, lowering the efficacy of TTField-
mediated mitotic disruption. Bone marrow, on the other hand, is naturally protected from TTFields 
Therapy by the high electric resistance of both bone and bone marrow compared to most other tissues in 
the body. To test the later assumption, the TTField intensity within the bone marrow of a long bone was 
modeled using the finite element mesh (FEM) method. It was found that the intensity of TTFields Therapy 
was 100-fold lower within the bone marrow compared to the surrounding tissues (including within solid 
tumors). Thus, hematopoietic cell replication should not be affected even when TTField intensities 10-fold 
higher than necessary to inhibit tumor growth are applied. 
1.5 
The Optune Device 
The Optune is a portable battery-operated device that produces TTFields within the human body using 
surface electrodes (transducer arrays). The TTFields Therapy is delivered to the patient by means of 
surface transducer arrays that are electrically insulated, so that resistively coupled electric currents are 
not delivered to the patient. The transducer arrays, which incorporate a layer of adhesive hydrogel and a 
layer of hypoallergenic medical tape, are placed on the patient’s shaved head. The transducer arrays 
must be replaced every 3 to 4 days and the scalp re-shaved in order to maintain optimal capacitative 
coupling between the transducer arrays and the patient’s head. All the treatment parameters are pre-set 
by Novocure so there are no electrical output adjustments available to the patient. The patient must learn 
to apply and change transducer arrays and change and recharge depleted device batteries and to 
connect to an external electrical outlet.  
 
 
Novocure Device Support Specialists and/or Clinical Science Liaisons will be available at all RTOG 
clinical sites participating in the trial to train and support patients, research staff, and health care 
professionals with the operation and management of the device. In addition, Novocure provides a 24/7 
support line for patients and the health care team.    
 
1.6 
Effect of Optune on Newly Diagnosed GBM Patients – Clinical Pilot Study 
A pilot study was performed enrolling 10 newly diagnosed GBM patients treated with the Optune device. 
(Kirson  2009) All patients underwent surgery and chemoradiotherapy for the primary tumor. All patients 
received temozolomide as adjuvant chemotherapy, in addition to Optune treatment.  Patients were 
treated with multiple 4-week treatment courses using continuous, 24-hour a day, 200 kHz, 0.7 V/cm 
TTFields Therapy. TTFields Therapy were applied through two sets of opposing insulated transducer 
arrays and alternated at a 1 second duty cycle between two perpendicular field directions through the 
tumor. Patients completed between 1 and 17 treatment courses, leading to maximal treatment duration of 
16.5 months. Overall, more than 96, 4-week treatment courses were completed (> 9.6 courses per patient 
on average). The treatment was well tolerated with no treatment-related serious adverse events seen in 
any patients. Patients received treatment on average about 80% of the scheduled time. Despite the 
continuous nature of TTFields treatment (i.e., 24 hours a day for many months) the compliance with 
treatment was very high, with patients taking very few days off treatment and stopping only for short 
periods of time during treatment for personal needs.  
 
Mild to moderate contact dermatitis appeared beneath the transducer array gel in all patients during 
treatment. In most cases this dermatitis appeared for the first time during the second treatment course. 
The skin reaction improved with use of topical corticosteroids. Slight back and forth shifting of the location 
of the transducer arrays was necessary in order to allow for continuous treatment and allow the skin to 
recover. 
 
The median PFS of the patients in this study exceeded concurrent and historical controls1 (greater than 
18 months versus 7.1 months, respectively). At the time of the last report, 2 of the 10 patients had died 
and the remaining 8 patients were still alive, of which 5 were progression free. Median OS from diagnosis 
is greater than 39 months at the time of the last report [compared to 14.6 months in historical controls 
(Stupp 2005)].  
 
Although the number of patients in this pilot trial is small, the excellent safety profile of this treatment 
modality and the highly promising efficacy data gathered so far indicate the potential of Optune treatment 
as an effective therapy for newly diagnosed GBM patients.  As result of this pilot study Novocure is 
conducting an international phase III clinical trial in newly diagnosed GBM. Patients will be randomized 


 
 
 
 
 
 
13 
RTOG 3503 version date: December 12, 2017 
2:1 following surgery and chemoradiation to temozolomide alone or temozolomide and Optune.  Out of 
the planned enrollment of 700 patients, over 300 patients have been enrolled to date. 
 
1.7 
Effect of Optune on Recurrent GBM Patients – Clinical Pilot Study 
A pilot study was performed enrolling 10 recurrent GBM patients treated with the Optune device as 
monotherapy. (Kirson 2007; Kirson 2009) All patients underwent surgery and radiotherapy for the primary 
tumor. Only 1 patient was chemotherapy naïve, the rest having received temozolomide or other 
chemotherapeutic agents, as adjuvant treatment, prior to recurrence. 
 
All patients were treated with multiple 4-week treatment courses using continuous, 24-hour a day, 200 
kHz, 0.7 V/cm TTFields Therapy. TTFields Therapy were applied through two sets of opposing insulated 
transducer arrays and alternated at a 1 second duty cycle between two perpendicular field directions 
through the tumor. Patients completed between 1 and 15 treatment courses, leading to maximal 
treatment duration of 14.5 months. Overall, more than 70, 4-week treatment courses were completed (> 7 
courses per patient on average). The treatment was well tolerated with no treatment related serious 
adverse events seen in any of the patients. Patients received treatment on average about three quarters 
of the scheduled time. Considering the continuous nature of TTFields treatment (i.e., 24 hours a day for 
many months) this figure indicates that compliance with treatment, similar to the newly diagnosed pilot 
study, was very high, with patients taking very few days off treatment and stopping only for short periods 
of time during treatment for personal needs. Mild to moderate contact dermatitis appeared beneath the 
transducer gel in 8 of the 10 patients during treatment. The skin reaction improved with use of topical 
corticosteroids and regular shifting of the location of the transducer arrays. 
 
The PFS of the patients in this study exceeded historical controls (26.1 weeks versus 9 weeks, 
respectively) (Wong 1999). The PFS at 6 months (PFS6) was 50% compared to 15% in historical controls 
(Wong 1999). At the time of the last report, 7 of the 10 patients had died. The remaining 3 patients were 
still alive and 2 of them were progression free. Median OS was 62 weeks. Response rate was 25% (1 CR 
and1 PR) and only 2 patients had progressive disease despite treatment.  
 
1.8 
Effect of Optune on Recurrent GBM Patients – Pivotal Study  
 
 
NovoTTF: Recurrent GBM Phase III Trial (EF-11)
Surgery/Biopsy
RT/TMZ + Maintenance TMZ
Recurrence
10% - 1st recurrence
90% - 2-4th recurrence
Randomization 1:1
NovoTTF-100A 
Monotherapy
n=120
Active 
Chemotherapy
n=117

Efficacy Endpoints:
– Primary:  overall survival
– Secondary:
• PFS
• Radiologic response
• QOL (QLQ C-30)
0
1
2
3
4
5
6
7
8
9
10
Ineffective
Effective
Overall Survival (months)
Chemotherapy
Bevacizumab
Temozolomide
Nitrosureas
Placebo
Stupp et al., European Journal of Cancer 2012
 
Figure 6. Schema of the EF-11 trial, Optune versus physician choice chemotherapy in recurrent GBM 
 
Based on the promising data from the pilot trial, Novocure conducted a prospective, randomized, open-
label, active parallel control trial to compare the effectiveness and safety outcomes of recurrent GBM 
subjects treated with Optune monotherapy (n=120) to those treated with an effective best standard of 


 
 
 
 
 
 
14 
RTOG 3503 version date: December 12, 2017 
care chemotherapy (including bevacizumab; n=117).  Best standard of care chemotherapy was 
investigator chosen, with the most common treatments as follows: 31% bevacizumab-based regimens, 
31% irinotecan and 25% nitrosoureas. Patient characteristics were well balanced between treatment 
arms and 90% of patients were at their second or beyond recurrence (Figure 6). Optune subjects had 
comparable OS to subjects receiving the best available chemotherapy in the US today (OS 6.6 vs. 6.0 
months; HR 0.86; p=0.98, shown in Figure 7) (Stupp 2012).  Similar results showing comparability of 
Optune to chemotherapy were seen in all secondary endpoints (e.g., PFS6 = 21.4% for Optune vs. 15.2% 
for chemotherapy). In addition, objective response rates of 14% were seen with Optune monotherapy vs. 
9.6% for chemotherapy (p = 0.19). Responses on the Optune arm were durable as demonstrated by the 
tail end of the PFS curve in Figure 7.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 7. Overall survival (A) and progression free survival (B) Kaplan Meier curves  
 
Months
Fraction Overall Survival
0
6
12
18
24
30
36
42
48
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
TTF Therapy
BPC chemotherapy
 
 
OptuneOPOptune 
 
Chemotherapy 
Median survival  (months) 
Optune System  
(n = 120) 
6.6 
Chemotherapy 
(n = 117) 
6.0 
Cox Proportional Model 
Hazard Ratio 
0.86  
P value 
0.27 
95% CI of ratio 
0.66 – 1.12 


 
 
 
 
 
 
15 
RTOG 3503 version date: December 12, 2017 
Optune 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 Optune subjects as a group when compared to subjects receiving effective best standard of care 
chemotherapy.  
 
Given the clinical interest in bevacizumab in the setting of recurrent GBM two exploratory survival 
analyses were performed in a subset of bevacizumab treated patients: 1) Optune treatment versus 
patients that had received bevacizumab-based regimens on the chemotherapy arm of the trial, and 2) 
Optune versus chemotherapy in the subset of patients that had progressed on bevacizumab prior to 
entering the trial (~20%).  In the first exploratory analysis, median OS was significantly longer for the 
Optune–treated patients than for those treated with a bevacizumab-based regimen (6.6 vs. 5.0 months; 
HR 0.65, p = 0.048; CI 0.51 to 0.90)28  (Figure 8).  In the second exploratory analysis, median OS in 
patients who had progressed on bevacizumab was significantly longer when treated with Optune 
compared to chemotherapy (6.3 vs. 3.3 months; HR 0.39; p = 0.01; CI 0.19 to 0.79) (Figure 9).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median survival  
Optune System  
(n = 120) 
6.6 m 
Bevacizumab 
(n = 36) 
5.0 m 
Cox Proportional Model 
Hazard Ratio 
0.65  
P value 
0.048 
95% CI of ratio 
0.51 to 
0.90 
OS (months) 
Fraction survival 
0 
12 
24 
36 
48 
0.0 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
1.0 
Optune 
Bevacizumab 


 
 
 
 
 
 
16 
RTOG 3503 version date: December 12, 2017 
Figure 8. Exploratory analysis of overall survival: Optune vs. subset of bevacizumab treated patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 9. Exploratory analysis of overall survival: Optune vs. active BPC control (best physicians choice 
chemotherapy) in bevacizumab failures 
 
 
Treatment options for patients with recurrent GBM progressing on bevacizumab remains a significant 
clinical challenge and an important area of study. The post hoc analysis of the EF-11 trial demonstrated 
single-agent activity of TTFields, especially in patients who have progressed on bevacizumab. In addition 
the mechanism of action of TTFields is not limited by normalization of the BBB by use of concomitant 
bevacizumab. This makes a rational and compelling case for evaluation of the combination of TTFields 
and bevacizumab in patients with recurrent GBM who progress on bevacizumab. In addition, the 
favorable safety profile of TTFields suggests that the combination will add little additional toxicity.  
 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To determine the efficacy of TTFields Therapy with bevacizumab as measured by the overall survival rate 
at 6 months from time of registration  
 
2.2 
Secondary Objectives  
2.2.1 
To determine the efficacy of TTFields Therapy with bevacizumab as measured by overall survival from 
time of registration 
2.2.2 
To determine the efficacy of TTFields Therapy with bevacizumab as measured by progression-free 
survival from time of registration 
2.2.3 
To determine the response rate of TTFields Therapy with bevacizumab  
2.2.4 
To evaluate and record the toxicities of TTFields Therapy with bevacizumab  
 
 
OS (months)
Fraction survival
0
3
6
9
12
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
24
36
NovoTTF-100A
Active BPC Control
Log-rank Test 
  
Chi square 
6.637 
df 
1 
P value 
0.0100 
Median survival 
  
Optune  System 
(n = 23) 
6.33m 
Chemotherapy 
(n = 21) 
3.30m 
Hazard Ratio 
  
Ratio 
0.3899 
95% CI of ratio 
0.19 to 
0.79
Optune 


 
 
 
 
 
 
17 
RTOG 3503 version date: December 12, 2017 
3.0 
PATIENT SELECTION  
For questions concerning eligibility, contact the study Data Managers (see the title page for contact 
information). 
 
3.1 
Conditions for Patient Eligibility  
3.1.1 
Histologically proven diagnosis of glioblastoma or other grade IV malignant glioma (including variants of 
glioblastoma ie, gliosarcoma, giant cell glioblastoma, etc.). 
3.1.2 
Confirmation of tumor recurrence or progression on contrast MRI (with and without gadolinium contrast) 
as determined by RANO criteria within 14 days prior to registration for patients who did not have recent 
resection of their glioblastoma or only had a stereotactic biopsy. 
3.1.3 
Patients having undergone recent resection (within 5 weeks prior to registration) of their glioblastoma to 
treat current recurrence prior to study treatment must have recovered from the effects of surgery 
(including patient’s skin having fully recovered from the surgical wound) Note: a 4-week window is 
required after surgery prior to starting treatment per protocol Section 7.0. For CNS-related stereotactic 
biopsies, a minimum of 7 days must have elapsed prior to registration.  
 
Residual disease of recurrent glioblastoma is not mandated for eligibility into the study. To best 
assess the extent of residual disease post-operatively, a post-operative MRI scan must be performed 
prior to registration and is recommended to be within 96 hours post-surgery (although 24-48 hours 
would be optimum). Note: Patients who did have surgery with a post-operative contrast-enhanced 
scan falling outside the 5-week window prior to registration, per definition of recent surgery in 3.1.3, 
must have a repeat MRI scan within 14 days prior to registration.  
3.1.4  
Patients with up to two recurrences are allowed. 
3.1.5 
Failure on bevacizumab (either as a monotherapy or a combination) as most recent regimen confirmed by 
tumor recurrence on MRI as described in Section 3.1.2.  
 
The patient must have failed no more than one regimen of bevacizumab.  
 
The patient must not have received bevacizumab as an upfront treatment in newly diagnosed 
glioblastoma.  
 
There must be a minimum of 14 days (i.e., an interval equal to or greater than 14 days) since last 
treatment with bevacizumab and registration  
3.1.6 
History/physical examination within 14 days prior to registration; 
3.1.7 
Karnofsky performance status ≥ 70 within 14 days prior to registration; 
3.1.8 
Age ≥ 22; 
3.1.9 
CBC/differential obtained within 14 days prior to registration, with adequate bone marrow function defined 
as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;  
 
Platelets ≥ 75,000  cells/mm3;  
 
Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is 
acceptable.); 
3.1.10 Adequate renal function within 14 days prior to registration, as defined below: 
 
Creatinine ≤ 1.5 mg/dl  
 
Urine protein: creatinine (UPC) ratio < 1.0 within 14 days prior to registration OR urine dipstick for 
proteinuria ≤ 2+ (patients discovered to have > 2+ proteinuria on dipstick urinalysis at baseline must 
have a UPC ratio done that is <1.0 to be eligible. If the UPC ratio is ≥ 1.0 then the patients should 
undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible). 
 
Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion; a UPC ratio of 1 
is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using one of 
the following formulas: 
 [urine protein]/[urine creatinine]: if both protein and creatinine are reported in 
mg/dL 
 [(urine protein) x0.088]/[urine creatinine]: if urine creatinine is reported in mmol/L 
3.1.11 Serum total bilirubin ≤ 1.5 x ULN within 14 days prior to registration 
3.1.12 ALT and AST ≤ 3.0 x ULN within 14 days prior to registration  
3.1.13 Patients on full dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following 
criteria: 
1. 
No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor 
involving major vessels or known varices) within 14 days prior to registration 
2. 
One of the below criteria must be met based on patient’s therapy: 


 
 
 
 
 
 
18 
RTOG 3503 version date: December 12, 2017 
a) 
Warfarin: In-range INR (usually between 2 and 3) within 14 days prior to 
registration  
b) 
Low molecular weight heparin or Novel oral anti-coagulant:  stable dose within 14 
days prior to registration 
3.1.14 Patients must have recovered from the toxic effects of prior therapy at the time of registration as follows: 
 
28 days from the administration of any investigational agent 
 
28 days from administration of prior cytotoxic therapy with the following exceptions: 
o 
14 days from administration of vincristine or irinotecan 
o 
42 days from administration of nitrosoureas 
o 
21 days from administration of procarbazine  
 
7 days from administration of non-cytotoxic agents [e.g., interferon, tamoxifen, thalidomide, cis-
retinoic acid, etc. (radiosensitizer does not count)].  Any questions related to the definition of non-
cytotoxic agents should be directed to the study chair. 
3.1.15 Female patients of child-bearing potential must have a negative serum pregnancy test within 14 days 
prior to registration.  
3.1.16 Patient must be maintained on a stable or decreasing dose of corticosteroid for at least 5 days before the 
baseline scan. 
3.1.17 Minimum interval since completion of radiation treatment at the time of registration is 90 days.  
3.1.18 Patient must provide study specific informed consent prior to study entry. 
 
 
3.2 
Conditions for Patient Ineligibility (10/31/16) 
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 
3 years. (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible);  
3.2.2 
Infra-tentorial tumor. 
3.2.3 
> 1 cm diameter of blood seen on the MRI described in Section 3.1.2.  
3.2.4 
Severe, active co-morbidity, defined as follows:  
 
Major surgery such as intra-thoracic, intra-abdominal or intra-pelvic (with the exception of craniotomy 
unless craniotomy was performed ≤4 weeks prior to protocol treatment), open biopsy or significant 
traumatic injury ≤ 4 weeks prior to registration, or patients who have had minor procedures, 
percutaneous biopsies or placement of vascular access device ≤ 1 week prior to registration,  or who 
have not recovered from side effects of such procedure or injury. 
 
Non-healing surgical incisions or wounds on the scalp where the transducers will be placed. 
 
Implanted pacemaker, defibrillator or deep brain stimulator, other implanted electronic devices in the 
brain 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior 
to registration; 
 
Transmural myocardial infarction within the last 6 months prior to registration; 
 
Cerebrovascular accident (CVA), transient ischemic attack (TIA) within the last 6 months prior to 
registration 
 
Pulmonary embolism (PE) within the last 6 months prior to registration 
 
Uncontrolled hypertension (defined by a SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg while on anti-
hypertensive medications) within 14 days prior to registration 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 
 
Chronic lung disease or Chronic Obstructive Pulmonary Disease exacerbation or other respiratory 
illness requiring hospitalization or precluding study therapy at the time of registration; 
 
Severe hepatic disease, defined as a diagnosis of Child-Pugh Class B or C hepatic disease. 
 
Known HIV positive patients. Note also that HIV testing is not required for eligibility for this protocol.  
 
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. 
 
Skull defects such as missing bone flap, a shunt, or bullet fragments.  
 
Significant intracranial pressure as per treating physician that may require surgical intervention. 
3.2.5 
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to 
use medically acceptable forms of contraception; this exclusion is necessary because the treatment 
involved in this study may be significantly teratogenic. Note: Contraception is required during treatment 
with bevacizumab and for 180 days after the last dose for women of childbearing potential and 90 days 
after the last dose for males. 


 
 
 
 
 
 
19 
RTOG 3503 version date: December 12, 2017 
3.2.6 
Women who are breast feeding 
3.2.7 
Prior allergic reaction to bevacizumab or severe adverse event with bevacizumab.     
3.2.8 
Known sensitivity to conductive hydrogels 
3.2.9 
Prior treatment with the Optune system.  
3.2.10 Active treatment on another clinical trial. 
 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment 
that do not affect eligibility. 
 
4.1 
Recommended Evaluations/Management 
Albumin, alkaline phosphatase, BUN, calcium, chloride, glucose, potassium, total protein, and sodium 
chloride are recommended within 30 days prior to treatment start. 
 
 
5.0 
REGISTRATION PROCEDURES 
Note: This is a limited institution study; see participating institutions on the RTOG web site.  
 
5.1 
Regulatory Requirements (12-DEC-2017) 
5.1.1 
Please refer to the study-specific guide for investigators and research staff for detailed 
procedures regarding the following: requirements for regulatory collection and patient 
enrollment. The RTOG Foundation 3503 Study Guide is posted on the RTOG website: 
https://www.rtog.org/ClinicalTrials/RTOGFoundationStudies/RTOGFoundationStudy3503.aspx 
 
5.1.2 
Patient Enrollment 
 
See the study specific guide on the RTOG Foundation 3503 protocol page of the RTOG 
website, www.rtog.org for details.  
 
5.1.3 
Pre-Registration Requirements for Investigator Certification  
 
All investigators must successfully complete the training provided by Novocure for clearance to 
submit prescriptions for the Optune device.  (Training can be arranged directly with Novocure at 
855-281-9301 or support@novocure.com). Novocure will issue a Certified Prescriber Certificate 
after investigator training is completed.  This certificate is required in order to receive the 
device. 
 
6.0 
RADIATION THERAPY 
 
Not applicable. 
 
7.0 
DRUG AND DEVICE THERAPY (12-DEC-2017) 
Protocol treatment must begin within 14 calendar days after registration for all patients. In 
addition, patients who had recent resection of their GBM must start treatment ≥4 weeks post-
surgery. 
 
7.1 
Treatment: Bevacizumab Plus Optune (see section 12.0 for details on treatment form collection) 
Patients will receive bevacizumab at a dose of 10 mg/kg every 2 weeks over 30 minutes on a 4-week 
cycle and Optune will be worn continuously. Treatment will be given until progression or development of 
adverse events that require complete discontinuation. Bevacizumab should start on the first day (+/- 1 
day) of Optune therapy. 
 
7.2 
Bevacizumab Treatment Guidelines  
Refer to the package insert for detailed pharmacologic and safety information. 
7.2.1 
Bevacizumab is administered intravenously as a continuous infusion. The initial dose can be administered 
over a minimum of 30 minutes if no adverse reactions occurred during previous infusions of 
bevacizumab. If infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated. 
 
Patients will receive bevacizumab at a dose of 10 mg/kg every 2 weeks. 
 


 
 
 
 
 
 
20 
RTOG 3503 version date: December 12, 2017 
7.3 
Optune Treatment Guidelines (12-DEC-2017) 
Optune is an FDA approved device. Optune is being made available under an IDE sponsored by the 
RTOG Foundation and distributed by Novocure.  
 
Prescription Process and Supply 
Please see study specific guide on the RTOG website, www.rtog.org. 
 
7.3.1 
Treatment Planning 
Transducer array layout will be determined based on the location of the patient’s tumor(s) on MRI.   
Investigators are required to send the baseline MRI scans to Novocure for NovoTAL™ array layout 
planning no later than one day from submitting the prescription (shipping labels are provided at 
certification).  Novocure will acknowledge receipt of the prescription form and the MRI.  An array layout 
will be supplied prior to treatment start.  Investigator may modify the transducer array layout at any time 
during the trial based on radiological data analysis and clinical considerations.   NovoTAL™ software 
supplied by Novocure for layout planning may be used ONLY by study investigators who are NovoTAL™ 
certified by Novocure and wish to use it on this trial.  The NovoTAL™ certified sites must send the 
NovoTAL-generated array layout PDFs to support@novocure.com within 1-5 days of submission of 
the Rx. 
 
Patients will receive an instructional call from Novocure prior to training to highlight important items such 
as the need to shave the head and to answer any technical or logistics questions the patient or caregiver 
may have. All other Patient training: Patients will be trained on the technical aspects of using the device 
by a Novocure Device Support Specialist in their home. 
 
7.3.2 
Treatment Initiation 
Optune treatment will be initiated by the investigator as per protocol.  All patients will be required to shave 
their heads to initiate array placement and TTField therapy.  Array placement will be performed based on 
the transducer array map calculated during treatment planning. 
 
7.3.3 
Treatment Duration 
Treatment with the device will be continuous with breaks allowed for personal needs (eg. showering, 
array exchange). Patients must use the device for at least 18 hours a day on average. Patients will be 
allowed an additional 1-3 days off treatment between courses (one course is 4 weeks) according to 
personal needs. Treatment will be continued until disease progression in the brain, death, or 
unacceptable side effects to patient.  
 
7.3.4 
Treatment Programming 
The Optune device will be programmed by Novocure to deliver 200kHz TTFields Therapy in two 
sequential, perpendicular field directions at a maximal intensity of 707mA RMS. There will be no 
adjustments made to the device by investigators or patients/caregivers.  
 
7.3.5 
Transducer Array Replacement  
Patients will replace the transducer arrays twice to 3 times per week with the help of a caregiver. At each 
array replacement the patient’s scalp will be re-shaved and skin treated according to Section 7.3.7. 
Instructions for replacing the arrays will be part of the initial training. Novocure Device Support Specialists 
will be available to provide support as needed.   
 
Technical Support:  Technical support is available 24/7 by Novocure through a toll free number (855-281-
9301).  
 
7.3.6 
Compliance Assessment 
The device will be interrogated on a monthly basis to assess patient compliance with therapy.  Novocure 
device technicians will conduct the monthly compliance assessment.  Compliance reports will be provided 
to the investigators by Novocure’s technical support center.  
The Investigator will anonymize the monthly patient compliance reports and send to RTOG Headquarters 
via fax 215-940-8926. Please see the study specific guide for further details. 
 


 
 
 
 
 
 
21 
RTOG 3503 version date: December 12, 2017 
 
7.3.7 
Skin Care Guidelines 
The following skin care guidelines should be closely adhered to: 
 
If the skin beneath the transducer arrays is inflamed, a high potency topical steroid should be 
prescribed to the patient. The patient or caregiver should apply the ointment after removing the 
arrays, removing remaining array adhesive from the skin with baby oil and cleaning the skin with 
medical alcohol. The ointment should be left on the skin for at least 30 minutes prior to washing the 
skin with a mild soap and applying a new set of arrays.  
 
At each array replacement, the new set of arrays should be shifted by approximately 2 cm compared 
to the previous layout so that the array discs are placed between the areas of skin irritation. At the 
next array replacement the arrays should be shifted back to their original location. 
 
If the epidermis is breached (skin erosions, punctate lesions, cuts, open sores etc.) an antibiotic 
ointment (e.g. mupirocin) should be prescribed and used in place of the topical steroid treatment. Any 
evidence of infection should result in bacterial cultures being taken.  
 
There will be no “dose” adjustments to the device for adverse events. Reasons for breaks in 
treatment for longer than 24 hours will be documented in the CRFs. The maximum duration of 
treatment break allowed for adverse events related to TTFields Therapy is 4 weeks. 
 
7.3.8 
Potential Adverse Events 
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 to the gel 
 
Skin irritation or skin breakdown 
 
Infection at the sites of transducer array contact with the skin 
 
Transducer array overheating leading to pain and/or local skin burns 
 
Headache 
 
Fatigue 
 
Malaise 
 
Muscle twitching 
 
Fall, if the system interferes with walking  
 
In the phase III trial of Optune monotherapy versus physician’s choice chemotherapy in recurrent GBM, the 
following moderate to severe adverse events (regardless of causality) were seen: 
 
 
TTF (n=116) 
Active Control (n=91) 
System 
Adverse event term 
%  (% gr. 3+4) 
%  (% gr. 3+4) 
Hematological 
3 (0) 
17 (4) 
 
Leukopenia 
0 (0) 
5 (1) 
 
Neutropenia  
0 (0) 
2 (1) 
 
Thrombocytopenia 
1 (1)† 
7 (2) 
Gastrointestinal disorders 
4 (1) 
17 (3) 
 
Abdominal pain 
0 (0) 
3 (0) 
 
Diarrhea 
0 (0) 
6 (2) 
 
Nausea / Vomiting 
2 (0) 
7 (0) 
General deterioration and malaise 
5 (1) 
6 (1) 
Infections 
4 (0) 
8 (1) 
Skin rash (transducer arrays) 
2 (0) 
0 (0) 
Metabolism and nutrition disorders 
4 (1) 
6 (3) 
Musculoskeletal Disorders 
2 (0) 
5 (0) 


 
 
 
 
 
 
22 
RTOG 3503 version date: December 12, 2017 
Nervous system disorders 
30 (7) 
28 (7) 
 
Brain edema 
0 (0) 
2 (0) 
 
Cognitive disorder 
2 (1) 
2 (1) 
 
Convulsion 
7 (2) 
5 (2) 
 
Dysphasia 
2 (0) 
1 (0) 
 
Headache 
8 (1) 
6 (0) 
 
Hemianopsia 
1 (0) 
3 (1) 
 
Hemiparesis 
3 (1) 
2 (1) 
 
Neuropathy peripheral 
2 (0) 
2 (0) 
Psychiatric disorders 
5 (0) 
4 (0) 
Renal and urinary disorders 
3 (1) 
3 (0) 
Respiratory Disorders 
1 (0) 
3 (1) 
Vascular disorders 
3 (1) 
4 (3) 
 
Pulmonary embolism 
1 (1) 
2 (2) 
 
Hypertension 
1 (0) 
1 (1) 
 
Deep vein thrombosis 
1 (0) 
1 (0) 
† thrombocytopenia from prior chemotherapy, normalized subsequently. 
 
 
7.4 
Dose Modifications  
7.4.1 
Optune 
There will be no “dose” adjustments to the device for adverse events. Reasons for breaks in treatment for 
longer than 24 hours will be documented in the CRFs. The maximum duration of treatment break allowed 
for adverse events related to Optune therapy is 4 weeks. However, if Optune therapy is interrupted for 
ANY reason for > 4 weeks, the patient must discontinue bevacizumab and the device on protocol.  
 
7.4.2 
Bevacizumab 
The dose of bevacizumab will be 10 mg/kg delivered intravenously. There will be no dose reduction for 
bevacizumab.  Treatment should be interrupted or discontinued for certain adverse events, as described 
below. If the treatment with bevacizumab is held, the patient can continue with the device. However if 
bevacizumab is interrupted for ANY reason for > 8 weeks, the patient must discontinue bevacizumab and 
the device on protocol.  
 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE.v4.0 Grade 
Action To Be Taken 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
Event 
CTCAE.v4.0 Grade 
Action To Be Taken 
Allergic reactions 
 
or  
 
Acute infusional 
reactions/ cytokine 
release syndrome  
 
Grade 1-3 
 
 
If infusion-related or allergic reactions occur, 
premedications should be given with the next dose 
and infusion time may not be reduced for the 
subsequent infusion.  Follow the guidelines in the 
package insert  for bevacizumab administration.  
 
For patients with grade 3 reactions, bevacizumab 
infusion should be stopped and not restarted on the 
same day.  At the physicians’ discretion, 
bevacizumab may be permanently discontinued or 
re-instituted with premedications and at a rate of 
90+15 min.  If bevacizumab is re-instituted, the 
patient should be closely monitored for duration 
comparable to or longer than the duration of the 
previous reactions.   
Grade 4 
Discontinue bevacizumab  
Arterial Thrombosis 
- Cardiac ischemia/ 
infraction 
- CNS ischemia (TIA, 
CVA) 
- any peripheral or 
visceral arterial 
ischemia/thrombosis 
Grade 2 ( if new or 
worsened since 
bevacizumab 
therapy) 
Discontinue bevacizumab  
Grade 3-4 
Discontinue bevacizumab 
Venous Thrombosis  
 
 
 
Grade 3 
 
 Hold bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is < 2 weeks, 
bevacizumab should be held until the full-dose 
anticoagulation period is over. 
 If the planned duration of full-dose anticoagulation 
is >2 weeks, bevacizumab  may be resumed 
during the period of full-dose anticoagulation IF all 
of the criteria below are met: 
- The subject must have an in-range INR (usually 
2-3) on a stable dose of warfarin or be on a 
stable dose of heparin prior to restarting 
bevacizumab  
- The subject must not have pathological 
conditions that carry high risk of bleeding (eg, 
tumor involving major vessels or other 
conditions) 
- The subject must not have had hemorrhagic 
events while on study 
 
 If thromboemboli worsen/recur upon resumption 
of study therapy, discontinue bevacizumab  
Grade 4 = 
Discontinue bevacizumab  
Hypertension* 
 
[Treat with antihypertensive medication as needed.  The goal of BP 
control should be consistent with general medical practice] 
Grade 1  
Consider increased BP monitoring 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
Event 
CTCAE.v4.0 Grade 
Action To Be Taken 
Grade 2 
asymptomatic and  
diastolic BP < 100 
mmHg 
Begin anti-hypertensive therapy and continue 
bevacizumab 
-Grade 2-3 
Symptomatic OR 
-Diastolic BP > 100 
mmHg  
Hold bevacizumab until symptoms resolve AND BP 
< 160/90mmHg  
 
Grade 4 
Discontinue bevacizumab  
Congestive Heart 
Failure 
Grade 3 
Discontinue bevacizumab  
Grade 4 
Discontinue bevacizumab 
Proteinuria 
 
Proteinuria should be monitored by urine dipstick or urine protein 
creatinine (UPC) ratio before every dose of bevacizumab, if dipstick is > 2 
+ then a UPC ratio should be performed.  
UPC ratio  
< 3.5 
Continue bevacizumab  
UPC ratio  
> 3.5 
Hold bevacizumab until UPC recovers to < 3.5 
Nephrotic syndrome Discontinue bevacizumab  
Hemorrhage (CNS or 
pulmonary) 
Grade 2-4 
Discontinue bevacizumab  
Hemorrhage (non-
CNS; non-
pulmonary) 
Grade 3 
 
 Patients receiving full-dose anticoagulation 
should discontinue bevacizumab  
 For patients not on full-dose anticoagulation, hold 
bevacizumab until ALL of the following criteria 
are met: 
- 
the bleeding has resolved and Hb is stable 
- 
there is no bleeding diathesis that would 
increase the risk of therapy 
- 
there is no anatomic or pathologic condition 
that could increase the risk of hemorrhage 
recurrence. 
 Patients who experience recurrence of grade 3 
hemorrhage should discontinue study therapy 
Grade 4 
Discontinue bevacizumab  
RPLS (reversible posterior 
leukoencephalopathy syndrome or PRES 
(posterior reversible encephalopathy 
syndrome) 
 Hold bevacizumab  in patients with 
symptoms/signs suggestive of RPLS; 
subsequent management should include MRI 
scans and control of HTN 
 Discontinue bevacizumab upon diagnosis of 
RPLS  
Wound dehiscence requiring medical or 
surgical intervention 
 Discontinue bevacizumab  
GI perforation, GI leak or fistula 
Discontinue bevacizumab  
Bowel obstruction 
Grade 2 requiring 
medical 
intervention 
Hold bevacizumab until complete resolution, with a 
minimum of 4 weeks after surgery.  
 
Grade 3-4 
 Hold bevacizumab until complete resolution 
 If surgery is required, patient may restart 
bevacizumab after full recovery from surgery, and 
at investigator’s discretion 
Other unspecified 
bevacizumab-related 
Grade 3 
Hold bevacizumab until symptoms resolve to < 
grade 1 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
Event 
CTCAE.v4.0 Grade 
Action To Be Taken 
AEs (except controlled 
nausea/vomiting). 
Grade 4 
 Discontinue bevacizumab 
 Upon consultation with the study chair, 
resumption of bevacizumab may be considered if 
a patient is benefiting from therapy and the grade 
4 toxicity is transient, has recovered to < grade 1 
and unlikely to recur with retreatment 
 
7.5 
Modality Review (12-DEC-2017) 
The Principal Investigator, Manmeet Ahluwalia, MD, or Neuro-Oncology Co-chair, Karan Singh 
Dixit, MD, will perform a Quality Assurance Review of all patients who receive or are to receive 
bevacizumab and device therapy in this trial.  The goal of the review is to evaluate protocol 
compliance. The review process is contingent on timely submission of chemotherapy treatment 
data as specified in Section 12.1. The scoring mechanism is: Per Protocol, Acceptable 
Variation, Unacceptable Deviation, and Not Evaluable.  A report is sent to each institution 
once per year to notify the institution about compliance for each case reviewed in that year. 
   
 
The Principal Investigator, Manmeet Ahluwalia, MD, or Neuro-Oncology Co-Chair, Karan Singh 
Dixit, MD, will perform a Quality Assurance Review after complete data for the first 20 cases 
enrolled has been received at RTOG Headquarters. Dr. Ahluwalia or Dr. Dixit will perform the 
next review after complete data for the next 20 cases enrolled has been received at RTOG 
Headquarters. The final cases will be reviewed within 3 months after this study has reached the 
target accrual or as soon as complete data for all cases enrolled has been received at RTOG 
Headquarters, whichever occurs first. 
 
 
7.6 
Adverse Events (12-DEC-2017) 
This study will use the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table below will 
be reported via the SAE reporting form accessed via the RTOG website. 
7.6.1 
Adverse Events (AEs)  
 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Therefore, an AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, 
possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6).  
 
AEs, as defined above, experienced by patients accrued to this protocol should be reported on 
the AE section of the appropriate case report form (see Section 12.1).  
 
NOTE: If the event is a Serious Adverse Event (SAE) [see next section], further reporting 
will be required. Reporting AEs only fulfills Data Management reporting requirements.  
7.6.2 
Serious Adverse Events (SAEs) –Serious Adverse Events that meet expedited reporting 
criteria defined in the table in Section 7.7 will be reported via the SAE report form.  SAEs that 
require 24h notification are defined in the expedited reporting table in Section 7.7. 
 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results 
in any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect; 
 
Other serious/important medical events; 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported in an expedited manner. 
 
7.7 
Serious Adverse Event (SAE) Reporting Requirements (10/31/16) 
 
It is the responsibility of the investigator to document all adverse events which occur during the 
study. All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the RTOG SAE Report Form. The SAE Report Form and 
Instructions are available on the RTOG website, www.RTOG.org.  RTOG Headquarters will report 
unexpected and related SAEs to the FDA and NovoCure via the MedWatch Form per the 
requirements set forth in the Code of Federal Regulations, Section 312.32.  
7.7.1 
Reporting SAEs  
An SAE that occurs during any part of protocol treatment and 30 days after whether or not 
related to protocol treatment, must be reported by the investigator per the reporting table below. 
In addition, any SAEs which occur as a result of protocol specific diagnostic procedures or 
interventions also must be reported.  NOTE: please see specific protocol exceptions to 
expedited reporting. 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the SAE 
in question. The SAE summary also must include the investigator’s assessment of relatedness 
to specific protocol treatment (e.g., bevacizumab or Optune). When applicable, information from 
relevant hospital case records and autopsy reports should be included. Initial and follow-up 
information, when it becomes available, should be e-mailed to RTOG3503AE@acr.org. In the 
rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the 
RTOG Operations Office by phone, (1-800-227-5463, ext. 4189).  An electronic report must be 
submitted immediately upon re-establish of the Internet connection.  
 
SAEs that occur during the follow-up period beginning 30 days after end of treatment and are 
considered by the investigator to be possibly, probably, or definitely related to protocol 
treatment must be reported expeditiously via the SAE Report Form.  
 
All SAEs must be e-mailed to RTOG3503AE@acr.org within the designated timeframe 
outlined in the reporting table below.  RTOG will complete a preliminary review of the 
SAE details and may contact the site with suggested revisions. RTOG will report the SAE 
to NovoCure and to the FDA if applicable. Note: The individual completing the SAE 
Report Form should remain vigilant for RTOG’s review and be prepared to make 
recommended revisions expeditiously in order to ensure reporting within FDA-mandated 
timeframes. 
 
 
Pregnancy  
Patients who become pregnant during the study should discontinue the study immediately.  
Investigators should report a pregnancy, including a male participant’s impregnation of his 
partner, expeditiously as a grade 3 SAE coded in the CTCAE v.4 as “pregnancy, puerperium 
and perinatal conditions, other—pregnancy” on the SAE report form and submit  the Pregnancy 
Report Form within 14 days of notification (see Section 12.1 for data form submission). RTOG 
will report the pregnancy to Novocure. Patients should be instructed to notify the investigator if 
it is determined after completion of the study that they become pregnant, including a male 
participant’s impregnation of his partner, either during the treatment phase of the study or within 
30 calendar days after the end of treatment. The pregnancy outcome for patients on study 
should be reported to RTOG. RTOG will report the status to Novocure. 
 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur within 30 Days of the Last Administration of the Investigational Devise/Commercial Agent 1 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to RTOG 
via the SAE Report Form within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via the SAE Report Form 
within 24 hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
 
 
 
 
 
Specific Protocol Exceptions to Expedited Reporting (SPEER) for Bevacizumab: 
 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
Specific Protocol Exceptions to Expedited Reporting (SPEER)  
 
 
 BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 Anemia (Gr 3) 
 Febrile neutropenia (Gr 3) 
  
 CARDIAC DISORDERS 
 Cardiac disorders - Other (supraventricular arrhythmias)1 (Gr 3) 
  
 GASTROINTESTINAL DISORDERS 
 Abdominal pain (Gr 3) 
 Colitis (Gr 3) 
 Constipation (Gr 3) 
 Diarrhea (Gr 3) 
 Dyspepsia (Gr 2) 
 Gastrointestinal hemorrhage2 (Gr 2) 
 Mucositis oral (Gr 3) 
 Nausea (Gr 3) 
 Vomiting (Gr 3) 
  
 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 Fatigue (Gr 3) 
 Infusion related reaction (Gr 2) 
 Non-cardiac chest pain (Gr 3) 
 Pain (Gr 3) 
  
 IMMUNE SYSTEM DISORDERS 
 Allergic reaction (Gr 2) 
  
 INFECTIONS AND INFESTATIONS 
 Infection3 (Gr 3) 
  
 INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 Wound complication (Gr 2) 
 Wound dehiscence (Gr 2) 
  
 INVESTIGATIONS 
 Alanine aminotransferase increased (Gr 3) 
 Alkaline phosphatase increased (Gr 3) 
 Aspartate aminotransferase increased (Gr 3) 
 Blood bilirubin increased (Gr 2) 
 Neutrophil count decreased (Gr 3) 
 Platelet count decreased (Gr 4) 
 Weight loss (Gr 3) 
 White blood cell decreased (Gr 3) 
  
 METABOLISM AND NUTRITION DISORDERS 
 Anorexia (Gr 3) 
 Dehydration (Gr 3) 
 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 Arthralgia (Gr 3) 
 Myalgia (Gr 3) 
  
 NERVOUS SYSTEM DISORDERS 
 Dizziness (Gr 2) 
 Headache (Gr 3) 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
  
 RENAL AND URINARY DISORDERS 
 Hematuria (Gr 3) 
 Proteinuria (Gr 2) 
  
 REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 Vaginal hemorrhage (Gr 3) 
 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 Allergic rhinitis (Gr 3) 
 Cough (Gr 3) 
 Dyspnea (Gr 2) 
 Epistaxis (Gr 3) 
 Hoarseness (Gr 3) 
  
 SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 Pruritus (Gr 2) 
 Rash maculo-papular (Gr 2) 
 Urticaria (Gr 2) 
  
 VASCULAR DISORDERS 
 Hypertension (Gr 3) 
 Thromboembolic event (Gr 3) 
 
1Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. 
 
2Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
3Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
 
8.0 
SURGERY 
Not applicable to this study. 
 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the discretion of 
the attending physician(s) within the parameters of the protocol and documented on each site’s source 
documents as concomitant medication.  
9.1.1 
Anticonvulsants:  Anticonvulsants may be used as clinically indicated. Doses at study entry and at 
specific time points of the treatment must be recorded (See Appendix I).  
9.1.2 
Corticosteroids: Corticosteroids may be administered at the treating physician’s discretion. Doses at study 
entry and at specific time points of the treatment must be recorded.  
 
9.2 
Non-Permitted Supportive Therapy 
9.2.1 
Growth factors are not permitted to induce elevations in neutrophil count  
9.2.2 
Erythropoietin may not be administered because of possible synergistic toxicity with bevacizumab. 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
Not applicable to this study.  
 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters 
See Appendix I for study assessments pre-treatment, during treatment, and follow-up assessments. 
 
11.2 
Measurement of Response/Progression/Recurrence  
It is important to use the same method of assessment from one scan to the subsequent scans.  
 
Modified Response Assessment in Neuro-Oncology (RANO) Response Criteria will be used to define 
response and progression.  In the past, the Macdonald criteria were used to define response and 
progression.  This system is largely based on standardized response criteria using bi-dimensional 
measurements of the largest contrast-enhancing tumor area (Macdonald 1990). However, it has been 
demonstrated that contrast-enhanced images can be altered by agents inhibiting angiogenesis with 
occasional progression of T2-weighted or FLAIR abnormality as well as clinical decline despite 
improvement in the contrast-enhancing signal.  (Batchelor 2007) In light of this, FLAIR imaging and 
clinical status has become part of the response criteria in addition to the widely used Macdonald criteria.  
Hence, the largest cross-sectional area on the T1w contrast-enhanced images will be selected and 
measured in 2 dimensions with linear measures on the baseline MRI axial sequence.  In addition, the 
largest cross-sectional area of a contiguous hyperintense lesion on FLAIR sequences will be measured 
on the baseline MRI axial sequence.  All subsequent scans will be compared against these baseline 
measures (for both CE and FLAIR).  New foci of FLAIR signal abnormality will be recorded on each 
subsequent evaluation.  Response will be scored based on a combination of imaging and clinical features 
as defined by the modified RANO criteria. (Wen 2010) Objective response rate is defined as the sum of 
partial responses plus complete responses. 
 
 
Response 
T1 Contrast Enhancement 
(CE) 
FLAIR Images 
Steroids 
Neurologic 
Exam 
Complete 
Response  
(CR) 
No residual CE (complete 
disappearance of all 
enhancing measurable 
disease for at least 4 
weeks; confirmatory MRI at 
4 weeks is required to score 
as CR) and no new lesions. 
Stable or reduced area of 
FLAIR signal abnormality  
No steroids  
Stable or 
improved 
from prior 
evaluation  
Partial 
Response  
(PR) 
>50% reduction in sum of 
products of the 
perpendicular diameters of 
all measurable enhancing 
lesions sustained for at 
least 4 weeks and no new 
lesions or progression of 
non-measurable lesions   
Stable or reduced area of 
FLAIR signal abnormality  
Stable or 
reduced 
glucocorticoids 
from baseline 
MRI  
Stable or 
improved 
from prior 
evaluation 
Stable Disease 
(SD) 
<25% reduction in area of 
CE maintained for at least 4 
weeks duration.  Does not 
qualify for CR, PR or 
progression  
Stable or reduced area of 
FLAIR signal abnormality  
Stable or 
reduced 
glucocorticoids 
from baseline 
MRI  
Stable or 
improved 
from prior 
evaluation 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
Progressive  
Disease 
>25% in the sum of 
products of the 
perpendicular diameters of 
CE lesions; evidence of 
new lesion(s).  
Measurable increase in 
the sum of products of the 
perpendicular diameters of 
FLAIR signal abnormality 
from the baseline scan or 
the scan representing the 
best response (if there 
was a response) following 
therapy and not 
attributable to other co-
morbid events (seizure, 
radiation, injury, infection, 
ischemia, etc.) OR 
presence of a new focus 
of FLAIR signal 
abnormality that cannot be 
explained by any other 
pathologic process.  
Stable or 
increased dose 
of 
glucocorticoids 
Stable or 
worsening 
neurologic 
symptoms  
 
Radiological tumor assessments will be performed as outlined in the schedule of assessments in Appendix I.   
 
11.3 
Criteria for Discontinuation of Protocol Treatment (10/31/16) 
 
Progression of disease as defined in the table in section 11.2; 
 
A delay in protocol treatment, as specified in 7.0; 
 
Unacceptable adverse events; also see Section 7.0 for further information.  
 
If protocol treatment is discontinued, follow-up and data collection will continue as specified in the 
protocol. 
 
The patient may withdraw from the study at any time for any reason. The institution must notify RTOG 
Headquarters Data Management about this in writing and follow the guidelines set forth in the RTOG 
procedure manual. Follow-up and data collection will not continue in cases of patient withdrawal. 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
 
12.0 
DATA COLLECTION 
Data should be submitted to: 
RTOG Headquarters* 
 1818 Market Street, Suite 1720 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 
 
12.1 
Summary of Data Submission (12-DEC-2017) 
 
Item 
Due 
 
 
Demographic Form (A5) 
Within 2 weeks after registration 
 
 
Initial Evaluation Form (I1) 
Within 2 weeks after registration 
 
 
Pathology Report (P1, not an RTOG form but a 
copy of the pathology report to be faxed to RTOG 
Headquarters 215-940 8926). Personal health 
information must be removed from the report prior 
to faxing. Also the report must be identified with 
study #, case #, patient initials, and RTOG 
institution #. 
Within 2 weeks after registration 
 
 
 
Compliance Reports (CR, not an RTOG form but a 
copy of the compliance reports to be faxed to 
RTOG Headquarters 215-940 8926). These reports 
will be sent to the site by Novocure. 
Monthly 
 
 
Treatment Form (TF) 
 
Arm (bevacizumab + Optune): 
At completion of each 4-week period (2 doses of 
bevacizumab and use of Optune for 4 weeks per 
TF Form if no protocol modification)  
 
 
 
Follow-up Form (F1) 
At the time of progression and at death.  
AFTER progression or treatment discontinuation:  
every 8 weeks for 1 year, then every 12 weeks for 
1 year, then every 6 months. 
 
 
Pregnancy Form (to be faxed to RTOG 
Headquarters: 215-940 8926) 
Within 14 days of notification (see Section 7.7.1) 
 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Primary Endpoint 
Overall survival rate at 6 months from registration 
 
13.2 
Secondary Endpoints 
13.2.1 Overall survival (OS) 
13.2.2 Progression-free survival (PFS) 
13.2.3 Objective response rate  
13.2.4 Frequencies of treatment-related adverse events 
 
13.3  
Sample Size and Power Justification 
The primary objective of this study is to determine whether the addition of TTFields Therapy with 
bevacizumab improves the 6m OS rate for BEV-refractory recurrent GBM patients. The data reported by 
Hovey (2015) and by Iwamoto (2009) are used as the historical control for this study. The null hypothesis 
is a 6m OS rate of 35%. The alternative hypothesis is that patients receiving TTFields Therapy plus 
bevacizumab will have an improved 6m OS rate at 50%, corresponding to a 33% reduction in mortality 
hazard (i.e. a hazard ratio of 0.67). With 80 eligible patients, there will be 85% power to detect this 
projected effect size at a significance level of 0.05 (1-sided).  Guarding against up to a 5% ineligibility 
rate, the final target accrual for this study will be 85 cases. 
Based on the monthly accrual for prior RTOG recurrent glioblastoma phase II studies (RTOG 0625 and 
0929), this study is projected to accrue 10 cases/month. Therefore, the target accrual should be 
completed within 15 months of study activation, allowing slow accrual in the first 6 months.  If the average 
monthly accrual (6 months after trial activation) is less than 5 patients, the study will be re-evaluated with 
respect to feasibility. 
 
13.4 
Analysis Plan 
13.4.1 Statistical Methods 
 
OS and PFS will be estimated using the Kaplan-Meier method.  OS will be measured from the date of 
registration to the date of death or, otherwise, the last follow-up date on which the patient was reported 
alive. PFS will be measured from the date of registration to the date of first progression or death or, 
otherwise, the last follow-up date on which the patient was reported alive. The primary analysis will be 
conducted among all eligible patients with at least 6-month follow-up information. The following rules will 
be used to judge the efficacy of the treatment: out of the 80 eligible patients, if 36 or more experience 6m 
OS, we will reject the null hypothesis that the 6m OS rate is 35% or less and conclude that the 6m OS 
rate is at least 35%; If 35 or fewer patients experience 6m OS, we will not be able to reject the null 
hypothesis. The median OS and PFS time will be estimated, along with their respective 95% confidence 
interval (CI). Secondary efficacy analyses may also be conducted among patients who have had the 
opportunity to use the device according to requirements in Section 7.3.3 for at least 4 weeks from 
treatment initiation.  
 
 
The objective response rate and rate of grade 3 or greater toxicities will be estimated using the exact 
binomial method with accompanying 95% CIs. In terms of grade 3 or greater toxicity, all eligible patients 
receiving any protocol treatment will be included.   
13.4.2 Interim Analysis to Monitor Study Progress 
 
Interim reports with statistical analyses are prepared every 6 months until the initial manuscript reporting 
the treatment results has been submitted.  The reports contain: 
 
The patient accrual rate with a projected accrual completion date  
 
Accrual by institution 
 
The pretreatment characteristics of accrued patients  
 
The frequency and severity of toxicities  
 
The results of any completed study chair modality reviews 
 
The interim reports will not contain the results from the treatment comparisons with respect to the efficacy 
endpoints (OS, PFS, treatment response).  The RTOG Foundation DMC will review the accrual to the 
study and the rate of adverse events on the study at least twice per year until the initial results of the 
study have been presented to the scientific community. 
13.4.3 Analysis for Reporting the Initial Treatment Results 


 
 
 
 
 
 
34 
RTOG 3503 version date: December 12, 2017 
 
The analysis to report the final results of treatment will be undertaken when each eligible patient has been 
potentially followed for a minimum of 6 months after registration (eligible patients who die within 6 months 
after registration will be included). All eligible patients receiving any protocol drug will be included in the 
efficacy analysis. Patients not included in the final analysis will be listed, with reasons for exclusion. The 
analysis plan is described in detail in Section 13.4.1. All information reported in the interim analyses (see 
Section 13.4.2) will also be included in the final report.  
 
13.5 
Gender and Minorities 
In conformance with the National Institutes of Health (NIH) Revitalization Act of 1993 with regard to 
inclusion of women and minorities in clinical research, we aim to be inclusive, as we will also evaluate the 
trial for any evidence of treatment differences by gender, race, and ethnicity. The table below lists the 
projected accrual for each racial and ethnic group based upon previous RTOG GBM trials. 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
34 
47 
81 
Ethnic Category: Total of all subjects 
36 
49 
85 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
1 
2 
3 
Black or African American 
2 
2 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
33 
45 
78 
Racial Category: Total of all subjects 
36 
49 
85 


 
 
 
 
 
 
35 
RTOG 3503 version date: December 12, 2017 
REFERENCES 
 
Basset, CA. The development and application of pulsed electromagnetic fields (PEMFs) for ununited fractures 
and arthrodeses. Clin Plast Surg 1985;12:259-77. 
 
Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, 
normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95.  
 
Carson KA, Grossman SA, Fisher JD, Shaw EG. Prognostic factors for survival in adult patients with recurrent 
glioma enrolled onto the new approaches to brain tumor therapy CNS consortium phase I and II clinical trials. J 
Clin Oncol 2007;25:2601-6. 
 
Chou CK. Radiofrequency Hyperthermia in Cancer Therapy. Connecticut: CRC Press Inc; 1995  
 
Dogterom M, Yurke B. Measurement of the force-velocity relation for growing microtubules. Science 
1997;278:856-60. 
 
Elson EBEoRaMFIVaiVERIJDBeTBEH, pp. 1417-1423. Connecticut: CRC Press Inc., 1995. Biologic Effects of 
Radiofrequency and Microwave Fields: In Vivo and in Vitro Experimental Results. Connecticut: CRC Press Inc; 
1995. 
 
Fishkind DJ, Silverman JD, Wang YL. Function of spindle microtubules in directing cortical movement and actin 
filament organization in dividing cultured cells. J Cell Sci 1996;109 ( Pt 8):2041-51. 
 
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent 
glioblastoma. J Clin Oncol 2009;27:4733-40. 
 
Gagliardi LJ. Electrostatic force in prometaphase, metaphase, and anaphase-A chromosome motions. Phys Rev 
E Stat Nonlin Soft Matter Phys 2002;66:011901. 
 
Holzapfel C, Vienken J, Zimmermann U. Rotation of cells in an alternating electric field: theory and experimental 
proof. J Membr Biol 1982;67:13-26. 
 
Hovey EJ, Field KM, Rosenthal M, et al. Continuing or ceasing bevacizumab at disease progression: results from 
the CABARET study, a prospective randomized phase II trial in patients with recurrent glioblastoma. ASCO 
Meeting Abstracts 2015;33:2003. 
 
Iwamoto FM, Abrey LE, Beal K, et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent 
glioblastoma. Neurology 2009;73:1200-6. 
 
Jordan MA, Thrower D, Wilson L. Effects of vinblastine, podophyllotoxin and nocodazole on mitotic spindles. 
Implications for the role of microtubule dynamics in mitosis. J Cell Sci 1992;102 ( Pt 3):401-16. 
 
Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ. Probing spindle assembly mechanisms with monastrol, a 
small molecule inhibitor of the mitotic kinesin, Eg5. J Cell Biol 2000;150:975-88. 
 
Kirson ED, Gurvich Z, Schneiderman R, et al. Disruption of cancer cell replication by alternating electric fields. 
Cancer Res 2004;64:3288-95. 
 
Kirson ED, Dbaly V, Tovarys F, et al. Alternating electric fields arrest cell proliferation in animal tumor models and 
human brain tumors. Proc Natl Acad Sci U S A 2007;104:10152-7. 
 
Kirson ED, Schneiderman RS, Dbaly V, et al. Chemotherapeutic treatment efficacy and sensitivity are increased 
by adjuvant alternating electric fields (TTFields). BMC Med Phys 2009;9:1. 
 
Kline-Smith SL, Walczak CE. The microtubule-destabilizing kinesin XKCM1 regulates microtubule dynamic 
instability in cells. Mol Biol Cell 2002;13:2718-31. 
 
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus 


 
 
 
 
 
 
36 
RTOG 3503 version date: December 12, 2017 
irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5. 
 
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 
 
Magnuson W, Robins IH, Mohindra P, Howard S. Large volume reirradiation as salvage therapy for glioblastoma 
after progression on bevacizumab. J Neurooncol 2014;117:133-9. 
 
Maiato H, Sampaio P, Lemos CL, et al. MAST/Orbit has a role in microtubule-kinetochore attachment and is 
essential for chromosome alignment and maintenance of spindle bipolarity. J Cell Biol 2002;157:749-60. 
 
Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and 
patterns of recurrence. Neurology 2008;70:779-87. 
 
Palti Y. Stimulation of internal organs by means of externally applied electrodes. J Appl Physiol 1966;21:1619-23. 
 
Pawlowski P, Szutowicz I, Marszalek P, Fikus M. Bioelectrorheological model of the cell. 5. Electrodestruction of 
cellular membrane in alternating electric field. Biophys J 1993;65:541-9. 
 
Polk C. Therapeutic Applications of Low-Frequency Sinusoidal and Pulsed Electric and Magnetic Fields 
Connecticut: CRC Press, Inc.; 1995. 
 
Quant EC, Norden AD, Drappatz J, et al. Role of a second chemotherapy in recurrent malignant glioma patients 
who progress on bevacizumab. Neuro Oncol 2009;11:550-5. 
 
Ram Z, Wong ET, Gutin PH. Comparing the effect of NovoTTF to Bevacizumab in recurrent GBM: A post-hoc 
sub-analysis of the phase III trial data. Neuro-Oncology 2011;13:iii41-iii68. 
 
Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med 1995;332:1004-14. 
 
Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase II trials 
and a proposal for phase II screening trials. J Clin Oncol 2005;23:7199-206. 
 
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. 
 
Stupp R, Wong ET, Kanner AA, 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. 
 
Takashima S, Schwan HP. Alignment of microscopic particles in electric fields and its biological implications. 
Biophys J 1985;47:513-8. 
 
Wen PY, Macdonald DR, Reardon DA et al. Updated response assessment criteria for high-grade gliomas: 
response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72.   
 
Wieand S, Schroeder G, O'Fallon JR. Stopping when the experimental regimen does not appear to help. Stat 
Med. 1994; 13(13-14):1453-8.  
 
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. 
 
Zhao M, Forrester JV, McCaig CD. A small, physiological electric field orients cell division. Proc Natl Acad Sci U S 
A 1999;96:4942-6. 


 
 
 
 
 
 
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RTOG 3503 version date: December 12, 2017 
APPENDIX I 
STUDY PARAMETER TABLES 
 
Pre-Treatment Assessments 
 
Assessments 
≤14 d prior to 
registration 
≤5 d prior to baseline 
scan and from 
baseline to 
registration 
Prior to treatment 
Tumor imaging MRI/CT 
scan (pts without recent 
resection; see Section 3.1 
for details) 
X 
 
 
Tumor imaging MRI/CT 
scan (pts with recent 
resection; see Section 3.1 
for details) 
≤prior to 
registration and 
recommended to 
be ≤96 h post-
surgery 
 
 
History/Physical/ 
Performance Status (KPS) 
X 
 
 
CBC w/ diff, ANC, platelets, 
Hgb 
X 
 
 
Albumin, alkaline 
phosphatase, BUN, 
calcium, chloride, glucose,  
potassium, total protein, 
sodium chloride 
(recommended per Section 
4.1)  
 
 
≤30 d  
Urine protein: urine dipstick 
or UPC ratio (If UPC >1.0 
then 24 hour urine will be 
performed) 
X 
 
 
Creatinine 
X 
 
 
Serum total bilirubin  
X 
 
 
ALT and AST 
X 
 
 
Pregnancy test (if 
applicable) 
X 
 
 
Steroid dose documentation 
and anticonvulsant dose 
documentation  
 
X 
 
Systolic/diastolic blood 
pressure 
X 
 
 
 
PT INR (pts on full-dose 
anticoagulants) 
X 
 
 
Informed consent 
X 
 
 
 


 
 
 
 
 
 
38 
RTOG 3503 version date: December 12, 2017 
APPENDIX I (continued) 
 
Assessments During Treatment (12-DEC-2017) 
 
1  
 
 
 
 
 
 
 
 
 
*Distributed by Novocure to site on monthly basis and to be retained in the patient’s medical record. These 
reports 
also 
must 
be 
submitted 
to 
RTOG 
Headquarters 
monthly 
via 
fax 
215-940-8926.
Assessments 
d 28 (± 4d) of each cycle 
Physical/ Performance Status (KPS) 
X 
CBC w/ diff, ANC, platelets, Hgb 
X 
Albumin, alkaline phosphatase, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, sodium 
chloride 
X 
Urine protein: urine dipstick or UPC ratio (If UPC >1.0 
then 24 hour urine will be performed)  
X 
Serum total bilirubin  
X 
ALT and AST  
X 
Systolic/diastolic blood pressure 
X 
Adverse event evaluation 
X 
Device compliance assessment  
X* 
MRI w/ and w/o contrast 
Every 8 weeks 


 
 
 
 
 
 
39 
RTOG 3503 version date: December 12, 2017 
APPENDIX I (continued) 
Assessments in Follow-Up (10/31/16) 
 
Assessments 
At progression, q 8 weeks for 1 yr, then q 12 weeks for 1 yr, then q 
6 mos  
(+/-7days) 
History/physical 
X 
MRI w/ and w/o contrast 
X* 
*After progression, MRI schedule is left at the discretion of the treating physician 


 
 
 
 
 
 
40 
RTOG 3503 version date: December 12, 2017 
APPENDIX II 
 
 
KARNOFSKY PERFORMANCE SCALE 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some sign or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 

ICF_001.pdf: 
RTOG FOUNDATION 
 
 
RTOG 3503 
 
(ClinicalTrials.gov NCT #: 02743078) 
 
 
PHASE II TRIAL OF OPTUNE® PLUS BEVACIZUMAB IN 
BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA 
 
 
Amendment 5:  December 12, 2017 


 
 
Sample consent form version:  December 12, 2017 
To be attached to protocol version:  December 12, 2017 
 
RTOG 3503 
 
Page 1 of 9 
Schulman Use Only: SR# 0 
SCHULMAN APPROVED 
IRB #201606279 
Finalized Date: 02/02/2018 
Schulman Version: 2.0 
 
Consent Form 
 
Study Title for Study Participants: Testing the benefit of tumor treating fields Optune® therapy in glioblastoma 
that has progressed after treatment with bevacizumab 
 
<<PI_FIRST_NAME>> <<PI_LAST_NAME>> 
<<PHONE_NUMBER>> 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov:  
RTOG Foundation Study 3503, Phase II Trial of Optune®  Plus Bevacizumab in Bevacizumab-
Refractory Recurrent Glioblastoma 
 
What is the usual approach to my brain tumor? 
You are being asked to take part in this study because you have a glioblastoma (a type of brain tumor) that has 
grown back (recurred) or not gotten better after being treated with bevacizumab. People who are not in a study 
are usually treated with a combination of chemotherapy or some form of radiation if their tumors recur after 
treatment with bevacizumab. For patients who receive the usual approach for this cancer, between 2 and 15 out 
of 100 are free of further cancer growth at 6 months and on average 0 out of 100 are free of further cancer 
growth at 2 years. 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above 
• you may choose to take part in a different study, if one is available 
• or you may choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms. 
 
Why is this study being done? 
Bevacizumab is a commercially available drug that is FDA (U.S. Food and Drug Administration) approved for 
the treatment of glioblastoma that has returned after treatment (recurrent glioblastoma). However, treatment 
with bevacizumab alone has not improved survival in patients with this type of brain tumor by a lot. For this 
reason, researchers are evaluating other treatments, including bevacizumab combined with other therapies.  


 
 
Sample consent form version:  December 12, 2017 
To be attached to protocol version:  December 12, 2017 
 
RTOG 3503 
 
Page 2 of 9 
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SCHULMAN APPROVED 
IRB #201606279 
Finalized Date: 02/02/2018 
Schulman Version: 2.0 
The purpose of this study is to test any good and bad effects of adding bevacizumab to a type of therapy for 
brain tumors called Optune. Optune is a portable device that produces electrical signals, called Tumor Treating 
Fields (“TTFields”).  The use of the Optune device in this study is considered investigational. Although Optune 
is FDA approved for use in treating newly diagnosed and recurrent glioblastoma, it is intended for use alone for 
patients with recurrent tumors after failing standard therapies and with temozolomide in newly diagnosed 
patients. Optune is not approved by the FDA for use with bevacizumab.  
Optune uses very low intensity, “wave-like” electric signals to slow or stop cancer cell growth. The Optune 
device administers therapy through electrodes applied to the head of the patient. Because cancer cells are 
dividing, Optune affects cancer cells and generally does not harm healthy cells.  
The addition of Optune to bevacizumab could shrink your tumor or prevent it from growing, but it could also 
cause side effects. This study will allow the researchers to know whether this different approach is better, the 
same, or worse than the usual approach. To be better, the addition of Optune to bevacizumab would increase 
life by 2 months or more compared to the usual approach of using chemotherapy.  
For some patients, it may be possible to receive this combination treatment of Optune and bevacizumab 
together without participating in a study. This is called “off label” use because it is not an FDA approved 
combination treatment and it has not been formally studied to determine if it is better than the usual treatment. 
There will be about 85 people taking part in this study. 
 
What are the study groups? 
Before any study-related tests and procedures are performed, you will be asked to read and sign this consent 
document. All study participants will receive bevacizumab (10 mg/kg) intravenously (by inserting a needle into 
a vein in your arm) once every 2 weeks over 30 minutes on a 4 – week cycle, along with Optune. Bevacizumab 
is a usual treatment for patients with recurrent glioblastoma. Optune is experimental for patients with recurrent 
glioblastoma when used in combination with bevacizumab.  
 
Optune is a portable device worn on your head that includes special adhesive electrodes called “transducer 
arrays” that send wave-like electric signals directly into your tumor. The layout of the electrodes will be 
mapped to the location of your tumor. The electrodes are placed directly on your scalp as part of an adhesive 
bandage that covers your head. You will be required to shave your head in order to place the arrays. Optune also 
includes a portable battery, a carrying case, a battery charger, power cords, and a connection cable. You will 
receive training and support to learn how to use the device from both your study team and the Optune support 
team. You will wear Optune continuously throughout the day for at least 18 hours a day with breaks allowed for 
personal needs. The transducer arrays will be replaced 2 to 3 times per week with help of a caregiver. The 
device records your time on therapy to help you meet the treatment goal.  


 
 
Sample consent form version:  December 12, 2017 
To be attached to protocol version:  December 12, 2017 
 
RTOG 3503 
 
Page 3 of 9 
Schulman Use Only: SR# 0 
SCHULMAN APPROVED 
IRB #201606279 
Finalized Date: 02/02/2018 
Schulman Version: 2.0 
How long will I be in this study? 
You will receive the study treatment for as long as it is working and there are no intolerable side effects. After 
you finish the study treatment, your doctor will continue to watch you for side effects and follow your condition 
indefinitely.  
 
What possible risks can I expect from taking part in this study? (9/13/16) 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s office than usual 
• The study approach may not be better, and could possibly be worse, than the usual approach for your 
cancer. 
 
The treatment used in this study may affect how different parts of your body work such as your liver, kidneys, 
heart, and blood. The study doctor will be testing your blood and will let you know if changes occur that may 
affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drug to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know about. There 
might be other side effects that researchers do not yet know about. If important new side effects are found, the 
study doctor will discuss these with you. 


 
 
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RTOG 3503 
 
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IRB #201606279 
Finalized Date: 02/02/2018 
Schulman Version: 2.0 
Possible side effects of bevacizumab, which is a usual approach for this type of cancer: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, more than 20 and up to 100 may have: 
• High blood pressure which may cause headache or blurred vision  
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Low white cell count that may increase the risk of infection 
• Infection, including collection of pus in the belly or rectum 
• Abnormal heartbeat which may cause palpitations or fainting 
• Pain in the belly, rectum, chest, joints, muscles, or tumor 
• Dry mouth, low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or dehydration 
• Changes in taste 
• Internal bleeding which may cause black tarry stool, blood in vomit, coughing up of blood, or 
blood in urine  
• Bleeding from other sites, including the vagina or nose 
• Blockage of internal organs which may cause vomiting or inability to pass stool 
• Sores in mouth 
• Allergic reaction during or after infusion of bevacizumab which may cause fever, chills, rash, 
itching, hives, low blood pressure, wheezing, shortness of breath, swelling of the face or throat 
• Delay in healing of wounds or spontaneous opening of wounds 
• Weight loss, tiredness, or dizziness 
• Muscle weakness 
• Damage to bones which may cause loss of teeth or loss of motion 
• Headache 
• Numbness, tingling, or pain in the fingers or toes 
• Hoarseness, voice changes, stuffy or runny nose, or cough 
• Dry skin 
• Swelling and redness of the skin 
• Blood clot in limbs or lungs which may cause swelling, pain, or shortness of breath 
• Leakage of protein in the urine, which can rarely lead to damage to the kidney 
 
 


 
 
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To be attached to protocol version:  December 12, 2017 
 
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RARE, AND SERIOUS 
In 100 people receiving bevacizumab, 3 or fewer may have: 
• Clots in the arteries, causing stroke (which may cause paralysis or weakness) or heart attack 
(which may cause chest pain or shortness of breath). This risk is significantly increased in patients 
who are elderly or with history of diabetes 
• Heart failure which may cause shortness of breath, swelling of ankles, or tiredness 
• Bowel perforation (a tear in the bowel) that can cause pain or bleeding and require surgery to 
repair 
• A tear or hole (fistula) in internal organs such as the nose, throat, lungs, esophagus, rectum, or 
vagina.  These conditions may cause serious infections or bleeding and require surgery to repair 
• Sores in the throat 
• Flesh-eating bacteria syndrome, an infection in the deep layers of skin 
• Bleeding in the tumor, brain, belly, or lungs which may cause confusion, blood in stool or 
coughing up blood 
• Brain damage which may cause headache, seizure, blindness (also known as Reversible Posterior 
Leukoencephalopathy Syndrome) 
• Kidney damage which may require dialysis 
• Redness, pain or peeling of palms and soles 
 
Additional Notes on Possible Side Effects for Bevacizumab: 
• Risk in children or adolescents: abnormal bone changes which may interfere with growth. 
• Risk in pre-menopausal women: more likely to develop menopause when taking bevacizumab. 
 
Possible side effects of Optune therapy, which is an experimental approach for this type of cancer when used 
in combination with bevacizumab 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving  Optune Therapy, more than 20 and up to 100 may have: 
• Skin irritation, swelling, itching, and redness in the area of the transducers 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving  Optune Therapy, from 4 to 20 may have: 
• 
Malaise (feeling of discomfort or uneasiness) 
• 
Muscle twitching 
• 
Fall 
• 
Skin ulcer 
• 
Rash 
• 
Headache 
• 
Seizures 
• 
Tiredness 
• 
Infection 
• 
Allergic reaction to the adhesive  


 
 
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RTOG 3503 
 
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RARE, AND SERIOUS 
In 100 people receiving  Optune Therapy, 3 or fewer may have: 
• 
Blood clot which may cause swelling, pain, shortness of breath 
• 
Pain, burn at the site of the transducers 
 
Do not use Optune if you are known to be sensitive to conductive gels like the gel used on EKG stickers. In this 
case, skin contact with the gel used with Optune may cause increased redness and itching, and rarely may lead 
to severe allergic reactions such as shock and breathing problems.  
 
Falls have been reported by patients using the Optune system. Patients wearing the portable device should be 
cautious of the wires and be sure the portable equipment is secure and comfortable prior to walking to prevent 
tripping and falls.  
 
Let your study doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time. 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. The treatments 
used in this study could be very damaging to an unborn baby. Check with the study doctor about what types of 
birth control, or pregnancy prevention, to use while in this study. Women of childbearing potential must use an 
adequate method to avoid pregnancy while receiving bevacizumab and for 180 days after the last dose of 
bevacizumab. Men must use an adequate method to avoid pregnancy while receiving bevacizumab and for 90 
days after the last dose of bevacizumab. 
 
What possible benefits can I expect from taking part in this study? 
It is not possible to know at this time if the study approach is better than the usual approach so this study may or 
may not help you. This study will help researchers learn things that will help people in the future. 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the 
study doctor continue to provide your medical information to the organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB or FDA. 


 
 
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To be attached to protocol version:  December 12, 2017 
 
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What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, 
there will be no penalty to you. You will not lose medical care or any legal rights. 
 
For questions about your rights while in this study, call the ________________________ (insert name of 
center) Institutional Review Board at __________________ (insert telephone number). (Note to Local 
Investigator: Contact information for patient representatives or other individuals at a local institution who are 
not on the IRB or research team but take calls regarding clinical trial questions can also be listed here.) 
 
What are the costs of taking part in this study?(12-DEC-2017) 
As the participant in this study, you will not have any out of pocket costs related to the rental of the Optune 
System if you have Medicare or Medicaid, insurance that covers such costs, or you qualify for financial 
assistance provided by Novocure, the manufacturer of Optune. If you have insurance, you may have coverage 
for Optune while participating in this clinical trial and Novocure will attempt to seek reimbursement from your 
insurance company for use in this clinical trial. If your insurance company does not provide coverage for 
Optune or your financial cost share would be unaffordable, you may be eligible for need-based financial 
assistance. It is recommended that you contact Novocure prior to signing this consent at 855-282-9301 in order 
to understand your potential financial responsibility prior to signing this consent.  If your insurance company or 
Novocure do not provide coverage for Optune, then you will be responsible for the costs of the Optune rental. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of your cancer while 
in this study, including the cost of tests, procedures, chemotherapy, or medicines to manage any side effects, 
unless you are told that certain tests are supplied at no charge. Before you decide to be in the study, you should 
check with your health plan or insurance company to find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured or hurt because I took part in this study? (12-DEC-2017) 
If you get physically ill or injured as the direct result of being in this study, then, depending on what insurance 
you may have, the company providing the device, Novocure, will pay for the reasonable and necessary costs for 
your immediate medical treatment of the illness or injury if it: 
(a) is not a medical condition that you had before you started the study; 
(b) is not the result of the natural progress of your disease or condition; 
(c) is not caused by your failure to follow the study plan; and   
(d) is not proven to be directly caused by the negligence of a [site] employee.  “Negligence” is the failure to 
follow a standard duty of care. 
If your case meets all four of these requirements and you are uninsured or have Medicare or Medicaid, then 
Novocure will pay all of the costs of your medical treatment for the illness or injury. If you have Medicare or 
Medicaid, Novocure may need information about your identity and your treatment. They will give this 
information to the government agencies that run these programs.  


 
 
Sample consent form version:  December 12, 2017 
To be attached to protocol version:  December 12, 2017 
 
RTOG 3503 
 
Page 8 of 9 
Schulman Use Only: SR# 0 
SCHULMAN APPROVED 
IRB #201606279 
Finalized Date: 02/02/2018 
Schulman Version: 2.0 
If your case meets all four of these requirements and you have private insurance, your insurer may be told that 
you are in a research study and given information about your treatment. You will have to pay for any costs that 
Novocure or your insurer does not pay.  Novocure will not pay for costs such as co-payments that your insurer 
says you have to pay.  
If you feel this injury was a result of medical error, you will not lose any of your legal rights or release the 
Sponsor, the study doctor, the study staff, or study site from liability for mistakes or intentional misconduct by 
signing this consent document. 
 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your information 
may be given out if required by law. For example, certain states require doctors to report to health boards if they 
find a disease like tuberculosis. However, the researchers will do their best to make sure that any information 
that is released will not identify you. Some of your health information, and/or information about your specimen, 
from this study will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make sure your 
information is kept private, unless required by law to provide information. Some of these organizations are: 
• The study sponsor (RTOG Foundation Inc.) 
• Novocure, the manufacture of Optune, which is supporting the study 
• The Institutional Review Board, IRB, which is a group of people who review the research with the goal 
of protecting the people who take part in the study.  
• The Food and Drug Administration, (FDA), the federal agency that regulates use of drugs and devices in 
the United States. 
 
If a study staff witnesses or believes that you have been a victim of abuse, neglect, domestic violence, or 
exploitation in the home environment a protective services agency or government authorities will be notified as 
required by law. 
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general information 
about cancer. You may also call the NCI Cancer Information Service to get the same information at: 1-800-4-
CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 


 
 
Sample consent form version:  December 12, 2017 
To be attached to protocol version:  December 12, 2017 
 
RTOG 3503 
 
Page 9 of 9 
Schulman Use Only: SR# 0 
SCHULMAN APPROVED 
IRB #201606279 
Finalized Date: 02/02/2018 
Schulman Version: 2.0 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to report side 
effects or injuries. Contact the study doctor at the phone number listed on page 1 of this document.  
 
My Signature Agreeing to Take Part in the Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions 
have been answered. I will be given a signed copy of this form. I agree to take part in the study.  
 
Participant’s signature ________________________________ 
 
Participant’s printed name ______________________________ 
 
Date of signature _____________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion ___________________________________ 
 
Printed name of person conducting the informed consent discussion ___________________________________ 
 
Date of signature _____________________________________